Purixan (mercaptopurine)
Purine Analogues Oral Suspension, Oral (FINAL DOSE FORM)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Mercaptopurine, a purine antagonist, is an antineoplastic agent and immunosuppressant.
Mercaptopurine, a purine analog, is a nucleoside metabolic inhibitor. The drug undergoes intracellular transport and activation to form metabolites including thioguanine nucleotides (TGNs). Incorporation of TGNs into DNA or RNA results in cell-cycle arrest and cell death.
TGNs and other mercaptopurine metabolites are also inhibitors of de novo purine synthesis and purine nucleotide interconversions. Mercaptopurine is cytotoxic to proliferating cancer cells in vitro and has antitumor activity in mouse tumor models. It is not known which of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.
Mercaptopurine is also an immunosuppressant that inhibits the primary immune response.
Following a single oral dose of mercaptopurine 50mg under fasted conditions in healthy individuals, the peak plasma concentration was 69 ng/mL. Food has been shown to decrease the exposure of mercaptopurine. Plasma protein binding is approximately 19% over the concentration range 10-50 mcg/mL (a concentration achieved only by IV administration of mercaptopurine at doses >5-10mg/kg).
There isnegligible entry of mercaptopurine into the cerebrospinal fluid. Mercaptopurine is inactivated via 2 major pathways. One is thiol methylation, which is catalyzed by the polymorphic enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-mercaptopurine.
The second inactivation pathway is oxidation, which is catalyzed by xanthine oxidase. The product of oxidation is the inactive metabolite 6-thiouric acid. Mercaptopurine is excreted principally in the urine as unchanged drug and metabolites within the first 24 hours.
The elimination half-life is less than 2 hours following a single oral dose.
USES: This medication is used to treat a certain type of cancer (acute lymphocytic leukemia). It is a chemotherapy drug that works by slowing or stopping the growth of cancer cells. Talk to the doctor about the risks and benefits of mercaptopurine, especially when used by children and young adults.
Generic name: mercaptopurine
Pronunciation: (mer-KAP-toe-PURE-een)
Drug class: Purine Analogues
Therapeutic class: Antineoplastics
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Purixan
Indications
The following indications are listed for Purixan:
- Acute Lymphoid Leukemia
Also known as: Acute Lymphatic Leukemia, Acute Lymphocytic Leukemia, Acute Lymphogenous Leukemia, Lymphoblastic Leukemia.
Dosing
TPMT intermediate or TPMT possible intermediate metabolizer:CPIC guidelines recommend to start withreduced doses of mercaptopurine(30-80% of normal dose) if starting dose is >=75 mg/m2/day or >=1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust doses based on degree of myelosuppression and disease specific guidelines. Allow 2-4 weeks to reach steady state after each dosage adjustment. If myelosuppression occurs,emphasis should be on reducing the dosage ofmercaptopurine over other agents, depending on other therapy. If thenormal starting dose is already <75 mg/m2/day or <1.5 mg/kg/day,dosage reduction may not be recommended.
TPMT poor metabolizer: For malignancy, CPIC guidelines state to start with drastically reduced doses of mercaptopurine(reduce daily doseby 10-fold and reduce frequency to three times weekly instead of daily(e.g., 10 mg/m2/day given just 3 days/week) and adjust doses based on degree of myelosuppression and disease specific guidelines. Allow 4-6 weeks to reach steady state after each dosage adjustment. If myelosuppression occurs, an emphasis should be on reducing the dosage ofmercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.
NUDT15 intermediate or NUDT15 possible intermediate metabolizer:Start with reduced mercaptopurinedoses (30-80% of normal dose) if normal starting doseis >=75 mg/m2/day or >=1.5 mg/kg/day (e.g., start at 22.5-60 mg/m2/day or 0.45-1.2 mg/kg/day) and adjust dosesbased on degree of myelosuppression and disease-specific guidelines. Allow 2-4 weeks to reach steady state after each dosage adjustment. If myelosuppression occurs,emphasis should be on reducing mercaptopurine over other agents, depending on other therapy. If thenormal starting dose is already <75 mg/m2/day or <1.5 mg/kg/day, dosage reduction may not berecommended.
NUDT15 poor metabolizer: For malignancy, CPIC guidelines state to initiate the mercaptopurinedose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4-6 weeks to reach steady state after each dosage adjustment. If myelosuppression occurs,emphasis should be on reducing the dosage ofmercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy.
