Immunosuppressants

ACRONYMS AND DEFINITIONS

AAD - American Academy of Dermatology

ACG - American College of Gastroenterology

ACR - American College of Rheumatology

ALT - Alanine aminotransferase

CD - Crohn's disease

CK - Creatinine kinase

DMARD - Disease-modifying antirheumatic drug

DVT - Deep vein thrombosis

HBV - Hepatitis B virus

MTX - Methotrexate

NMSC - Non-melanoma skin cancers

NPF - National Psoriasis Foundation

PI - Package insert

PE - Pulmonary embolism

RA - Rheumatoid arthritis

RCT - Randomized controlled trial

TNF - Tumor necrosis factor

UC - Ulcerative colitis

ULN - Upper limit of normal

AMINOSALICYLATES

Balsalazide | Colazal® | Giazo®

Dosage forms

Capsule (Colazal®)

750 mg

Tablet (Giazo®)

1100 mg

Dosing - Ulcerative colitis

Colazal®

Active disease: 3 capsules (2250 mg) three times a day [32]
Maintenance of remission: 2000 - 6750 mg a day given in divided doses [31]
May take without regard to food
Capsules may be opened and sprinkled on applesauce. Teeth and/or tongue staining may occur if opened.
Contents of capsule may be chewed

Giazo®

Active disease: 3 tablets (3300 mg) two times a day [32]
Maintenance of remission: 2000 - 6750 mg a day given in divided doses [31]
May take without regard to food

Generic / Price

Colazal® (270 capsules) - YES/$$$
Giazo® (180 tablets) - NO/$$$$

Mechanism of action

Balsalazide reaches the colon intact where it is cleaved by bacteria to release mesalamine
The mechanism by which mesalamine exerts its therapeutic effect is not completely understood
Mesalamine (5-aminosalicylic acid, 5-ASA) is believed to work locally in the colon by inhibiting cyclooxygenase and lipoxygenase pathways and decreasing inflammatory mediators (e.g. prostaglandins, leukotrienes, etc.)

FDA-approved indications

Colazal® - treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older
Giazo® - treatment of mildly to moderately active ulcerative colitis in male patients ≥ 18 years

Side effects

NOTE: Only side effects that occurred at an incidence of ≥ 2% overall, and ≥ 2% more than placebo are listed. Data presented below are from Colazal studies.

Side effect	Balsalazide	Placebo
Abdominal pain	6%	3%
Diarrhea	5%	3%
Arthralgia	4%	0%
Rhinitis	2%	0%
Insomnia	2%	0%
Fatigue	2%	0%
Flatulence	2%	0%
Fever	2%	0%
Dyspepsia	2%	0%
Pharyngitis	2%	0%
Coughing	2%	0%
Anorexia	2%	0%

Drug interactions

Nephrotoxic drugs including NSAIDs - concurrent use of mesalamine and nephrotoxic drugs including NSAIDs may increase the risk of kidney damage. Monitor renal function in patients taking nephrotoxic drugs with mesalamine.
Azathioprine and mercaptopurine - concurrent use of mesalamine with azathioprine or mercaptopurine may increase the risk of blood disorders. Monitor CBC and platelet counts in patients who are taking azathioprine or mercaptopurine with mesalamine.

Lab interactions

Urinary normetanephrine - mesalamine may cause falsely elevated urinary normetanephrine levels when measured by liquid chromatography with electrochemical detection

Contraindications / Precautions

Salicylate or aminosalicylate hypersensitivity - DO NOT USE
Sulfasalazine allergy - sulfasalazine is metabolized to mesalamine and sulfapyridine. Patients allergic to sulfasalazine may also be allergic to mesalamine, the active moiety of balsalazide. Use caution.
Mesalamine-induced acute intolerance syndrome - in trials, 3% of patients experienced an acute intolerance syndrome when starting mesalamine that may be difficult to distinguish from an exacerbation of ulcerative colitis. The syndrome was marked by cramping, acute abdominal pain and bloody diarrhea that was sometimes accompanied by fever, headache, and rash. If these symptoms develop, mesalamine should be discontinued.
Upper GI obstruction - upper GI obstruction may cause prolonged retention of mesalamine and delay release into the colon. Do not use in patients who are at risk of upper GI tract obstruction.
Nephrotoxicity - nephrotoxicity including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure have been reported in patients taking mesalamine. Check kidney function before therapy and periodically thereafter.
Hypersensitivity reactions - hypersensitivity reactions including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic abnormalities have been reported in rare cases
Photosensitivity - severe photosensitivity reactions have been reported in patients with pre-existing skin conditions such as atopic dermatitis and eczema. Susceptible patients should take proper precautions (e.g. sunscreen, clothing).
Severe cutaneous reactions - severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving mesalamine, the active moiety of balsalazide. Discontinue balsalazide if a serious skin reaction occurs.
Sodium content of Giazo - each 1.1 g tablet of Giazo contains 126 mg of sodium. The recommended dosage of Giazo (6.6 g/day) provides about 756 mg of sodium per day. Use caution when treating patients with congestive heart failure and other sodium-sensitive conditions.
Kidney stones - cases of kidney stones, including kidney stones with 100% mesalamine content, have been reported during therapy. Mesalamine stones are radiolucent, and therefore, are undetectable by X-ray or CT scan. Susceptible patients should drink plenty of fluids while taking mesalamine.
Liver failure - rare cases of liver failure have been reported in patients with pre-existing liver disease who took mesalamine. Use caution in patients with liver disease.
Kidney disease - mesalamine undergoes substantial renal elimination, and exposure is increased in kidney disease. Check kidney function before therapy and periodically thereafter. Use caution and monitor for adverse effects in patients with renal impairment, and discontinue mesalamine if renal function worsens.
Liver disease - mesalamine may worsen liver disease. Use caution.

Dosage forms

Capsule, extended-release (Apriso®)

375 mg

Capsule, delayed-release (Delzicol®)

400 mg

Capsule, extended-release (Pentasa®)

250 mg
500 mg

Tablet, delayed-release (Asacol® HD)

800 mg

Tablet, delayed-release (Lialda®)

1200 mg

Suppository (Canasa®)

1000 mg

Enema (Rowasa®, sfRowasa®)

4 grams/60 ml
Rowasa contains sulfites where sfRowasa does not

Dosing - Ulcerative colitis

Apriso®

Maintenance of remission: 1500 mg (4 capsules) once daily in the morning
May take without regard to food
Do not take with antacids

Asacol® HD

Active disease: 1600 mg three times a day
May take without regard to food
May take for up to 6 weeks
Do not cut, chew, or break tablets

Canasa® suppository

Active disease: 1000 mg once daily at bedtime [32]
Maintenance of remission: 1000 mg once daily at bedtime [31]
Suppository should be retained for 1 - 3 hours
Usual course of therapy is 3 - 6 weeks
Suppository effects been shown to reach ∼ 10 cm into the colon [31]

Delzicol®

Active disease: 800 mg three times a day for 6 weeks
Maintenance of remission: 1600 mg a day given in divided doses
May take without regard to food
Do not open capsules. Swallow whole.

Lialda®

Active disease: 2400 - 4800 mg once daily with food
Maintenance of remission: 2400 mg once daily with food

Pentasa®

Active disease: 1000 mg four times a day
Has been studied for up to 8 weeks
May take without regard to food
Capsule may be opened and sprinkled on applesauce or yogurt. Do not chew capsule contents.

Rowasa® and sfRowasa® enema

Active disease: 4000 mg once daily at bedtime [32]
Maintenance of remission: 2 - 4 grams once daily, every other day, or less frequently in some regimens [31]
Enema should be retained for 8 hours
Effect is seen within 3 - 21 days
Usual course of therapy is 3 - 6 weeks
Enema effects been shown to reach as far as the splenic flexure in some patients [31]
Rowasa contains sulfites where sfRowasa does not

Generic / Price

Apriso® - NO/$$$$
Asacol® HD (90 tablets) - YES/$$$$
Delzicol® - YES/$$$$
Lialda® (60 tablets) - YES/$$-$$$
Pentasa® (240 capsules) - NO/$$$$
Canasa® (30 supp) - YES/$$$$
Rowasa® and sfRowasa® (28 enemas) - YES/$$$$

Mechanism of action

The mechanism by which mesalamine exerts its therapeutic effect is not completely understood
Mesalamine (5-aminosalicylic acid, 5-ASA) is believed to work locally in the colon by inhibiting cyclooxygenase and lipoxygenase pathways and decreasing inflammatory mediators (e.g. prostaglandins, leukotrienes, etc.)

FDA-approved indications

Ulcerative colitis

Apriso® - maintenance of remission
Asacol® HD - treatment of active disease
Delzicol® - treatment of active disease and maintenance of remission
Lialda® - treatment of active disease and maintenance of remission
Pentasa® - treatment of active disease
Canasa® - treatment of active disease
Rowasa® and sfRowasa® - treatment of active disease

Side effects

NOTE: Only side effects that occurred at an incidence of ≥ 2% overall, and ≥ 2% more than placebo are listed. Data presented below are from Delzicol studies in active UC.

Side effect	Mesalamine	Placebo
Abdominal pain	18%	14%
Pain	14%	8%
Back pain	7%	5%
Dyspepsia	6%	1%
Rash	6%	3%
Arthralgia	5%	3%
Vomiting	5%	2%
Constipation	5%	1%
Myalgia	3%	1%
Sweating	3%	1%
Pruritus	3%	0%
Arthritis	2%	0%

Drug interactions

Antacids (Apriso) - DO NOT take Apriso with antacids. Antacids may affect dissolution of the drug.
Nephrotoxic drugs including NSAIDs - concurrent use of mesalamine and nephrotoxic drugs including NSAIDs may increase the risk of kidney damage. Monitor renal function in patients taking nephrotoxic drugs with mesalamine.
Azathioprine and mercaptopurine - concurrent use of mesalamine with azathioprine or mercaptopurine may increase the risk of blood disorders. Monitor CBC and platelet counts in patients who are taking azathioprine or mercaptopurine with mesalamine.

Lab interactions

Urinary normetanephrine - mesalamine may cause falsely elevated urinary normetanephrine levels when measured by liquid chromatography with electrochemical detection

Contraindications / Precautions

Salicylate or aminosalicylate hypersensitivity - DO NOT USE
Sulfasalazine allergy - sulfasalazine is metabolized to mesalamine and sulfapyridine. Patients allergic to sulfasalazine may also be allergic to mesalamine. Use caution.
Sulfite sensitivity (Rowasa) - Rowasa enemas contain potassium metabisulfite. Patients with sulfite sensitivity may have a reaction (e.g. asthma, anaphylaxis) if given Rowasa. sfRowasa or "sulfite-free" Rowasa does not contain sulfites.
Mesalamine-induced acute intolerance syndrome - in trials, 3% of patients experienced an acute intolerance syndrome when starting mesalamine that may be difficult to distinguish from an exacerbation of ulcerative colitis. The syndrome was marked by cramping, acute abdominal pain and bloody diarrhea that was sometimes accompanied by fever, headache, and rash. If these symptoms develop, mesalamine should be discontinued.
Upper GI obstruction - upper GI obstruction may cause prolonged retention of mesalamine and delay release into the colon. Do not use in patients who are at risk of upper GI tract obstruction.
Nephrotoxicity - nephrotoxicity including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure have been reported in patients taking mesalamine. Check kidney function before therapy and periodically thereafter.
Hypersensitivity reactions - hypersensitivity reactions including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic abnormalities have been reported in rare cases
Photosensitivity - severe photosensitivity reactions have been reported in patients with pre-existing skin conditions such as atopic dermatitis and eczema. Susceptible patients should take proper precautions (e.g. sunscreen, clothing).
Severe cutaneous reactions - severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving mesalamine. Discontinue mesalamine if a serious skin reaction occurs.
Kidney stones - cases of kidney stones, including kidney stones with 100% mesalamine content, have been reported during therapy. Mesalamine stones are radiolucent, and therefore, are undetectable by X-ray or CT scan. Susceptible patients should drink plenty of fluids while taking mesalamine.
Phenylketonuria (Apriso) - each Apriso capsule contains 0.56 mg of phenylalanine. Use caution in patients with phenylketonuria.
Liver failure - rare cases of liver failure have been reported in patients with pre-existing liver disease who took mesalamine. Use caution in patients with liver disease.
Kidney disease - mesalamine undergoes substantial renal elimination, and exposure is increased in kidney disease. Check kidney function before therapy and periodically thereafter. Use caution and monitor for adverse effects in patients with renal impairment, and discontinue mesalamine if renal function worsens.
Liver disease - mesalamine may worsen liver disease. Use caution.

Olsalazine (Dipentum®)

Dosage forms

Capsule

250 mg

Dosing

Ulcerative colitis

Active disease: 1500 - 3000 mg/day given in 2 divided doses [31]
Maintenance of remission: 500 mg two times a day [32]
Take with food

Generic / Price

- NO/$$$$

Mechanism of action

Olsalazine reaches the colon intact where it is cleaved by bacteria to release two molecules of mesalamine
The mechanism by which mesalamine exerts its therapeutic effect is not completely understood
Mesalamine (5-aminosalicylic acid, 5-ASA) is believed to work locally in the colon by inhibiting cyclooxygenase and lipoxygenase pathways and decreasing inflammatory mediators (e.g. prostaglandins, leukotrienes, etc.)

FDA-approved indications

Ulcerative colitis - maintenance of remission in patients who are intolerant of sulfasalazine

Side effects

NOTE: Only side effects that occurred at incidence of ≥ 2% overall, and ≥ 2% more than placebo are listed

Side effect	Olsalazine	Placebo
Diarrhea	11%	7%
Abdominal pain	10%	7%

Drug interactions

Nephrotoxic drugs including NSAIDs - concurrent use of mesalamine and nephrotoxic drugs including NSAIDs may increase the risk of kidney damage. Monitor renal function in patients taking nephrotoxic drugs with mesalamine.
Azathioprine and mercaptopurine - concurrent use of mesalamine with azathioprine or mercaptopurine may increase the risk of blood disorders. Monitor CBC and platelet counts in patients who are taking azathioprine or mercaptopurine with mesalamine.
Heparins - concomitant use of salicylates with heparin may increase the risk of bleeding following neuraxial anesthesia. If possible, discontinue salicylates prior to initiating heparins.
Warfarin - increases in the prothrombin time have been reported when mesalamine has been given with warfarin. Monitor INR closely when combining.
Varicella vaccine - it is recommended not to give salicylates including mesalamine for six weeks after the varicella vaccine to avoid a possible increased risk of developing Reye’s syndrome

Lab interactions

Urinary normetanephrine - mesalamine may cause falsely elevated urinary normetanephrine levels when measured by liquid chromatography with electrochemical detection

Contraindications / Precautions

Salicylate or aminosalicylate hypersensitivity - DO NOT USE
Sulfasalazine allergy - sulfasalazine is metabolized to mesalamine and sulfapyridine. Patients allergic to sulfasalazine may also be allergic to mesalamine. Use caution.
Mesalamine-induced acute intolerance syndrome - in trials, 3% of patients experienced an acute intolerance syndrome when starting mesalamine that may be difficult to distinguish from an exacerbation of ulcerative colitis. The syndrome was marked by cramping, acute abdominal pain and bloody diarrhea that was sometimes accompanied by fever, headache, and rash. If these symptoms develop, mesalamine should be discontinued.
Upper GI obstruction - upper GI obstruction may cause prolonged retention of mesalamine and delay release into the colon. Do not use in patients who are at risk of upper GI tract obstruction.
Nephrotoxicity - nephrotoxicity including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure have been reported in patients taking mesalamine. Check kidney function before therapy and periodically thereafter.
Hypersensitivity reactions - hypersensitivity reactions including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic abnormalities have been reported in rare cases
Photosensitivity - severe photosensitivity reactions have been reported in patients with pre-existing skin conditions such as atopic dermatitis and eczema. Susceptible patients should take proper precautions (e.g. sunscreen, clothing).
Severe cutaneous reactions - severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving mesalamine, the active moiety of olsalazine. Discontinue olsalazine if a serious skin reaction occurs.
Kidney stones - cases of kidney stones, including kidney stones with 100% mesalamine content, have been reported during therapy. Mesalamine stones are radiolucent, and therefore, are undetectable by X-ray or CT scan. Susceptible patients should drink plenty of fluids while taking mesalamine.
Liver failure - rare cases of liver failure have been reported in patients with pre-existing liver disease who took mesalamine. Use caution in patients with liver disease.
Kidney disease - mesalamine undergoes substantial renal elimination, and exposure is increased in kidney disease. Check kidney function before therapy and periodically thereafter. Use caution and monitor for adverse effects in patients with renal impairment, and discontinue mesalamine if renal function worsens.
Liver disease - mesalamine may worsen liver disease. Use caution.

Sulfasalazine | Azulfidine® | Azulfidine EN-tabs®

Dosage forms

Tablet (Azulfidine®)

500 mg

Tablet, delayed-release (Azulfidine EN-tabs®)

500 mg

Dosing - Azulfidine® tablet

Ulcerative colitis

Active disease

PI: 3 - 4 grams/day given in divided doses (dosing interval should not exceed 8 hours) [32]
ACG: 4 - 6 grams/day given in 4 divided doses [31]

Maintenance

PI: 2 grams/day given in evenly divided doses [32]
ACG: 2 - 4 grams/day given in divided doses [31]

Other

May start with 1 - 2 grams/day to limit GI side effects
Take after meals
Tablets may be halved

Dosing - Azulfidine EN-tabs®

Rheumatoid arthritis

Starting: 500 - 1000 mg once daily
Maintenance: 1000 mg twice a day
Increase dose by 500 mg/day at intervals of one week
A response may be seen in as early as 4 weeks, but may take up to 12 weeks
In some patients, 3000 mg/day may be necessary
Take after meals. Do not cut or crush tablets.

Ulcerative colitis

Active disease

PI: 3 - 4 grams/day given in divided doses (dosing interval should not exceed 8 hours) [32]
ACG: 4 - 6 grams/day given in 4 divided doses [31]

Maintenance

PI: 2 grams/day given in evenly divided doses [32]
ACG: 2 - 4 grams/day given in divided doses [31]

Other

May start with 1 - 2 grams/day to limit GI side effects
Take after a meal. Do not cut or crush tablets.

Efficacy

Rheumatoid arthritis

Addition of Etanercept vs Sulfasalazine + Hydroxychloroquine in RA Patients who Failed Methotrexate [SH review]

Lab monitoring

Initial

CBC with diff
Liver function tests
BMP

Months 0 - 3

CBC with diff, liver function tests every 2 weeks

Months 3 - 6

CBC with diff, liver function tests once a month

6 months and on

CBC with diff, liver function tests every 3 months as clinically indicated

Urinalysis and kidney function

Check periodically

Sulfapyridine levels

May be useful in some cases
Levels > 50 mcg/ml may be associated with more adverse events
Test is not widely available

Generic / Price

Azulfidine® (120 tablets) - YES/$
Azulfidine EN-tabs® (120 tablets) - YES/$

Mechanism of action

Sulfasalazine (SSZ) is metabolized by intestinal bacteria to mesalamine (5-aminosalicylic acid, 5-ASA) and sulfapyridine (SP). SP is well absorbed from the intestine while 5-ASA and SSZ are not.
Sulfasalazine and its metabolites have a high affinity for connective tissue, and high concentrations are reached in synovial fluids, the liver, and intestinal walls
The mechanism by which SSZ and its metabolites exert their therapeutic effect in rheumatoid arthritis has not been completely elucidated
Drug effects observed in laboratory studies include the following: inhibition of chemotaxis of inflammatory cells; inhibition of cytokine expression in mononuclear cells; inhibition of lymphocyte proliferation and activation; inhibition of angiogenesis; and inhibition of tumor necrosis factor-alpha expression in macrophages [23,24]

FDA-approved indications

Sulfasalazine

Ulcerative colitis

Sulfasalazine delayed-release tablet

Ulcerative colitis
Rheumatoid arthritis
Polyarticular-course juvenile rheumatoid arthritis

Side effects

NOTE: Placebo incidence not reported. Strength of association is unknown. Data is from RA trials with delayed-release tablet.

Nausea - 19%
Upset stomach - 13%
Rash - 13%
Immunoglobulin suppression - 10%
Headache - 9%
Abdominal pain - 8%
Vomiting - 8%
Fever - 5%
Dizziness - 4%
Stomatitis - 4%
Itching - 4%
Abnormal liver tests - 4%
Decreased white blood cells - 3%
Decreased platelets - 1%
Skin and urine discoloration - orange-yellow discoloration of the skin and urine has been reported

Drug interactions

Folic acid - folic acid absorption may be reduced by sulfasalazine
Digoxin - digoxin absorption may be reduced by sulfasalazine
Nephrotoxic drugs including NSAIDs - concurrent use of mesalamine and nephrotoxic drugs including NSAIDs may increase the risk of kidney damage
Azathioprine and mercaptopurine - concurrent use of mesalamine with azathioprine or mercaptopurine may increase the risk of blood disorders

Lab interactions

Urinary normetanephrine - mesalamine may cause falsely elevated urinary normetanephrine levels when measured by liquid chromatography with electrochemical detection
Laboratory assays that use NAD(H) or NADP(H) to measure ultraviolet absorbance - sulfasalazine or its metabolite, sulfapyridine, may interfere with ultraviolet absorbance, particularly at 340 nm, and may cause interference with some laboratory assays that use NAD(H) and NADP(H) to measure ultraviolet absorbance around that wavelength. Examples of such assays may include ALT, AST, CK-MB, ammonia, thyroxine, and glucose. Erroneous laboratory results may be observed in patients receiving higher than recommended dosages of sulfasalazine.

