ORENCIA CLICKJECT (abatacept)

There are 5 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Efalizumab; Natalizumab/Immunosuppressives; Immunomodulators 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)	TYSABRI
Abatacept/Selected Biologic DMARDs 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: Possibly additive or synergistic effects on the immune system. CLINICAL EFFECTS: Concurrent use of abatacept with anakinra, rituximab, or a tumor necrosis factor (TNF) blocking agent may increase the risk of severe infections without providing any clinical benefit.(1-5) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of abatacept states that abatacept should not be used with TNF blocking agents or other biologic DMARDs. Patients transitioning from TNF blocking agent therapy to abatacept should be closely monitored for signs of infection.(1) The US manufacturers of adalimumab,(2) certolizumab,(3) golimumab,(4) and infliximab(5) state that concurrent therapy with abatacept is not recommended. DISCUSSION: In clinical trials, patients who received concurrent abatacept and TNF blocking agents experienced more infections (63% versus 43%) and more serious infections (4.4% versus 0.8%) than patients who received TNF agents alone. There was no significant additional efficacy over use of TNF agents alone.(1) In other trials, infections and serious infections were reported in 54% and 3%, respectively, of patients who received abatacept alone.(1)	ABRILADA(CF), ABRILADA(CF) PEN, ABRILADA(CF) PEN (2 PACK), ADALIMUMAB-AACF(CF), ADALIMUMAB-AACF(CF) (2 PK), ADALIMUMAB-AACF(CF) PEN (2 PK), ADALIMUMAB-AACF(CF) PEN CROHNS, ADALIMUMAB-AACF(CF) PEN PS-UV, ADALIMUMAB-AATY(CF) (2 PACK), ADALIMUMAB-AATY(CF) (2 PK), ADALIMUMAB-AATY(CF) AI CROHNS, ADALIMUMAB-AATY(CF) AUTOINJ(2), ADALIMUMAB-AATY(CF) AUTOINJECT, ADALIMUMAB-ADAZ(CF), ADALIMUMAB-ADAZ(CF) PEN, ADALIMUMAB-ADBM(CF), ADALIMUMAB-ADBM(CF) PEN, ADALIMUMAB-ADBM(CF) PEN CROHNS, ADALIMUMAB-ADBM(CF) PEN PS-UV, ADALIMUMAB-ADBM(CF)PEN, ADALIMUMAB-FKJP(CF), ADALIMUMAB-FKJP(CF) PEN, ADALIMUMAB-RYVK(CF), ADALIMUMAB-RYVK(CF) AUTOINJECT, AMJEVITA(CF), AMJEVITA(CF) AUTOINJECTOR, AVSOLA, CIMZIA, CIMZIA (2 PACK), CYLTEZO(CF), CYLTEZO(CF) PEN, CYLTEZO(CF) PEN CROHN'S-UC-HS, CYLTEZO(CF) PEN PSORIASIS-UV, ENBREL, ENBREL MINI, ENBREL SURECLICK, HADLIMA, HADLIMA PUSHTOUCH, HADLIMA(CF), HADLIMA(CF) PUSHTOUCH, HULIO(CF), HULIO(CF) PEN, HUMIRA, HUMIRA PEN, HUMIRA(CF), HUMIRA(CF) PEN, HUMIRA(CF) PEN CROHN'S-UC-HS, HUMIRA(CF) PEN PSOR-UV-ADOL HS, HYRIMOZ, HYRIMOZ PEN, HYRIMOZ(CF), HYRIMOZ(CF) PEDIATRIC CROHN'S, HYRIMOZ(CF) PEN, HYRIMOZ(CF) PEN CROHN-UC START, HYRIMOZ(CF) PEN PSORIASIS, INFLECTRA, INFLIXIMAB, KINERET, REMICADE, RENFLEXIS, RIABNI, RITUXAN, RITUXAN HYCELA, RUXIENCE, SIMLANDI(CF), SIMLANDI(CF) AUTOINJECTOR, SIMPONI, SIMPONI ARIA, TRUXIMA, YUFLYMA(CF) (2 PACK), YUFLYMA(CF) AI CROHN'S-UC-HS, YUFLYMA(CF) AUTOINJECT (2 PCK), YUFLYMA(CF) AUTOINJECTOR, YUSIMRY(CF) PEN, ZYMFENTRA, ZYMFENTRA (2 PACK), ZYMFENTRA PEN (2 PACK)
Live Vaccines; Live BCG/Selected Immunosuppressive Agents 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) 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)	ACAM2000 (NATIONAL STOCKPILE), ADENOVIRUS TYPE 4, ADENOVIRUS TYPE 4 AND TYPE 7, ADENOVIRUS TYPE 7, BCG (TICE STRAIN), BCG VACCINE (TICE STRAIN), DENGVAXIA, ERVEBO (NATIONAL STOCKPILE), FLUMIST TRIVALENT 2024-2025, IXCHIQ, M-M-R II VACCINE, PRIORIX, PROQUAD, ROTARIX, ROTATEQ, STAMARIL, VARIVAX VACCINE, VAXCHORA ACTIVE COMPONENT, VAXCHORA VACCINE, VIVOTIF, YF-VAX
Talimogene laherparepvec/Selected Immunosuppressants 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)	IMLYGIC
Nadofaragene Firadenovec/Selected Immunosuppressants 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)	ADSTILADRIN

Drug contraindication overview.