No dosing information is available for this tab.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Purixan 20 Mg/Ml Oral Susp | Maintenance | Take 1.5 mg/kg by oral route once daily. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Mercaptopurine 20 Mg/Ml Suspen | Maintenance | Take 1.5 mg/kg by oral route once daily. |
Drug interactions
There is no enhanced messaging for this drug.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Azathioprine; Mercaptopurine/Febuxostat
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Febuxostat may inhibit the metabolism of azathioprine and mercaptopurine by xanthine oxidase.(1)
CLINICAL EFFECTS: Concurrent use of febuxostat may result in elevated levels of and toxicity from azathioprine and mercaptopurine.(1)
PREDISPOSING FACTORS: Higher doses of the thiopurine would increase the risk for severe toxicity. Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression, since two thiopurine metabolism pathways would be blocked. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(2)
PATIENT MANAGEMENT: The US manufacturer of febuxostat states that the concurrent use of azathioprine or mercaptopurine is contraindicated.(1)
DISCUSSION: Azathioprine and mercaptopurine are metabolized by xanthine oxidase. Although no formal interaction studies with febuxostat have been performed, allopurinol, another xanthine oxidase inhibitor, has been shown to increase azathioprine and mercaptopurine levels. Febuxostat is expected to also increase levels of these agents, which could result in severe toxicity.(1) A review found 19 case reports of myelosuppressive adverse events with the combination of febuxostat and thiopurines including anemia, leukopenia, pancytopenia, and decreased red blood cells. Sixteen of the 19 cases resulted in hospitalization, and 17 of the 19 cases required one or more additional treatments including blood products, granulocyte or erythropoietin stimulating agents, antimicrobials, and immune globulin.(3) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.
Immunosuppressive; Immunomod/Cladribine Onc Inj (10 MG/5 ML)
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The UK and AU manufacturers of Litak state that concomitant use of other myelosuppressive medicinal products with cladribine is contraindicated.(1-2) The Israeli manufacturer of Litak states that cladribine should not be used concomitantly with other myelosuppressive medicinal products.(3)
DISCUSSION: The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment.(1-3)
Immunosuppressives; Immunomodulators/Efalizumab; Natalizumab
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).
PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000.
PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7)
DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)
Mercaptopurine/Azathioprine
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Azathioprine is a pro-drug of mercaptopurine.(1)
CLINICAL EFFECTS: Concurrent use of azathioprine and mercaptopurine is a duplication of therapy.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Azathioprine and mercaptopurine should not be used concurrently.(2)
DISCUSSION: A Crohn's disease pt. was given azathioprine (150mg/day). Another physician prescribed mercaptopurine (100mg/day). The patient took both medications and developed profound myelosuppression, severe sepsis, and later died.(2)
Selected Immunosuppressants/Nadofaragene Firadenovec
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1)
CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1)
DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)
Selected Immunosuppressants/Talimogene Laherparepvec
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1)
CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician.
DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)
Selected Immunosuppressive Agents/Live Vaccines; Live Bcg
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1)
CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2)
PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency.
PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) The US manufacturer of sibeprenlimab-szsi states live vaccines should not be given within 30 days prior to initiation or during treatment with sibeprenlimab-szsi.(15)
DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Azathioprine; Mercaptopurine/Methotrexate
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The mechanism of this interaction has not been fully characterized. It has been suggested that methotrexate may inhibit the metabolism of mercaptopurine by xanthine oxidase.(1-3)
CLINICAL EFFECTS: Concurrent use of methotrexate with azathioprine or mercaptopurine may increase the risk for elevated levels of and toxicity from mercaptopurine, including bone marrow suppression, neutropenia and hepatotoxicity.(1-3)
PREDISPOSING FACTORS: Larger doses of methotrexate may produce larger increases in mercaptopurine levels.(1-3) Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(5)
PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy closely for myelosuppression and hepatotoxicity. The dose of azathioprine or mercaptopurine may need to be adjusted when administered concomitantly with high-dose methotrexate.(1-4)
DISCUSSION: In a study in 14 pediatric patients with leukemia, methotrexate (20 mg/m2) increased the maximum concentration (Cmax) and area-under-curve (AUC) of mercaptopurine by 26% and 31%, respectively.(1,3) In a study in 10 pediatric patients with acute lymphoblastic leukemia, 2 g/m2 of methotrexate increased the Cmax and AUC of mercaptopurine (25 mg/m2) by 108% and 69%, respectively. Administration of 5 g/m2 of methotrexate increased the Cmax and AUC of mercaptopurine (25 mg/m2) by 121% and 93%, respectively.(2-3)
Azathioprine; Mercaptopurine/Tnf Blockers
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The exact mechanism is unknown, but may involve additive or synergistic effects on the immune system.