Contraindications / Precautions

Salicylate, mesalamine, or sulfonamide hypersensitivity - DO NOT USE
Intestinal or urinary obstruction - DO NOT USE
Porphyria - DO NOT USE
Asthma - salicylates may worsen asthma. See aspirin allergy for more.
Hypersensitivity reactions - serious hypersensitivity reactions including hepatitis, nephritis, myocarditis, mononucleosis-like syndrome, hematological abnormalities (including hematophagic histiocytosis), and/or pneumonitis have been reported in patients receiving sulfasalazine
Ulcerative colitis exacerbation - in trials, up to 3% of patients have reported exacerbation of ulcerative colitis symptoms when starting mesalamine, a metabolite of sulfasalazine.
Blood dyscrasias - sulfasalazine may cause or worsen blood dyscrasias. Use caution and monitor CBC regularly.
Hepatotoxicity - sulfasalazine may cause or worsen liver disease. Rare cases of liver failure have been reported in patients with pre-existing liver disease who took mesalamine, a metabolite of sulfasalazine. Monitor LFTs regularly and use caution in patients with liver disease.
Nephrotoxicity - nephrotoxicity including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure have been reported in patients taking mesalamine, a metabolite of sulfasalazine. Check kidney function before therapy and periodically thereafter.
Decreased sperm count - oligospermia and infertility have been observed in men treated with sulfasalazine. The effect appears to be reversible upon discontinuation.
Serious infections - serious infections, including fatal sepsis and pneumonia, have occurred in patients receiving sulfasalazine. Some infections were associated with agranulocytosis, neutropenia, or myelosuppression. Sulfasalazine should be discontinued if serious infection occurs.
G6PD deficiency - patients with G6PD deficiency should be monitored for hemolytic anemia
Severe skin reactions - severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving sulfasalazine. Most events occurred within the first month of initiating therapy. Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Discontinue sulfasalazine at the first sign of a hypersensitivity reaction.
Urine crystals and stone formation - mesalamine, a metabolite of sulfasalazine, is known to cause radiolucent kidney stones in some people. Patients receiving sulfasalazine should maintain good fluid intake to help prevent stone and crystal formation.
Slow acetylators - sulfapyridine is metabolized by acetylation. Slow acetylators may have higher exposure to sulfapyridine and be at greater risk for adverse events.
Liver disease - use with caution. Monitor LFTs regularly. Manufacturer makes no dosage recommendation.
Kidney disease - mesalamine undergoes substantial renal elimination, and exposure is increased in kidney disease. Check kidney function before therapy and periodically thereafter. Use caution and monitor for adverse effects in patients with renal impairment, and discontinue mesalamine if renal function worsens.

Apremilast (Otezla®)

Dosage forms

Tablet

30 mg

Starter pack (2 week)

4 X 10 mg
4 X 20 mg
19 X 30 mg

Starter pack (28 day)

4 X 10 mg
4 X 20 mg
49 X 30 mg

Dosing

Plaque psoriasis, Psoriatic arthritis, Behcet's disease

Day 1: 10 mg in AM
Day 2: 10 mg in AM and 10 mg in PM
Day 3: 10 mg in AM and 20 mg in PM
Day 4: 20 mg in AM and 20 mg in PM
Day 5: 20 mg in AM and 30 mg in PM
Day 6 and on: 30 mg twice daily
May take without regard to food
Do not crush, cut, or chew tablets

Severe kidney disease (CrCl < 30 ml/min)

Starting: omit the PM dose from the regular titration schedule
Maintenance: 30 mg once daily

Efficacy

Plaque psoriasis

Psoriatic arthritis

Apremilast vs Placebo for Psoriatic arthritis, Ann Rheum Dis (2014) [PubMed Abstract]

Generic / Price

- NO/$$$$

Mechanism of action

Apremilast is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels. The specific mechanism(s) by which apremilast exerts its therapeutic action is not well defined, but increased levels of intracellular cAMP are believed to result in downregulation of inflammatory responses involving T helper 1, T helper 17, and type 1 interferon pathways. [32, 40]

FDA-approved indications

Plaque psoriasis in adults who are candidates for phototherapy or systemic therapy
Active psoriatic arthritis in adults
Oral ulcers associated with Behçet's Disease in adults

Side effects

NOTE: Only side effects that occurred at an incidence of ≥ 4% overall, and more than placebo are listed

Side effect	Placebo (N=506)	Apremilast 30 BID (N=920)
Diarrhea	6%	17%
Nausea	7%	17%
Upper respiratory tract infection	6%	9%
Tension headache	4%	8%
Headache	4%	6%
Abdominal pain	2%	4%
Vomiting	2%	4%

Drug interactions

CYP3A4 strong inducers - DO NOT COMBINE. Apremilast is a sensitive CYP3A4 substrate and CYP3A4 inducers may reduce exposure and efficacy

Contraindications / Precautions

Pregnancy - risk is unknown. Advise pregnant women of the potential risk of fetal loss. Consider pregnancy planning and prevention for females of reproductive potential.
Hypersensitivity reactions - hypersensitivity reactions, including angioedema and anaphylaxis, have been reported in the postmarketing setting. Discontinue apremilast if reactions occur.
Diarrhea, nausea, and vomiting - severe cases of nausea, vomiting, and diarrhea have been reported in patients taking apremilast. Most cases occurred within the first few weeks of starting therapy. Use caution when initiating therapy in patients who are at risk for dehydration.
Depression - depression has been reported in patients taking apremilast. In psoriasis trials lasting 16 weeks, 1.3% of apremilast-treated patients reported depression compared to 0.4% of placebo-treated patients. Use caution in susceptible individuals.
Weight loss - weight loss has been observed in patients taking apremilast. In psoriasis trials, weight loss of 5 - 10% of body weight occurred in 12% of apremilast-treated patients compared to 5% of placebo-treated patients, and weight loss ≥ 10% occurred in 2% and 1% of patients, respectively. Monitor weight regularly during therapy and discontinue apremilast if necessary.
Liver disease - no dose adjustment is necessary
Kidney disease

CrCl ≥ 30 ml/min: no dose adjustment necessary
CrCl < 30 ml/min: see Dosing above

Hydroxychloroquine (Plaquenil®)

Dosage forms

Tablet

100 mg
200 mg
300 mg
400 mg

Dosing

Systemic lupus erythematosus (SLE)

5 mg/kg/day (max 400 mg/day)
Use actual body weight [38]

Rheumatoid arthritis (RA)

200 - 400 mg once daily

Sarcoidosis

200 - 400 mg once daily

Efficacy

Rheumatoid arthritis

Addition of Etanercept vs Sulfasalazine + Hydroxychloroquine in RA Patients who Failed Methotrexate [SH review]

Osteoarthritis

Hydroxychloroquine vs Placebo for Hand Osteoarthritis, Ann Intern Med (2018) [PubMed abstract]

Lab monitoring

Hydroxychloroquine (HCQ) levels

There are no formal recommendations to monitor HCQ levels
HCQ levels have large interindividual variability, and levels do not appear to correlate with weight or BMI [36]
Several studies have found that response to HCQ therapy is strongly associated with HCQ blood levels in patients with RA and SLE
One study found that a level of at least 1000 ng/ml was optimal for preventing flares in patients with SLE. Another study found that dosing to a level of at least 750 ng/ml improved responses in cutaneous lupus. [35,36]
HCQ has a long half-life (> 40 days) making day-to-day and intraday variations in levels small. Timing of level checks in relation to dosing should not have a significant effect on values. Not all labs offer HCQ levels. [36]

Blood cell counts (CBC)

Periodic CBCs are recommended to monitor for blood dyscrasias in patients receiving prolonged therapy

Generic / Price

- YES/$

Mechanism of action

Hydroxychloroquine changes lysosomal pH and has immunomodulatory action through changing activation of toll-like receptor 7 and toll-like receptor 9

FDA-approved indications

Systemic lupus erythematosus - effective for control of articular, cutaneous, and constitutional symptoms [5]
Discoid lupus
Rheumatoid arthritis
Malaria

Side effects

Frequency of side effects not well-defined
In a randomized controlled trials involving hydroxychloroquine (doses 200 - 400 mg/day), frequency of side effects was not significantly different than placebo [6,7]

Drug interactions

Ampicillin - hydroxychloroquine may reduce the bioavailability of ampicillin
Antacids and kaolin - antacids and kaolin may reduce the absorption of hydroxychloroquine. Take at least 4 hours apart.
Antiepileptics - hydroxychloroquine may lower the seizure threshold and decrease the effectiveness of seizure medications
Cimetidine - DO NOT COMBINE. Cimetidine may increase hydroxychloroquine levels.
Cyclosporine - hydroxychloroquine may increase cyclosporine levels. Monitor cyclosporine levels when combining.
CYP2D6 substrates - hydroxychloroquine may be a CYP2D6 inhibitor. Use caution when taken with CYP2D6 substrates. [8]
Diabetes medications - hydroxychloroquine may lower blood sugars and cause hypoglycemia when taken with diabetes medications. Monitor blood sugars closely when taking hydroxychloroquine with diabetes medications, particularly during initiation and dose adjustments.
Digoxin - hydroxychloroquine may increase digoxin levels. Monitor digoxin levels when combining.
Drugs that lower the seizure threshold - hydroxychloroquine can lower the seizure threshold and this effect may be potentiated by other threshold-lowering drugs (e.g. mefloquine, bupropion)
Drugs that prolong the QT interval - DO NOT COMBINE. Hydroxychloroquine prolongs the QT interval and should not be given with other drugs that prolong the QT interval
Methotrexate - concomitant use of hydroxychloroquine and methotrexate may increase the incidence of adverse reactions
Metoprolol - hydroxychloroquine may increase metoprolol levels
Praziquantel - hydroxychloroquine may reduce praziquantel bioavailability
Rifampicin - DO NOT COMBINE. Rifampicin may reduce hydroxychloroquine exposure and decrease its effectiveness.

Contraindications / Precautions

Pregnancy - prolonged clinical experience over decades of use and available data from published epidemiologic and clinical studies with hydroxychloroquine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal, or fetal outcomes
Retinal toxicity - chronic hydroxychloroquine therapy can cause irreversible retinopathy. Risk factors for hydroxychloroquine-induced retinopathy include cumulative dose ≥ 1000 grams, treatment for more than 7 years, obesity, significant liver or kidney disease, older age (> 55 years), pre-existing retinal disease, macular disease, concurrent tamoxifen therapy, and cataracts. In one cohort study, the overall risk of retinopathy was 2.5% after 10 years of use and 8.6% after 15. The risk was dose-dependent, with 15-year incidences of 21.6% for doses > 6 mg/kg/day, 11.4% for 5 - 6 mg/kg/day, and 2.7% for ≤ 5 mg/kg/day. Most retinopathy cases were mild. [PMID 36645889]

Recommended screening for hydroxychloroquine-induced retinopathy:

Initial (all patients): baseline eye/retina exam within the first year of treatment
Low-risk patients: reexamine in 5 years, followed by yearly exams
High-risk patients: yearly exam [4,9,10]

Cardiomyopathy - cases of cardiomyopathy have been reported in patients receiving hydroxychloroquine with both short-term and chronic use. In multiple cases, endomyocardial biopsy showed phospholipidosis in the absence of inflammation, infiltration, or necrosis; drug-induced phospholipidosis may also affect the kidneys, muscles, and nerves. Cardiomyopathy may present as conduction disorders (e.g. bundle branch block, AV heart block, sick sinus syndrome), ventricular hypertrophy, and/or pulmonary hypertension. Discontinue hydroxychloroquine if cardiotoxicity develops.
Prolonged QT interval - hydroxychloroquine may prolong the QT interval, and it should not be used in patients who have, or have risk factors for, prolonged QT syndrome. The QT-prolonging effect of hydroxychloroquine increases with higher doses.
Proximal Myopathy or Neuropathy - cases of proximal skeletal muscle myopathy or neuropathy have been reported in patients receiving hydroxychloroquine. Muscle and nerve biopsies of affected patients have shown phospholipidosis; drug-induced phospholipidosis may also affect the heart and kidneys. Symptoms of proximal myopathy or neuropathy include proximal muscle weakness/atrophy, depressed tendon reflexes, and/or abnormal nerve conduction. Discontinue hydroxychloroquine if myopathy or neuropathy develops.
Renal toxicity - cases of proteinuria with and without reduced GFR have been reported with hydroxychloroquine use. Renal biopsies of affected patients have shown phospholipidosis without immune deposits, inflammation, and/or increased cellularity; drug-induced phospholipidosis may also affect the heart, muscles, and nerves. Discontinue hydroxychloroquine if renal toxicity develops.
Hypoglycemia - hydroxychloroquine has been shown to cause severe hypoglycemia in both diabetics and nondiabetics. Patients who are receiving diabetes medications should monitor their blood sugars closely when taking hydroxychloroquine, particularly during initiation and dose adjustments. Nondiabetics should be aware of hypoglycemia symptoms (e.g. tremor, sweating, headache, anxiety) and seek care if they occur.
Seizures - hydroxychloroquine may lower the seizure threshold and increase the risk of seizures in susceptible individuals
Serious skin reactions (Stevens-Johnson, etc.) - serious skin reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP) have been reported in patients receiving hydroxychloroquine. Advise patients to seek immediate attention for any unusual rashes or symptoms.
Psoriasis - patients with psoriasis may experience a severe flare-up when given hydroxychloroquine
Porphyria - hydroxychloroquine may exacerbate porphyria
G6PD deficiency - hemolysis has been reported in patients with G6PD deficiency who were treated with hydroxychloroquine. Use caution in susceptible individuals.
Depression and suicide - depression including suicidal behavior has been reported in patients receiving hydroxychloroquine. Advise patients to report any depressive symptoms immediately.
Blood dyscrasias - blood dyscrasias including aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia have been reported in patients receiving hydroxychloroquine. Monitor CBCs periodically during chronic therapy.
Liver disease - dose reduction may be necessary. Manufacturer makes no specific recommendation.
Kidney disease - dose reduction may be necessary. Manufacturer makes no specific recommendation.

Leflunomide (Arava®)

Dosage forms

Tablet

10 mg
20 mg
100 mg

Dosing

Rheumatoid arthritis

Starting: a loading dose of 100 mg once daily for 3 days may be used
Maintenance: 20 mg once daily
Loading dose may not be appropriate in some patients (e.g. high risk for hepatotoxicity and hematological side effects, concurrent methotrexate or other immunosuppressive agents)
Dose may be decreased to 10 mg once daily if side effects occur
Leflunomide has a long half-life ∼ 2 weeks. It takes a long time for blood levels to decrease.
May take without regard to food

Psoriasis (off label)

Starting: a loading dose of 100 mg once daily for 3 days
Maintenance: 20 mg once daily [40]

Lab monitoring

Routine

Initial

Baseline ALT
CBC with diff

Months 0 - 6

ALT, CBC with diff monthly

Months 7 and on

ALT, CBC with diff every 6 - 8 weeks

If given with methotrexate

Monitor liver function tests monthly

Abnormal lab management

ALT > 3 X ULN

Stop leflunomide. If leflunomide is the probable cause, give cholestyramine 8g three times a day for 24 hours. This decreases leflunomide plasma levels by 40% in 24 hours. Repeat if necessary.
Monitor liver tests weekly until normal

Generic / Price

Arava® 10 and 20 mg - YES/$
Arava® 100 mg - NO/?

Mechanism of action

Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase, an enzyme involved in de novo pyrimidine synthesis
Leflunomide has antiproliferative activity
Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect

FDA-approved indication

Rheumatoid arthritis - to reduce signs and symptoms; to inhibit structural damage as evidenced by X-ray erosions and joint space narrowing; to improve physical function.

Side effects

NOTE: Only side effects that occurred at an incidence of ≥ 3% overall, and ≥ 3% more than placebo are listed

Side effect	Leflunomide	Placebo
Diarrhea	27%	12%
Rash	12%	7%
Abnormal liver enzymes	10%	2%
Hair loss	9%	1%
High blood pressure	9%	4%
Back pain	6%	3%
Itching	5%	2%
Bronchitis	5%	2%
Rhinitis	5%	2%
Allergic reaction	5%	2%
Pneumonia	3%	0%

Drug interactions

Cholestyramine (Questran®) - cholestyramine causes rapid clearance of leflunomide
Activated charcoal - activated charcoal causes rapid clearance of leflunomide
Methotrexate - risk of liver toxicity is increased. Increase monitoring.
CYP2C9 substrates - Leflunomide is a CYP2C9 inhibitor. It may affect CYP2C9 substrates.
Rifampin - leflunomide levels are increased by 40% when given with rifampin. Use caution.
NSAIDs (diclofenac and ibuprofen) - leflunomide may increase NSAID levels. Clinical significance of this finding is unknown.
Warfarin (Coumadin®) - increased INR has been reported when combined with leflunomide
Tolbutamide - leflunomide may increase tolbutamide levels

Contraindications / Precautions

Women who are pregnant or may become pregnant - DO NOT USE. May cause fetal harm. It is also recommended that males who are trying to impregnate partners not use leflunomide.
Nursing mothers - DO NOT USE
Liver disease - DO NOT USE. Leflunomide may cause or worsen liver disease. Leflunomide is contraindicated in patients with acute or chronic liver disease and/or ALT > 2 X ULN. See Lab monitoring for recommendations.
Tuberculosis (TB) - patients should be screened for latent TB before starting. Leflunomide has not been studied in patients with a positive TB test.
Blood pressure - leflunomide may raise blood pressure. Monitor during therapy.
Blood dyscrasias - may cause or worsen. See Lab monitoring for recommendations.
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). Consider the long half-life of leflunomide (19 days) when administering vaccines after stopping therapy. The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Serious infections - discontinue if occurs
Serious skin reactions - including Stevens-Johnson, toxic epidermal necrolysis, and DRESS syndrome have occurred
Malignancy - may increase the risk of malignancies
Peripheral neuropathy - has been reported in some patients
Interstitial lung disease - has been reported in some patients. In studies, an increased risk of pulmonary events with leflunomide has not been seen. [PMID 26980577]
Drug elimination protocol - if rapid removal of leflunomide is needed, cholestyramine 8g three times a day for 11 days can be given. Verify plasma levels less than 0.02 mg/L (0.02 µg/mL) by two separate tests at least 14 days apart.
Kidney disease - levels may be increased. Use caution. Manufacturer makes no specific dosage recommendations.

Dosage forms

Tablet

2.5 mg

Tablet (Trexall®)

5 mg
7.5 mg
10 mg
15 mg

Solution (Xatmep™)

2.5 mg/ml
Comes in 120 ml bottle
Store in refrigerator

Vial

25 mg/ml
Comes in 2, 4, 10, and 40 ml vials

Single-dose pen (Otrexup™)

10 mg/0.4 ml
12.5 mg/0.4 ml
15 mg/0.4 ml
17.5 mg/0.4 ml

20 mg/0.4 ml
22.5 mg/0.4 ml
25 mg/0.4 ml
Comes in package with 4 pens

Single-dose pen (Rasuvo®)

7.5 mg/0.15 ml
10 mg/0.2 ml
12.5 mg/0.25 ml
15 mg/0.3 ml
17.5 mg/0.35 ml

20 mg/0.4 ml
22.5 mg/0.45 ml
25 mg/0.5 ml
30 mg/0.6 ml
Comes in package with 4 pens

Single-dose syringe (RediTrex™)

15 mg/0.6 ml
20 mg/0.8 ml
25 mg/1 ml
Comes in carton with 4 pens

Dosing

Crohn's disease

25 mg sub-Q or IM once weekly [1]

Polyarticular Juvenile Idiopathic Arthritis

Starting: 10 mg/m² once weekly
Max: 30 mg/m² once weekly
When switching from oral to injectable, consider that for the same dose, systemic exposure will be higher with injectable when compared to oral

Polymyalgia rheumatica

Dosing: 7.5 - 10 mg/week [39]

Psoriasis

Starting: 10 - 25 mg once weekly
Max: 30 mg once weekly
When switching from oral to injectable, consider that for the same dose, systemic exposure will be higher with injectable when compared to oral

Rheumatoid arthritis

Starting: 10 - 15 once weekly
Maintenance: 20 - 30 once weekly
Increase dose by 5 mg/week every 2 - 4 weeks [16]
Response typically seen within 3 - 6 weeks
When switching from oral to injectable, consider that for the same dose, systemic exposure will be higher with injectable when compared to oral

Sarcoidosis

5 - 15 mg a week
Give with folic acid 1 mg/day [17]

Systemic lupus erythematosus

Induction: 10 - 25 mg/week
Maintenance: 10 mg/week [38]

Folic acid

Some experts recommend prescribing folic acid with methotrexate
In some studies, folic acid supplementation reduced gastrointestinal and liver toxicity without reducing efficacy
At least 5 mg a week of folic acid should be prescribed with methotrexate [16]

Efficacy

Rheumatoid arthritis

Polymyalgia rheumatica

Methotrexate vs Placebo Added to Prednisone in Polymyalgia Rheumatica, Ann Intern Med (2004) [SH review]

Plaque psoriasis

Psoriatic arthritis

Methotrexate vs Etanercept vs Etanercept + Methotrexate for Psoriatic Arthritis, Arthritis Rheumatol (2019) [PubMed abstract]

Lab monitoring

Routine

Baseline

Liver function tests (AST, ALT, Albumin)
CBC with differential
Serum Creatinine
Hepatitis B and C screening
Consider pregnancy test, HIV, and TB testing in at-risk patients

< 3 months of therapy or dose change

CBC, AST, ALT, serum creatinine every 4 weeks

3 - 6 months of therapy

CBC, AST, ALT, serum creatinine every 8 - 12 weeks

> 6 months of therapy

CBC, AST, ALT, serum creatinine every 12 weeks [16,18]

Stopping therapy for abnormal labs

Liver function tests

Stop therapy if AST/ALT > 3 X ULN, restart at lower dose after normalization
Decrease dose if AST/ALT persistently > ULN but < 3 X ULN

Stop therapy if white blood cell count < 3000/mm³
Stop therapy if platelet count < 50,000/mm³

Serum Creatinine

Stop therapy if CrCl < 30ml/min [18]

Psoriasis patients (hepatotoxicity)

NOTE: Patients with psoriasis are at greater risk for hepatotoxicity from MTX. The AAD/NPF make the following recommendations for hepatotoxicity monitoring in patients who do not have risk factors for hepatotoxicity. Recommendations for patients who are at increased risk of hepatotoxicity differ slightly and are not presented here.

