Adrucil

Drug overview for ADRUCIL (fluorouracil):

Generic name: FLUOROURACIL (flewr-oh-YOUR-uh-sill)
Drug class: 5 Fluoropyrimidines
Therapeutic class: Antineoplastics

Fluorouracil, a pyrimidine antagonist, is an antimetabolite antineoplastic agent.

Fluorouracil is used for the treatment of adenocarcinoma of the colon, rectum, breast, stomach, and pancreas. Fluorouracil is used off-label for a variety of other oncologic indications; refer to current treatment guidelines for the most up-to-date recommendations for use in such indications.

DRUG IMAGES

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The following indications for ADRUCIL (fluorouracil) have been approved by the FDA:

Indications:
Adenocarcinoma of pancreas
Colorectal cancer
Gastric cancer
Metastatic breast carcinoma
Metastatic colorectal cancer

Professional Synonyms:
Adenocarcinoma of colon and rectum
Advanced breast carcinoma
Cancer of the colon and rectum
Gastric malignancy
Malignancy of colon and rectum
Malignant neoplasm of stomach
Malignant tumor of colon and rectum
Malignant tumor of stomach
Metastatic breast cancer
Metastatic malignancy of breast
Metastatic malignant neoplasm of breast
Metastatic malignant tumor of breast
Pancreatic adenocarcinoma

The following dosing information is available for ADRUCIL (fluorouracil):

Dosing
Administration
Dosing Information
Generic

Dosage and dosage schedules of fluorouracil should be individualized based on the tumor type, specific regimen, clinical response, and concomitant comorbidities. Clinicians should consult published protocols for the dosage of fluorouracil and other chemotherapeutic agents and the method and sequence of administration.

If grade 3 or 4 diarrhea or mucositis, grade 4 myelosuppression, or grade 2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) occurs, withhold fluorouracil. When the toxicity has resolved or improved to grade 1, resume fluorouracil at a reduced dosage.

Withhold fluorouracil if cardiotoxicity (i.e., angina, myocardial infarction or ischemia, arrhythmia, heart failure) develops in patients with no history of coronary artery disease or cardiac dysfunction. Therapy with the medication also should be withheld if hyperammonemic encephalopathy or neurologic effects (i.e., acute cerebellar syndrome, confusion, disorientation, ataxia, visual disturbance) develop. The manufacturers state there is no recommended dosage for resumption of fluorouracil following development of cardiotoxicity, hyperammonemic encephalopathy, or neurologic effects.

Fluorouracil is administered IV as a bolus or infusion. Do not inject the entire contents of the fluorouracil vial directly. The 2.5-

or 5-g pharmacy bulk package of fluorouracil is intended for preparation of individual doses of the medication and is not for direct IV infusion; after the vial has been entered, any unused portion should be discarded within 4 hours. An established IV line should be used to administer fluorouracil by direct IV injection. For IV infusion regimens, the medication should be administered via a central venous catheter using a controlled-infusion device (e.g., pump). Store fluorouracil injection in the original carton at 20-25degreesC; protect from light and do not freeze.

No dosing information available.

No generic dosing information available.

The following drug interaction information is available for ADRUCIL (fluorouracil):

Contraindicated
Severe
Moderate

There are 4 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)	TYRUKO, TYSABRI
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) 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)	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 2025-2026, FLUMIST HOME 2025-2026, 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