CLINICAL EFFECTS: Concurrent use of a TNF blocker with either azathioprine or mercaptopurine may increase the risk of hepatosplenic T-cell lymphoma (HSTCL), a rare but usually fatal cancer.(1-3)
PREDISPOSING FACTORS: The majority of reports of hepatosplenic T cell lymphoma in patients receiving concurrent TNF blockers with either azathioprine or mercaptopurine have occurred in patients with Crohn's disease or ulcerative colitis; however, there is one report in a psoriasis patient and two reports in rheumatoid arthritis patients.(1) The majority of patients were adolescent or young males.(2)
PATIENT MANAGEMENT: Patients receiving concurrent therapy with TNF blockers and either azathioprine or mercaptopurine should be counseled on the risk of developing hepatosplenic T-cell lymphoma, a rare but usually fatal cancer. They should be counseled on the signs and symptoms of malignancies such as HSTCL, which may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.
DISCUSSION: From initiation of TNF marketing to December 31, 2010, the FDA has received 28 reports of hepatosplenic T-cell lymphoma (HSTCL) in patients receiving TNF blockers: infliximab (20), etanercept (1), adalimumab (2), infliximab/adalimumab (5), certolizumab (0), golimumab (0). In 22 of these cases, the patients were also receiving azathioprine or mercaptopurine (18 with infliximab, 4 with infliximab/adalimumab).(1)
Immunosuppres;Immunomodul/Selected Multiple Sclerosis Agents
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ocrelizumab or ofatumumab in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2)
CLINICAL EFFECTS: Concurrent use of ocrelizumab or ofatumumab with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ocrelizumab US prescribing information states: - Ocrelizumab and other immune-modulating or immunosuppressive therapies, (including immunosuppressant doses of corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating ocrelizumab.(1) The ofatumumab US prescribing information states: - Ofatumumab and other immunosuppressive therapies (including systemic corticosteroids) may have the potential for increased immunosuppressive effects and increase the risk of infection. When switching between therapies, the duration and mechanism of action of each therapy should be considered due to the potential for additive immunosuppressive effects. Ofatumumab for MS therapy has not been studied in combination with other MS agents that suppress the immune system.(2)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(3)
Immunosuppressives; Immunomodulators/Baricitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of baricitinib with other biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine or cyclosporine may result in additive or synergistic effects on the immune system.
CLINICAL EFFECTS: Concurrent use of baricitinib with other biologic DMARDs or potent immunosuppressants such as azathioprine or cyclosporine may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1)
DISCUSSION: Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1)
Immunosuppressives; Immunomodulators/Cladribine Oral
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(2)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2)
Immunosuppressives; Immunomodulators/Deuruxolitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Deuruxolitinib, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of deuruxolitinib and potent immunosuppressants may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of deuruxolitinib states that concurrent use of deuruxolitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) If concurrent use cannot be avoided, patients should be monitored for signs and symptoms of infection. If a patient develops a serious or opportunistic infection, interrupt deuruxolitinib treatment until the infection is controlled.
DISCUSSION: Serious infections have been reported in patients receiving treatment with deuruxolitinib.(1)
Immunosuppressives; Immunomodulators/Etrasimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system.
CLINICAL EFFECTS: Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects.
PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1)
Immunosuppressives; Immunomodulators/Filgotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or other Janus kinase (JAK) inhibitors may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The UK manufacturer of filgotinib states that concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors is not recommended.(1)
DISCUSSION: Serious infections have been reported in patients receiving filgotinib. Caution should be used in patients with a higher incidence of serious infection, including elderly patients aged 75 years and older.(1)
Immunosuppressives; Immunomodulators/Fingolimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3)
CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3)
Immunosuppressives; Immunomodulators/Inebilizumab
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1)
Immunosuppressives; Immunomodulators/Ozanimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Ponesimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Ritlecitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1)
DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1)
Immunosuppressives; Immunomodulators/Siponimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Tofacitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of tofacitinib and azathioprine, other biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants use may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Tofacitinib should not be used concurrently with azathioprine, other biologic DMARDs, or cyclosporine.(1) Patient should be monitored for decreases in lymphocytes and neutrophils. Therapy should be adjusted based on the indication. - For all indications: If absolute neutrophil count (ANC) or lymphocyte count is less than 500 cells/mm3, discontinue tofacitinib. - For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil count (ANC) 500 to 1000 cells/mm3: interrupt dosing. When ANC is greater than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. - For ulcerative colitis and ANC 500 to 1000 cells/mm3: -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily. When ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on clinical response. -If taking Xeljanz 5 mg twice daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 5 mg twice daily. -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily. When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based on clinical response. -If taking Xeljanz XR 11 mg once daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 11 mg once daily. - For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500 to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000 cells/mm3.(1)
DISCUSSION: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) Serious infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Some patients presented with disseminated disease and were often taking concomitant immunomodulating agents. In the ulcerative colitis population, a greater risk of serious infections was seen with a higher tofacitinib dose. In 7 placebo-controlled rheumatoid arthritis trials (0-3 months exposure), the overall frequency of infections was 20% in the tofacitinib 5 mg twice daily group and 22% in the tofacitinib 10 mg twice daily group compared to 18% in the placebo group. Serious infections were reported in 11 patients (1.7 events per 100 patient-years) with a rate difference between treatment groups of 1.1 (-0.4, 2.5) events per 100 patient-years for both tofacitinib 5 mg twice daily and 10 mg twice daily. During 0-12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient years) in the tofacitinib 5 mg twice daily group and 33 patients (2.7 events per 100 patient years) in the tofacitinib 10 mg twice daily group.(1)
Immunosuppressives; Immunomodulators/Upadacitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Upadacitinib, immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of upadacitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of upadacitinib states that concurrent use of upadacitinib with immunosuppressives or immunomodulators is not recommended.