*None.

Adverse reaction overview.

Adverse effects reported in >=10% of patients receiving abatacept for rheumatoid arthritis include headache, upper respiratory tract infection, nasopharyngitis, and nausea. Adverse effects generally are similar following IV infusion or subcutaneous injection for patients receiving abatacept for rheumatoid arthritis. In general, adverse events in pediatric patients with polyarticular juvenile idiopathic arthritis treated with IV abatacept were similar in frequency and type to those seen in adult patients with rheumatoid arthritis treated with IV abatacept.

The adverse effect profile in patients with juvenile idiopathic arthritis treated with subcutaneous abatacept were consistent with the adverse effect profile in patients with IV abatacept. The safety profile of abatacept was comparable when given IV or subcutaneously for the treatment of psoriatic arthritis, and also consistent with the safety profile of abatacept in patients with rheumatoid arthritis. Adverse effects reported in >=10% of patients receiving abatacept for prophylaxis of acute GVHD include anemia, hypertension, CMV reactivation or infection, pyrexia, pneumonia, epistaxis, decreased CD4 lymphocyte count, hypermagnesemia, and acute kidney injury.

Safety and efficacy of abatacept for the management of moderately to severely active polyarticular juvenile idiopathic arthritis have been established in pediatric patients >=2 years of age; the drug may be used as monotherapy or in combination with methotrexate. Safety and efficacy of abatacept used in combination with a calcineurin inhibitor and methotrexate for prophylaxis of acute GVHD in patients undergoing HSCT from a matched or 1-allele mismatched unrelated donor have been established in pediatric patients >=2 years of age. Safety and efficacy of abatacept for the treatment of psoriatic arthritis have been established in pediatric patients>=2 years of age; the drug may be used as monotherapy or in combination with methotrexate.

Safety and efficacy of abatacept have not been established in pediatric patients younger than 2 years of age or for pediatric uses other than polyarticular juvenile idiopathic arthritis,acute GVHD, and psoriatic arthritis. Use of IV abatacept (in combination with a calcineurin inhibitor and methotrexate) for the prophylaxis of acute GVHD in pediatric patients >=6 years of age undergoing HSCT from a matched or 1-allele mismatched unrelated donor is supported by controlled trials in adults and pediatric patients >=6 years who were administered a dosage of 10 mg/kg on the day prior to transplantation and days 5, 14, and 28 posttransplantion. Use of IV abatacept for the prophylaxis of acute GVHD in pediatric patients 2 to less than 6 years of age is supported by pharmacokinetic modeling and simulations of drug exposure in such patients administered a dose of 15 mg/kg one day prior to HSCT, followed by a 12-mg/kg dose on days 5, 14, and 28 posttransplantation.

The course of disease among patients <6 years of age and those >=6 years of age is sufficiently similar to allow for this extrapolation of data. Use of IV abatacept for the management of polyarticular juvenile idiopathic arthritis is supported by results of a randomized-withdrawal study evaluating efficacy, safety, and pharmacokinetics of IV abatacept in 190 pediatric patients 6-17 years of age; IV administration has not been evaluated in children younger than 6 years of age. Use of subcutaneous abatacept for the management of polyarticular juvenile idiopathic arthritis is supported by results of an open-label pharmacokinetic and safety study of subcutaneous abatacept in 205 pediatric patients 2-17 years of age and evidence of efficacy for IV abatacept in pediatric patients with polyarticular juvenile idiopathic arthritis and for subcutaneous abatacept in adults with rheumatoid arthritis.

Use of subcutaneous abatacept for the treatment of psoriatic arthritis in pediatric patients>=2 years of age is supported by results from well-controlled studies in adults with psoriatic arthritis; pharmacokinetic data from adults with rheumatoid arthritis or psoriatic arthritis and pediatric patients with polyarticular juvenile idiopathic arthritis; and safety data from pediatric studies of patients with polyarticular juvenile idiopathic arthritis using subcutaneous abatacept. The efficacy and safety of IV abatacept in pediatric patients with psoriatic arthritis have not been established. Population pharmacokinetic analyses indicate that clearance of abatacept increases with body weight in pediatric patients 6-17 years of age receiving the drug by IV infusion.

Consistent with these data for IV administration, population pharmacokinetic analyses of subcutaneous administration in pediatric patients 2-17 years of age indicate a trend toward higher clearance with increasing body weight. In juvenile rats, administration of abatacept prior to immune system maturity (from day 4 to day 94) was associated with an increased incidence of fatal infections compared with that observed in control animals. Changes in T-cell subsets (e.g., increased T-helper cells, decreased T-regulatory cells) and inhibition of T-cell-dependent antibody responses also were observed.

In addition, lymphocytic inflammation of the thyroid and pancreatic islets was observed once these animals reached adulthood. The relevance of these findings to humans is unknown since the immune system of rats is undeveloped in the first few weeks after birth. In studies in adult mice and monkeys, inhibition of T-cell-dependent antibody responses was observed, but increased rates of infection and mortality, altered T-helper cells, and inflammation of the thyroid and pancreas were not observed. It is not known if abatacept can cross the placenta when administered to a pregnant woman or whether the immune response of infants exposed to abatacept in utero and subsequently administered a live vaccine is affected.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None