There are 23 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Selected Anticoagulants (Vitamin K antagonists)/Capecitabine; Fluorouracil SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Capecitabine inhibits the CYP2C9 mediated metabolism of warfarin.(1) The interaction mechanism with fluorouracil is not clear. CLINICAL EFFECTS: Concurrent use of fluorouracil (5-FU) or its prodrug, capecitabine, and a Vitamin K antagonist anticoagulant may result in elevated levels of the anticoagulant(2-10) and increase the risk for bleeding. PREDISPOSING FACTORS: Patients who are older than 60 years of age may be predisposed to this interaction.(2) The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 1/3, 2/2, 2/3, and 3/3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants. PATIENT MANAGEMENT: Patients receiving concurrent therapy with capecitabine or fluorouracil and a Vitamin K antagonist anticoagulant (e.g. warfarin) should have their INR closely monitored and adjusted for an extended period of time as the maximal increase in INR may not occur for 30 - 40 days or more.(10) If patient has been stabilized on the combination of a Vitamin K antagonist and fluorouracil or capecitabine, and the fluoropyrimidine is subsequently discontinued, the dosage of anticoagulant may need to be gradually increased to maintain a therapeutic INR. When concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. DISCUSSION: In four patients with cancer, concurrent use of capecitabine (1250 mg/m2 twice daily) with a single dose of warfarin (20 mg) increased the area-under-curve (AUC) of the more active S-isomer of warfarin by 57%. The clearance S-warfarin was decreased by 37%. The baseline corrected AUC of the International Normalized Ration (INR) and the maximum observed mean INR value increase by 2.8-fold and 91%, respectively. A retrospective cohort study evaluated changes in INR for 24 patients treated with either 5-fluorouracil or capecitabine and warfarin over a 90 day period. The median change in INR was 2.8. Altered coagulation parameters and/or bleeding, including death have been reported in patients taking capecitabine with warfarin or phenprocoumon. There have been postmarketing reports of clinically significant increases in prothrombin time and INR in patients who were previously stabilized on anticoagulants when capecitabine was introduced. These events occurred within several days or months of beginning concurrent therapy or within a month of discontinuing concurrent therapy.(1) There are several case reports of elevated warfarin response, including hemorrhage, during the concurrent administration of warfarin and fluorouracil.(2-8)	ANISINDIONE, DICUMAROL, JANTOVEN, WARFARIN SODIUM
Fluorouracil/Metronidazole; Tinidazole SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Metronidazole(1) and tinidazole(2) may decrease the clearance of fluorouracil. CLINICAL EFFECTS: Concurrent use of metronidazole(1) or tinidazole with fluorouracil may result in elevated levels of fluorouracil and toxicity, including severe and fatal myelosuppression including neutropenia, thrombocytopenia, or anemia, severe diarrhea, cardiotoxicity, or neurotoxicity. PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3) PATIENT MANAGEMENT: Avoid using metronidazole as an adjunct agent to fluorouracil therapy. If possible, also avoid treating infections with metronidazole or tinidazole in patients receiving fluorouracil. If concurrent therapy for the treatment of infection is required, the dosage of fluorouracil