DISCUSSION: Serious infections have been reported in patients receiving upadacitinib. Reported infections included pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis. Reports of viral reactivation, including herpes virus reactivation and hepatitis B reactivation, were reported in clinical studies with upadacitinib.(1)
Myelosuppressives; Immunomodulators/Sodium Iodide I 131
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)
DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)
Selected Immunosuppressants/Leflunomide; Teriflunomide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1)
CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2)
DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2)
Selected Myelosuppressive Agents/Clozapine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)
CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.
PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.
PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)
DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)
Selected Myelosuppressive Agents/Deferiprone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)
CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.
PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)
PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)
DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)
Selected Myelosuppressive Agents/Dipyrone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)
CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)
DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)
Slt Immunosuppress; Immunomodulator/Ropeginterferon Alfa-2B
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ropeginterferon alfa-2b and immunosuppressives both suppress the immune system.
CLINICAL EFFECTS: Concurrent use of ropeginterferon alfa-2b with immunosuppressives may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concurrent use of myelosuppressive agents.(1-2) If concurrent use cannot be avoided, monitor for effects of excessive immunosuppression.
DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2)
Thiopurines/Allopurinol; Oxypurinol
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inhibition of xanthine oxidase leads to decreased thiopurine metabolism.
CLINICAL EFFECTS: Potentiation of thiopurine effects, with increased bone marrow suppression. Fatalities have been reported.
PREDISPOSING FACTORS: Higher doses of the thiopurine would increase the risk for severe toxicity. Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression, since two thiopurine metabolism pathways would be blocked. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.
PATIENT MANAGEMENT: Due to the magnitude and severity of this interaction, avoid the concurrent use of allopurinol and thiopurines without a dosage adjustment of the thiopurine, especially in patients with thiopurine S-methyltransferase (TPMT) deficiency. Consult the thiopurine prescriber prior to initiation of a xanthine oxidase inhibitor. Reduce the dose of azathioprine or mercaptopurine to one third to one quarter of the usual dose (a 66% to 75% reduction) in patients receiving allopurinol to decrease the risk for toxicity. A further dose reduction or alternative therapy is recommended in patients with low or absent TPMT activity. It would be prudent to reduce the dose of other thiopurines in patients receiving allopurinol, as well as decreasing the dose of these agents in patients taking oxypurinol. Patients should be closely monitored during concurrent therapy.
DISCUSSION: The concurrent administration of either mercaptopurine or azathioprine with allopurinol has been shown to result in increases in the pharmacologic and toxic effects of the thiopurines. In one study in five patients, pretreatment with allopurinol increased the peak plasma concentration of mercaptopurine by 500%. The combination of dose-adjusted thiopurines and allopurinol has been used effectively in the treatment of auto-immune diseases such as inflammatory bowel disease. Oxypurinol is the major metabolite of allopurinol and is a non-competitive inhibitor of xanthine oxidase.
Moderate Interaction: Assess the risk to the patient and take action as needed.
Azathioprine/Ace Inhibitors
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The exact mechanism is unknown. Azathioprine-induced impairment of hematopoiesis and ACE inhibitor-induced decreases in erythropoietin may result in additive effects on bone marrow.(1,2)
CLINICAL EFFECTS: The concurrent use of azathioprine and an ACE inhibitor may result in anemia or leucopenia.(1-6) ACE inhibitors have been used to correct post-transplantation erythrocytosis in patients who also received azathioprine.(7)
PREDISPOSING FACTORS: Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(8)
PATIENT MANAGEMENT: Patients receiving concurrent therapy with azathioprine and an ACE inhibitor should be closely monitored for hematological changes. One of the agents may need to be discontinued.
