IMMUNOSUPPRESSANTS









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


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. 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).
  • 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 patients with kidney disease. Check kidney function before therapy and periodically thereafter. Use caution and monitor for adverse effects when using in patients with renal impairment.
  • Liver disease - mesalamine may worsen liver disease. Use caution.

Mesalamine | Apriso® | Asacol® HD | Canasa® | Delzicol® | Lialda® | Rowasa® | sfRowasa® | Pentasa®

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
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.
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]
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


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).
  • 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 patients with kidney disease. Check kidney function before therapy and periodically thereafter. Use caution and monitor for adverse effects when using in patients with renal impairment.
  • 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


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).
  • 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 patients with kidney disease. Check kidney function before therapy and periodically thereafter. Use caution and monitor for adverse effects when using in patients with renal impairment.
  • 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


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 or aminosalicylate hypersensitivity - DO NOT USE
  • Intestinal or urinary obstruction - DO NOT USE
  • Porphyria - DO NOT USE
  • Asthma - may worsen. See aspirin allergy for more.
  • Ulcerative colitis exacerbation - in trials, up to 3% of patients have reported exacerbation of ulcerative colitis symptoms when starting mesalamine
  • Blood dyscrasias - may cause or worsen. Use caution.
  • Liver damage - may cause or worsen. Use caution.
  • Decreased sperm count - has occurred. Effect appears to be reversible upon discontinuation.
  • Serious infections - discontinue if occurs
  • G6PD deficiency - monitor for hemolytic anemia
  • Serious skin reactions - including Stevens-Johnson, toxic epidermal necrolysis, and DRESS syndrome have occurred
  • 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 and pericarditis have been reported in rare cases
  • 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.
  • Urine crystals and stone formation - maintain good fluid intake to prevent
  • Pregnancy - sulfasalazine appears to be safe in pregnancy (category B)
  • Slow acetylators - sulfapyridine is metabolized by acetylation. Slow acetylators may have more adverse events.
  • Liver disease - use with caution. Manufacturer makes no dosage recommendation.
  • Kidney disease - use with caution. Manufacturer makes no dosage recommendation.



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


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
  • Psoriatic arthritis
  • Oral ulcers associated with Behçet's Disease

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.
  • 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



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


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


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 - do not give live or attenuated vaccines during therapy. The response to non-live vaccines may be attenuated.
  • Liver disease - clearance is decreased. Use caution. Manufacturer makes no specific dosage recommendation.
  • Kidney disease - DO NOT USE



Hydroxychloroquine (Plaquenil®)

Dosage forms

Tablet
  • 200 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


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

  • Cimetidine - DO NOT COMBINE. Cimetidine may increase hydroxychloroquine levels.
  • 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
  • Diabetes medications - hydroxychloroquine may lower blood sugars and lead to hypoglycemia when given with antidiabetic agents
  • Metoprolol - hydroxychloroquine may increase metoprolol levels
  • Antacids and kaolin - antacids and kaolin may reduce the absorption of hydroxychloroquine. Take at least 4 hours apart.
  • Ampicillin - hydroxychloroquine may reduce the bioavailability of ampicillin
  • CYP2D6 substrates - hydroxychloroquine may be a CYP2D6 inhibitor. Use caution when taken with CYP2D6 substrates. [8]
  • Digoxin - hydroxychloroquine may increase digoxin levels
  • Cyclosporine - hydroxychloroquine may increase cyclosporine levels
  • Praziquantel - hydroxychloroquine may reduce praziquantel bioavailability