may need to be reduced. Patients receiving concurrent therapy should be closely monitored for signs of fluorouracil toxicity. DISCUSSION: In a study in 27 patients, metronidazole (750 mg/m2) was given one hour before fluorouracil (600 mg/m2) daily for five days. The regimen was repeated every 4 weeks. Fluorouracil toxicity was greatly enhanced, with 74% of patients experiencing granulocytopenia (less than 1500/ml). Pharmacokinetic studies showed that metronidazole decreased fluorouracil clearance by 26.9%. In vitro studies revealed no synergism with the two agents on the HCT-8 colon cancer cell line.(1)	BISMUTH-METRONIDAZOLE-TETRACYC, LIKMEZ, METRO IV, METRONIDAZOLE, METRONIDAZOLE BENZOATE, METRONIDAZOLE MICRONIZED, PYLERA, TINIDAZOLE
Hydantoins/Fluorouracil & Fluorouracil Prodrugs SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Fluorouracil may inhibit the metabolism of hydantoins by CYP2C9.(1) CLINICAL EFFECTS: Concurrent use of fluorouracil or fluorouracil prodrugs may result in hydantoin toxicity. Phenytoin has a narrow therapeutic range. Early symptoms of phenytoin toxicity may include nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting. Severe toxicity may produce organ dysfunction (e.g. coma, irreversible cerebellar dysfunction and atrophy, hypotension, bradycardia, seizures, and cardiac arrest) and may be fatal.(6) PREDISPOSING FACTORS: Renal impairment, hepatic impairment, or hypoalbuminemia. PATIENT MANAGEMENT: Monitor hydantoin levels and for signs of hydantoin toxicity (e.g. nystagmus, ataxia, dysarthria, tremor, hyperreflexia, lethargy, slurred speech, blurred vision, nausea, and vomiting) in patients receiving concurrent fluorouracil or fluorouracil prodrugs. The dosage of the hydantoin may need to be adjusted if fluorouracil or a fluorouracil prodrug is added to or discontinued from concurrent therapy. DISCUSSION: There have been four reports of elevated phenytoin levels and phenytoin toxicity following fluorouracil therapy in patients who had been stabilized on phenytoin for several years.(1-3) There is one case report of phenytoin toxicity in a patient previously stabilized on phenytoin following capecitabine therapy.(1) Elevated phenytoin levels have been reported in patients receiving concurrent tegafur.(4,5) Fluorouracil prodrugs linked to this monograph include: capecitabine, doxifluridine, and tegafur.	CEREBYX, DILANTIN, DILANTIN-125, FOSPHENYTOIN SODIUM, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED
Deferiprone/Selected Myelosuppressive Agents 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)	DEFERIPRONE, DEFERIPRONE (3 TIMES A DAY), FERRIPROX, FERRIPROX (2 TIMES A DAY), FERRIPROX (3 TIMES A DAY)
Tofacitinib/Immunosuppressives; Immunomodulators 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)	TOFACITINIB CITRATE, XELJANZ, XELJANZ XR
Clozapine/Selected Myelosuppressive Agents 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)	CLOZAPINE, CLOZAPINE ODT, CLOZARIL, VERSACLOZ
Selected Multiple Sclerosis Agents/Immunosuppressants; Immunomodulators 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)	KESIMPTA PEN, OCREVUS, OCREVUS ZUNOVO
