IMMUNOSUPPRESSANTS









Balsalazide | Colazal® | Giazo®

Dosage form
Colazal® - capsule
  • 750 mg
Giazo® - tablet
  • 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® tablet
  • 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
  • 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®
  • Ulcerative colitis - treatment of mildly to moderately active ulcerative colitis in patients 5 years of age and older
Giazo®
  • Ulcerative colitis - treatment of mildly to moderately active ulcerative colitis in male patients ≥ 18 years

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

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


Drug Interactions
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 form
Apriso® - Capsule, extended-release
  • 375 mg
Asacol® HD - Tablet, delayed-release
  • 800 mg
Delzicol® - Capsule, delayed-release
  • 400 mg
Lialda® - Tablet, delayed-release
  • 1200 mg
Pentasa® - Capsule, extended-release
  • 250 mg
  • 500 mg
Canasa® - Suppository
  • 1000 mg
Rowasa® - Enema
  • 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
    • 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
    Apriso®
    • Ulcerative colitis - maintenance of remission
    Asacol® HD
    • Ulcerative colitis - treatment of active disease
    Delzicol®
    • Ulcerative colitis - treatment of active disease and maintenance of remission
    Lialda®
    • Ulcerative colitis - treatment of active disease and maintenance of remission
    Pentasa®
    • Ulcerative colitis - treatment of active disease
    Canasa®
    • Ulcerative colitis - treatment of active disease
    Rowasa®
    • Ulcerative colitis - treatment of active disease

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

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


    Drug interactions
    • Antacids (Apriso) - DO NOT take Apriso with antacids. Antacids may affect dissolution of the drug.
    • Nephrotoxic drugs including NSAIDs - concurrent use of mesalamine and nephrotoxic drugs including NSAIDs may increase the risk of kidney damage
    • 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 form
    Dipentum® 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
    • Olsalazine reaches the colon intact where it is cleaved by bacteria to release two molecules of mesalamine
    • The mechanism by which mesalamine exerts its therapeutic effect is not completely understood
    • Mesalamine (5-aminosalicylic acid, 5-ASA) is believed to work locally in the colon by inhibiting cyclooxygenase and lipoxygenase pathways and decreasing inflammatory mediators (e.g. prostaglandins, leukotrienes, etc.)

    FDA-approved indications
    • Ulcerative colitis - maintenance of remission in patients who are intolerant of sulfasalazine

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

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


    Drug interactions
    • Nephrotoxic drugs including NSAIDs - concurrent use of mesalamine and nephrotoxic drugs including NSAIDs may increase the risk of kidney damage
    • 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 form
    Azulfidine® - Tablet
    • 500 mg
    Azulfidine EN-tabs® - Delayed-release tablet
    • 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.

    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
    • 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 form
    Gengraf® | Neoral® - Microemulsion (modified) capsule
    • 25 mg
    • 50 mg
    • 100 mg
    Gengraf® | Neoral® - Microemulsion (modified) solution
    • 100 mg/ml
    • Comes in 50 ml bottle
    Sandimmune® - Standard capsule
    • 25 mg
    • 100 mg
    Sandimmune® - Standard solution
    • 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
    • Cyclosporine competitively binds to and inhibits calmodulin-dependent calcineurin, leading to suppression of T-cell and immunoglobulin E receptor signaling pathways [25]
    • Cyclosporine inhibits immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release including interleukin-2. [28]

    FDA-approved indications
    Neoral® | Gengraf®
    • Prevention of kidney, liver, and heart transplant rejection
    • Rheumatoid arthritis
    • Psoriasis
    Sandimmune®
    • Prevention of kidney, liver, and heart transplant rejection

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

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


    Drug Interactions

    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 form
    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
    • 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 dyscrasia - have been reported
    • Liver disease - has not been studied extensively; use caution
    • Kidney disease - has not been studied extensively, use caution



    Leflunomide (Arava®)

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

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

    Side effects
    NOTE: Only side effects with incidence ≥ 3% and ≥ 3% more than placebo are listed

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


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

    Contraindications / Precautions
    • Women who are pregnant or may become pregnant - DO NOT USE. May cause fetal harm. It is also recommended that males who are trying to impregnate partners not use leflunomide.
    • Nursing mothers - DO NOT USE
    • Liver disease - DO NOT USE. Leflunomide may cause or worsen liver disease. Leflunomide is contraindicated in patients with acute or chronic liver disease and/or ALT > 2 X ULN. See Lab monitoring for recommendations.
    • Tuberculosis (TB) - patients should be screened for latent TB before starting. Leflunomide has not been studied in patients with 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 form
    Tablet
    • 2.5 mg
    Trexall® - tablet
    • 5 mg
    • 7.5 mg
    • 10 mg
    • 15 mg
    Xatmep™ - solution
    • 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
    Otrexup™ - single-dose pen
    • 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
    Rasuvo® - single-dose pen
    • 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]

    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]

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

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

    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 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
    • 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
    • Theophylline - methotrexate may decrease theophylline clearance [22]

    Contraindications / Precautions
    • 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
    • White blood cell count < 3000/mm³ - DO NOT USE
    • Platelet count < 50,000/mm³ - DO NOT USE
    • Myelodysplasia - DO NOT USE
    • Treated lymphoproliferative disease of ≤ 5 years - DO NOT USE
    • Hepatitis B or C infection (active or chronic) - DO NOT USE
    • Pregnancy or breastfeeding - DO NOT USE
    • Methotrexate-induced pneumonitis - rare side effect (≤ 1%). Hypersensitivity reaction that occurs early in therapy.
    • Liver disease - ALT or AST ≥ 2 X ULN - DO NOT USE
    • Kidney disease
      • CrCl < 30ml/min: DO NOT USE [18]



    Azathioprine (Imuran®)

    Dosage form
    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
    • 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 infections 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 form
    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
    • 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.
    • 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 infections 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.