Baseline

Perform one of the following noninvasive tests: FIB-4 index, Fibrosure, Fibrometer, Hepascore
If test is normal, proceed with MTX and repeat annually
If test is abnormal, GI consult or Fibroscan. If low risk for cirrhosis, proceed with MTX.

Perform LFT monitoring every 3 - 6 months

If elevations < 3 X ULN, repeat in 2 - 4 weeks
If elevations ≥ 3 X ULN, repeat in 2 - 4 weeks and decrease dose as needed
For persistent elevations or low serum albumin, refer to GI or perform liver biopsy

After reaching 3.5 - 4 grams cumulative dose

GI consult and/or Fibroscan
If signs of ≥ stage 3 fibrosis, consider discontinuation

Generic / Price

Methotrexate tablet - YES/$
Vial - YES/$
Trexall® - NO/$$$-$$$$
Xatmep™ - NO/$$$$
Rasuvo® - NO/$$$$
Otrexup™ - NO/$$$$
RediTrex™ - NO/$$$$

Mechanism of action

The precise mechanism by which methotrexate reduces inflammation is unknown
Methotrexate inhibits the enzyme dihydrofolic acid reductase. Dihydrofolic acid reductase is necessary for cellular DNA synthesis, repair, and replication.
At high doses used to treat cancer, methotrexate is cytotoxic to rapidly dividing cells
At low doses used in inflammatory conditions, several mechanisms of action have been proposed including methotrexate-induced increases in extracellular adenosine (an anti-inflammatory agent), promotion of apoptosis in activated lymphocytes, and inhibition of toxic oxygen species [19]

FDA-approved indications

Methotrexate, Trexall

Rheumatoid arthritis
Polyarticular juvenile idiopathic arthritis
Psoriasis
Neoplastic diseases and certain cancers

Xatmep

Polyarticular juvenile idiopathic arthritis
Acute Lymphoblastic Leukemia

Otrexup, Rasuvo, RediTrex

Rheumatoid arthritis
Polyarticular juvenile idiopathic arthritis
Psoriasis

Side effects

NOTE: Strength of association not well-defined

Nausea - 30%
Rash - 23%
Elevated liver enzymes - 19%
Mouth ulcers - 14%
Diarrhea - 12%
Hair loss - 12%
Upset stomach - 10%
Decreased blood counts - 5% [20,21]

Drug interactions

Nitrous oxide - DO NOT COMBINE. Nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, resulting in the potential for increased toxicity.
NSAIDs - high-dose methotrexate (typically used to treat malignancies) administered with NSAIDs has been shown to increase methotrexate levels and its toxicity. Despite the potential interactions, studies of methotrexate in patients with RA have usually included concurrent use of NSAIDs without apparent problems.
Highly protein-bound drugs - methotrexate is partially bound to albumin. Methotrexate may be displaced by highly protein-bound drugs (ex. phenytoin) and toxicity may occur
Mercaptopurine - methotrexate increases mercaptopurine exposure. Dose adjustments may be necessary.
Proton pump inhibitors (e.g. Nexium, Protonix) - high-dose methotrexate (typically used to treat malignancies) administered with PPIs may elevate and prolong methotrexate blood levels and increase the risk of toxicity
Probenecid - probenecid may block methotrexate excretion and raise levels
Broad-spectrum antibiotics - may decrease methotrexate absorption by interfering with enterohepatic reabsorption
Penicillins - may reduce renal clearance of methotrexate and increase levels
Trimethoprim/sulfamethoxazole (Bactrim®) - rare cases of bone marrow suppression have been reported when combined with methotrexate
Valproic acid - methotrexate may decrease valproate exposure, increasing the risk of seizures or bipolar symptoms. Monitor valproate levels and clinical response closely when combining.
Hepatotoxic drugs - use caution when administering methotrexate with other hepatotoxic drugs (e.g. azathioprine, retinoids, sulfasalazine)
Theophylline - methotrexate may decrease theophylline clearance [22]

Contraindications / Precautions

Pregnancy or breastfeeding - DO NOT USE. Methotrexate can cause fetal death and toxicity. Women should avoid pregnancy during therapy and for at least 6 months after the last dose. Men should use effective contraception during therapy and for at least 3 months after the last dose. Do not breastfeed while taking methotrexate and for at least one week after stopping therapy.
Infertility - in women, methotrexate can cause infertility and menstrual dysfunction during and after cessation of therapy. In men, infertility and oligospermia can occur during and after cessation of therapy. The long-term effects of methotrexate on fertility in women and men is unknown.
Hepatitis B or C infection (active or chronic) - DO NOT USE
Alcohol consumption - methotrexate should not be used in patients with alcoholic liver disease. A study that looked at the risk of liver toxicity among patients with RA who were taking methotrexate found that consumption of < 14 drinks per week was not associated with an increased risk of ALT/AST > 3 X ULN. [PMID 28341765]
Immunodeficiency syndrome - DO NOT USE
Myelodysplasia - DO NOT USE
Acute serious infection - DO NOT USE
Untreated latent Tuberculosis (TB) or active TB infection - DO NOT USE
Active Herpes Zoster (Shingles) - DO NOT USE
Interstitial pneumonitis - DO NOT USE
Treated lymphoproliferative disease of ≤ 5 years - DO NOT USE
Anemia - methotrexate may cause anemia. In a trial where 2391 patients were treated with methotrexate (median dose 16 mg/week) for a median of 23 months, anemia occurred in 30.2% of methotrexate-treated patients compared to 23.2% of placebo-treated patients. Severe anemia (Hg < 8 g/dl) occurred in 0.4% of patients in both groups. [41]
Leukopenia - methotrexate may cause leukopenia. In a trial where 2391 patients were treated with methotrexate (median dose 16 mg/week) for a median of 23 months, leukopenia occurred in 9.2% of methotrexate-treated patients compared to 6.4% of placebo-treated patients. Severe leukopenia (< 2000/mm³) occurred in 0% of patients in both groups. [41]
Thrombocytopenia - methotrexate may suppress platelet counts. In a trial where 2391 patients were treated with methotrexate (median dose 16 mg/week) for a median of 23 months, thrombocytopenia occurred in 8.5% of methotrexate-treated patients compared to 10.7% of placebo-treated patients. Severe thrombocytopenia (< 50,000/mm³) occurred in 0% of patients in both groups. If the platelet count falls to < 50,000/mm³, methotrexate should be discontinued. [41]
Liver toxicity - methotrexate has the potential to cause acute (elevated transaminases) and chronic (cirrhosis) liver toxicity. Pooled data from 2062 RA patients who used methotrexate for a mean of 3.3 years showed that the cumulative incidence for any elevated ALT/AST was 48.9% with 16.8% of patients having elevations 2-3 X ULN. Among 1113 RA patients who took methotrexate an average of 4.1 years, the incidences of mild fibrosis, severe fibrosis, and cirrhosis were 15.3%, 1.3%, and 0.5%, respectively. The manufacturer's PI recommends periodic liver biopsy during methotrexate treatment, particularly in psoriasis patients (initially and at every 1.5 gram cumulative dose). The AAD/NPS guidelines are less stringent (see Lab monitoring above) Professional guidelines on RA and sarcoidosis only recommend a biopsy in the setting of persistently elevated liver enzymes. [16]
Gastrointestinal toxicity - methotrexate may cause GI irritation and toxicity. If vomiting, diarrhea, or ulcerative stomatitis occurs, methotrexate therapy should be stopped until recovery. Severe, unexpected GI toxicity has occurred when methotrexate has been combined with NSAIDs.
Renal toxicity - in rare cases, methotrexate may cause renal damage including acute renal failure
Severe skin reactions - severe skin reactions including toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme have been reported
Infections - methotrexate may suppress the immune system and increase the risk of infections. Opportunistic infections including Pneumocystis jiroveci pneumonia have occurred. In a trial where 2391 patients were treated with methotrexate (median dose 16 mg/week) for a median of 23 months, infections occurred in 22.2% of methotrexate-treated patients compared to 19.5% of placebo-treated patients. Severe infections occurred in 2.1% of patients in both groups.
Malignancy - malignancies, including Non-Hodgkin's lymphoma, have been reported in patients receiving methotrexate. In some cases, lymphomas have regressed following methotrexate discontinuation. In a randomized trial where 2391 patients were treated with methotrexate (median dose 16 mg/week) for a median of 23 months, the overall risk of cancer was not increased in methotrexate-treated patients compared to placebo, but the incidence of skin cancers, particularly squamous cell skin cancers, was significantly higher in methotrexate-treated patients (2.2% vs 1.1%). [PMID 32066146] Another study found that methotrexate had a negligible effect on melanoma risk. [PMID 36044236]
Influenza vaccine - the ACR recommends high-dose or adjuvanted influenza vaccine in patients 18 and older receiving methotrexate. They also recommend holding methotrexate for 2 weeks after vaccination if disease activity allows. A study published in 2023 found that holding for 1 week induced a similar immune response as a 2-week hold. [PMID 35930728]
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Neurotoxicity - cases of leukoencephalopathy and other neurotoxicities have been reported in patients treated with IV methotrexate.
Methotrexate-induced pneumonitis - methotrexate-induced pneumonitis is a rare side effect (≤ 1%) that can occur at any time during therapy and has been reported at low doses. Symptoms include fever, dry nonproductive cough, dyspnea, hypoxemia, and an infiltrate on chest X-ray. In a trial where 2391 patients were treated with methotrexate (median dose 16 mg/week) for a median of 23 months, pneumonitis occurred in 6 patients treated with methotrexate compared to 1 patient treated with placebo. [41]
Ascites and/or pleural effusions - methotrexate exits slowly from third space compartments, and elimination is reduced in patients with ascites and/or pleural effusions. Consider dose adjustments and monitor closely.
Tumor lysis syndrome - methotrexate may induce tumor lysis syndrome in patients with rapidly growing tumors
Radiation therapy - methotrexate may increase the risk of soft tissue necrosis and osteonecrosis when given with radiation therapy
Liver disease - ALT or AST ≥ 2 X ULN - DO NOT USE. Methotrexate is contraindicated in significant liver disease.
Kidney disease

CrCl < 30ml/min: DO NOT USE [18]

Mycophenolate | Cellcept® | Myfortic®

Dosage forms

Capsule (Cellcept®)

250 mg

Tablet (Cellcept®)

500 mg

Suspension (Cellcept®)

200 mg/ml
Comes in 225 ml bottle

Tablet, delayed-release (Myfortic®)

180 mg
360 mg

Cellcept is mycophenolate mofetil. Mycophenolate mofetil is absorbed following oral administration and hydrolyzed to mycophenolic acid, the active metabolite.
Myfortic is an enteric formulation of mycophenolate sodium that delivers the active moiety mycophenolic acid

Dosing - Cellcept

Kidney transplant rejection prophylaxis (adults)

Dosing (oral): 1000 mg twice daily
Give on an empty stomach. Stable transplant patients may take with food if necessary.
Do not open capsules or crush tablets
Do not mix suspension with other liquids. Suspension may be given via an NG tube.
Take a missed dose as soon as remembered, unless it is within 2 hours of the next scheduled dose, in which case, take at regular time

Heart and liver transplant rejection prophylaxis (adults)

Dosing (oral): 1500 mg twice daily
Give on an empty stomach. Stable transplant patients may take with food if necessary.
Do not open capsules or crush tablets
Do not mix suspension with other liquids. Suspension may be given via an NG tube.
Take a missed dose as soon as remembered, unless it is within 2 hours of the next scheduled dose, in which case, take at regular time

Kidney, heart, and liver transplant rejection prophylaxis (≥ 3 months old)

Suspension

600 mg/m², administered twice daily (maximum total daily dose of 2 g or 10 ml of the oral suspension)
For heart and liver transplant recipients, the dose can be increased to a maintenance dose of 900 mg/m² twice daily (maximum total daily dose of 3 grams or 15 ml of the oral suspension)

Capsules or tablets

BSA 1.25 m² to < 1.5 m²: 750 mg twice daily
BSA ≥ 1.5 m²: 1000 mg twice daily
For heart and liver transplant recipients, the dose may be increased to a maximum of 3 grams/day.

Other

See body surface area (BSA) calculator
Give on an empty stomach. Stable transplant patients may take with food if necessary.
Do not open capsules or crush tablets
Do not mix the suspension with other liquids. Suspension may be given via an NG tube.
Take a missed dose as soon as remembered, unless it is within 2 hours of the next scheduled dose, in which case, take it at regular time

Dosing - Myfortic

Kidney transplant rejection prophylaxis (adults)

Dosing: 720 mg twice daily
Take on an empty stomach, 1 hour before or 2 hours after food intake
Do not crush, cut, or chew tablets. Tablets are enteric coated.

Kidney transplant rejection prophylaxis at least 6 months post-transplant (≥ 5 years old)

Dosing: 400 mg/m² body surface area (BSA) administered twice daily (up to a maximum dose of 720 mg administered twice daily)
Pediatric patients with a BSA of 1.19 m² to 1.58 m² may be dosed either with three Myfortic 180 mg tablets, or one 180 mg tablet plus one 360 mg tablet twice daily (1080 mg daily dose). Patients with a BSA of > 1.58 m² may be dosed either with four Myfortic 180 mg tablets, or two Myfortic 360 mg tablets twice daily (1440 mg daily dose). Pediatric doses for patients with BSA < 1.19 m² cannot be accurately administered using currently available formulations of Myfortic tablets.
See body surface area (BSA) calculator
Take on an empty stomach, 1 hour before or 2 hours after food intake
Do not crush, cut, or chew tablets. Tablets are enteric coated.

Lab monitoring

Mycophenolate levels

Mycophenolate acid (MPA) is metabolized in the liver to its inactive metabolite, 7-O-mycophenolic acid glucuronide (MPAG). MPAG is excreted in the urine, and it also undergoes enterohepatic circulation where it is excreted in the bile, converted back to MPA in the gut, and then reabsorbed. Because of this, MPA has 2 peak concentrations; one peak occurs within 1 - 2 hours of dosing, and another occurs 6 - 12 hours after dosing.
Lab assays are available that measure MPA and MPAG concentrations. The benefits of monitoring MPA and MPAG levels have not been completely defined, and therefore, routine monitoring is not widely recommended. MPA trough levels do not correlate well with overall MPA exposure, nor are they reliable predictors of toxicity. Monitoring may be beneficial in patients who are at high risk for graft rejection.
MPA reference range trough levels: 1 - 3.5 µg/ml
MPAG reference range trough levels: 35 - 100 µg/ml

Other labs

CBC with differential - Mycophenolate can cause neutropenia. Check CBC with differential weekly for the first month, twice monthly for the second and third months, and monthly for the remainder of the first year.
Hepatitis B and C serology in infected patients to monitor for reactivation
Epstein-Barr virus (EBV) serology - patients who are EBV seronegative are at greater risk for post-transplant lymphoproliferative disorder (PTLD) if they contract EBV. Monitoring EBV serology may be appropriate in some patients, particularly children.

Efficacy

Immune thrombocytopenia (ITP)

Mycophenolate + Steroids vs Steroids Only for ITP, NEJM (2021) [SH review]

Pemphigus vulgaris

Mycophenolate vs Rituximab in Patients with Pemphigus Vulgaris, NEJM (2021) [PubMed abstract]

Generic / Price

Cellcept tablet and capsule (#120) - YES/$
Cellcept suspension (225 ml) - YES/$$$$
Myfortic (#120) - YES/$$-$$$$

Mechanism of action

Mycophenolate mofetil (MMF) is absorbed following oral administration and hydrolyzed to mycophenolic acid (MPA), the active metabolite. MPA is a selective uncompetitive inhibitor of the two isoforms (type I and type II) of inosine monophosphate dehydrogenase (IMPDH) leading to inhibition of the de novo pathway of guanosine nucleotide synthesis and blocks DNA synthesis. The mechanism of action of MPA is multifaceted and includes effects on cellular checkpoints responsible for metabolic programming of lymphocytes. MPA shifts transcriptional activities in lymphocytes from a proliferative state to catabolic processes. In vitro studies suggest that MPA modulates transcriptional activities in human CD4+ T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways that are relevant to metabolism and survival, leading to an anergic state of T-cells whereby the cells become less responsive to antigenic stimulation. Additionally, MPA enhanced the expression of negative co-stimulators such as CD70, PD-1, CTLA-4, and transcription factor FoxP3 as well as decreased the expression of positive co-stimulators CD27 and CD28.
MPA decreases proliferative responses of T- and B-lymphocytes to both mitogenic and allo-antigenic stimulation, antibody responses, as well as the production of cytokines from lymphocytes and monocytes such as GM-CSF, IFN-Ɣ, IL-17, and TNF-α. Additionally, MPA prevents the glycosylation of lymphocyte and monocyte glycoproteins that are involved in intercellular adhesion to endothelial cells and may inhibit recruitment of leukocytes into sites of inflammation and graft rejection.
Overall, the effect of MPA is cytostatic and reversible

FDA-approved indications

Cellcept

Prophylaxis of organ rejection, in adult and pediatric recipients 3 months of age and older of allogeneic kidney, heart, or liver transplants, in combination with other immunosuppressants

Myfortic

Prophylaxis of organ rejection in adult patients receiving a kidney transplant
Prophylaxis of organ rejection in pediatric patients 5 years of age and older who are at least 6 months post kidney transplant

Side effects

NOTE: Cellcept was compared to placebo in 12-month trials involving kidney transplant recipients. All participants also received cyclosporine and corticosteroids. Only side effects that occurred at an incidence ≥ 20% are included.

Side effect	Mycophenolate	Placebo
Bacterial infections	39.9%	37.3%
Diarrhea	30.4%	13.9%
Leukopenia	28.6%	4.2%
Hypertension	27.5%	19.3%
Musculoskeletal pain	24.8%	9.6%
Abdominal pain	22.4%	11.4%
Edema	21%	8.4%
Anemia	20%	2.4%

Drug interactions

Antacids - co-administration of magnesium and aluminum hydroxide containing antacids may decrease mycophenolate exposure. Administer magnesium and aluminum hydroxide containing antacids at least 2 hours after mycophenolate.
Azathioprine - mycophenolate and azathioprine both inhibit purine metabolism, and coadministration may increase the risk of hematologic toxicity. Their combined use is generally not recommended.
Calcium free phosphate binders - calcium free phosphate binders like sevelamer have been shown to reduce mycophenolate exposure. Administer calcium free phosphate binders at least 2 hours after mycophenolate.
Combined oral contraceptives - mycophenolate may affect exposure to hormones in combined oral contraceptives. In one small study (N=18) that covered 3 menstrual cycles, levonorgestrel levels were decreased by about 15% in women treated with mycophenolate. Ethinyl estradiol and desogestrel levels were not significantly different, nor were levels of FSH, LH, and progesterone. An additional contraceptive barrier method is recommended when mycophenolate is taken with combination OCPs.
Cyclosporine - cyclosporine decreases mycophenolate exposure by inhibiting its enterohepatic circulation. This effect should be taken into consideration when cyclosporine is added to or removed from mycophenolate therapy.
Drugs that affect enterohepatic circulation - drugs that affect enterohepatic circulation may reduce exposure to mycophenolate. Some drugs directly interfere (e.g. bile acid sequestrants) with enterohepatic circulation while other drugs indirectly interfere by altering the GI flora (e.g. antibiotics). Examples of these drugs include cyclosporine A, trimethoprim/sulfamethoxazole, cholestyramine, colestipol, colesevelam, rifampin, aminoglycosides, cephalosporins, fluoroquinolones and penicillins. Monitor patients for reduced efficacy when combining these drugs with mycophenolate.
Drugs that modulate glucuronidation - drugs that increase glucuronidation may decrease mycophenolate exposure while drugs that inhibit glucuronidation may increase its exposure. Examples of these drugs include telmisartan (induces glucuronidation) and isavuconazole (inhibits glucuronidation). Monitor patients for reduced efficacy or increased adverse effects when combining these drugs with mycophenolate.
Drugs that undergo renal tubular secretion - MPAG, a mycophenolate metabolite, is eliminated in the kidneys through renal tubular secretion. Drugs that undergo renal tubular secretion may compete with MPAG and increase its exposure, and likewise, MPAG may increase the exposure of competing drugs. Examples of drugs that undergo renal secretion include acyclovir, ganciclovir, probenecid, valacyclovir, and valganciclovir. Monitor for adverse effects including blood cell counts when combining these medications with mycophenolate.
Norfloxacin and metronidazole - the combination of norfloxacin and metronidazole can decrease mycophenolate exposure, and they should not be taken with it. Individually, the drugs do not appear to affect mycophenolate exposure.
Proton pump inhibitors (PPIs) - increased gastric pH may decrease the solubility of mycophenolate mofetil (Cellcept®) and prevent its conversion to mycophenolic acid, the active metabolite. Use caution when combining mycophenolate mofetil (Cellcept®) with PPIs. Myfortic® contains the active moiety mycophenolic acid and does not appear to be affected by PPIs.
Rifampin - rifampin may decrease mycophenolate exposure, and it should not be taken with mycophenolate