DISCUSSION: In a study in 15 kidney-transplant patients receiving azathioprine, enalapril and captopril were replaced by nifedipine or clonidine. Hematocrit and hemoglobin levels increased from 37.5% to 39.7% and from 12.8 g/dl to 13.5 g/dl, respectively,10 to 12 weeks after ACE inhibitor withdrawal. Reticulocytes and erythropoietin concentrations rose from 14.1/1000 to 20.6/1000 and from 14.3 mU/ml to 29.3m U/ml, respectively. There were no changes in azathioprine levels.(1) A retrospective review compared azathioprine-treated patients to patients receiving azathioprine and ACE inhibitors. Hematocrit, hemoglobin, and haptoglobin levels were significantly lower in the group receiving ACE inhibitors, 19.7%, 17.2%, and 45%, respectively.(2) Three case reports document the development of leucopenia during the concurrent administration of captopril and azathioprine.(3-5) Another case report documented the development of anemia with concurrent enalapril and azathioprine.(6) Enalapril has been used to treat post-renal transplant erythrocytosis in patients receiving azathioprine.(7)
Azathioprine/Ribavirin
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ribavirin inhibits inosine monophosphate dehydrogenase (IMDH), which leads to accumulation of 6-methylthioinosine monophosphate (6-MTITP), a metabolite of azathioprine that is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia).(1,2)
CLINICAL EFFECTS: Concurrent use of ribavirin and azathioprine may increase the risk of severe pancytopenia, bone marrow suppression, and azathioprine-related myelotoxicity. Pancytopenia and/or bone marrow suppression has typically developed within 3 to 7 weeks after initiation of concurrent therapy and has reversed within 4 to 6 weeks of withdrawing concurrent therapy.(1,2)
PREDISPOSING FACTORS: Concurrent use of interferon may make the interaction more severe and/or likely.(1) Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(3)
PATIENT MANAGEMENT: Patients receiving concurrent azathioprine and ribavirin should have complete blood counts, including platelet counts, weekly during the first month of therapy, then twice monthly for the second and third months of treatment, then monthly or more frequently if therapy changes are made.(1,2) If pancytopenia develops, discontinue concurrent therapy and do not reintroduce concurrent therapy.(1) The UK manufacturer of mercaptopurine states that concomitant administration of ribavirin and mercaptopurine is not advised.(7)
DISCUSSION: Pancytopenia, bone marrow suppression, and azathioprine-related myelotoxicity have been reported with concurrent use of azathioprine and ribavirin.(1,2,4-6) Pancytopenia and/or bone marrow suppression has typically developed within 3 to 7 weeks after initiation of concurrent therapy and has reversed within 4 to 6 weeks of withdrawing concurrent therapy.(1)
Azathioprine/Selected Anticoagulants (VITAMIN K ANTAGONISTS)
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The exact mechanism is unknown. Azathioprine has been shown to decrease warfarin and acenocoumarol concentrations.(1)
CLINICAL EFFECTS: Concurrent use of azathioprine may result in decreased effectiveness of warfarin or acenocoumarol.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Patients maintained on warfarin or acenocoumarol should be closely monitored if azathioprine is initiated or discontinued. The dosage of warfarin or acenocoumarol may need to be adjusted.