Contraindications / Precautions

  • Retinal toxicity - most concerning side effect. Extremely rare at doses < 6.5mg/kg/day. Possible risk factors for toxicity include cumulative dose of 1000 grams, treatment for more than 7 years, obesity, significant liver or kidney disease, advanced age, pre-existing retinal disease, macular disease, concurrent tamoxifen therapy, and cataracts.
    • Recommended screening:
      • Baseline eye/retina exam within first year of treatment
      • If low risk - next exam in 5 years, then yearly
      • If high-risk - yearly exam [4,9,10]
  • Cardiomyopathy - cases of cardiomyopathy have been reported in patients receiving hydroxychloroquine. Cardiomyopathy should be considered when conduction disorders (e.g. bundle branch block, AV heart block) or ventricular hypertrophy are diagnosed.
  • Prolonged QT interval - hydroxychloroquine prolongs the QT interval and should not be used in patients with prolonged QT syndrome
  • Proximal Myopathy and Neuropathy - proximal muscle myopathy and neuropathy have been reported in patients taking hydroxychloroquine
  • Hypoglycemia - hydroxychloroquine has been shown to cause severe hypoglycemia. Cases have occurred in both diabetics and nondiabetics.
  • Seizures - hydroxychloroquine may lower the seizure threshold and increase the risk of seizures in susceptible individuals
  • Serious skin reactions (Stevens-Johnson, etc.) - have been reported
  • Exanthematous pustulosis - acute outbreak of pustular lesions on the skin and mucous membranes
  • Psoriasis - hydroxychloroquine may precipitate a flare
  • Porphyria - hydroxychloroquine may worsen
  • G6PD deficiency - use caution
  • Blood dyscrasias - have been reported
  • Liver disease - has not been studied extensively; use caution
  • Kidney disease - has not been studied extensively, use caution



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


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.
  • Immunizations - do not give live or attenuated vaccines during therapy. The response to non-live vaccines may be attenuated. Consider the long half-life of leflunomide (19 days) when administering vaccines after stopping therapy.
  • 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.



Methotrexate | Trexall® | Xatmep™ | Otrexup™ | Rasuvo®

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
  • 27.5 mg/0.55 ml
  • 30 mg/0.6 ml
  • Comes in package with 4 pens

Dosing

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]
Crohn's disease
  • 25 mg sub-Q or IM once weekly [1]
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
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]
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


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
  • CBC
    • 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

Generic / Price

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

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
  • 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
  • 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 therapy. Men should use effective contraception during therapy and for at least 3 months after therapy. Do not breastfeed while taking methotrexate and for at least one week after stopping therapy.
  • Hepatitis B or C infection (active or chronic) - DO NOT USE
  • 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.
  • 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 discontinuation of methotrexate. In a 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 when 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%). [41]
  • Vaccines - do not give live or attenuated vaccines during therapy. The response to non-live vaccines may be attenuated.
  • 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 transplant rejection prophylaxis (≥ 3 months old)
  • BSA 1.25 m2 to < 1.5 m2: 750 mg twice daily
  • BSA ≥ 1.5 m2: 1000 mg twice daily
  • 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 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

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.

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, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines, whereas other cell types can utilize salvage pathways, MPA has potent cytostatic effects on lymphocytes. MPA inhibits proliferative responses of T- and B-lymphocytes to both mitogenic and allospecific stimulation.
  • MPA also suppresses antibody formation by B-lymphocytes. 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. MMF did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 (IL-1) and interleukin-2 (IL-2), but did block the coupling of these events to DNA synthesis and proliferation.

FDA-approved indications

Cellcept
  • Prophylaxis of organ rejection, in recipients 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 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) - PPIs may reduce mycophenolate exposure. Monitor patients for reduced efficacy when combining PPIs with mycophenolate.
  • 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.
  • 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
  • Immunizations - when possible, immunizations should be completed before mycophenolate therapy. Do not give live or attenuated vaccines during therapy. The response to non-live vaccines may be attenuated.
  • 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

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, and heart transplant rejection prophylaxis (adults)
  • Tacrolimus dosing depends upon the type of transplant, concomitant immunosuppressants, treatment stage, and target blood levels
  • 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.
  • See the prescribing information of each drug for more information - Prograf PI, Astagraf XL PI, Envarsus XR

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, and heart 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.
  • 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.
  • 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 infection including 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 - in clinical trials, tacrolimus has been associated with acute and chronic nephrotoxicity in up to 60% of patients. 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 drugs (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.
  • Immunizations - when possible, immunizations should be completed before tacrolimus therapy. Do not give live or attenuated vaccines during therapy. The response to non-live vaccines may be attenuated.
  • 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.