5-Fluorouracil/High-Dose Folic Acid SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Folic acid has been shown to enhance both the therapeutic and toxic effects of fluoropyrimidines, such as 5-fluorouracil (5-FU).(1,2) CLINICAL EFFECTS: Folic acid, when used concurrently with 5-FU, has been shown to increase side effects of 5-FU.(1,2) PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3) PATIENT MANAGEMENT: Folic acid intake may need to be limited in patients experiencing toxicity from 5-fluorouracil.(1,2) DISCUSSION: Due to increased toxic effects, stomatitis and diarrhea are observed more commonly, may be more severe, and may occur for a prolonged duration when compared to therapy with 5-FU alone. It is postulated that the lower standard dose of 5-FU in the US versus other regions may be due to increased folic acid supplementation within the US food supply.(1) In a case report, a woman developed grade 4 diarrhea, grade 3 vomiting, and grade 3 hand-foot syndrome 8 days after the addition of capecitabine (2500 mg/m2/day) to high-dose folic acid supplementation. She developed necrotic colitis and died, despite the discontinuation of folic acid and capecitabine.(3) There are two other reports of excessive fluorouracil toxicity in patients treated with folic acid.(4)	FOLIC ACID
Upadacitinib/Immunosuppressives; Immunomodulators 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)	RINVOQ, RINVOQ LQ
Inebilizumab/Immunosuppressives; Immunomodulators 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)	UPLIZNA
Baricitinib/Immunosuppressives; Immunomodulators 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)	OLUMIANT
Leflunomide; Teriflunomide/Selected Immunosuppressants 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)	ARAVA, AUBAGIO, LEFLUNICLO, LEFLUNOMIDE, TERIFLUNOMIDE
Ponesimod/Immunosuppressives; Immunomodulators 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)	PONVORY
Sodium Iodide I 131/Myelosuppressives; Immunomodulators 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)	HICON, SODIUM IODIDE I-131
Fingolimod/Immunosuppressives; Immunomodulators 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)	FINGOLIMOD, GILENYA, TASCENSO ODT
Ozanimod/Immunosuppressives; Immunomodulators 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)	ZEPOSIA
Siponimod/Immunosuppressives; Immunomodulators 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)	MAYZENT
Cladribine Oral/Immunosuppressives; Immunomodulators 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)	CLADRIBINE, MAVENCLAD
Fluorouracil & Fluorouracil Prodrugs/Allopurinol SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Allopurinol may decrease conversion of fluorouracil to its active metabolites, FdUMP and FUTP.(1-4) Capecitabine and tegafur are prodrugs of fluorouracil. CLINICAL EFFECTS: Concurrent use of allopurinol with fluorouracil or fluorouracil prodrugs (e.g., capecitabine, tegafur) may result in decreased levels of the active metabolites of fluorouracil and loss of efficacy. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The concurrent use of fluorouracil or fluorouracil prodrugs with allopurinol should be avoided.(1-4) DISCUSSION: This is a theoretical interaction based on non-clinical data. Allopurinol may decrease the levels of the active metabolites of fluorouracil, FdUMP and FUTP. Capecitabine and tegafur are prodrugs of fluorouracil.(1-4)	ALLOPURINOL, ALLOPURINOL SODIUM, ALOPRIM, ZYLOPRIM
Ritlecitinib/Immunosuppressives; Immunomodulators 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)	LITFULO
Etrasimod/Immunosuppressives; Immunomodulators 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)	VELSIPITY
Ropeginterferon alfa-2b/Slt Immunosuppress; Immunomodulator 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)	BESREMI
Deuruxolitinib/Immunosuppressives; Immunomodulators 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)	LEQSELVI

