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
  • 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

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.
  • Ulcerative colitis exacerbation - in trials, up to 7% of patients have reported exacerbation of ulcerative colitis symptoms when starting balsalazide
  • Upper GI obstruction - may cause prolonged retention of mesalamine and delay release into the colon
  • 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.
  • Kidney disease - exposure is increased. Use caution.
  • Liver disease - mesalamine may worsen liver disease. Use caution.

Mesalamine | Apriso® | Asacol® HD | Canasa® | Delzicol® | Lialda® | Rowasa® | 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®)
  • 4 grams/60 ml

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® 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]

Generic / Price

  • Apriso® - NO/$$$$
  • Asacol® HD (90 tablets) - YES/$$$$
  • Delzicol® - NO/$$$$
  • Lialda® (120 tablets) - YES/$$$$
  • Pentasa® (240 capsules) - NO/$$$$
  • Canasa® (30 supp) - YES/$$$$
  • Rowasa® (28 enemas) - YES/$$$$

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® - 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
  • 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

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.
  • Ulcerative colitis exacerbation - in trials, up to 3% of patients have reported exacerbation of ulcerative colitis symptoms when starting mesalamine
  • Upper GI obstruction - may cause prolonged retention of mesalamine and delay release into the colon
  • 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.
  • Kidney disease - exposure is increased. Use caution.
  • 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
  • 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

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.
  • Ulcerative colitis exacerbation - in trials, up to 3% of patients have reported exacerbation of ulcerative colitis symptoms when starting mesalamine
  • Upper GI obstruction - may cause prolonged retention of mesalamine and delay release into the colon
  • 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.
  • Kidney disease - exposure is increased. Use caution.
  • 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

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.



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
  • After the first 4 weeks of therapy, dose may be increased by 0.5 mg/kg/day at intervals of 2 weeks if necessary
  • Maximum dose is 4 mg/kg/day [30]

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 - patients may receive non-live vaccines. Do not give live or attenuated vaccines (e.g. MMR, Varicella, BCG).
  • 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

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 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 positive TB test.
  • Blood pressure - leflunomide may raise blood pressure. Monitor during therapy.
  • Blood dyscrasias - may cause or worsen. See Lab monitoring for recommendations.
  • Live vaccines - no data available. Not recommended.
  • 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]

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
  • Leukopenia - methotrexate may cause leukopenia. In a small RA trial (N=128), leukopenia (WBC < 3000/mm³) was seen in 2 patients. If the white blood cell count falls to < 3000/mm³, methotrexate should be stopped.
  • Thrombocytopenia - methotrexate may suppress platelet counts. In a small RA trial (N=128), thrombocytopenia (< 100,000/mm³) was seen in 6 patients. If the platelet count falls to < 50,000/mm³, methotrexate should be discontinued.
  • 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). Professional guidelines on RA and sarcoidosis are less stringent, and 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.
  • Malignancy - malignancies including Non-Hodgkin's lymphoma have been reported in patients receiving methotrexate. In some cases, lymphomas have regressed following discontinuation of methotrexate.
  • Vaccines - immunological response to vaccines may be blunted. Live vaccines are not recommended during therapy. See list of live and killed vaccines.
  • 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.
  • 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]



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]

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.
  • 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.
  • 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

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
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.

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

  • 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.
  • 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.
  • 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