DISCUSSION: In a case report, a 50 year-old female had been maintained on warfarin at a dosage of 40 mg weekly for 2 years with INR values around 3. During azathioprine therapy, her warfarin dosage requirements increased to 100-150 mg weekly with resultant INR values of 1.5-1.95. Following the discontinuation of azathioprine, her INR value increased to 8.3 and the dose of warfarin was decreased to 40 mg weekly.(1) In a case report, a 32 year-old female had received a six week course of warfarin at a dosage of 35 mg weekly. Ten days after warfarin completion, azathioprine was initiated and 9 days later the patient developed a deep vein thrombosis. While on azathioprine, the patient required a dose of warfarin of 120 mg weekly to maintain an INR of 2.0-3.0.(2) In a case report, a 41 year-old female had been maintained on warfarin at a dosage of 5 mg daily with therapeutic INR values. Following the addition of azathioprine to her regimen, she required a daily dose of warfarin of 12 mg to achieve a therapeutic INR.(3) In a case report, a patient maintained on azathioprine required a daily dose of warfarin of 17 mg daily to maintain a therapeutic prothrombin time. Following the discontinuation of azathioprine, the patient developed intermittent epistaxis over a 6 week period. The patient was admitted with hematemesis and a prothrombin time of 32 seconds. Warfarin was held and later restarted at a daily dose of 5 mg.(4) In a case report, a 30 year-old female maintained on azathioprine and prednisolone required a daily warfarin dose of 20 mg. Warfarin dosage required decreasing to 11 mg daily during azathioprine tapering from 150 mg to 50 mg daily. When azathioprine was reintroduced, the patient's INR fell to 1.3 and warfarin had to be increased to 17 mg daily to maintain and INR of 2.4.(5) In a case report, a 67 year-old female was treated with warfarin (24 mg weekly) for over three years. After the initiation of azathioprine (150 mg daily), warfarin dosage was increased to a mean dose of 60 to 75 mg weekly over the next 18 months. Her dose of azathioprine was then increased to 200 mg daily and her warfarin dosage was increased to a mean dose of 130 mg weekly to compensate for subtherapeutic INR levels. Her INR value before azathioprine discontinuation was 1.8. Four weeks following azathioprine discontinuation her INR was 14.0.(6) In a case report, a 3 year-old female was treated with acenocoumarol 2 mg and 3 mg alternating days (17.5 mg/week) for 17 days (INR 2.6). Three days after initiation of azathioprine, the INR was 1.48 and heparin was started because of thromboembolic risk. The dose of acenocoumarol was increased to 5 mg per day (35 mg/week)(INR 2.56).(7) In a case report, a 53 year-old female was treated with acenocoumarol 21 mg/week (mean INR 3.3) for 3.5 years. After initiation of azathioprine 100 mg daily, methotrexate, and all-trans retinoic acid, the dose of acenocoumarol had to be increased to 70 mg/week (INR 1.9). Five months later the INR was 3.4. A week after discontinuing azathioprine, the INR increased to 12. The acenocoumarol dose was reduced to original 3 mg/day dose without complications.(8)
Azathioprine; Mercaptopurine/Aminosalicylate Derivatives
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The exact mechanism is not known. Aminosalicylic acid and its derivatives (balsalazide, mesalamine, olsalazine, sulfasalazine) may inhibit azathioprine or mercaptopurine inactivation via the thiopurine methyltransferase (TPMT) pathway. Aminosalicylates, azathioprine and mercaptopurine are all associated risk for neutropenia, thrombocytopenia, and anemia and so these risks could be additive.
CLINICAL EFFECTS: Concurrent use of azathioprine or mercaptopurine with aminosalicylates may increase the risk for anemia, neutropenia, or thrombocytopenia.
PREDISPOSING FACTORS: Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency. Added risk for myelosuppression would be expected in patients who also receive allopurinol or other agents which block xanthine oxidase (XO), the other major inactivation pathway for azathioprine and mercaptopurine.
PATIENT MANAGEMENT: Use the lowest possible dose of each drug and monitor closely for myelosuppression.
DISCUSSION: Manufacturer prescribing information states that concurrent use of aminosalicylates with azathioprine or mercaptopurine has been reported to cause bone marrow suppression. In a prospective study, 22 inflammatory bowel disease (IBD) patients on concurrent 5-aminosalicylate with (2 g daily and later increased to 4 g daily) with azathioprine had increased levels of 6-thioguanine (6-TGN) metabolites. One patient had signs of myelosuppression.(3) A prospective study in 183 IBD patients on concurrent 5-aminosalicylic acid and thiopurines found no significant interaction between thiopurines and 5-aminosalicylic acid.(4) A retrospective study in 199 IBD patients reported an increased rate of adverse events in the dual 5-aminosalicylates and azathioprine dual therapy group compared (48%) to the monotherapy azathioprine group (30%)(chi = 6.4, p = 0.05). Discontinuation of azathioprine because of adverse events was higher in the dual therapy group (52% vs. 24%).