There are 7 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
5-Fluorouracil/Leucovorin SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Leucovorin has been shown to enhance both the therapeutic and toxic effects of fluoropyrimidines, such as 5-fluorouracil(5-FU).(1) CLINICAL EFFECTS: Leucovorin, when used concurrently with 5-FU, has been shown to increase side effects of 5-FU.(1) PREDISPOSING FACTORS: Patients who are intermediate or poor dihydropyrimidine dehydrogenase (DPYD) metabolizers have diminished or no DPYD function. Since DPYD is the rate-limiting enzyme involved in fluoropyrimidine metabolism, these patients may be more susceptible to the effects of this interaction.(3) PATIENT MANAGEMENT: When leucovorin is added to 5-FU therapy, the dose of 5-FU must be reduced from that of the normally administered dose. Patients should be closely monitored for appearance and severity of side effects to determine whether it is appropriate to alter the dose of 5-FU.(1) DISCUSSION: A retrospective study reviewed all patients over the age of 18 years treated with combination fluorouracil and leucovorin either as adjuvant or palliative treatment. A total of 122 patients (60% male) were included in the study. Ninety-four patients received fluorouracil (425 mg/m2, IV) and leucovorin (20 mg/m2, IV) daily for five days and repeated every four weeks. Twenty-eight patients received fluorouracil (400 mg/m2, IV) and leucovorin (80 mg/m2, IV) once per week for six weeks of an eight week course. All patients were treated for up to six months. Forty-eight patients (39%) experienced toxicity including fatigue (21%), mucositis (17%), diarrhea (11%), and nausea (11%).(2) A study involving 35 patients evaluated a combination of cisplatin (20 mg/m2) on Day 1 through Day 3, leucovorin (200 mg/m2) on Day 1 through Day 5, and 5-fluorouracil (500 mg/m2) on Day 1 through Day 5. If patients tolerated the low dose of 5-fluorouracil, the dose was increased to a maximum of 750 mg/m2/day during the remaining courses. Grade I mucositis occurred in three patients, Grade II in 16 patients, and Grade III in 13 patients. The dose of 5-fluorouracil was decreased in patients with Grade II and Grade III mucositis, which helped to decrease symptoms.(3) A randomized trial in advanced colorectal carcinoma patients compared fluorouracil (500 mg/m2 on Days 1-5) every four weeks with escalation as tolerated with high-dose leucovorin (500mg/m2) with fluorouracil (600 mg/m2) given weekly for six weeks with a two-week rest period and with low-dose leucovorin (25 mg/m2) with fluorouracil (600 mg/m2) given weekly for six weeks with a two-week rest period. Severe or worse diarrhea was reported in 25% and 13% of patients receiving high-dose leucovorin and low-dose leucovorin with fluorouracil, respectively. Nine elderly patients experienced fatal toxicity during the initial treatment cycle with combination therapy.(4) A study in five patients with metastatic colorectal carcinoma examined the effects of high dose leucovorin (500 mg/m2) on fluorouracil pharmacokinetics. Subjects received a single dose of fluorouracil (600 mg/m2) with leucovorin and, one week later, without leucovorin. With concurrent leucovorin, the time of distribution of fluorouracil increased 44% (p<0.0005) and fluorouracil volume of distribution increased 84% (p<0.03). There were no changes in fluorouracil plasma clearance or AUC. Although fluorouracil anabolite levels were lower at two minutes and five minutes post-dose when administered following leucovorin, levels were similar thereafter.(5)	CALCIUM FOLINATE, KHAPZORY, LEUCOVORIN CALCIUM, LEVOLEUCOVORIN CALCIUM, VYKOURA
Ustekinumab/Immunosuppressives; Immunomodulators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Ustekinumab, immunosuppressives, and immunomodulators all suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of ustekinumab 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 ustekinumab recommends caution because the concurrent use of ustekinumab 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: Ustekinumab has not been studied in combination with other immunosuppressants in psoriasis studies. In psoriatic arthritis studies, concomitant methotrexate use did not appear to influence the safety or efficacy of ustekinumab. In Crohn's disease and ulcerative colitis studies, concomitant use of immunosuppressants or corticosteroids did not appear to influence the safety or efficacy of ustekinumab. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by ustekinumab treated patients in the clinical trial periods included nasopharyngitis(8%) and upper respiratory tract infection(5%). Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving ustekinumab. Cases of interstitial pneumonia, eosinophilic pneumonia, and cryptogenic organizing pneumonia resulting in respiratory failure or prolonged hospitalization have been reported in patients receiving ustekinumab.(1)	IMULDOSA, OTULFI, PYZCHIVA, PYZCHIVA AUTOINJECTOR, SELARSDI, STARJEMZA, STELARA, STEQEYMA, USTEKINUMAB, USTEKINUMAB-AAUZ, USTEKINUMAB-AEKN, USTEKINUMAB-TTWE, WEZLANA, YESINTEK
COVID-19 Vaccines/Immunosuppressives; Immunomodulators 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)	COMIRNATY 2025-2026 (12Y UP), COMIRNATY 2025-2026(5-11Y), MNEXSPIKE 2025-2026 (12Y UP), NUVAXOVID 2025-2026, SPIKEVAX 2025-2026 (12Y UP), SPIKEVAX 2025-2026 (6M-11Y)
Sarilumab/Immunosuppressives; Immunomodulators 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)	KEVZARA
Ublituximab/Immunosuppressives; Immunomodulators 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)	BRIUMVI
Tocilizumab/Immunosuppressives; Immunomodulators 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)	ACTEMRA, ACTEMRA ACTPEN, AVTOZMA, AVTOZMA AUTOINJECTOR, TOFIDENCE, TYENNE, TYENNE AUTOINJECTOR
Cladribine Oncology Inj/Immunosuppressives; Immunomodulators 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)	CLADRIBINE