Azathioprine (Imuran®)

Dosage forms

Tablet
  • 50 mg

Dosing

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.
Crohn's disease
  • Dosing: 2 - 3 mg/kg/day [1]
  • Typically given once daily
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)
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]

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


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 ]
  • 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
  • Liver disease - manufacturer makes no specific recommendation
  • Kidney disease - lower dose may be advisable. Manufacturer makes no specific recommendation.



Baricitinib (Olumiant®)

Dosage forms

Tablet
  • 1 mg
  • 2 mg

Dosing

Rheumatoid arthritis
  • 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)
Kidney disease
  • CrCl > 60 ml/min: no dose adjustment necessary
  • CrCl 30 - 60 ml/min: 1 mg once daily
  • CrCl < 30 ml/min: not recommended
Liver disease
  • Child-Pugh A/B: no dose adjustment necessary
  • Child-Pugh C: not recommended
With OAT3 strong inhibitors
  • 1 mg once daily

Efficacy


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]
Lymphocytes
  • Check lymphocyte counts at baseline and periodically thereafter. Manufacturer makes no recommendation on frequency.
  • Do not initiate if lymphocyte count is < 500 cells/mm³

Lymphocyte count Recommendation
≥ 500 cells/mm³ Maintain dose
< 500 cells/mm³ Discontinue until count ≥ 500 cells/mm³

Neutrophils
  • Check neutrophil count at baseline and periodically thereafter. Manufacturer makes no recommendation on frequency.
  • Do not initiate if absolute neutrophil count is < 1000 cells/mm³

Absolute neutrophil count (ANC) Recommendation
> 1000 cells/mm³ Maintain dose
< 1000 cells/mm³ Discontinue until count is ≥ 1000 cells/mm³

Hemoglobin
  • Check hemoglobin at baseline and periodically thereafter. Manufacturer makes no recommendation on frequency.
  • Do not initiate if hemoglobin < 8 g/dl

Hemoglobin Recommendation
≥ 8 g/dl Maintain dose
< 8 g/dl Discontinue until Hemoglobin ≥ 8 g/dl

Liver enzymes
  • Should be monitored routinely
Lipid parameters
  • Check 12 weeks after starting therapy

Generic / Price

- NO/$$$$

Mechanism of action

  • 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. Baricitinib inhibits JAKs and prevents these processes.

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.

Side effects



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. The recommended dose of baricitinib when given with a strong OAT3 inhibitor is 1 mg once daily.

Contraindications / Precautions

  • Live vaccines - DO NOT GIVE live vaccines to patients receiving baricitinib. Use caution when giving live vaccines to household members. See list of live and killed vaccines.
  • 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. Baricitinib should be stopped if a patient develops a serious infection and not be restarted until the infection resolves. 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.
  • 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) have occurred during treatment. Monitor susceptible patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Increased risk of thrombosis - thrombosis, including deep venous thrombosis (DVT) and pulmonary embolism (PE), has been observed at an increased incidence in patients treated with baricitinib compared to placebo. In addition, arterial thrombosis events in the extremities have been reported in clinical studies with baricitinib. Use caution in patients who are 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).
  • Malignancy - may increase risk of malignancy
  • Neutropenia - baricitinib may cause neutropenia. During 16-week trials, neutrophil counts < 1000 cells/mm3 occurred in 0% of patients treated with placebo, 0.6% of patients treated with baricitinib 2 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 trials, ALT elevations ≥ 3 X ULN occurred in 1.0% of placebo-treated patients and 1.7% of baricitinib-treated patients (2 mg). AST elevations ≥ 3 X ULN occurred in 0.8% of placebo-treated patients and 1.3% of baricitinib-treated patients (2 mg).
  • Lipid parameters - baricitinib may raise lipid parameters. In 12-week trials, average LDL increased by 8 mg/dl, average HDL increased by 7 mg/dl, and average triglycerides increased by 7 mg/dl in patients treated with baricitinib 2 mg.
  • Platelet increase - baricitinib may raise platelet levels. In 16-week trials, average platelet counts increased by 15,000 cells/mm³ in patients treated with baricitinib 2 mg.
  • Liver disease - see Dosing above
  • Kidney disease - see Dosing above