(5) In a prospective study, 16 Crohn's disease patients on a stable dose of azathioprine with sulfasalazine or mesalamine discontinued the aminosalicylate after 3 months, which resulted in an average decrease 0f 10% in 6-TGN levels. Myelosuppression may be related to increased levels of 6-TGN.(6) In a 8 week non-randomized parallel group drug interaction study, 34 patients with Crohn's disease receiving azathioprine or 6-mercaptopurine with mesalamine (4 g/day), or sulfasalazine (4 g/day), or balsalazide (6.75 g/day) had a high frequency of leukopenia (20-55%) and significant increases in whole blood 6-TGN levels.(7) A 16 year-old Crohn's disease patient on concurrent 6-mercaptopurine (75 mg) and olsalazine (1000 mg) developed leukopenia (WBC count 1.7 x 10*9/L, ANC 1.309 x 10*9/L, hemoglobulin 113 gm/L, platelet count 550 x 10*9/L) and required a dose reduction for 6-mercaptopurine. Another episode occurred later on after increasing her dose of olsalazine and 6-mercaptopurine which resulted in discontinuation of olsalazine.(8) An in vitro study showed that sulfasalazine and other aminosalicylate derivatives were able to inhibit recombinant human TPMT.(9) In a prospective study, 17 IBD patients on stable mercaptopurine and mesalamine therapy had a 23% reduction in 6-TGN levels after discontinuing mercaptopurine.(10)
Azathioprine; Mercaptopurine/Sulfamethoxazole-Trimethoprim
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: The combination of antimetabolite properties of either azathioprine or mercaptopurine with the inhibition of dihydrofolate reductase by sulfamethoxazole-trimethoprim may result in cytopenias.(1)
CLINICAL EFFECTS: Concurrent use of either azathioprine or mercaptopurine with sulfamethoxazole-trimethoprim may result in leucopenia,(2,3) neutropenia, or thrombocytopenia,(1)
PREDISPOSING FACTORS: Renal transplant patients(2), especially those within 60 days of transplant,(3) may be predisposed to this interaction. Patients with reduced or absent thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) activity are at higher risk of accumulating thiopurine metabolites and severe myelosuppression. Approximately 0.3 % of patients of European, Latino, or African descent have mutations of the TPMT gene resulting in little to no TPMT activity (homozygous deficiency), and approximately 10 % have intermediate TPMT activity (heterozygous deficiency). NUDT15 deficiency is not seen in patients of African descent and is seen in less than 1 % of patients of European descent. Approximately 1 % of patients of East Asian descent, 0.5 % of patients of central/south Asian descent, and 2 % of patients of Latino descent have homozygous NUDT15 deficiency. About 17 % of patients of East Asian descent, 13 % of patients of central/south Asian descent, and 8 % of patients of Latino descent have heterozygous NUDT15 deficiency.(4)
PATIENT MANAGEMENT: Patients receiving this combination should be closely monitored for cytopenias. The Australian manufacturer of sulfamethoxazole-trimethoprim states that alternatives to sulfamethoxazole-trimethoprim should be considered for patients receiving azathioprine or mercaptopurine.(6)
DISCUSSION: In a retrospective review of 40 renal transplant patients, 25 received azathioprine alone, 6 received azathioprine with sulfamethoxazole-trimethoprim prophylaxis, and 9 received sulfamethoxazole-trimethoprim for treatment of a urinary tract infection (UTI). Patients in the prophylaxis group had an increased incidence and duration of neutropenia and thrombocytopenia compared to patients receiving azathioprine alone. There were no differences in the incidence or duration of neutropenia or thrombocytopenia between patients receiving azathioprine alone or with concurrent sulfamethoxazole-trimethoprim for UTI treatment. In a study of renal transplant patients, 4 of 14 patients maintained on azathioprine developed leucopenia following the addition of sulfamethoxazole-trimethoprim for the treatment of UTI. In 3 patients, the leucopenia developed within 2 days of the initiation of sulfamethoxazole-trimethoprim.(3) In contrast to these reports, a retrospective review of 94 renal transplant patients found that the incidence of leucopenia with concurrent azathioprine and sulfamethoxazole-trimethoprim was not significantly different than the incidence with concurrent azathioprine and other antibiotics.(5)
Immunosuppressives; Immunomodulators/Cladribine Oncology Inj
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-4)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-4)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US, UK, and Australian prescribing information state: -Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.(1-3) The cladribine Canadian prescribing information states: -Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.(4)
DISCUSSION: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine injection, especially at high doses.(1-4)
Immunosuppressives; Immunomodulators/Covid-19 Vaccines
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)
CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.
DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)
Immunosuppressives; Immunomodulators/Sarilumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Sarilumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sarilumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sarilumab recommends caution because the concurrent use of sarilumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Sarilumab was studied as monotherapy and in combination with methotrexate or conventional disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis studies. Sarilumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by sarilumab treated patients in the clinical trial periods included pneumonia and cellulitis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving sarilumab. Cases of tuberculosis, candidiasis, and pneumocystis with sarilumab have been reported.(1)
Immunosuppressives; Immunomodulators/Tocilizumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tocilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tocilizumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of tocilizumab recommends caution because the concurrent use of tocilizumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Tocilizumab was studied as monotherapy and in combination with methotrexate, non-biologic DMARDs or corticosteroids, depending on the indication. Tocilizumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by tocilizumab treated patients in the clinical trial periods included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving tocilizumab. Cases of tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have been reported.(1)
Immunosuppressives; Immunomodulators/Ublituximab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ublituximab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ublituximab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The US manufacturer of ublituximab recommends caution because the concurrent use of ublituximab with immunomodulating or immunosuppressive agents, including immunosuppressant doses of corticosteroids, may increase the risk of infection.(1) If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents. When switching from agents with immune effects, the half-life and mechanism of action of these drugs must be taken into consideration in order to prevent additive immunosuppressive effects.(1)
DISCUSSION: The most common infections reported by ublituximab-treated patients in the clinical trial periods included upper respiratory tract infections and urinary tract infections. Serious, including life-threatening or fatal, bacterial and viral infections were observed in patients receiving ublituximab.(1) Serious and/or fatal bacterial, fungal, and new or reactivated viral infections have been associated with other anti-CD20 B-cell depleting therapies. There were no cases of progressive multifocal leukoencephalopathy (PML) reported during the clinical trials; however, there have been reports of PML during or following completion of other anti-CD20 B-cell depleting therapies.(1)
Contraindications
*None.
- Hepatosplenic t-cell lymphoma
- Anemia
- Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
- Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
- Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
- Chronic kidney disease stage 5 (failure) GFr<15 ml/min
- Disease of liver
- Leukopenia
- Neutropenic disorder
- NUDt15 intermediate metabolizer
- NUDt15 poor metabolizer
- Pregnancy
- Thrombocytopenic disorder
- TPMT intermediate metabolizer
- TPMT poor metabolizer
- Kidney disease with likely reduction in glomerular filtration rate (GFr)
Adverse reactions
There is no enhanced messaging for this drug.
More Frequent
- Anemia
- Cholestasis
- Immunosuppression
- Infection
- Jaundice
- Leukopenia
- Neutropenic disorder
- Thrombocytopenic disorder
Less Frequent
- Abnormal hepatic function tests
- Gastrointestinal ulcer
- Hyperbilirubinemia
- Stomatitis
- Tumor lysis syndrome
- Uric acid nephropathy
Rare or Very Rare
- Endometrial carcinoma
- Hemophagocytic lymphohistiocytosis
- Hepatic necrosis
- Hepatosplenic t-cell lymphoma
- Kaposi's sarcoma
- Lymphopenia
- Macrophage activation syndrome
- Malignant melanoma
- Pancreatitis
- Pellagra
- Portal hypertension
- Pulmonary fibrosis
More Frequent
- Anorexia
- Diarrhea
- Malaise
- Nausea
- Skin rash
- Vomiting
Less Frequent
- Alopecia
- General weakness
- Oligospermia
- Skin pigmentation enhancement
- Urticaria
Rare or Very Rare
- Basal cell carcinoma of skin
- Drug fever
- Erythema nodosum
- Hypoglycemic disorder
- Skin photosensitivity
- Squamous cell carcinoma of skin
Precautions
No enhanced messaging available.
Safety and effectiveness of mercaptopurine have not been established in pediatric patients, but useof the drug in pediatrics is supported by evidence from the published literature andclinical experience.
Symptomatic hypoglycemia has been reported in pediatric patientswith ALL receiving mercaptopurine. Reported cases were in patients <6 yearsof age or those with a low body mass index.
Mercaptopurine can cause fetal harm when administered to a pregnant woman. Advise pregnant women of thepotential risk to a fetus.
Women receiving mercaptopurine in the first trimester of pregnancy have an increasedincidence of miscarriage; the risk of malformation in offspring surviving first trimesterexposure is not known. In a series of 28 women receiving mercaptopurine after the firsttrimester of pregnancy, 3 died prior to delivery, 1 delivered a stillborn child, and1 aborted; there were no cases of macroscopically abnormal fetuses.
In animal studies, mercaptopurine was embryo-lethal and teratogenic in several animal species (rat,mouse, rabbit, and hamster) at doses less than the recommended human dose.
There are no data on the presence of mercaptopurine or its metabolites in human milk,the effects on the breastfed child, oreffects on milk production. Because of thepotential for serious adverse reactions in the breastfed child, advise women not tobreastfeed during treatment with mercaptopurine and for 1 week after the final dose.
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Clinical studies of mercaptopurine did not include sufficient numbers of patients>=65 years of age to determine whether they respond differently from younger patients. Otherreported clinical experience has not identified differences in responses between theelderly and younger patients.
ICD codes
| Code | Type | Description |
|---|---|---|
| Acute lymphoid leukemia | ||
| C91.0 | ICD10CM | Acute lymphoblastic leukemia [ALl] |
| C91.00 | ICD10CM | Acute lymphoblastic leukemia not having achieved remission |
| C91.02 | ICD10CM | Acute lymphoblastic leukemia, in relapse |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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