Contraindications / Precautions

Pregnancy and females of reproductive potential - use of mycophenolate during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of multiple congenital malformations in multiple organ systems. Mycophenolate should be avoided during pregnancy if possible, and women who can become pregnant should take precautions to prevent pregnancy.
Malignancies - immunosuppressants like mycophenolate may increase the risk of malignancies, particularly lymphomas and skin cancer. In trials lasting 12 months, non-melanoma skin carcinomas occurred in 1.6% - 4.2% of patients, and other types of malignancies occurred in 0.7% - 2.1% of patients. Patients on mycophenolate should be screened regularly for skin cancer and take preventative measures including limiting sun exposure, wearing protective clothing, and using sunscreen.
Post-transplant lymphoproliferative disorder (PTLD) - post-transplant lymphoproliferative disorder (PTLD) is a rare immune syndrome seen in organ transplant recipients that can range in severity from benign lymphocytosis to lymphoma. In trials of kidney, liver, and heart transplant recipients, PTLD occurred in 0.4% - 1% of patients receiving 2 - 3 grams of Cellcept. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection, and patients who are seronegative for EBV are at greatest risk. EBV serology should be monitored during mycophenolate therapy in seronegative patients.
Acute Inflammatory Syndrome Associated with Mycophenolate Products - acute inflammatory syndrome (AIS) associated with mycophenolate products is a paradoxical pro-inflammatory reaction characterized by fever, arthralgias, arthritis, muscle pain, and elevated inflammatory markers (C-reactive protein and ESR), without evidence of infection or underlying disease recurrence. Symptoms occur within weeks to months of initiation of therapy or dose increases. After discontinuation, improvement of symptoms and inflammatory markers usually occurs within 24 to 48 hours. Monitor patients for AIS when starting treatment or increasing the dosage. Discontinue mycophenolate and consider other treatments if AIS occurs.
Infections - immunosuppressants like mycophenolate increase the risk of infection including bacterial, viral, fungal, protozoal and opportunistic infections. Serious virus infections reported in mycophenolate-treated patients include polyomavirus-associated nephropathy (mostly due to BK virus infection), JC virus-associated progressive multifocal leukoencephalopathy (PML), and Cytomegalovirus infections. In studies, the most common opportunistic infections seen in mycophenolate-treated patients were mucocutaneous candida, CMV viremia/syndrome, and herpes simplex. Fatal infections/sepsis occurred in approximately 2% of kidney and heart patients and 5% of liver patients.
Hepatitis B and C infection - reactivation of hepatitis B and C infections has occurred in patients receiving mycophenolate. Monitor viral activity in susceptible patients.
Neutropenia - mycophenolate may cause neutropenia. In trials, severe neutropenia (ANC < 0.5 X 10³/µL) occurred in up to 2% of kidney transplant patients, 2.8% of heart transplant patients, and 3.6% of liver transplant patients receiving Cellcept 3 g daily. Neutropenia is most typically observed in the interval between 31 and 180 days post-transplant. Consider monitoring with complete blood counts weekly for the first month, twice monthly for the second and third months, and monthly for the remainder of the first year. If neutropenia develops (ANC < 1.3 X 10³/µL), consider reducing the mycophenolate dose or interrupting therapy.
Pure red cell aplasia - cases of pure red cell aplasia (PRCA) have been reported in patients receiving mycophenolate. In some cases, PRCA resolved when mycophenolate was stopped or doses were reduced. If PRCA occurs, consider discontinuing mycophenolate or reducing the dose.
Gastrointestinal complications - in trials, cases of gastrointestinal bleeding, perforation, and ulceration were observed in patients treated with mycophenolate
Hypoxanthine-Guanine Phosphoribosyl-Transferase Deficiency (HGPRT) - mycophenolate is an inosine monophosphate dehydrogenase (IMPDH) inhibitor; therefore it should be avoided in patients with hereditary deficiencies of hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndromes because it may cause an exacerbation of disease symptoms characterized by the overproduction and accumulation of uric acid leading to symptoms associated with gout such as acute arthritis, tophi, nephrolithiasis or urolithiasis and renal disease including renal failure
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Blood donation - patients should not donate blood during mycophenolate therapy and for at least 6 weeks following discontinuation because their blood or blood products might be administered to a female of reproductive potential or a pregnant woman
Semen donation - men should not donate semen during mycophenolate therapy and for 90 days following discontinuation
Concomitant medications - a variety of drugs may alter mycophenolate exposure. Checking MPA and MPAG levels before and after drug changes may be helpful in determining the effects of concomitant medications on mycophenolate exposure. See Lab monitoring above for more.
Impaired ability to drive or operate machinery - mycophenolate may impair the ability to drive or operate machinery. Patients who experience somnolence, confusion, dizziness, tremor, or hypotension during treatment should avoid these activities.
Local reactions (intravenous Cellcept) - intravenous Cellcept should not be given by rapid or bolus IV injection because this increases the risk of local reactions including phlebitis and thrombosis
Phenylketonuria (suspension) - mycophenolate oral suspension contains aspartame, a source of phenylalanine (0.56 mg phenylalanine/ml suspension)
Allergy to polysorbate 80 - intravenous mycophenolate contains polysorbate 80.
Kidney disease

Kidney transplant - no dose adjustments are needed in kidney transplant patients experiencing delayed graft function postoperatively but patients should be carefully monitored. In kidney transplant patients with severe chronic impairment of the graft (GFR < 25 ml/min), no dose adjustments are necessary; however, doses greater than 1000 mg administered twice a day should be avoided.
Heart and liver transplant - no data are available for heart or liver transplant patients with severe chronic renal impairment. Mycophenolate may be used for heart or liver transplant patients with severe chronic renal impairment if the potential benefits outweigh the potential risks.

Liver disease

Kidney transplant - no dose adjustments are recommended for kidney transplant patients with severe hepatic parenchymal disease. However, it is not known whether dose adjustments are needed for hepatic disease with other etiologies.
Heart transplant - no data are available for heart transplant patients with severe hepatic parenchymal disease

Cyclosporine | Sandimmune® | Neoral® | Gengraf®

Dosage forms

Microemulsion (modified) capsule (Gengraf® | Neoral®)

25 mg
50 mg
100 mg

Microemulsion (modified) solution (Gengraf® | Neoral®)

100 mg/ml
Comes in 50 ml bottle

Standard capsule (Sandimmune®)

25 mg
100 mg

Standard solution (Sandimmune®)

100 mg/ml
Comes in 50 ml bottle

Dosing

Ulcerative colitis, severe, refractory

Starting: 2 - 4 mg/kg/day via IV infusion. May be given in doses or as a continuous infusion. Most patients respond within 7 days. Target blood concentration is 200 - 250 ng/ml.
After response is seen with IV therapy, patients are switched to oral therapy at a dose that is twice the daily IV dose. (Ex. Daily IV dose = 200 mg. Oral dose would be 400 mg/day)
Daily oral cyclosporine dose (Neoral or Gengraf) is given in 2 divided doses. Target trough concentration for oral therapy is 200 - 250 ng/ml.
Oral cyclosporine should be overlapped with a thiopurine and continued for 2 - 3 months before tapering [25,26]
Neoral and Gengraf (capsule and solution) have greater bioavailability than Sandimmune. Providers should use caution and expect greater exposure when switching from Sandimmune to Neoral or Gengraf. [30]

Rheumatoid arthritis

Starting: 2.5 mg/kg/day given in 2 divided doses
Dose may be increased by 0.5 - 0.75 mg/kg/day after 8 weeks, and at 12 weeks to a maximum of 4 mg/kg/day
Effect typically seen in 4 - 8 weeks [30]

Psoriasis

Starting: 2.5 mg/kg/day given in 2 divided doses
Maintenance: 2.5 - 5 mg/kg/day given in 2 divided doses
Maximum: 5 mg/kg/day
After the first 4 weeks of therapy, dose may be increased by 0.5 mg/kg/day at intervals of 2 weeks if necessary
Adjust dose downward (by 0.25 - 1.0 mg/kg) when clearance of psoriasis is achieved or when hypertension or decreased renal function are observed [40]

Lab monitoring

NOTE: Lab monitoring for cyclosporine varies by indication. No formal recommendations for monitoring during ulcerative colitis have been published.

Rheumatoid arthritis

Baseline

BMP, LFTs, Urinary protein
Serum creatinine should be measured on 2 separate occasions

First 3 months

BMP every 2 weeks

Month 4 and on

BMP every month [29]

Concomitant methotrexate

If taking with methotrexate, CBC and LFTs should be monitored monthly [30]

Psoriasis

Baseline

BMP, CBC, Magnesium, Uric Acid, Lipids
Serum creatinine should be measured on 2 separate occasions

First 3 months

BMP, CBC, Magnesium, Uric Acid, Lipids every 2 weeks

Month 4 and on

BMP, CBC, Magnesium, Uric Acid, Lipids every month [30]

Monitoring blood levels in ulcerative colitis

During IV therapy

At 24 hours, then every 48 hours
Target blood concentration is 200 - 250 ng/ml
Cyclosporine may be given in doses or as a continuous infusion

During oral therapy

Weekly trough levels for first 4 weeks, then every 2 weeks
Target trough concentration for oral therapy is 200 - 250 ng/ml [26,27]

Adjusting dose for serum creatinine

If serum creatinine is ≥ 25% above baseline, repeat within 2 weeks. If repeat is ≥ 25% above baseline, reduce dose by 25 - 50%
If serum creatinine is ≥ 50% above baseline at any time, reduce dose by 25 - 50%
If serum creatinine does not return to < 125% of baseline after 2 dose adjustment, stop cyclosporine [30]

Generic / Price

Neoral®/Gengraf® (180 capsules) - YES/$$
Neoral®/Gengraf® (50 ml solution) - YES/$$-$$$
Sandimmune® (60 capsules) - YES/$$$$
Sandimmune® (50 ml solution) - NO/$$$$

Mechanism of action

Cyclosporine competitively binds to and inhibits calmodulin-dependent calcineurin, leading to suppression of T-cell and immunoglobulin E receptor signaling pathways [25]
Cyclosporine inhibits immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release including interleukin-2. [28]

FDA-approved indications

Neoral® | Gengraf®

Prevention of kidney, liver, and heart transplant rejection
Rheumatoid arthritis
Psoriasis

Sandimmune®

Prevention of kidney, liver, and heart transplant rejection

Side effects

NOTE: Only side effects that occurred at an incidence of ≥ 3% overall, and ≥ 3% more than placebo are listed. Data listed below is from rheumatoid arthritis trials.

Side effect	Cyclosporine	Placebo
Nausea	23%	14%
Hypertrichosis	19%	3%
Headache	17%	9%
Abdominal pain	15%	10%
Diarrhea	12%	8%
Dyspepsia	12%	4%
Vomiting	9%	5%
Paresthesia	8%	1%
Hypertension	8%	2%
Dizziness	8%	3%
Tremor	8%	4%
Edema	5%	< 1%
Dyspnea	5%	2%
Flatulence	5%	1%
Gingivitis	4%	1%
Chest pain	4%	1%
Purpura	3%	0%

Drug interactions

Cyclosporine has a narrow therapeutic index. It is also a sensitive CYP3A4 substrate and inhibitor and a P-glycoprotein substrate and inhibitor. Because of this, it has a long list of potential drug interactions.
See the Neoral PI drug interaction section for more

Contraindications / Precautions

NOTE: precautions presented here pertain to use in psoriasis, rheumatoid arthritis, and ulcerative colitis. They do not pertain to use in transplant patients.

Rheumatoid arthritis (RA) - RA patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine
Psoriasis - psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive cyclosporine. Psoriasis patients treated with cyclosporine should not receive concomitant PUVA or UVB therapy, methotrexate, or other immunosuppressive agents, coal tar, or radiation therapy.
Skin malignancies - psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or radiation therapy, are at an increased risk of developing skin malignancies when taking cyclosporine
Microemulsion (Neoral, Gengraf) - Neoral and Gengraf (capsule and solution) have greater bioavailability than Sandimmune. Providers should use caution and expect greater exposure when switching from Sandimmune to Neoral or Gengraf.
Nephrotoxicity - cyclosporine may be nephrotoxic in some patients. The risk for nephrotoxicity increases with higher doses and longer duration of treatment. In RA trials, serum creatinine elevations ≥ 30% were seen in 43% of cyclosporine-treated patients and 13% of placebo-treated patients. Creatinine elevations ≥ 50% were seen in 24% of cyclosporine-treated patients and 3% of placebo-treated patients. If not addressed promptly, kidney damage may be permanent in some cases.
Hepatotoxicity - cyclosporine may be hepatotoxic in some patients. The risk for hepatotoxicity is greatest at higher doses.
High blood pressure - cyclosporine may raise blood pressure in some patients. In RA trials, up to 33% of cyclosporine-treated patients had elevated SBP compared to 22% of placebo-treated patients. Monitor blood pressure every 2 weeks during the first 3 months of therapy and monthly thereafter. Dose reductions of 25 - 50% or antihypertensives may be necessary to control blood pressure.
Malignancies - cyclosporine may increase the risk of malignancy, particularly lymphoma and skin cancers
Serious infections - cyclosporine may increase the risk of serious infections including bacterial, viral, fungal, protozoal, and opportunistic infections
Polyomavirus infections - cyclosporine may increase the risk of polyomavirus infections including JC virus-associated progressive multifocal leukoencephalopathy (PML) and BK-associated polyomavirus-associated nephropathy (PVAN). Consider PML diagnosis in patients with new-onset or deteriorating neurological signs and symptoms.
Neurotoxicity - seizures and encephalopathy have been reported in patients taking cyclosporine
Hyperkalemia - cyclosporine may cause hyperkalemia in some patients
Low magnesium - cyclosporine may cause low magnesium in some patients. Low magnesium may increase the risk of seizures.
Low cholesterol - low cholesterol may increase the risk of seizures in patients taking cyclosporine
Uric acid/gout - cyclosporine may increase uric acid levels and precipitate a gout attack
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Liver disease - clearance is decreased. Use caution. Manufacturer makes no specific dosage recommendation.
Kidney disease - DO NOT USE

Tacrolimus | Prograf® | Astagraf XL® | Envarsus XR®

Dosage forms

Capsule (Prograf®)

0.5 mg
1 mg
5 mg

Capsule, extended-release (Astagraf XL®)

0.5 mg
1 mg
5 mg

Tablet, extended-release (Envarsus XR®)

0.75 mg
1 mg
4 mg

Granules for oral suspension (Prograf®)

0.2 mg
1 mg

Dosing

Kidney, liver, heart, or lung transplant rejection prophylaxis (adults)

Tacrolimus dosing depends upon the type of transplant, concomitant immunosuppressants, treatment stage, and target blood levels. See the prescribing information of each drug for specific dosing recommendations - Prograf PI, Astagraf XL PI, Envarsus XR
Starting doses for the immediate-release form of tacrolimus (Prograf) range from 0.075 - 0.2 mg/kg/day. Immediate-release tacrolimus should be given in two divided doses that are 12 hours apart.
Extended-release forms of tacrolimus are only approved for kidney transplants. Starting doses for Astagraf XL range from 0.1 - 0.2 mg/kg/day, and the starting dose of Envarsus XR is 0.14 mg/kg/day. Astagraf XL and Envarsus XR are given once daily.
Black patients typically require higher doses of tacrolimus to achieve the same blood levels as Caucasians
Prograf may be taken without regard to food. Astagraf XL and Envarsus XR should be taken on an empty stomach at least 1 hour before a meal, or at least 2 hours after a meal.
Tacrolimus products are not considered interchangeable on a mg:mg basis. Envarsus XR should be started at 80% of the total daily immediate-release tacrolimus dose. The prescribing information for Astagraf XL does not give recommendations for switching between products. After any change, tacrolimus levels should be monitored closely.

Lab monitoring

Tacrolimus levels

Tacrolimus has a narrow therapeutic index so monitoring blood levels is important during therapy
Ninety percent of circulating tacrolimus is inside of blood cells, particularly erythrocytes, so whole blood specimens are recommended when measuring levels
Target concentrations are based on trough levels drawn immediately before the next scheduled dose. Most labs list a reference range of 5 - 15 ng/ml, but some professional organizations and institutional protocols give more specific ranges that vary by type of transplant, stage of therapy, and concomitant immunosuppressants.
The half-life of immediate-release tacrolimus (Prograf) varies widely between patient populations (4 - 40+ hours), but on average, is around 12 hours. Steady-state should be achieved after 3 days in most individuals.
The average half-life of extended-release tacrolimus is 38 hours for Astagraf XL and 31 hours for Envarsus XR. Steady-state is achieved after approximately 7 days for both drugs. [42,43,PI]

Other labs

Blood sugar - tacrolimus may increase the risk of new-onset diabetes. Blood sugars should be checked periodically during therapy.
Serum creatinine and eGFR - tacrolimus can cause nephrotoxicity. Renal function should be checked periodically during therapy.
Serum potassium - tacrolimus can raise potassium levels. Potassium levels should be checked periodically during therapy.
Epstein-Barr virus (EBV) serology - patients who are EBV seronegative are at greater risk for post-transplant lymphoproliferative disorder (PTLD) if they contract EBV. Monitoring EBV serology may be appropriate in some patients, particularly children.

Generic / Price

Prograf capsule - YES/$$$$
Envarsus XR - NO/$$$$
Astagraf XL - NO/$$$$

Mechanism of action

Tacrolimus binds to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin (a ubiquitous mammalian intracellular enzyme) is then formed, after which the phosphatase activity of calcineurin is inhibited. Such inhibition prevents the dephosphorylation and translocation of various factors such as the nuclear factor of activated T-cells (NF-AT), and nuclear factor kappa-light-chain enhancer of activated B-cells (NF-κB).
Tacrolimus inhibits the expression and/or production of several cytokines that include interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, gamma interferon, tumor necrosis factor-alpha, and granulocyte macrophage colony-stimulating factor. Tacrolimus also inhibits IL-2 receptor expression and nitric oxide release, induces apoptosis and production of transforming growth factor beta that can lead to immunosuppressive activity. The net result is the inhibition of T-lymphocyte activation and proliferation, as well as T-helper-cell-dependent B-cell response (i.e., immunosuppression).

FDA-approved indications

Prograf

Prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic kidney transplants, liver transplants, heart transplants, or lung transplants, in combination with other immunosuppressants

Astagraf XL

Prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants in adult and pediatric patients who can swallow capsules intact

Envarsus XR

Prophylaxis of organ rejection in kidney transplant patients in combination with other immunosuppressants
Prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants

Side effects

NOTE: No trials have compared tacrolimus to placebo, and it is commonly prescribed with other immunosuppressants. The data below is from a 12-month study that compared tacrolimus to cyclosporine in kidney transplant recipients. Only side effects that occurred at an incidence ≥ 15% are listed.

MMF - mycophenolate mofetil
Side effect	Tacrolimus + MMF	Cyclosporine + MMF
Diarrhea	44%	26%
Nausea	39%	47%
Constipation	36%	41%
Edema Peripheral	35%	46%
Tremor	34%	20%
Hypertension	32%	35%
Insomnia	30%	21%
Anemia	30%	28%
Post-Procedural Pain	29%	27%
Incision Site Complication	28%	23%
Hypomagnesemia	28%	22%
Hypophosphatemia	28%	21%
Vomiting	26%	25%
Hyperkalemia	26%	19%
Urinary Tract Infection	26%	22%
Graft Dysfunction	24%	18%
Headache	24%	25%
Blood Creatinine Increased	23%	23%
Hyperglycemia	21%	15%
Dyspepsia	18%	15%
Hyperlipidemia	18%	25%
Hypokalemia	16%	18%
Leukopenia	16%	12%

Drug interactions

Alcohol (Astagraf XL and Envarsus XR) - alcohol may increase the rate of tacrolimus release from Astagraf XL and Envarsus XR. Alcohol should be avoided when taking these products.
Antacids - co-administration of magnesium and aluminum hydroxide containing antacids may increase tacrolimus exposure. Monitor tacrolimus levels and decrease the dose as necessary when combining. Separating dosing by 4 hours may help to prevent an interaction.
Caspofungin - caspofungin may decrease tacrolimus trough concentrations. Monitor tacrolimus trough levels and adjust the dose as necessary when combining.
CYP3A4 inducers - tacrolimus is a sensitive CYP3A4 substrate, and CYP3A4 inducers may decrease its exposure. Monitor tacrolimus levels and increase the dose as necessary when combining.
CYP3A4 inhibitors - tacrolimus is a sensitive CYP3A4 substrate, and CYP3A4 inhibitors may increase its exposure. Monitor tacrolimus levels and decrease the dose as necessary when combining.
Drugs that raise potassium levels - tacrolimus can raise potassium levels and this effect may be potentiated by other potassium-raising medications (e.g. ACE inhibitors, ARBs, aldosterone antagonists). Use caution when combining.
Grapefruit juice - grapefruit juice is a CYP3A4 inhibitor. Grapefruit and grapefruit juice should be avoided when taking tacrolimus.
Metoclopramide - metoclopramide may increase tacrolimus exposure. Monitor tacrolimus levels and decrease the dose as necessary when combining.
Mycophenolate (Cellcept®) - mycophenolate exposure is higher when it is prescribed with tacrolimus as opposed to cyclosporine because cyclosporine interrupts enterohepatic circulation of mycophenolate. When switching from cyclosporine to tacrolimus, doses of concomitant mycophenolate may need to be adjusted.
Posaconazole - posaconazole is a strong CYP3A4 inhibitor, and it can increase tacrolimus exposure. When prescribing posaconazole with tacrolimus, reduce the tacrolimus dose to one-third of its original dose.
Drugs that prolong the QT interval - tacrolimus can prolong the QT interval, and the effect may be potentiated by other QT-prolonging drugs. If concomitant therapy is necessary, frequent monitoring of tacrolimus levels, electrolytes, and ECGs should be performed.
Voriconazole - voriconazole is a strong CYP3A4 inhibitor, and it can increase tacrolimus exposure. When combining voriconazole with tacrolimus, reduce the tacrolimus dose to one-third of its original dose.