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 - Xeljanz®

Rheumatoid arthritis
  • Dosing: 5 mg twice daily
  • May take with or without food
Psoriatic arthritis
  • Dosing: 5 mg twice daily
  • May take with or without food
Ulcerative colitis
  • 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.
  • May take with or without food
Polyarticular Course Juvenile Idiopathic Arthritis (≥ 2 years old)
  • 10 - 19 kg: 3.2 mg twice daily
  • 20 - 39 kg: 4 mg twice daily
  • ≥ 40 kg: 5 mg twice daily
  • See Xeljanz PI [sec 2.4] for recommendations on dosing with CYP3A4 inhibitors, in renal impairment, and based on lab results
  • May take with or without food
With strong CYP3A4 inhibitors
  • If taking 10 mg twice daily, reduce to 5 mg twice daily
  • If taking 5 mg twice daily, reduce to 5 mg once daily
  • See CYP3A4 for more
With moderate CYP3A4 inhibitor + strong CYP2C19 inhibitor
  • If taking 10 mg twice daily, reduce to 5 mg twice daily
  • If taking 5 mg twice daily, reduce to 5 mg once daily
  • See CYP3A4 and CYP2C19 for more
Kidney disease
  • CrCl > 60 ml/min: No dose adjustment necessary
  • CrCl ≤ 60 ml/min: If taking 10 mg twice daily, reduce to 5 mg twice daily. If taking 5 mg twice daily, reduce to 5 mg once daily.
Liver disease
  • Mild (Child-Pugh A): No dose adjustment necessary
  • Moderate (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.
  • Severe (Child-Pugh C): has not been studied. Not recommended.

Dosing - Xeljanz® XR

Rheumatoid arthritis
  • Dosing: 11 mg once daily
  • May take with or without food
  • Do not crush, cut, or chew tablet
Psoriatic arthritis
  • Dosing: 11 mg once daily
  • May take with or without food
  • Do not crush, cut, or chew tablet
Ulcerative colitis
  • 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.
  • May take with or without food
With strong CYP3A4 inhibitors
  • 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
  • See CYP3A4 for more
With moderate CYP3A4 inhibitor + strong CYP2C19 inhibitor
  • 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
  • See CYP3A4 and CYP2C19 for more
Kidney disease
  • CrCl > 60 ml/min: No dose adjustment necessary
  • CrCl ≤ 60 ml/min: 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.
Liver disease
  • Mild (Child-Pugh A): No dose adjustment necessary
  • Moderate (Child-Pugh B): 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.
  • Severe (Child-Pugh C): has not been studied. Not recommended.

Efficacy


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]
Lymphocytes
  • Monitor lymphocyte counts at baseline and every 3 months thereafter
  • Do not initiate if lymphocyte count is < 500 cells/mm³

Lymphocyte count Recommendation
≥ 500 cells/mm³ Maintain dose
< 500 cells/mm³ Discontinue

Neutrophils
  • Monitor neutrophil counts at baseline and after 4 - 8 weeks of treatment and every 3 months thereafter
  • Do not initiate if absolute neutrophil count is < 1000 cells/mm³

Absolute neutrophil count (ANC) Recommendation
> 1000 cells/mm³ Maintain dose
500 - 1000 cells/mm³ Xeljanz
  • 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.
Xeljanz XR
  • 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.
< 500 cells/mm³ Discontinue

Hemoglobin
  • Monitor hemoglobin at baseline and after 4 - 8 weeks of treatment and every 3 months thereafter
  • Do not initiate if hemoglobin < 9 g/dl

Hemoglobin Recommendation
≤ 2 g/dl decrease and ≥ 9 g/dl Maintain dose
> 2 g/dl decrease or < 8 g/dl Hold Xeljanz until normalizes

Liver enzymes
  • Should be monitored routinely
Lipid parameters
  • Check 4 - 8 weeks after starting therapy

Generic / Price

- NO/$$$$

Mechanism of action

  • 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. Xeljanz inhibits JAKs and prevents these processes.