    Tofacitinib | Xeljanz® | Xeljanz® XR

    Dosage form
    Xeljanz® - tablet
    • 5 mg
    Xeljanz® XR - extended-release tablet
    • 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
    • Dosing: 10 mg twice daily for at least 8 weeks, then 5 - 10 mg twice daily
    • If adequate therapeutic benefit is not achieved after 16 weeks of 10 mg twice daily, discontinue Xeljanz
    • 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
    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
    Kidney disease
    • 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
    • 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
    • In situations where a dose reduction is indicated (see above), standard-release Xeljanz® should be used
    Psoriatic arthritis
    • Dosing: 11 mg once daily
    • May take with or without food
    • Do not crush, cut, or chew tablet
    • In situations where a dose reduction is indicated (see above), standard-release Xeljanz® should be used

    Lab monitoring
    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 For persistent decreases, hold Xeljanz until ANC > 1000 then resume Xeljanz® 5 mg twice daily or Xeljanz® XR 11 mg once daily
    < 500 cells/mm³ Discontinue Xeljanz
    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
    • 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 is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis. Use of Xeljanz in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

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

    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. Common live vaccines include MMR, shingles (zoster), varicella (chickenpox), rotavirus, oral polio, influenza nasal vaccine (Flumist), Yellow fever, and adenovirus.
    • Increased risk of pulmonary embolism (PE) and death - In 2/2019, the FDA issued a warning that a higher risk of PE and death were observed in an ongoing rheumatoid arthritis (RA) trial of Xeljanz. The higher risk was seen in patients receiving a dose of 10 mg twice a day. That dosing is currently only approved in patients with ulcerative colitis. Patients with RA should not receive a dose of 10 mg twice a day.
    • 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. Check lipid parameters 4 - 8 weeks after starting therapy.
    • Liver disease
      • See Dosing
    • Kidney disease
      • See Dosing



    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, anti-TNF monotherapy, or combination therapy, or being unexposed
    • Primary outcome: Incidence of lymphoma
    • 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.

    SONIC Study - Infliximab vs Azathioprine vs Both for Moderate to Severe Crohn's Disease, NEJM (2010) [PubMed abstract]
    • The SONIC study enrolled 508 patients with CD
    Main inclusion criteria
    • ≥ 21 years old
    • Moderate to severe disease (CDAI 220 - 450)
    • One of the following: corticosteroid-dependent, considered for 2nd course of steroids within 12 months, no response to mesalamine after 4 weeks, no response to budesonide after 4 weeks
    Main exclusion criteria
    • Previous treatment with azathioprine, 6MP, methotrexate, or anti-TNF
    • Decreased TPMT activity
    • Abdominal surgery within the previous 6 months
    Baseline characteristics
    • Median age 34 years
    • Average CDAI score - 287
    • Median disease duration - 2.3 years
    • Treatment with oral steroids - 27%
    • Receiving budesonide - 14%
    • Receiving 5-Aminosalicylic compounds - 54%
    Randomized treatment groups
    • Group 1 (170 patients) - Azathioprine 2.5 mg/kg/day
    • Group 2 (169 patients) - Infliximab 5 mg/kg at Weeks 0, 2, and 6, then every 8 weeks
    • Group 3 (169 patients) - Azathioprine + infliximab
    • Oral mesalamine was continued at a stable dose
    • Steroids (oral and budesonide) could be used up to Week 14, then they had to be tapered
    • Colonoscopy was performed at baseline and Week 26
    • At Week 30, patients were given the option to continue on current treatment while maintaining blinding to Week 50
    Primary outcome: Rate of corticosteroid-free clinical remission (CDAI < 150) at week 26
    Results

    Duration: 26 weeks
    Outcome Group 1 Group 2 Group 3 Comparisons
    Primary outcome 30% 44% 57%, 3 vs 2: p=0.02 | 3 vs 1: p<0.001 | 2 vs 3: p=0.006
    • Mucosal healing after 26 weeks: Group 1 - 16.5%, Group 2 - 30%, Group 3 - 44%
    • Clinical remission at Week 50 (only patients who entered extension): Group 1 - 55%, Group 2 - 61%, Group 3 - 72%
    • There was no significant difference in the incidence of serious infections between the groups (Group 1 - 5.6%, Group 2 - 5%, Group 3 - 4%)
    • There were significantly fewer serious adverse events in Group 3 than in Group 1 and 2 (Group 1 - 27%, Group 2 - 24%, Group 3 - 15%)

    Findings: Patients with moderate-to-severe Crohn's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy.



    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