Contraindications / Precautions

Concomitant sirolimus - tacrolimus should not be used with sirolimus. In studies of liver and heart transplant recipients, the use of sirolimus with tacrolimus worsened a number of outcomes, including mortality. The risk of thrombotic microangiopathy may also be increased with combined use.
Prolonged QT interval - tacrolimus can prolong the QT interval, and it should be avoided in patients with congenital long QT syndrome. Use caution in patients with congestive heart failure, bradyarrhythmias, hypokalemia, hypocalcemia, and hypomagnesemia as these conditions may increase the risk of a prolonged QT interval.
Female liver transplant recipients (Astagraf XL) - in a clinical trial of 471 liver transplant patients randomized to Astagraf XL or tacrolimus immediate-release, mortality at 12 months was 10% higher among patients treated with Astagraf XL compared to patients treated with tacrolimus immediate-release product (18% vs 8%). Astagraf XL is not approved for the prophylaxis of organ rejection in patients who received a liver transplant.
Treatment of hepatitis C - treatment of hepatitis C may change liver function and subsequently affect tacrolimus clearance. Monitor tacrolimus levels and adjust doses as necessary when treating hepatitis C.
Malignancies - immunosuppressants like tacrolimus may increase the risk of malignancies, particularly lymphomas and skin cancer. Patients on tacrolimus should be screened regularly for skin cancer and take preventative measures including limiting sun exposure, wearing protective clothing, and using sunscreen.
Post-transplant lymphoproliferative disorder (PTLD) - post-transplant lymphoproliferative disorder (PTLD) is a rare immune syndrome seen in organ transplant recipients that can range in severity from benign lymphocytosis to lymphoma. The majority of PTLD events appear related to Epstein-Barr Virus (EBV) infection, and patients who are seronegative for EBV are at greatest risk. EBV serology should be monitored during tacrolimus therapy in seronegative patients.
Infections - immunosuppressants like tacrolimus increase the risk of bacterial, viral, fungal, protozoal, and opportunistic infections. Serious virus infections reported in tacrolimus-treated patients include polyomavirus-associated nephropathy (mostly due to BK virus infection), JC virus-associated progressive multifocal leukoencephalopathy (PML), and Cytomegalovirus infections.
Switching between Prograf and extended-release products - immediate-release tacrolimus (Prograf) is not interchangeable on a mg-to-mg basis with the extended-release products. Serious adverse events have occurred when switching between these products. If a switch is to occur, close and careful monitoring of tacrolimus levels should be performed.
New-onset diabetes - new-onset diabetes has been observed in tacrolimus-treated patients. African-American and Hispanic kidney transplant recipients appear to be at the greatest risk. Monitor blood sugars during tacrolimus therapy.
Nephrotoxicity - tacrolimus can cause renal vascular vasocontstriction, toxic tubulopathy, and tubular-interstitial changes. In trials, up to 60% of tacrolimus-treated patients have experienced acute or chronic nephrotoxicity. Patients receiving CYP3A4 inhibitors and other nephrotoxic medications may be at increased risk. Renal function and tacrolimus levels should be monitored closely during therapy, and doses should be adjusted accordingly.
Neurotoxicity - tacrolimus has been associated with neurotoxic effects including posterior reversible encephalopathy syndrome (PRES), delirium, seizures and coma, tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions. Consider dose reductions or discontinuation in patients who develop neurologic symptoms.
Hyperkalemia - tacrolimus has been shown to raise potassium levels. Monitor potassium levels during therapy and consider the possible effects of concomitant potassium-elevating drugs (e.g. ACE inhibitors, ARBs, aldosterone antagonists)
Hypertension - hypertension is common in tacrolimus-treated patients. When treating hypertension, it is important to consider that certain antihypertensives (e.g. ACE inhibitors, ARBs) may potentiate the potassium-raising effects of tacrolimus and other agents (e.g. diltiazem, nifedipine) may increase tacrolimus exposure.
Myocardial hypertrophy - myocardial hypertrophy including concentric increases in left ventricular posterior wall and interventricular septum thickness has occurred in adults and children treated with tacrolimus, particularly those with high trough levels. The condition has been reversible in most cases following dose reduction or discontinuance of therapy. If patients develop renal failure or symptoms of ventricular dysfunction, a cardiac echo should be performed.
Thrombotic microangiopathy (TMA) - cases of thrombotic microangiopathy (TMA), including hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), have been reported in patients receiving tacrolimus. Factors that may increase the risk of TMA include severe infections, graft-versus-host disease, human leukocyte antigen mismatch, and concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus).
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Pure red cell aplasia - cases of pure red cell aplasia (PRCA) have been reported in patients receiving tacrolimus. All patients had other risk factors for PRCA (e.g. parvovirus B19), and a causal link has not been established. If PRCA occurs, consider discontinuing tacrolimus.
Anaphylaxis (intravenous Prograf) - anaphylactic reactions have been reported in about 0.6% of patients who received intravenous Prograf. Intravenous Prograf should be administered under close medical supervision.
Liver disease - tacrolimus clearance is decreased in patients with severe liver disease (Child-Pugh C). Use caution and monitor levels closely.
Kidney disease - the pharmacokinetics of tacrolimus in patients with renal impairment was similar to that in healthy volunteers with normal renal function. However, consideration should be given to dosing tacrolimus at the lower end of the therapeutic dosing range in patients who have received a liver or heart transplant and have pre-existing renal impairment.

Voclosporin (Lupkynis®)

Dosage forms

Capsule

7.9 mg

Dosing

Lupus nephritis (adults)

Starting: 23.7 mg (3 capsules) every 12 hours
Take on an empty stomach consistently as close to a 12-hour schedule as possible, and with a minimum of 8 hours between doses
Swallow capsules whole. Do not open, crush, or divide.
If a dose is missed, take it as soon as possible within 4 hours after missing the dose. Beyond the 4-hour time frame, wait until the usual scheduled time to take the next regular dose. Do not double the next dose.
Do not eat grapefruit or drink grapefruit juice while taking
Safety and efficacy have not been established beyond one year

Kidney disease

Voclosporin has not been studied in patients with baseline GFR ≤ 45 ml/min, and its use is not recommended in these patients unless benefits exceed risks
If used in patients with severe renal impairment at baseline, the recommended starting dose is 15.8 mg twice a day
See Therapy monitoring below for recommendations on adjusting doses during therapy

Liver disease

Child-Pugh A and B: recommended dose is 15.8 mg twice daily
Child-Pugh C: not recommended

With CYP3A4 inhibitors

Strong CYP3A4 inhibitors: DO NOT COMBINE
Moderate CYP3A4 inhibitors: dose should be reduced to 15.8 mg in the morning and 7.9 mg in the evening
Mild CYP3A4 inhibitors: no dose adjustment necessary
See CYP3A4 inhibitors for more

Efficacy

Lupus nephritis

Voclosporin vs Placebo for Lupus Nephritis, Lancet (2021) [PubMed abstract]

Therapy monitoring

Kidney function

Assess GFR every 2 weeks for the first month and every 4 weeks thereafter
Dose adjustments based on GFR:

If eGFR < 60 mL/min and reduced from baseline by > 20% and < 30%, reduce the dose by 7.9 mg twice a day. Re-assess eGFR within two weeks; if eGFR is still reduced from baseline by > 20%, reduce the dose again by 7.9 mg twice a day.
If eGFR < 60 mL/min and reduced from baseline by ≥ 30%, discontinue voclosporin. Re-assess eGFR within two weeks; consider re-initiating voclosporin at a lower dose (7.9 mg twice a day) only if eGFR has returned to ≥ 80% of baseline.
For patients that had a decrease in dose due to eGFR, consider increasing the dose by 7.9 mg twice a day for each eGFR measurement that is ≥ 80% of baseline; do not exceed the starting dose

Blood pressure

Monitor blood pressure every 2 weeks for the first month after initiating voclosporin and as clinically indicated thereafter
If BP > 165/ 105 mmHg or hypertensive emergency occurs, discontinue voclosporin

Generic / Price

- NO/$$$$

Mechanism of action

Voclosporin is a calcineurin-inhibitor immunosuppressant. The mechanism of voclosporin suppression of calcineurin has not been fully established. Activation of lymphocytes involves an increase in intracellular calcium concentrations that bind to the calcineurin regulatory site and activate calmodulin binding catalytic subunit and through dephosphorylation activates the transcription factor, Nuclear Factor of Activated T-Cell Cytoplasmic (NFATc). The immunosuppressant activity results in inhibition of lymphocyte proliferation, T-cell cytokine production, and expression of T-cell activation surface antigens. Studies in animal models also support a non-immunological role for calcineurin inhibition in kidney function to stabilize actin cytoskeleton and stress fibers in podocytes leading to increased podocyte integrity in glomeruli.

FDA-approved indications

Lupus nephritis - Voclosporin is indicated in combination with a background immunosuppressive therapy regimen (mycophenolate mofetil and corticosteroids) for the treatment of adult patients with active lupus nephritis. Safety and efficacy of voclosporin have not been established in combination with cyclophosphamide. Use of voclosporin is not recommended in this situation.

Side effects

NOTE: Data below is from two trials where voclosporin was compared to placebo. All patients were receiving background mycophenolate and corticosteroids. Only side effects that occurred at an incidence ≥ 3% overall, and ≥ 2% more than placebo are listed.

Side effect	Voclosporin (N=267)	Placebo (N=266)
Glomerular filtration rate decreased	26%	9%
Hypertension	19%	9%
Diarrhea	19%	13%
Headache	15%	8%
Anemia	12%	6%
Cough	11%	2%
Urinary tract infection	10%	6%
Abdominal pain upper	7%	2%
Dyspepsia	6%	3%
Alopecia	6%	3%
Renal Impairment	6%	3%
Abdominal pain	5%	2%
Mouth ulceration	4%	1%
Fatigue	4%	1%
Tremor	3%	1%
Acute kidney injury	3%	1%
Decreased appetite	3%	1%

Drug interactions

CYP3A4 strong and moderate inducers - DO NOT COMBINE. Voclosporin is a sensitive CYP3A4 substrate, and CYP3A4 strong and moderate inducers may decrease its exposure and efficacy.
CYP3A4 strong inhibitors - DO NOT COMBINE. Voclosporin is a sensitive CYP3A4 substrate, and CYP3A4 strong inhibitors may increase its exposure and toxicity.
CYP3A4 moderate inhibitors - voclosporin is a sensitive CYP3A4 substrate, and CYP3A4 moderate inhibitors may increase its exposure and toxicity. When combining voclosporin with CYP3A4 moderate inhibitors, the dose of voclosporin should be reduced to 15.8 mg in the morning and 7.9 mg in the evening.
P-glycoprotein substrates - voclosporin is a p-glycoprotein inhibitor, and it may increase the exposure of p-glycoprotein substrates. Use caution when combining and reduce substrate dosing if necessary.
OATP1B1 substrates - voclosporin is an OATP1B1 inhibitor in vitro, and it may increase the exposure of OATP1B1 substrates. Use caution when combining and reduce substrate dosing if necessary.
Drugs that raise potassium levels - voclosporin can raise potassium levels, and this effect may be potentiated by other potassium-raising medications (e.g. ACE inhibitors, ARBs, aldosterone antagonists).
Drugs that prolong the QT interval - voclosporin prolongs the QT interval, and the effect may be potentiated by other QT-prolonging drugs. Use caution when combining and monitor ECG and electrolytes appropriately.

Food interactions

Grapefruit juice - grapefruit juice is a CYP3A4 inhibitor. Grapefruit and grapefruit juice should be avoided when taking voclosporin.

Contraindications / Precautions

Pregnancy - avoid use of voclosporin in pregnant women due to the alcohol content of the drug formulation. The available data on the use of voclosporin in pregnant patients are insufficient to determine whether there is a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Malignancies - immunosuppressants like voclosporin may increase the risk of malignancies, particularly lymphomas and skin cancer. Patients on voclosporin should be screened regularly for skin cancer and take preventative measures including limiting sun exposure, wearing protective clothing, and using sunscreen.
Infections - immunosuppressants like voclosporin increase the risk of bacterial, viral, fungal, protozoal, and opportunistic infections. In one trial (N=356) lasting 52 weeks, infections were reported in 65% of voclosporin-treated patients and 57% of placebo-treated patients. Serious infections occurred in 10% and 11% of patients, respectively.
Nephrotoxicity - while voclosporin is used to treat kidney disease, it can also be nephrotoxic in some patients. GFR should be monitored closely in patients receiving voclosporin (see Therapy monitoring above), and appropriate dose adjustments should be made. The risk of nephrotoxicity increases with longer treatment duration and concomitant nephrotoxic drugs. In trials, decreases in GFR within the first 3 months of voclosporin treatment occurred in 71% of patients. After dose modification, 78% of these patients had a return to baseline or improvement in their GFR.
Hypertension - voclosporin may cause hypertension in some patients, and blood pressure should be monitored during therapy (see Therapy monitoring above). In trials, 19% of voclosporin-treated patients had hypertension compared to 9% of placebo-treated patients. When treating hypertension, it is important to consider that certain antihypertensives (e.g. ACE inhibitors, ARBs) may potentiate the potassium-raising effects of voclosporin and other agents (e.g. diltiazem, nifedipine) may increase voclosporin exposure.
Neurotoxicity - voclosporin may cause neurotoxicity. The most frequent neurological adverse events reported in trials were headache, tremor, dizziness, postherpetic neuralgia, migraine, paresthesia, hypoaesthesia, seizure, tension headache, and disturbance in attention. Serious neurological events that were reported included headache, migraine, seizure, and posterior reversible encephalopathy syndrome (PRES). Consider dose reductions or discontinuation in patients who develop neurologic symptoms.
Hyperkalemia - voclosporin may raise potassium levels. In trials, hyperkalemia in voclosporin-treated patients occurred at an incidence of 2.1 cases per 100 patient-years. Monitor potassium levels during therapy and consider the possible effects of concomitant potassium-elevating drugs (e.g. ACE inhibitors, ARBs, aldosterone antagonists).
Prolonged QT interval - voclosporin can prolong the QT interval. In trials, prolonged QT interval in voclosporin-treated patients occurred at an incidence of 0.9 cases per 100 patient-years. Factors that may increase the risk of torsade de pointes and/or sudden death in prolonged QT syndrome include the following: (1) bradycardia, (2) hypokalemia or hypomagnesemia, (3) concomitant use of other drugs that prolong the QTc interval, (4) presence of congenital prolongation of the QT interval.
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Pure red cell aplasia - cases of pure red cell aplasia (PRCA) have been reported in patients receiving calcineurin inhibitors. All patients had other risk factors for PRCA (e.g. parvovirus B19), and a causal link has not been established. If PRCA occurs, consider discontinuing voclosporin.
Liver disease - see Dosing above
Kidney disease - see Dosing above

Azathioprine (Imuran®)

Dosage forms

Tablet

50 mg

Dosing

Crohn's disease

Dosing: 2 - 3 mg/kg/day [1]
Typically given once daily

Rheumatoid arthritis

Dosing: 1 mg/kg/day given once daily or in 2 divided doses
Maximum: 2.5 mg/kg/day
Response typically seen in 6 - 8 weeks
May increase dose by 0.5 mg/kg/day at intervals of 4 weeks. Use lowest effective dose.

Systemic lupus erythematosus

Dosing: 2 - 3 mg/kg/day [3]
Typically given once daily

Lupus nephritis

Dosing: 2 mg/kg/day [2]

Psoriasis (off label)

Starting: 0.5 mg/kg
Typical maintenance dose: 75 - 150 mg/day
Monitor for cytopenias and increase dose by 0.5/kg/day as tolerated [40]

Ulcerative colitis

Active disease: 2.5 mg/kg/day given once daily or in divided doses
Maintenance of remission: 2.5 mg/kg/day given once daily or in divided doses [31]
Primary benefit is in maintenance therapy because of slow onset of action (up to 3 - 6 months)

Lab monitoring

TPMT (thiopurine methyltransferase)

TPMT is an enzyme involved in the metabolism of azathioprine. Genetic polymorphisms affect TPMT activity. See thiopurine metabolism for more.
Approximately 10% of Caucasians and African-Americans have intermediate TPMT activity, and 0.3% have low or absent TPMT activity. Decreased TPMT activity is less common in Asians.
Measuring TPMT activity before therapy may be helpful in predicting which patients may develop myelotoxicity from azathioprine. Testing for TPMT and NUDT15 deficiency should be considered in patients who experience severe bone marrow toxicities while taking thiopurines.
TPMT activity can be measured directly (in red blood cells) or through genotyping. Patients with recent blood transfusion (30 - 60 days) cannot have TPMT activity measured directly.
For patients with low or deficient TPMT activity, consider an alternate agent or extreme dose reduction. For patients with intermediate TPMT activity, start at 30 - 70% of the target dose. See PharmGKB website for recommendations on dosing based on TPMT genotyping. [32,37]

NUDT15 enzyme (nucleotide diphosphatase)

NUDT15 is an enzyme involved in the metabolism of azathioprine. Genetic polymorphisms affect NUDT15 activity. See thiopurine metabolism for more.
Patients with reduced NUDT15 activity may accumulate 6-TGNs and have an increased risk of myelosuppression. Testing for TPMT and NUDT15 deficiency should be considered in patients who experience severe bone marrow toxicities while taking thiopurines.
NUDT15 deficiency is seen in about 22.6% of East Asians (e.g. Chinese, Japanese, Vietnamese) with 2% having two loss-of-function alleles. NUDT15 deficiency is present in 13.6% of South Asians, up to 21% of Native Americans, and < 1% of people with African and European ancestry.
NUDT15 activity can be estimated through NUDT15 genotyping
For patients with low or deficient NUDT15 activity, consider an alternate agent. For patients with intermediate NUDT15 activity, consider dose reductions. See PharmGKB website for more. [32,37]

Cytopenias

PI recommendation: check CBC weekly during the first month, twice monthly for months 2 - 3, then monthly thereafter
ACG recommendation: check CBC every 1 - 2 weeks initially, then at least every 3 months

Thiopurine metabolites (6-TGN and 6-MMPN)

The utility of checking thiopurine metabolites to monitor therapy has not been validated in clinical trials
In certain scenarios, checking metabolites may be useful (e.g. compliance, leukopenia, elevated LFTs, refractory disease)
Levels should be checked after 3 - 6 months of therapy
See thiopurine metabolism for more

^✝Valid for inflammatory bowel disease only

Reference: LabCorp® website
6-TGN^✝
Suboptimal dosing	< 235 pmol
Optimal dosing	235 - 450 pmol
Increased risk of myelotoxicity	> 450 pmol
6-MMPN
Hepatotoxicity risk	> 5700 pmol

Efficacy

Crohn's disease

Azathioprine vs Infliximab vs Both for Moderate to Severe Crohn's Disease, NEJM (2010) [SH review]

Other

May give after meals to reduce stomach upset
May give in divided doses to reduce stomach upset
Azathioprine is metabolized to 6-mercaptopurine. See thiopurine metabolism.
The FDA recommends TPMT testing before initiating therapy

Generic / Price

- YES/$ (60 tablets)

Mechanism of action

Immunosuppressant - the exact mechanism by which thiopurines suppress inflammation is not completely understood. Thiopurines inhibit ribonucleotide synthesis which either directly or indirectly leads to T-cell suppression.

FDA-approved indications

Rheumatoid arthritis
Prevention of kidney transplant rejection

Side effects

NOTE: incidence of side effects are not well-defined. Data below are from RA trials.

Leukopenia (any degree) - 28%
Leukopenia (< 2500 cells/mm³) - 5.3%
Nausea/vomiting - 12%
Infections - <1%
Hepatotoxicity - <1%

Drug interactions

Febuxostat (Uloric®) - DO NOT COMBINE. Febuxostat may inhibit the metabolism of azathioprine, and they should not be given together.
Allopurinol - allopurinol inhibits one pathway of azathioprine metabolism and may lead to toxicity if given concomitantly. Reduce azathioprine dose to a fourth or a third of the usual dose when given with allopurinol. If patients have low TPMT activity, allopurinol should not be given with azathioprine.
Aminosalicylates (e.g. sulfasalazine, mesalazine) - there is in vitro evidence that aminosalicylates inhibit the TPMT enzyme. This may cause increased exposure to azathioprine. Use caution.
Sulfamethoxazole/trimethoprim - there have been case reports of increased leukopenia in patients receiving azathioprine with sulfamethoxazole/trimethoprim. Use caution.
ACE inhibitors - there have reports of anemia and severe leukopenia in patients receiving ACE inhibitors with azathioprine. Use caution.
Warfarin - azathioprine may inhibit the anticoagulant effect of warfarin
Ribavirin - ribavirin may inhibit azathioprine metabolism and lead to azathioprine toxicity including myelosuppression. When combining ribavirin with azathioprine, the following is recommended: monitor blood counts weekly for the first month, twice monthly for the second and third months, then monthly or more frequently if dosage or other therapy changes are necessary.