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 methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). 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 are indicated for the treatment of adult patients with active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other disease-modifying antirheumatic drugs (DMARDs). 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 an inadequate response or who are intolerant to 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) - use in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended

Side effects


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

  • Increased risk of serious heart-related problems and cancer - on February 4, 2021, the FDA issued a drug safety warning stating that tofacitinib was associated with an increased risk of serious heart-related problems and cancer when compared to TNF inhibitors. The findings were based on preliminary results from an ongoing trial. More information will be published as it becomes available. [FDA Xeljanz drug safety communication]
  • Live vaccines - DO NOT GIVE live vaccines to patients receiving Xeljanz. Use caution when giving live vaccines to household members. See list of live and killed vaccines.
  • Thrombosis (DVT, PE, Arterial) - thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with Xeljanz. In an ongoing study, RA patients who were ≥ 50 years old with at least one CV risk factor that were treated with Xeljanz 10 mg twice daily had a higher risk of thrombosis when compared to patients treated with 5 mg twice daily or a TNF inhibitor. Patients at increased risk of thrombosis should not take Xeljanz.
  • 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 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) have occurred during treatment. Monitor susceptible patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Hypersensitivity reactions - hypersensitivity reactions including angioedema and urticaria have been reported. If a serious reaction occurs, stop Xeljanz.
  • Malignancy - may increase risk of malignancy
  • 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.
  • Liver disease - see Dosing above
  • Kidney disease - see Dosing above

Upadacitinib (Rinvoq®)

Dosage forms

Tablet, extended-release
  • 15 mg

Dosing

Rheumatoid arthritis
  • Dosing: 15 mg once daily
  • May take with or without food
  • Do not split, crush, cut, or chew tablets
  • May be used as monotherapy or in combination with methotrexate or other conventional DMARDs (see DMARD classes for more)

Efficacy


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]
Lymphocytes
  • Check lymphocyte counts at baseline and periodically thereafter. Manufacturer makes no recommendation on frequency.
  • Do not initiate if lymphocyte count is < 500 cells/mm³

Lymphocyte count Recommendation
≥ 500 cells/mm³ Maintain dose
< 500 cells/mm³ Discontinue until count ≥ 500 cells/mm³

Neutrophils
  • Check neutrophil count at baseline and periodically thereafter. Manufacturer makes no recommendation on frequency.
  • Do not initiate if absolute neutrophil count is < 1000 cells/mm³

Absolute neutrophil count (ANC) Recommendation
≥ 1000 cells/mm³ Maintain dose
< 1000 cells/mm³ Discontinue until count is ≥ 1000 cells/mm³

Hemoglobin
  • Check hemoglobin at baseline and periodically thereafter. Manufacturer makes no recommendation on frequency.
  • Do not initiate if hemoglobin < 8 g/dl

Hemoglobin Recommendation
≥ 8 g/dl Maintain dose
< 8 g/dl Discontinue until Hemoglobin ≥ 8 g/dl

Liver enzymes
  • Should be monitored routinely
  • Interrupt therapy if drug-induced hepatotoxicity is suspected
Lipid parameters
  • Check 12 weeks after starting therapy

Generic / Price

- NO/$$$$

Mechanism of action

  • 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. Upadacitinib inhibits JAKs and prevents these processes.

FDA-approved indications

  • Rheumatoid arthritis - treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. Use of upadacitinib in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (bDMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

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


Contraindications / Precautions

  • Pregnancy - DO NOT USE. May cause fetal harm. Avoid pregnancy for 4 weeks following completion of therapy.
  • Live vaccines - DO NOT GIVE live vaccines to patients receiving upadacitinib. Use caution when giving live vaccines to household members. See list of live and killed vaccines.
  • 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) have occurred during treatment. Monitor susceptible patients closely. See AASLD recommendations for immunosuppressants in patients with HBV.
  • Malignancy - 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.
  • Increased risk of thrombosis - thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, has occurred in patients treated with Janus kinase inhibitors including upadacitinib. Use caution in patients who are 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
    • Child-Pugh A/B: no dose adjustment necessary
    • Child-Pugh C: DO NOT USE
  • Kidney disease - no dose adjustment is required in patients with mild, moderate or severe renal impairment



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.



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