Contraindications / Precautions

Pregnancy and nursing - DO NOT USE
Malignancy - may increase risk of malignancy, particularly lymphoma, leukemia, and skin cancer. See cancer risk studies for more.
Cytopenias - azathioprine may cause leukopenia, thrombocytopenia, anemia (including macrocytic), and pancytopenia. Patients with decreased TPMT and/or NUDT15 activity are at increased risk (see Lab monitoring for more). Monitor blood cell counts during therapy.
TPMT and NUDT15 deficiency - TPMT and NUDT15 are enzymes involved in the metabolism of azathioprine. Deficiencies in these enzymes can lead to myelosuppression. See Lab monitoring for more.
Serious infections - immunosuppressants may increase the risk for serious infection including bacterial, viral, fungal, protozoal, and opportunistic infections. Reactivation of latent infections (e.g. tuberculosis, hepatitis) may also occur.
Progressive Multifocal Leukoencephalopathy (PML) - JC virus infection resulting in PML and death have occurred. Consider PML diagnosis in patients with new-onset or deteriorating neurological signs and symptoms.
Sperm - in mice, azathioprine has been shown to reduce sperm count and viability
Pancreatitis - observational studies have found an increased risk of acute pancreatitis in adults and children with inflammatory bowel disease who were treated with azathioprine [PMID 30685366 ]
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Liver disease - manufacturer makes no specific recommendation
Kidney disease - manufacturer makes no specific recommendation

Mercaptopurine | 6-MP | Purixan®

Dosage forms

Tablet

50 mg

Oral suspension (Purixan®)

20 mg/ml
Comes in 100 ml bottle

Dosing

Crohn's disease

Dosing: 1.0 - 1.5 mg/kg/day [1]
Typically given once daily

Ulcerative colitis

Active disease: 1.0 - 1.5 mg/kg/day given once daily
Maintenance of remission: 1.0 - 1.5 mg/kg/day given once daily [33]
Primary benefit is in maintenance therapy because of slow onset of action (up to 3 - 6 months)

Homozygous deficiency in either TPMT or NUDT15

Patients with homozygous deficiency of either enzyme typically require 10% or less of the standard mercaptopurine dosage

Heterozygous deficiency in TPMT and/or NUDT15

Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended mercaptopurine doses, but some require dose reduction based on toxicities

Lab monitoring

TPMT (thiopurine methyltransferase)

TPMT is an enzyme involved in the metabolism of mercaptopurine. Genetic polymorphisms affect TPMT activity. See thiopurine metabolism for more.
Approximately 10% of Caucasians and African-Americans have intermediate TPMT activity, and 0.3% have low or absent TPMT activity. Decreased TPMT activity is less common in Asians.
Measuring TPMT activity before therapy may be helpful in predicting which patients may develop myelotoxicity from mercaptopurine. Testing for TPMT and NUDT15 deficiency should be considered in patients who experience severe bone marrow toxicities while taking thiopurines.
TPMT activity can be measured directly (in red blood cells) or through genotyping. Patients with recent blood transfusion (30 - 60 days) cannot have TPMT activity measured directly.
For patients with low or deficient TPMT activity, consider an alternate agent or extreme dose reduction. For patients with intermediate TPMT activity, start at 30 - 70% of the target dose. See PharmGKB website for recommendations on dosing based on TPMT genotyping. [32,37]

NUDT15 (nucleotide diphosphatase)

NUDT15 is an enzyme involved in the metabolism of mercaptopurine. Genetic polymorphisms affect NUDT15 activity. See thiopurine metabolism for more.
Patients with reduced NUDT15 activity may accumulate 6-TGNs and have an increased risk of myelosuppression. Testing for TPMT and NUDT15 deficiency should be considered in patients who experience severe bone marrow toxicities while taking thiopurines.
NUDT15 deficiency is seen in about 22.6% of East Asians (e.g. Chinese, Japanese, Vietnamese) with 2% having two loss-of-function alleles. NUDT15 deficiency is present in 13.6% of South Asians, up to 21% of Native Americans, and < 1% of people with African and European ancestry.
NUDT15 activity can be estimated through NUDT15 genotyping
For patients with low or deficient NUDT15 activity, consider an alternate agent. For patients with intermediate NUDT15 activity, consider dose reductions. See PharmGKB website for more. [32,37]

Cytopenias

ACG recommendation: check CBC every 1 - 2 weeks initially, then at least every 3 months

Thiopurine metabolites (6-TGN and 6-MMPN)

The utility of checking thiopurine metabolites to monitor therapy has not been validated in clinical trials
In certain scenarios, checking metabolites may be useful (e.g. compliance, leukopenia, elevated LFTs, refractory disease)
Levels should be checked after 3 - 6 months of therapy
See thiopurine metabolism for more

^✝Valid for inflammatory bowel disease only

Reference: LabCorp® website
6-TGN^✝
Suboptimal dosing	< 235 pmol
Optimal dosing	235 - 450 pmol
Increased risk of myelotoxicity	> 450 pmol
6-MMPN
Hepatotoxicity risk	> 5700 pmol

Other

Azathioprine is metabolized to 6-mercaptopurine. See thiopurine metabolism.
The FDA recommends TPMT testing before initiating therapy

Generic / Price

Tablet (60 tablets) - YES/$$
Suspension - NO/$$$$

Mechanism of action

Immunosuppressant - the exact mechanism by which thiopurines suppress inflammation is not completely understood. Thiopurines inhibit ribonucleotide synthesis which either directly or indirectly leads to T-cell suppression.

FDA-approved indications

Acute lymphatic leukemia - maintenance therapy as part of a combination regimen

Side effects

NOTE: The incidence of side effects with mercaptopurine is not well-defined. Data below are from RA trials involving azathioprine. Azathioprine is metabolized to mercaptopurine.

Leukopenia (any degree) - 28%
Leukopenia (< 2500 cells/mm³) - 5.3%
Nausea/vomiting - 12%
Infections - <1%
Hepatotoxicity - <1%

Drug interactions

Febuxostat (Uloric®) - DO NOT COMBINE. Febuxostat may inhibit the metabolism of mercaptopurine, and they should not be given together.
Allopurinol - allopurinol inhibits one pathway of mercaptopurine metabolism and may lead to toxicity if given concomitantly. Reduce mercaptopurine dose to a fourth or a third of the usual dose when given with allopurinol. If patients have low TPMT activity, allopurinol should not be given with azathioprine.
Aminosalicylates (e.g. sulfasalazine, mesalazine) - there is in vitro evidence that aminosalicylates inhibit the TPMT enzyme. This may cause increased exposure to mercaptopurine. Use caution.
Methotrexate - methotrexate increases mercaptopurine exposure. Dose adjustments may be necessary.
Sulfamethoxazole/trimethoprim - there have been case reports of increased leukopenia in patients receiving azathioprine with sulfamethoxazole/trimethoprim. The same risk may exist with mercaptopurine since it is a metabolite of azathioprine. Use caution.
ACE inhibitors - there have reports of anemia and severe leukopenia in patients receiving ACE inhibitors with azathioprine. The same risk may exist with mercaptopurine since it is a metabolite of azathioprine. Use caution.
Warfarin - mercaptopurine may inhibit the anticoagulant effect of warfarin
Ribavirin - ribavirin may inhibit azathioprine metabolism and lead to azathioprine toxicity including myelosuppression. The same risk may exist with mercaptopurine since it is a metabolite of azathioprine. When combining ribavirin with azathioprine, the following is recommended: monitor blood counts weekly for the first month, twice monthly for the second and third months, then monthly or more frequently if dosage or other therapy changes are necessary.

Contraindications / Precautions

Pregnancy and nursing - DO NOT USE
Malignancy - may increase risk of malignancies, particularly lymphoproliferative disorders, skin cancers, sarcomas, and cervical cancer. See cancer risk studies for more.
Cytopenias - mercaptopurine may cause leukopenia, thrombocytopenia, anemia (including macrocytic), and pancytopenia. Patients with decreased TPMT and/or NUDT15 activity are at increased risk (see Lab monitoring for more). Monitor blood cell counts during therapy.
TPMT and NUDT15 deficiency - TPMT and NUDT15 are enzymes involved in the metabolism of mercaptopurine. Deficiencies in these enzymes can lead to myelosuppression. See Lab monitoring for more.
Serious infections - immunosuppressants may increase the risk for serious infection including bacterial, viral, fungal, protozoal, and opportunistic infections. Reactivation of latent infections (e.g. tuberculosis, hepatitis) may also occur.
Macrophage activation syndrome (MAS) - MAS (also called hemophagocytic lymphohistiocytosis) is a life-threatening condition that may develop in patients with autoimmune diseases. Mercaptopurine may increase the risk of MAS. Signs of MAS include fever, hepatomegaly, lymphadenopathy, neurologic symptoms, and rash.
Hepatotoxicity - hepatotoxicity has occurred in patients taking mercaptopurine. The risk is greatest with doses ≥ 2.5 mg/kg/day.
Progressive Multifocal Leukoencephalopathy (PML) - JC virus infection resulting in PML and death have occurred in patients taking azathioprine. The same risk may exist with mercaptopurine since it is a metabolite of azathioprine. Consider PML diagnosis in patients with new-onset or deteriorating neurological signs and symptoms.
Sperm - decreased sperm counts have been reported in patients taking mercaptopurine
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Liver disease - manufacturer makes no specific recommendation
Kidney disease - lower dose may be advisable. Manufacturer makes no specific recommendation.

JANUS KINASE (JAK) INHIBITORS

Abrocitinib (Cibinqo®)

Dosage forms

Tablet

50 mg
100 mg
200 mg

Dosing

Atopic dermatitis (adults and children ≥ 12 years)

Starting: 100 mg once daily
If response is inadequate after 12 weeks, may increase to 200 mg once daily. Discontinue therapy if an adequate response is not seen at 200 mg once daily.
May use with or without topical corticosteroids
Missed dose: If a dose is missed, administer the dose as soon as possible unless it is less than 12 hours before the next dose, in which case, skip the missed dose. Thereafter, resume dosing at the regularly scheduled time.
May take with or without food. Do not split, crush, cut, or chew tablets.

Kidney disease

CrCl ≥ 60 ml/min: no dose adjustment necessary
CrCl 30 - 59 ml/min: starting dose is 50 mg once daily. If response is inadequate after 12 weeks, dose may be increased to 100 mg once daily. Do not exceed 100 mg/day.
CrCl < 30 ml/min: not recommended

Liver disease

Child-Pugh A and B: no dose adjustment necessary
Child-Pugh C: not recommended

With strong CYP2C19 inhibitors or poor CYP2C19 metabolizers

Starting dose is 50 mg once daily. If response is inadequate after 12 weeks, dose may be increased to 100 mg once daily. Do not exceed 100 mg/day.

Efficacy

Atopic dermatitis

Lab monitoring

Before therapy

Test for tuberculosis. The 2015 American College of Rheumatology guidelines for RA state that for tofacitinib, another JAK inhibitor, latent TB should be treated for at least a month before starting therapy, and active TB should be treated completely before initiating therapy. [34]
Screen for hepatitis B and C. Do not start abrocitinib in patients with active hepatitis.
Check liver function tests
Check a complete blood count (CBC)
Update immunizations, including varicella zoster vaccine, according to current guidelines. Do not give live vaccines immediately prior to therapy.

Cytopenias and anemia

Check a CBC at baseline, 4 weeks after treatment initiation, and 4 weeks after dose increases. Monitoring may be extended for patients with hematologic abnormalities.
Do not initiate if platelet count is < 150,000/mm³, absolute lymphocyte count is < 500 cells/mm³, absolute neutrophil count is < 1000 cells/mm³, or hemoglobin is < 8 g/dl

Blood parameter	Value	Recommendation
Platelet count	< 50,000/mm³	Discontinue until count > 100,000/mm³
Absolute lymphocyte count	≥ 500 cells/mm³	Maintain dose
Absolute lymphocyte count	< 500 cells/mm³	Discontinue until count ≥ 500 cells/mm³
Absolute neutrophil count (ANC)	≥ 1000 cells/mm³	Maintain dose
Absolute neutrophil count (ANC)	< 1000 cells/mm³	Discontinue until count is ≥ 1000 cells/mm³
Hemoglobin	≥ 8 g/dl	Maintain dose
Hemoglobin	< 8 g/dl	Discontinue until hemoglobin ≥ 8 g/dl

Lipid parameters

Check 4 weeks after starting therapy and periodically thereafter

Generic / Price

- NO/$$$$

Mechanism of action

Janus kinase (JAK) inhibitor - abrocitinib is a Janus kinase (JAK) inhibitor. Abrocitinib reversibly inhibits JAK1 by blocking the adenosine triphosphate (ATP) binding site. In a cell-free isolated enzyme assay, abrocitinib was selective for JAK1 over JAK2 (28-fold), JAK3 (> 340-fold), and tyrosine kinase (TYK) 2 (43-fold), as well as the broader kinome. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known. Both the parent compound and the active metabolites inhibit JAK1 activity in vitro with similar levels of selectivity.

FDA-approved indications

Atopic dermatitis - for the treatment of adults and pediatric patients 12 years of age and older with refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable

Side effects

Side effect	Cibinqo 200 mg (N=590)	Cibinqo 100 mg (N=608)	Placebo (N=342)
Nasopharyngitis	8.7%	12.4%	7.9%
Nausea	14.5%	6.0%	2.1%
Headache	7.8%	6.0%	3.5%
Herpes simplex	4.2%	3.3%	1.8%
Increased CK	2.9%	2.3%	1.5%
Dizziness	2.9%	1.8%	0.9%
Urinary tract infection	2.2%	1.7%	1.2%
Fatigue	1.3%	1.6%	0.5%
Acne	4.7%	1.6%	0.0%
Vomiting	3.2%	1.5%	0.9%
Impetigo	0.5%	1.5%	0.3%
Oropharyngeal pain	1.0%	1.4%	0.6%
Hypertension	0.8%	1.2%	0.7%
Influenza	1.1%	1.2%	0.0%
Gastroenteritis	1.3%	1.1%	0.6%
Dermatitis contact	0.5%	1.1%	0.3%
Abdominal pain upper	1.9%	0.6%	0.0%
Abdominal discomfort	1.2%	0.5%	0.3%
Herpes zoster	1.2%	0.3%	0.0%
Thrombocytopenia	1.5%	0.0%	0.0%

Drug interactions

CYP2C19 strong inhibitors - abrocitinib is a CYP2C19 sensitive substrate, and CYP2C19 strong inhibitors increase its exposure. See Dosing above for recommendations on combining abrocitinib with CYP2C19 strong inhibitors.
CYP2C19 strong inducers - DO NOT COMBINE. Abrocitinib is a CYP2C19 sensitive substrate, and CYP2C19 strong inducers decrease its exposure.
CYP2C9 strong inducers - DO NOT COMBINE. Abrocitinib is a CYP2C9 sensitive substrate, and CYP2C9 strong inducers decrease its exposure.
Moderate to strong inhibitors of both CYP2C19 and CYP2C9 - DO NOT COMBINE. Abrocitinib is a CYP2C19 and CYP2C9 sensitive substrate. Inhibitors of both enzymes increase abrocitinib exposure.
P-glycoprotein substrates - abrocitinib increases exposure of concomitant p-glycoprotein substrates. Use caution when combining with p-glycoprotein substrates where small concentration changes may lead to serious or life-threatening toxicities (e.g., digoxin).
Antiplatelet drugs - abrocitinib may cause thrombocytopenia, which can increase the risk of bleeding with antiplatelet drugs. Do not give antiplatelet drugs, except for low-dose aspirin (≤ 81 mg daily), during the first 3 months of abrocitinib treatment.

Contraindications / Precautions

Antiplatelet drugs - abrocitinib may cause thrombocytopenia, which can increase the risk of bleeding with antiplatelet drugs. Do not give antiplatelet drugs, except for low-dose aspirin (≤ 81 mg daily), during the first 3 months of abrocitinib treatment.
Serious infections - in AD trials lasting 16 weeks, the annual incidence of serious infections was 3.9% with abrocitinib 100 mg, 1.3% with abrocitinib 200 mg, and 2.6% with placebo. The most common serious infections were herpes simplex, herpes zoster, and pneumonia. Serious infections leading to death have occurred with other JAK inhibitors. Abrocitinib should be discontinued in patients with active, serious infections, including localized infections.
Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). For tofacitinib, another JAK inhibitor, The American College of Rheumatology recommends treating latent TB for at least one month before starting therapy, and active TB should be treated completely before initiating therapy. [34]
Herpes zoster - reactivation of herpes zoster has occurred during treatment. In AD trials lasting 16 weeks, the annual incidence of herpes zoster was 1.9% with abrocitinib 100 mg, 5.1% with abrocitinib 200 mg, and 0% with placebo. Consider holding abrocitinib in patients who develop herpes zoster.
Viral reactivation - reactivation of viruses (e.g. hepatitis B) has occurred during treatment. Abrocitinib is not recommended in patients with active hepatitis B or C. See the AASLD HBV guidelines for recommendations on using immunosuppressants in patients with HBV.
Mortality - in a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher mortality rates than those treated with TNF inhibitors. Annual all-cause mortality rates were 0.88% for tofacitinib 5 mg twice daily, 1.23% for tofacitinib 10 mg twice daily, and 0.69% for TNF inhibitors.
Malignancies - malignancies, including NMSC, have been observed in abrocitinib trials. Patients should have periodic skin exams and limit their exposure to UV light. In a large RA study with tofacitinib, another JAK inhibitor, higher rates of malignancies were observed in tofacitinib-treated patients compared to TNF inhibitor-treated patients. Annual malignancy rates (excluding NMSC) were 1.13% for tofacitinib 5 mg twice daily, 1.13% for tofacitinib 10 mg twice daily, and 0.77% for TNF inhibitors. For specific cancers, lymphomas occurred at a greater annual rate in tofacitinib-treated patients (0.07% vs 0.11% vs 0.02%, respectively), as did lung cancers among current and past smokers (0.48% vs 0.59% vs 0.27%, respectively). When prescribing abrocitinib, consider the risks and benefits, particularly in patients at increased risk for cancer.
Major adverse cardiovascular events (MACE) - in a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher rates of MACE (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) than those treated with TNF inhibitors. Annual MACE rates were 0.91% for tofacitinib 5 mg twice daily, 1.11% for tofacitinib 10 mg twice daily, and 0.79% for TNF inhibitors. Current and past smokers were at increased risk. When prescribing abrocitinib, consider the risks and benefits, particularly in past and current smokers and those at increased risk of CVD.
Thrombosis (DVT, PE, arterial) - thrombosis, including DVT and PE, has been reported in patients treated with abrocitinib. In a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher thrombosis rates than those treated with TNF inhibitors. Annual DVT rates were 0.22% for tofacitinib 5 mg twice daily, 0.28% for tofacitinib 10 mg twice daily, and 0.16% for TNF inhibitors. Annual rates of PE were 0.18%, 0.49%, and 0.05%, respectively. Use caution when prescribing abrocitinib to patients at increased risk of thrombosis.
Lymphopenia - in AD trials lasting up to 16 weeks, the annual incidence of lymphocyte counts < 500 cells/mm³ was 1.2% with abrocitinib 200 mg and 0% with abrocitinib 100 mg and placebo. All cases occurred within the first 4 weeks of exposure. Check a CBC at baseline, 4 weeks after treatment initiation, and 4 weeks after dose increases.
Thrombocytopenia - in AD trials lasting up to 16 weeks, the annual incidence of thrombocytopenia was 0.9% with abrocitinib 200 mg and 0% with abrocitinib 100 mg and placebo. Maximum effects on platelet counts occurred within the first 4 weeks of treatment. Check a CBC at baseline, 4 weeks after treatment initiation, and 4 weeks after dose increases.
Lipid parameters - abrocitinib may cause a dose-dependent increase in lipid parameters. Check lipids 4 weeks after starting therapy and periodically thereafter.
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
CPK elevations - in AD trials lasting up to 16 weeks, the annual incidence of CPK increases was 6.9% with abrocitinib 100 mg, 12.3% with abrocitinib 200 mg, and 7.5% with placebo. Most elevations were transient, and no cases of rhabdomyolysis were reported.
Liver disease

See Dosing above

Kidney disease

See Dosing above

Baricitinib (Olumiant®)

Dosage forms

Tablet

1 mg
2 mg
4 mg

Dosing

Rheumatoid arthritis (adults)

Dosing: 2 mg once daily
May take with or without food
May be used as monotherapy or in combination with methotrexate or other conventional DMARDs (see DMARD classes for more)

Alopecia areata (adults)

Starting: 2 mg once daily
Maintenance: 2 - 4 mg once daily
For patients with nearly complete or complete scalp hair loss, with or without substantial eyelash or eyebrow hair loss, consider treating with 4 mg once daily
Once patients achieve an adequate response to treatment with 4 mg, decrease the dosage to 2 mg once daily
May take with or without food

COVID-19 (adults)

4 mg once daily for 14 days or until hospital discharge, whichever occurs first

COVID-19 (pediatric patients 2 - 18 years old)

See FDA fact sheet

Kidney disease

Rheumatoid arthritis

CrCl ≥ 60 ml/min: no dose adjustment necessary
CrCl 30 - 59 ml/min: 1 mg once daily
CrCl < 30 ml/min: not recommended

Alopecia areata

CrCl ≥ 60 ml/min: no dose adjustment necessary
CrCl 30 - 59 ml/min: reduce 2 mg dose to 1 mg | reduce 4 mg dose to 2 mg
CrCl < 30 ml/min: not recommended

COVID-19

CrCl ≥ 60 ml/min: no dose adjustment necessary
CrCl 30 - 59 ml/min: 2 mg once daily
CrCl 15 - 29 ml/min: 1 mg once daily
CrCl < 15 ml/min: not recommended

Liver disease

Child-Pugh A/B: no dose adjustment necessary
Child-Pugh C:

Rheumatoid arthritis and alopecia areata: not recommended
COVID-19: benefits should outweigh the risks

With OAT3 strong inhibitors (e.g. probenecid)

Reduce 4 mg dose to 2 mg
Reduce 2 mg dose to 1 mg
If taking 1 mg, consider stopping probenecid

Efficacy

Rheumatoid arthritis

Baricitinib vs Adalimumab vs Placebo in RA Patients who Failed MTX, NEJM (2017) [SH review]

COVID-19

Alopecia Areata

Baricitinib vs Placebo in Adults with Alopecia Areata, NEJM (2022) [PubMed abstract]

Systemic lupus erythematous

Lab monitoring

TB testing

Test for tuberculosis (except those with COVID-19) before beginning therapy. The 2015 American College of Rheumatology guidelines for RA state that for tofacitinib, another JAK inhibitor, latent TB should be treated for at least a month before starting therapy, and active TB should be treated completely before initiating therapy. [34]

Cytopenias and anemia (rheumatoid arthritis and alopecia areata)

Check lymphocyte count, neutrophil count, and hemoglobin at baseline and periodically thereafter. Manufacturer makes no recommendation on frequency.
Do not initiate if absolute lymphocyte count is < 500 cells/mm³, absolute neutrophil count is < 1000 cells/mm³, or hemoglobin is < 8 g/dl

Blood parameter	Value	Recommendation
Absolute lymphocyte count	≥ 500 cells/mm³	Maintain dose
Absolute lymphocyte count	< 500 cells/mm³	Discontinue until count ≥ 500 cells/mm³
Absolute neutrophil count (ANC)	≥ 1000 cells/mm³	Maintain dose
Absolute neutrophil count (ANC)	< 1000 cells/mm³	Discontinue until count is ≥ 1000 cells/mm³
Hemoglobin	≥ 8 g/dl	Maintain dose
Hemoglobin	< 8 g/dl	Discontinue until hemoglobin ≥ 8 g/dl

Cytopenias and anemia (COVID-19)

Not recommended if absolute lymphocyte count is < 200 cells/mm³ or absolute neutrophil count is < 500 cells/mm³

Blood parameter	Value	Recommendation
Absolute lymphocyte count	≥ 200 cells/mm³	Maintain dose
Absolute lymphocyte count	< 200 cells/mm³	Discontinue until count ≥ 200 cells/mm³
Absolute neutrophil count (ANC)	≥ 500 cells/mm³	Maintain dose
Absolute neutrophil count (ANC)	< 500 cells/mm³	Discontinue until count is ≥ 500 cells/mm³

Liver enzymes

Monitor liver enzymes routinely. Discontinue baricitinib if ALT or AST elevations occur, and drug-induced hepatotoxicity is suspected.

Lipid parameters

Check 12 weeks after starting therapy

Generic / Price

- NO/$$$$

Mechanism of action

Janus kinase (JAK) inhibitor - Baricitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Baricitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.
JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In cell-free isolated enzyme assays, baricitinib had greater inhibitory potency at JAK1, JAK2 and TYK2 relative to JAK3. In human leukocytes, baricitinib inhibited cytokine induced STAT phosphorylation mediated by JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, or JAK2/TYK2 with comparable potencies. However, the relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.

FDA-approved indications

Rheumatoid arthritis - adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Use of baricitinib in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (bDMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Alopecia areata - adult patients with severe alopecia areata. Do not combine with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants.
COVID-19 - in hospitalized adults requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO)

Side effects

NOTE: Data is from 16-week RA trials

Side effect	Baricitinib 2 mg (N=479)	Placebo (N=1070)
Upper respiratory tract infections	16.3%	11.7%
Nausea	2.7%	1.6%
Herpes simplex infections	0.8%	0.7%
Herpes zoster	1%	0.4%

Drug interactions

Biologic disease-modifying antirheumatic drugs (bDMARDs) - DO NOT COMBINE. Has not been studied.
Other JAK inhibitors (e.g. tofacitinib) - DO NOT COMBINE
Strong OAT3 inhibitors (e.g. probenecid) - strong OAT3 inhibitors increase exposure to baricitinib. During concomitant therapy, reduce the baricitinib dose by half. If patient is taking baricitinib 1 mg, consider stopping probenecid.

Contraindications / Precautions

Pregnancy - in animal studies where rats and rabbits were exposed to 11 and 46 times the maximum recommended dose in humans, baricitinib caused fetal harm. The effect in humans at normal dosing is unknown. Consider pregnancy prevention in females of childbearing potential.
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Serious infections - Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving baricitinib. The most common serious infections reported were pneumonia, herpes zoster, and urinary tract infections. In 16-week trials, serious infections were reported at an incidence of 3.6%/year in baricitinib-treated patients (2 mg) and 4.2%/year in placebo-treated patients. Baricitinib should be stopped if a patient develops a serious infection and not be restarted until the infection resolves. For patients with COVID-19, the risks and benefits of continued baricitinib should be weighed.
Tuberculosis (TB) - test patients (except those with COVID-19) for TB before use (≥ 5 mm induration should be considered positive). For tofacitinib, another JAK inhibitor, The American College of Rheumatology recommends treating latent TB for at least one month before starting therapy, and active TB should be treated completely before initiating therapy. [34]
Viral reactivation - reactivation of viruses (e.g. herpes zoster, hepatitis B) has occurred during treatment. Monitor susceptible patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
Mortality - in a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher mortality rates than those treated with TNF inhibitors. Annual all-cause mortality rates were 0.88% for tofacitinib 5 mg twice daily, 1.23% for tofacitinib 10 mg twice daily, and 0.69% for TNF inhibitors.
Malignancies - in a large RA study with tofacitinib, another JAK inhibitor, higher rates of malignancies were observed in tofacitinib-treated patients compared to TNF inhibitor-treated patients. Annual malignancy rates (excluding NMSC) were 1.13% for tofacitinib 5 mg twice daily, 1.13% for tofacitinib 10 mg twice daily, and 0.77% for TNF inhibitors. For specific cancers, lymphomas occurred at a greater annual rate in tofacitinib-treated patients (0.07% vs 0.11% vs 0.02%, respectively), as did lung cancers among current and past smokers (0.48% vs 0.59% vs 0.27%, respectively). In 52-week RA trials, the annual incidence of malignancies excluding NMSC was 0.6% in patients treated with baricitinib 2 mg and 0.7% in those treated with 4 mg. Periodic skin checks are recommended. When prescribing baricitinib, consider the risks and benefits, particularly in patients at increased risk for cancer.
Major adverse cardiovascular events (MACE) - in a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher rates of MACE (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) than those treated with TNF inhibitors. Annual MACE rates were 0.91% for tofacitinib 5 mg twice daily, 1.11% for tofacitinib 10 mg twice daily, and 0.79% for TNF inhibitors. Current and past smokers were at increased risk. When prescribing baricitinib, consider the risks and benefits, particularly in past and current smokers and those at increased risk of CVD.
Thrombosis (DVT, PE, arterial) - thrombosis, including DVT, PE, and arterial thrombosis, has been reported in patients treated with baricitinib. During a 16-week RA trial, VTE occurred at an annual rate of 1.7% in the baricitinib 4 mg group and 0% in the placebo and baricitinib 2 mg groups. In a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher thrombosis rates than those treated with TNF inhibitors. Annual DVT rates were 0.22% for tofacitinib 5 mg twice daily, 0.28% for tofacitinib 10 mg twice daily, and 0.16% for TNF inhibitors. Annual rates of PE were 0.18%, 0.49%, and 0.05%, respectively. In 52-week RA trials, annual DVT rates for baricitinib 2mg and 4 mg were 0.6% and 0.8%, respectively. Use caution when prescribing baricitinib to patients at increased risk of thrombosis.
Hypersensitivity reactions - hypersensitivity reactions including angioedema, urticaria, and rash have been reported in patients receiving baricitinib. Discontinue baricitinib if such reactions occur.
Gastrointestinal perforation - events of gastrointestinal perforation have been reported in clinical studies with baricitinib. Use caution in patients at increased risk for perforation (e.g. diverticulitis).
Neutropenia - baricitinib may cause neutropenia. During 16-week RA trials, neutrophil counts < 1000 cells/mm³ occurred in 0% of placebo-treated patients, 0.6% of patients treated with baricitinib 2 mg, and 0.3% of patients treated with 4 mg. Counts < 500 cells/mm³ were not observed. See Lab monitoring above for recommendations on adjusting therapy for neutropenia.
Lymphopenia - baricitinib may cause lymphopenia. See Lab monitoring above for recommendations on adjusting therapy for lymphopenia.
Anemia - baricitinib may cause anemia. See Lab monitoring for recommendations on management.
Liver enzyme elevations - baricitinib may cause liver enzyme elevations. During 16-week RA trials, ALT elevations ≥ 3 X ULN occurred in 1.0% of placebo-treated patients, 1.7% of patients treated with baricitinib 2 mg, and 1.4% of those treated with 4 mg. AST elevations ≥ 3 X ULN occurred in 0.8% of placebo-treated patients, 1.3% of patients treated with baricitinib 2 mg, and 0.8% of those treated with 4 mg.
Lipid parameters - baricitinib may raise lipid parameters. In 12-week RA trials, average LDL, HDL, and triglycerides increased by 8 mg/dl, 7 mg/dl, and 7 mg/dl, respectively, in patients treated with baricitinib 2 mg. For patients treated with 4 mg, increases in LDL, HDL, and triglycerides were 14 mg/dl, 9 mg/dl, and 15 mg/dl, respectively.
Platelet increase - baricitinib may raise platelet levels. In 16-week RA trials, average platelet counts increased by 15,000 cells/mm³ in patients treated with baricitinib 2 mg and by 23,000 cells/mm³ in those treated with 4 mg.
Liver disease - see Dosing above
Kidney disease - see Dosing above

Deucravacitinib (Sotyktu®)

Dosage forms

Tablet

6 mg

Dosing

Plaque psoriasis (adults)

Dosing: 6 mg once daily
Do not crush, cut, or chew tablets
May take with or without food
Before initiating therapy, test for tuberculosis and consider completing all age-appropriate vaccines, including herpes zoster

Kidney disease

No dose adjustment is necessary for any degree of kidney disease

Liver disease

Child-Pugh A/B: no dose adjustment necessary
Child-Pugh C: not recommended
Evaluate liver enzymes at baseline and periodically thereafter in patients with liver disease

Efficacy

Plaque psoriasis

Lab monitoring

TB testing

Test for tuberculosis before initiating therapy. The 2015 American College of Rheumatology guidelines for RA state that for tofacitinib, another JAK inhibitor, latent TB should be treated for at least a month before starting therapy, and active TB should be treated completely before initiating therapy. [34]

Liver enzymes

In patients with liver disease, measure liver enzymes at baseline and periodically thereafter. Discontinue deucravacitinib if treatment-related liver enzyme elevations occur.

Triglycerides

Monitor triglyceride levels periodically

Generic / Price

- NO/$$$$

Mechanism of action

Janus kinase (JAK) inhibitor - Deucravacitinib is an inhibitor of tyrosine kinase 2 (TYK2). TYK2 is a member of the Janus kinase (JAK) family. Deucravacitinib binds to the regulatory domain of TYK2, stabilizing an inhibitory interaction between the regulatory and the catalytic domains of the enzyme. This results in allosteric inhibition of receptor-mediated activation of TYK2 and its downstream activation of Signal Transducers and Activators of Transcription (STATs) as shown in cell-based assays. JAK kinases, including TYK2, function as pairs of homo- or heterodimers in the JAK-STAT pathways. TYK2 pairs with JAK1 to mediate multiple cytokine pathways and also pairs with JAK2 to transmit signals as shown in cell-based assays. The precise mechanism linking inhibition of TYK2 enzyme to therapeutic effectiveness in the treatment of adults with moderate-to-severe plaque psoriasis is not currently known.

FDA-approved indications

Plaque psoriasis - treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy

Side effects

Side effect	Deucravacitinib 6 mg (N=840)	Placebo (N=419)
Upper respiratory infections	19.2%	14.8%
Blood creatine phosphokinase increased	2.7%	1.2%
Herpes simplex	2.0%	0.2%
Mouth ulcers	1.9%	0.0%
Folliculitis	1.7%	0.0%
Acne	1.4%	0.2%

Drug interactions

Deucravacitinib has no known drug interactions

Contraindications / Precautions

Pregnancy - there is insufficient data in humans to evaluate the pregnancy risks of deucravacitinib. In animal reproduction studies, no effects on embryo-fetal development were observed with oral administration of deucravacitinib to rats and rabbits during organogenesis at doses that were at least 91 times the maximum recommended human dose (MRHD) of 6 mg once daily.
Hypersensitivity reactions - hypersensitivity reactions, including angioedema, have been reported in patients receiving deucravacitinib. Discontinue deucravacitinib if such reactions occur.
Infections - deucravacitinib may increase the risk of infections. In 16-week trials, infections were reported in 29% of deucravacitinib-treated patients and 22% of placebo-treated patients, and serious infections occurred at rates of 2%/year and 1.6%/year, respectively. The most common serious infections were pneumonia and COVID-19. Monitor patients for infections and interrupt deucravacitinib therapy if necessary.
Herpes virus reactivation - in 16-week trials, herpes virus reactivation (e.g. herpes zoster, herpes simplex) occurred at a rate of 6.8%/year in deucravacitinib-treated patients and 0.8%/year in placebo-treated patients. If able, complete herpes zoster vaccination before starting therapy.
Hepatitis B and C - patients with hepatitis B and C were excluded from trials, and deucravacitinib is not recommended in these patients. Consider screening at-risk individuals before therapy. See AASLD recommendations for immunosuppressants in patients with HBV.
Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). For tofacitinib, another JAK inhibitor, The American College of Rheumatology recommends treating latent TB for at least one month before starting therapy, and active TB should be treated completely before initiating therapy. [34]
Malignancies - in trials, malignancies (excluding non-melanoma skin cancer) occurred at a rate of 0.3%/year in deucravacitinib-treated patients, and lymphomas occurred at a rate of 0.1%/year. Consider the risks and benefits of deucravacitinib before initiating therapy in at-risk individuals.
Rhabdomyolysis and Elevated CPK - cases of rhabdomyolysis have been reported in patients receiving deucravacitinib. In 16-week trials, increased CPK occurred at a rate of 9.3%/year in deucravacitinib-treated patients and 4.1%/year in placebo-treated patients. Instruct patients to report unexplained muscle pain, tenderness, or weakness, and discontinue deucravacitinib if CPK levels rise.
Triglyceride elevations - in 52-week trials, average triglyceride levels increased by 10 mg/dl in deucravacitinib-treated patients. Check triglyceride levels periodically.
Liver enzyme elevations - in 16-week trials, AST elevations ≥ 3 X ULN occurred at a rate of 5.2%/year in deucravacitinib-treated patients and 1.6%/year in placebo-treated patients. Check liver enzymes at baseline and periodically thereafter in patients with liver disease. Discontinue deucravacitinib if treatment-related elevations occur.
Vaccines - complete all appropriate immunizations, including herpes zoster, before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Potential risks related to JAK inhibitors - deucravacitinib is a part of the JAK inhibitor class of drugs, and tofacitinib, another JAK inhibitor, was found to increase the risk of cardiovascular events, thrombosis, and malignancies when compared to TNF inhibitors in a large RA trial. It is unknown if deucravacitinib carries the same risks.
Liver disease

Child-Pugh A/B: no dose adjustment necessary
Child-Pugh C: not recommended
Evaluate liver enzymes at baseline and periodically thereafter in patients with liver disease

Kidney disease - no dose adjustment is necessary for any degree of kidney disease

Tofacitinib | Xeljanz® | Xeljanz® XR

Dosage forms

Tablet (Xeljanz®)

5 mg

Tablet, extended-release (Xeljanz® XR)

11 mg

Solution (Xeljanz®)

1 mg/ml
Comes in 240 ml bottle
Store at room temperature

Dosing

Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis (adults)

Population	Xeljanz	Xeljanz XR
Adult patients	5 mg twice daily	11 mg once daily
Patients receiving: Strong CYP3A4 inhibitors (e.g., ketoconazole), or A moderate CYP3A4 inhibitor(s) with a strong CYP2C19 inhibitor(s) (e.g., fluconazole)	5 mg once daily	Reduce to XELJANZ 5 mg once daily
Patients with CrCl ≤ 60 ml/min Child-Pugh B	5 mg once daily	Reduce to XELJANZ 5 mg once daily
Dialysis	For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended in patients after dialysis.
Patients with lymphocyte count less than 500 cells/mm³, confirmed by repeat testing	Discontinue dosing.
Patients with ANC 500 to 1000 cells/mm³	Interrupt dosing. When ANC is greater than 1000, resume 5 mg twice daily.	Interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily.
Patients with ANC less than 500 cells/mm³	Discontinue dosing.
Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL	Interrupt dosing until hemoglobin values have normalized.

Ulcerative colitis (adults)

Population	Xeljanz	Xeljanz XR
Adult patients	Induction: 10 mg twice daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 10 mg twice daily for a maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg twice daily. For patients with loss of response during maintenance treatment, a dosage of 10 mg twice daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response.	Induction: 22 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 22 mg once daily for a maximum of 16 weeks. Discontinue 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 11 mg once daily. For patients with loss of response during maintenance treatment, a dosage of 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response.
Patients receiving: Strong CYP3A4 inhibitors (e.g., ketoconazole), or A moderate CYP3A4 inhibitor(s) with a strong CYP2C19 inhibitor(s) (e.g., fluconazole)	If taking 10 mg twice daily, reduce to 5 mg twice daily.If taking 5 mg twice daily, reduce to 5 mg once daily.	If taking 22 mg once daily, reduce to 11 mg once daily.If taking 11 mg once daily, reduce to XELJANZ 5 mg once daily
Patients with CrCl ≤ 60 ml/min Child-Pugh B	If taking 10 mg twice daily, reduce to 5 mg twice daily. If taking 5 mg twice daily, reduce to 5 mg once daily.	If taking 22 mg once daily, reduce to 11 mg once daily. If taking 11 mg once daily, reduce to XELJANZ 5 mg once daily.
Dialysis	For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended in patients after dialysis.
Patients with lymphocyte count less than 500 cells/mm³, confirmed by repeat testing	Discontinue dosing.
Patients with ANC 500 to 1000 cells/mm³	If taking 10 mg twice daily, reduce to 5 mg twice daily. When ANC is greater than 1000, increase to 10 mg twice daily based on clinical response. If taking 5 mg twice daily, interrupt dosing. When ANC is greater than 1000, resume 5 mg twice daily.	If taking 22 mg once daily, reduce to 11 mg once daily. When ANC is greater than 1000, increase to 22 mg once daily based on clinical response. If taking 11 mg once daily, interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily.
Patients with ANC less than 500 cells/mm³	Discontinue dosing.
Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL	Interrupt dosing until hemoglobin values have normalized.

Polyarticular Course Juvenile Idiopathic Arthritis (≥ 2 years old)

Population	Xeljanz oral solution/tablets
pcJIA patients	10 - 19 kg 3.2 mg twice daily 20 - 39 kg: 4 mg twice daily ≥ 40 kg: 5 mg twice daily
Patients receiving: Strong CYP3A4 inhibitors (e.g., ketoconazole), or A moderate CYP3A4 inhibitor(s) with a strong CYP2C19 inhibitor(s) (e.g., fluconazole)	If taking 3.2 mg twice daily, reduce to 3.2 mg once daily If taking 4 mg twice daily, reduce to 4 mg once daily If taking 5 mg twice daily, reduce to 5 mg once daily
Patients with CrCl ≤ 60 ml/min Child-Pugh B	If taking 3.2 mg twice daily, reduce to 3.2 mg once daily If taking 4 mg twice daily, reduce to 4 mg once daily If taking 5 mg twice daily, reduce to 5 mg once daily
Dialysis	For patients undergoing hemodialysis, dose should be administered after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended in patients after dialysis.
Patients with lymphocyte count less than 500 cells/mm³, confirmed by repeat testing	Discontinue dosing.
Patients with ANC 500 to 1000 cells/mm³	Interrupt dosing until ANC is greater than 1000 cells/mm3.
Patients with ANC less than 500 cells/mm³	Discontinue dosing.
Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL	Interrupt dosing until hemoglobin values have normalized.

Efficacy

Ankylosing spondylitis

Tofacitinib vs Placebo for Ankylosing Spondylitis in Adults, Ann Rheum Dis (2021) [PubMed abstract]

COVID-19

Tofacitinib vs Placebo for COVID-19 Pneumonia, NEJM (2021) [PubMed abstract]

Plaque Psoriasis

Tofacitinib vs Etanercept vs Placebo for Plaque Psoriasis, Lancet (2015) [PubMed abstract]

Psoriatic arthritis

See tofacitinib in psoriatic arthritis

Rheumatoid arthritis

Ulcerative colitis

Tofacitinib vs Placebo for Ulcerative Colitis, NEJM (2017) [PubMed abstract]

Lab monitoring

Before therapy

Test for tuberculosis. The American College of Rheumatology recommends treating latent TB for at least one month before starting tofacitinib. Active TB should be treated completely before starting tofacitinib. [34]

Cytopenias and anemia

Check lymphocyte count at baseline and every 3 months thereafter
Check neutrophil count and hemoglobin at baseline, 4 - 8 weeks after starting therapy, and every 3 months thereafter
Do not initiate tofacitinib if lymphocyte count is < 500 cells/mm³, absolute neutrophil count is < 1000 cells/mm³, or hemoglobin < 9 g/dl
See Dosing above for recommendations on adjusting therapy based on results

Liver enzymes

Monitor liver enzymes routinely. Discontinue tofacitinib if drug-induced hepatotoxicity is suspected.

Lipid parameters

Check 4 - 8 weeks after starting therapy

Generic / Price

- NO/$$$$

Mechanism of action

Janus kinase (JAK) inhibitor - Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.
JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

FDA-approved indications

Rheumatoid arthritis - Xeljanz/Xeljanz XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Use of Xeljanz/Xeljanz XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended
Psoriatic arthritis - Xeljanz/Xeljanz XR is indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Use of Xeljanz/Xeljanz XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended
Ulcerative colitis - Xeljanz/Xeljanz XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or intolerance to one or more TNF blockers. Use of Xeljanz/Xeljanz XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Polyarticular Course Juvenile Idiopathic Arthritis (≥ 2 years old) - Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers. Use of Xeljanz/Xeljanz oral solution in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.
Ankylosing spondylitis - Xeljanz/Xeljanz XR is indicated for the treatment of adult patients with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more TNF blockers. Use of Xeljanz/Xeljanz XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended

Side effects

NOTE: Only side effects that occurred at an incidence of ≥ 2% overall, and ≥ 1% more than placebo are listed. Data is from an ulcerative colitis trial with 10 mg twice daily dosing.

Side effect	Tofacitinib	Placebo
Nasopharyngitis	14%	6%
Elevated cholesterol	9%	1%
Increased CK	7%	2%
Upper respiratory infection	6%	4%
Rash	6%	4%
Diarrhea	5%	3%
Herpes zoster	5%	1%
Gastroenteritis	4%	3%
Nausea	4%	3%

Drug interactions

Other immunosuppressants (e.g. azathioprine, tacrolimus, cyclosporine) - DO NOT COMBINE. Combination therapy with other immunosuppressants has not been studied.
Biologicals - DO NOT COMBINE. Combination therapy with biologic DMARDs has not been studied.
Strong CYP3A4 inducers - DO NOT COMBINE. Xeljanz is a sensitive CYP3A4 substrate. Xeljanz exposure is decreased when given with a strong CYP3A4 inducer.
Strong CYP3A4 inhibitors - Xeljanz is a sensitive CYP3A4 substrate. Reduce dose when taken with strong CYP3A4 inhibitors. See Dosing for more.
Moderate CYP3A4 inhibitors + strong CYP2C19 inhibitors - Xeljanz is a sensitive CYP3A4 and CYP2C19 substrate. Reduce dose when taken with a combination of a moderate CYP3A4 inhibitor and a strong CYP2C19 inhibitor. See Dosing for more.

Contraindications / Precautions

Serious infections - Xeljanz may increase the risk for serious infection including bacterial, viral, fungal, and opportunistic infections. In trials, the incidence of serious infections was 2.7 events per 100 patient-years in patients receiving Xeljanz 5 mg twice daily. The most common serious infections included diverticulitis, pneumonia, cellulitis, herpes zoster, and urinary tract infection. Avoid use of Xeljanz in patients with active, serious infections
Tuberculosis (TB) - test patients for TB before and during use (≥ 5 mm induration should be considered positive). The American College of Rheumatology recommends treating latent TB for at least one month before starting tofacitinib. Active TB should be treated completely before starting tofacitinib. [34]
Viral reactivation - reactivation of viruses (e.g. herpes zoster, hepatitis B) has occurred during treatment. Screen appropriate patients before use and monitor affected patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
Mortality - in a large RA study, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher mortality rates than those treated with TNF inhibitors. Annual all-cause mortality rates were 0.88% for tofacitinib 5 mg twice daily, 1.23% for tofacitinib 10 mg twice daily, and 0.69% for TNF inhibitors.
Malignancies - in a large RA study, higher rates of malignancies were observed in tofacitinib-treated patients compared to TNF inhibitor-treated patients. Annual malignancy rates (excluding NMSC) were 1.13% for tofacitinib 5 mg twice daily, 1.13% for tofacitinib 10 mg twice daily, and 0.77% for TNF inhibitors. For specific cancers, lymphomas occurred at a greater annual rate in tofacitinib-treated patients (0.07% vs 0.11% vs 0.02%, respectively), as did lung cancers among current and past smokers (0.48% vs 0.59% vs 0.27%, respectively). [PMID 35081280] NMSC have also been reported in tofacitinib-treated patients, and periodic skin examination is recommended in patients at increased risk of skin cancer. When prescribing tofacitinib, consider the risks and benefits, particularly in patients at increased risk for cancer.
Major adverse cardiovascular events (MACE) - in a large RA study, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher rates of MACE (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) than those treated with TNF inhibitors. Annual MACE rates were 0.91% for tofacitinib 5 mg twice daily, 1.11% for tofacitinib 10 mg twice daily, and 0.79% for TNF inhibitors. Current and past smokers were at increased risk. [PMID 35081280] When prescribing tofacitinib, consider the risks and benefits, particularly in past and current smokers and those at increased risk of CVD.
Thrombosis (DVT, PE, arterial) - in a large RA study, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher thrombosis rates than those treated with TNF inhibitors. Annual DVT rates were 0.22% for tofacitinib 5 mg twice daily, 0.28% for tofacitinib 10 mg twice daily, and 0.16% for TNF inhibitors. Annual rates of PE were 0.18%, 0.49%, and 0.05%, respectively. Avoid tofacitinib in patients at increased risk for thrombosis.
Hypersensitivity reactions - hypersensitivity reactions including angioedema and urticaria have been reported. If a serious reaction occurs, stop Xeljanz.
Gastrointestinal perforation - cases of gastrointestinal perforation have been reported in patients receiving Xeljanz. In ulcerative colitis trials, the incidence of GI perforations was similar between Xeljanz-treated patients and placebo-treated patients.
Lymphopenia - Xeljanz may cause an initial increase in lymphocytes at 1 month followed by a gradual decrease. In trials, lymphocyte counts < 500 cells/mm³ were seen in 0.04% of patients. See Lab monitoring for recommendations on management.
Neutropenia - Xeljanz may cause neutropenia. In trials, absolute neutrophil counts of < 1000 cells/mm³ were seen in 0.07% of patients. See Lab monitoring for recommendations on management.
Anemia - Xeljanz may cause anemia. See Lab monitoring for recommendations on management.
Liver enzyme elevations - Xeljanz may cause elevated liver enzymes. In monotherapy trials, there was no difference in the incidence of elevated liver enzymes between Xeljanz-treated patients and placebo-treated patients. The addition of other immunosuppressants (particularly methotrexate) may increase the risk. Monitor liver functions periodically.
Lipid parameters - Xeljanz may increase lipid parameters. In trials, LDL levels increased an average of 15% (5 mg twice daily) and 19% (10 mg twice daily) at one month after initiation. HDL levels also increased by 10% (5 mg twice daily) and 12% (10 mg twice daily). Levels remained stable from thereafter. Check lipid parameters 4 - 8 weeks after starting therapy.
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Liver disease

See Dosing above
Child-Pugh C: not recommended

Kidney disease - see Dosing above

Upadacitinib (Rinvoq®)

Dosage forms

Tablet, extended-release

15 mg
30 mg

Dosing

Rheumatoid arthritis, Psoriatic arthritis, Ankylosing spondylitis, Non-radiographic axial spondyloarthritis (adults)

Dosing: 15 mg once daily
May take with or without food
Do not split, crush, cut, or chew tablets

Atopic dermatitis

Pediatric patients ≥ 12 years and weighing ≥ 88 lbs (40 kg) and Adults < 65 years

Starting: 15 mg once daily
Maintenance: 15 - 30 mg once daily. Use lowest effective dose.
Maximum: 30 mg once daily
May take with or without food
Do not split, crush, cut, or chew tablets

Adults ≥ 65 years

Dosing: 15 mg once daily
May take with or without food
Do not split, crush, cut, or chew tablets

Ulcerative colitis (adults)

Induction: 45 mg once daily for 8 weeks
Maintenance: 15 - 30 mg once daily. Use lowest effective dose.
Maximum: 30 mg once daily
May take with or without food
Do not split, crush, cut, or chew tablets

Kidney disease

Rheumatoid arthritis, Psoriatic arthritis, Ankylosing spondylitis, Non-radiographic axial spondyloarthritis

No dose adjustment is necessary for any degree of renal impairment

Atopic dermatitis

CrCl ≥ 30 ml/min: no dose adjustment necessary
CrCl 15 - 29 ml/min: 15 mg once daily
CrCl < 15 ml/min: not recommended

Ulcerative colitis

CrCl ≥ 30 ml/min: no dose adjustment necessary
CrCl 15 - 29 ml/min:

Induction: 30 mg once daily for 8 weeks
Maintenance: 15 mg once daily

CrCl < 15 ml/min: not recommended

Liver disease

Rheumatoid arthritis, Psoriatic arthritis, Atopic dermatitis, Ankylosing spondylitis, Non-radiographic axial spondyloarthritis

Child-Pugh (A/B): no dose adjustment necessary
Child-Pugh C: not recommended

Ulcerative colitis

Child-Pugh (A/B):

Induction: 30 mg once daily for 8 weeks
Maintenance: 15 mg once daily

Child-Pugh C: not recommended

With strong CYP3A4 inhibitors

Rheumatoid Arthritis, Psoriatic Arthritis, Atopic Dermatitis, Ankylosing spondylitis, Non-radiographic axial spondyloarthritis

Dosing should not exceed 15 mg once daily. Monitor patients for adverse reactions.

Ulcerative colitis

Induction: 30 mg once daily for 8 weeks
Maintenance: 15 mg once daily

Efficacy

Rheumatoid arthritis

Psoriatic arthritis

Upadacitinib vs Adalimumab in Adults with Psoriatic Arthritis who had Failed Nonbiologic DMARD, NEJM (2021) [PubMed abstract]

Atopic dermatitis

Ulcerative colitis

Non-radiographic axial spondyloarthritis

Upadacitinib vs Placebo for Non-radiographic Axial Spondyloarthritis, Lancet (2022) [PubMed abstract]

Lab monitoring

Before therapy

Test for tuberculosis. The 2015 American College of Rheumatology guidelines for RA state that for tofacitinib, another JAK inhibitor, latent TB should be treated for at least a month before starting therapy, and active TB should be treated completely before initiating therapy. [34]
Screen for hepatitis B and C. Do not start upadacitinib in patients with active hepatitis.
Check liver function tests
Check a complete blood count (CBC)
Perform pregnancy test when indicated. Upadacitinib may cause fetal harm. Women of childbearing potential should use contraception during use and for 4 weeks after stopping therapy.
Update immunizations, including varicella zoster vaccine, according to current guidelines. Do not give live vaccines immediately prior to therapy.

Cytopenias and anemia

Check lymphocyte count, neutrophil count, and hemoglobin at baseline and periodically thereafter. Manufacturer makes no recommendation on frequency.
Do not initiate if absolute lymphocyte count is < 500 cells/mm³, absolute neutrophil count is < 1000 cells/mm³, or hemoglobin is < 8 g/dl

Blood parameter	Value	Recommendation
Absolute lymphocyte count	≥ 500 cells/mm³	Maintain dose
Absolute lymphocyte count	< 500 cells/mm³	Discontinue until count ≥ 500 cells/mm³
Absolute neutrophil count (ANC)	≥ 1000 cells/mm³	Maintain dose
Absolute neutrophil count (ANC)	< 1000 cells/mm³	Discontinue until count is ≥ 1000 cells/mm³
Hemoglobin	≥ 8 g/dl	Maintain dose
Hemoglobin	< 8 g/dl	Discontinue until hemoglobin ≥ 8 g/dl

Liver enzymes

Monitor liver enzymes routinely. Discontinue upadacitinib if drug-induced hepatotoxicity is suspected.

Lipid parameters

Check 12 weeks after starting therapy

Generic / Price

- NO/$$$$

Mechanism of action

Janus kinase (JAK) inhibitor - upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression. Upadacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs.
JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In a cell-free isolated enzyme assay, upadacitinib had greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2. In human leukocyte cellular assays, upadacitinib inhibited cytokine-induced STAT phosphorylation mediated by JAK1 and JAK1/JAK3 more potently than JAK2/JAK2 mediated STAT phosphorylation. The relevance of inhibition of specific JAK enzymes to therapeutic effectiveness is not currently known.

FDA-approved indications

Rheumatoid arthritis - adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Use of upadacitinib in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.
Psoriatic arthritis - adults with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Use of upadacitinib in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.
Ankylosing spondylitis - adults with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more TNF blockers. Use of upadacitinib in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.
Atopic dermatitis - adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.
Ulcerative colitis - adult patients with moderately to severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers. Upadacitinib is not recommended for use in combination with other JAK inhibitors, biological therapies for ulcerative colitis, or with potent immunosuppressants such as azathioprine and cyclosporine.
Non-radiographic axial spondyloarthritis - adults with active non-radiographic axial spondyloarthritis with objective signs of inflammation who have had an inadequate response or intolerance to TNF blocker therapy.

Side effects

Side effect	Upadacitinib 15 mg (N=1035)	Placebo (N=1042)
Upper respiratory tract infections	13.5%	9.5%
Nausea	3.5%	2.2%
Cough	2.2%	1%
Fever	1.2%	0%

Drug interactions

CYP3A4 strong inducers - DO NOT COMBINE. Upadacitinib is a CYP3A4 sensitive substrate and exposure is decreased when taken with CYP3A4 strong inducers.
CYP3A4 strong inhibitors - upadacitinib is a CYP3A4 sensitive substrate and exposure is increased when taken with CYP3A4 strong inhibitors. Monitor for adverse reactions when combining. See Dosing above for disease-specific recommendations.

Contraindications / Precautions

Pregnancy - DO NOT USE. May cause fetal harm. Avoid pregnancy for 4 weeks following completion of therapy.
Vaccines - complete all appropriate immunizations before initiating therapy if possible. Live attenuated vaccines should not be given, and the response to inactivated vaccines may be reduced (list of U.S. vaccines including type). The ACR has published immunization recommendations for patients receiving immunosuppressants, which include advice on administering live attenuated vaccines when necessary (see ACR vaccination guidelines).
Hypersensitivity reactions - hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in trials. If a reaction occurs, discontinue upadacitinib.
Serious infections - Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving upadacitinib. The most common serious infections reported were pneumonia and cellulitis. Upadacitinib should be stopped if a patient develops a serious infection and not be restarted until the infection resolves. In trials lasting 12 - 48 weeks, serious infections were reported at an incidence of 4.6%/year in upadacitinib-treated patients and 2.3%/year in placebo-treated patients.
Tuberculosis (TB) - test patients for TB before use (≥ 5 mm induration should be considered positive). For tofacitinib, another JAK inhibitor, The American College of Rheumatology recommends treating latent TB for at least one month before starting therapy, and active TB should be treated completely before initiating therapy. [34]
Viral reactivation - reactivation of viruses (e.g. herpes zoster, hepatitis B) has occurred during treatment. Monitor susceptible patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
Mortality - in a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher mortality rates than those treated with TNF inhibitors. Annual all-cause mortality rates were 0.88% for tofacitinib 5 mg twice daily, 1.23% for tofacitinib 10 mg twice daily, and 0.69% for TNF inhibitors.
Malignancies - upadacitinib may increase the risk of malignancy. In trials lasting 12 - 48 weeks, malignancies were reported at an incidence of 0.4%/year in upadacitinib-treated patients and 0.4%/year in placebo-treated patients. Non-melanoma skin cancers have been reported in patients receiving upadacitinib. Periodic skin checks are recommended. In a large RA study with tofacitinib, another JAK inhibitor, higher rates of malignancies were observed in tofacitinib-treated patients compared to TNF inhibitor-treated patients. Annual malignancy rates (excluding NMSC) were 1.13% for tofacitinib 5 mg twice daily, 1.13% for tofacitinib 10 mg twice daily, and 0.77% for TNF inhibitors. For specific cancers, lymphomas occurred at a greater annual rate in tofacitinib-treated patients (0.07% vs 0.11% vs 0.02%, respectively), as did lung cancers among current and past smokers (0.48% vs 0.59% vs 0.27%, respectively). When prescribing upadacitinib, consider the risks and benefits, particularly in patients at increased risk for cancer.
Major adverse cardiovascular events (MACE) - in a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher rates of MACE (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) than those treated with TNF inhibitors. Annual MACE rates were 0.91% for tofacitinib 5 mg twice daily, 1.11% for tofacitinib 10 mg twice daily, and 0.79% for TNF inhibitors. Current and past smokers were at increased risk. When prescribing upadacitinib, consider the risks and benefits, particularly in past and current smokers and those at increased risk of CVD.
Thrombosis (DVT, PE, arterial) - thrombosis, including DVT, PE, and arterial thrombosis, has been reported in patients treated with upadacitinib. In a large RA study with tofacitinib, another JAK inhibitor, patients ≥ 50 years old with ≥ 1 CVD risk factor who were treated with tofacitinib had higher thrombosis rates than those treated with TNF inhibitors. Annual DVT rates were 0.22% for tofacitinib 5 mg twice daily, 0.28% for tofacitinib 10 mg twice daily, and 0.16% for TNF inhibitors. Annual rates of PE were 0.18%, 0.49%, and 0.05%, respectively. Use caution when prescribing upadacitinib to patients at increased risk of thrombosis.
Gastrointestinal perforation - events of gastrointestinal perforation have been reported in clinical studies with upadacitinib. In many of the cases, patients were taking concomitant NSAIDs. Use caution in patients at increased risk for perforation (e.g. diverticulitis, taking NSAID). Patients with new onset abdominal pain should be evaluated promptly.
Neutropenia - upadacitinib may cause neutropenia. In trials lasting 12 weeks, neutrophil counts < 1000 cells/mm³ occurred at least once in 1.3% of upadacitinib-treated patients and 0.3% of placebo-treated patients.
Lymphopenia - upadacitinib may cause lymphopenia. In trials lasting 12 weeks, lymphocyte counts < 500 cells/mm³ occurred at least once in 0.5% of upadacitinib-treated patients and 0.5% of placebo-treated patients.
Anemia - upadacitinib may cause anemia. In trials lasting 12 weeks, hemoglobin levels < 8 g/dl occurred at least once in 0% of upadacitinib-treated patients and 0.3% of placebo-treated patients.
Liver enzyme elevations - upadacitinib may cause liver enzyme elevations. In trials lasting 12 weeks, liver enzyme elevations ≥ 3 X ULN occurred at least once in 1% of upadacitinib-treated patients and 1.3% of placebo-treated patients.
Lipid parameters - upadacitinib may raise lipid parameters. In trials lasting 12 - 14 weeks, average LDL increased by 15 mg/dl, average HDL increased by 8 mg/dl, and average triglycerides increased by 14 mg/dl in upadacitinib-treated patients.
CPK elevations - upadacitinib may cause CPK elevations. In trials lasting 12 weeks, CPK elevations > 5 X ULN occurred in 1.6% of upadacitinib-treated patients and 0.3% of placebo-treated patients.
Liver disease

See Dosing above for disease-specific recommendations

Kidney disease

See Dosing above for disease-specific recommendations

STUDIES

Association Between Use of Thiopurines or Tumor Necrosis Factor Antagonists Alone or in Combination and Risk of Lymphoma in Patients With Inflammatory Bowel Disease, JAMA (2017) [PubMed abstract]

Design: Retrospective registry cohort study (N=189,289 | length - 6 years)
Exposure: Thiopurine monotherapy vs Anti-TNF monotherapy vs Thiopurine + anti-TNF vs Unexposed
Primary outcome: Incidence of lymphoma
Results:

Primary outcome (cases/1000 person-years): Thiopurine monotherapy - 0.54, Anti-TNF monotherapy - 0.41, Thiopurine + Anti-TNF - 0.95, Unexposed - 0.26 (p<0.001 for all comparisons to unexposed)

Findings: Among adults with IBD, the use of thiopurine monotherapy or anti-TNF monotherapy was associated with a small but statistically significant increased risk of lymphoma compared with exposure to neither medication, and this risk was higher with combination therapy than with each of these treatments used alone. These findings may inform decisions regarding the benefits and risks of treatment.

PRICE ($) INFO

Pricing legend

$ = 0 - $50
$$ = $51 - $100
$$$ = $101 - $150
$$$$ = > $151

Pricing based on one month of therapy at standard dosing in an adult
Pricing based on information from GoodRX.com®
Pricing may vary by region and availability

BIBLIOGRAPHY

1 - PMID 19174807 - ACG 2009 Crohn's GL
2 - PMID 22556106 - Lupus nephritis GL
3 - PMID 24881804 - Lupus review
4 - PMID 19892750 - EULAR monitoring GL
5 - PMID 23972423 - SLE treatment
6 - PMID 11513909 - Plaquenil RCT
7 - PMID 8239224 - Plaquenil RCT
8 - PMID 10848718 - Pharmacokinetic study
9 - ACR SLE position statement 2011
10 - PMID 25275721
11 - PMID 14963199
12 - PMID 11096165 - MTX RCT
13 - PMID 19581281 - MTX SEs
14 - Methotrexate PI
15 - PMID 18512708 - ACR MTX recs
16 - PMID 19033291 - Multinational MTX recs
17 - PMID 23880702 MTX recs
18 - PMID 18512708 - ACR MTX recs
19 - PMID 14963199
20 - PMID 11096165 - MTX RCT
21 - PMID 19581281 - MTX SEs
22 - PMID 25919528
23 - Azulfidine EN-tab PI
24 - PMID 11014343
25 - PMID 16530532 AGA GL for cyclosporine
26 - PMID 22835577 - Cyclosporine article
27 - PMID 23063316 - Cyclosporine vs infliximab
28 - Neoral PI
29 - PMID 9255119 - RA GL for cyclosporine
30 - Neoral PI
31 - PMID 20068560 - ACG GL
32 - Manufacturer's Package insert for listed drug
33 - PMID 22914296 - Lancet UC review
34 - PMID 26545940 - ACR 2015 RA GL
35 - PMID 26850655 - HCQ in refractory cutaneous lupus
36 - PMID 17009263 - HCQ in SLE
37 - Mayo Clinic Laboratories
38 - PMID 31180031 Novel paradigms in systemic lupus erythematosus, Lancet (2019)
39 - PMID 26359488 2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative Arthritis & Rheumatology, (2015)
40 - PMID 32119894 - Joint American Academy of Dermatology/National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies, J Am Acad Dermatol (2020)
41 - PMID 32066146 - Adverse Effects of Low-Dose Methotrexate: A Randomized Trial, Ann Inten Med (2020)
42 - PMID 26053114 - Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation, Am J Transplant (2015)
43 - Araya AA, Tasnif Y. Tacrolimus. [Updated 2020 Jun 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: [PubMed link]

IMMUNOSUPPRESSANTS

Dosage forms

Dosing - Ulcerative colitis

Generic / Price

Mechanism of action

FDA-approved indications

Side effects

Drug interactions

Lab interactions

Contraindications / Precautions

Dosage forms

Dosing - Ulcerative colitis

Generic / Price

Mechanism of action

FDA-approved indications

Side effects

Drug interactions

Lab interactions

Contraindications / Precautions

Dosage forms

Dosing

Generic / Price

Mechanism of action

FDA-approved indications

Side effects

Drug interactions

Lab interactions

Contraindications / Precautions

Dosage forms

Dosing - Azulfidine® tablet

Dosing - Azulfidine EN-tabs®

Efficacy

Lab monitoring

Generic / Price

Mechanism of action

FDA-approved indications

Side effects

Drug interactions

Lab interactions

Contraindications / Precautions

Dosage forms

Dosing

Efficacy

Generic / Price

Mechanism of action

FDA-approved indications

Side effects

Drug interactions

Contraindications / Precautions

Dosage forms

Dosing

Efficacy

Lab monitoring

Generic / Price

Mechanism of action

FDA-approved indications

Side effects

Drug interactions

Contraindications / Precautions

Dosage forms

Dosing

Lab monitoring

Generic / Price

Mechanism of action

FDA-approved indication

Side effects

Drug interactions

Contraindications / Precautions

Dosage forms

Dosing

Folic acid

Efficacy

Lab monitoring

Generic / Price

Mechanism of action

FDA-approved indications

Side effects

Drug interactions

Contraindications / Precautions

Dosage forms