The following contraindication information is available for ADRUCIL (fluorouracil):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*None.

There are 13 contraindications. Absolute contraindication.

Contraindication List
Bone marrow depression
Congenital long QT syndrome
Dihydropyrimidine dehydrogenase deficiency
Gastrointestinal hemorrhage
Hemorrhage
Lactation
Palmar-plantar erythrodysesthesia
Pharyngitis
Protein-calorie malnutrition
Severe infection
Severe thrombocytopenia
Severe vomiting
Stomatitis

There are 12 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Angina
Cardiac arrhythmia
Debilitation
Diarrhea
Disease of liver
Gastrointestinal ulcer
Kidney disease with reduction in glomerular filtration rate (GFr)
Leukopenia
Neutropenic disorder
Pregnancy
Secondary malignant neoplasm of bone marrow
Thrombocytopenic disorder

There are 0 moderate contraindications.

The following adverse reaction information is available for ADRUCIL (fluorouracil):

Overview
Severe
Less Severe

Adverse reaction overview.

Reported adverse effects for fluorouracil come from postmarketing reports and include pancytopenia, gastrointestinal ulceration, nausea, vomiting, anaphylaxis and generalized allergic reactions, nystagmus, headache, dry skin, fissuring, photosensitivity (manifested by erythema or increased skin pigmentation), vein pigmentation, lacrimal duct stenosis, visual changes, lacrimation, photophobia, euphoria, thrombophlebitis, epistaxis, and nail changes.

There are 24 severe adverse reactions.

More Frequent	Less Frequent
Allergic dermatitis Aphthous stomatitis Diarrhea Infection Leukopenia Skin rash	Anemia Gastrointestinal ulcer Neutropenic disorder Thrombocytopenic disorder

Rare/Very Rare
Acute cerebellar syndrome Acute myocardial infarction Agranulocytosis Anaphylaxis Angina Bone marrow depression Cardiac arrhythmia Coma Heart failure Hyperammonemia Maculopapular rash Myocardial ischemia Pancytopenia Thrombophlebitis

There are 24 less severe adverse reactions.

More Frequent	Less Frequent
Alopecia Anorexia Esophagitis Fatigue General weakness Nausea Pharyngitis Stomatitis Vomiting	Dry skin Skin photosensitivity Visual changes

Rare/Very Rare
Acute cognitive impairment Ataxia Epistaxis Euphoria Eye tearing Headache disorder Nail disorders Nasolacrimal duct stenosis Nystagmus Palmar-plantar erythrodysesthesia Photophobia Skin fissure

The following precautions are available for ADRUCIL (fluorouracil):

Pediatric
Pregnant
Lactation
Geriatric

Safety and effectiveness of fluorouracil have not been established in pediatric patients.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Fluorouracil may cause fetal harm when administered to pregnant females. The medication has been shown to be embryotoxic and teratogenic in animals at dosages lower than a human dose of 12 mg/kg. Fetal malformations included cleft palate, skeletal defects, and deformed appendages, paws, and tails.

In monkeys, doses greater than an approximate human dose of 12 mg/kg resulted in abortion. There are no adequate and controlled studies using fluorouracil in pregnant females. If the medication is used during pregnancy or if the patient becomes pregnant while receiving fluorouracil, the patient should be informed of the potential hazard to the fetus.

It is not known whether fluorouracil or its metabolites are distributed into milk. Because many medications are distributed into human milk and because of the potential for serious adverse reactions to fluorouracil in nursing infants, a decision should be made whether to discontinue nursing or the medication, taking into account the importance of the medication to the nursing mother.

Reported clinical experience with fluorouracil has not identified any differences in safety or effectiveness between geriatric patients and younger adults.

The following icd codes are available for ADRUCIL (fluorouracil)'s list of indications:

Adenocarcinoma of pancreas
C24.1	Malignant neoplasm of ampulla of vater
C25	Malignant neoplasm of pancreas
C25.0	Malignant neoplasm of head of pancreas
C25.1	Malignant neoplasm of body of pancreas
C25.2	Malignant neoplasm of tail of pancreas
C25.3	Malignant neoplasm of pancreatic duct
C25.7	Malignant neoplasm of other parts of pancreas
C25.8	Malignant neoplasm of overlapping sites of pancreas
C25.9	Malignant neoplasm of pancreas, unspecified
Colorectal cancer
C18	Malignant neoplasm of colon
C18.0	Malignant neoplasm of cecum
C18.1	Malignant neoplasm of appendix
C18.2	Malignant neoplasm of ascending colon
C18.3	Malignant neoplasm of hepatic flexure
C18.4	Malignant neoplasm of transverse colon
C18.5	Malignant neoplasm of splenic flexure
C18.6	Malignant neoplasm of descending colon
C18.7	Malignant neoplasm of sigmoid colon
C18.8	Malignant neoplasm of overlapping sites of colon
C18.9	Malignant neoplasm of colon, unspecified
C19	Malignant neoplasm of rectosigmoid junction
C20	Malignant neoplasm of rectum
C21.8	Malignant neoplasm of overlapping sites of rectum, anus and anal canal
Gastric cancer
C16	Malignant neoplasm of stomach
C16.0	Malignant neoplasm of cardia
C16.1	Malignant neoplasm of fundus of stomach
C16.2	Malignant neoplasm of body of stomach
C16.3	Malignant neoplasm of pyloric antrum
C16.4	Malignant neoplasm of pylorus
C16.5	Malignant neoplasm of lesser curvature of stomach, unspecified
C16.6	Malignant neoplasm of greater curvature of stomach, unspecified
C16.8	Malignant neoplasm of overlapping sites of stomach
C16.9	Malignant neoplasm of stomach, unspecified
Metastatic breast carcinoma
C50	Malignant neoplasm of breast
C50.1	Malignant neoplasm of central portion of breast
C50.11	Malignant neoplasm of central portion of breast, female
C50.111	Malignant neoplasm of central portion of right female breast
C50.112	Malignant neoplasm of central portion of left female breast
C50.119	Malignant neoplasm of central portion of unspecified female breast
C50.12	Malignant neoplasm of central portion of breast, male
C50.121	Malignant neoplasm of central portion of right male breast
C50.122	Malignant neoplasm of central portion of left male breast
C50.129	Malignant neoplasm of central portion of unspecified male breast
C50.2	Malignant neoplasm of upper-inner quadrant of breast
C50.21	Malignant neoplasm of upper-inner quadrant of breast, female
C50.211	Malignant neoplasm of upper-inner quadrant of right female breast
C50.212	Malignant neoplasm of upper-inner quadrant of left female breast
C50.219	Malignant neoplasm of upper-inner quadrant of unspecified female breast
C50.22	Malignant neoplasm of upper-inner quadrant of breast, male
C50.221	Malignant neoplasm of upper-inner quadrant of right male breast
C50.222	Malignant neoplasm of upper-inner quadrant of left male breast
C50.229	Malignant neoplasm of upper-inner quadrant of unspecified male breast
C50.3	Malignant neoplasm of lower-inner quadrant of breast
C50.31	Malignant neoplasm of lower-inner quadrant of breast, female
C50.311	Malignant neoplasm of lower-inner quadrant of right female breast
C50.312	Malignant neoplasm of lower-inner quadrant of left female breast
C50.319	Malignant neoplasm of lower-inner quadrant of unspecified female breast
C50.32	Malignant neoplasm of lower-inner quadrant of breast, male
C50.321	Malignant neoplasm of lower-inner quadrant of right male breast
C50.322	Malignant neoplasm of lower-inner quadrant of left male breast
C50.329	Malignant neoplasm of lower-inner quadrant of unspecified male breast
C50.4	Malignant neoplasm of upper-outer quadrant of breast
C50.41	Malignant neoplasm of upper-outer quadrant of breast, female
C50.411	Malignant neoplasm of upper-outer quadrant of right female breast
C50.412	Malignant neoplasm of upper-outer quadrant of left female breast
C50.419	Malignant neoplasm of upper-outer quadrant of unspecified female breast
C50.42	Malignant neoplasm of upper-outer quadrant of breast, male
C50.421	Malignant neoplasm of upper-outer quadrant of right male breast
C50.422	Malignant neoplasm of upper-outer quadrant of left male breast
C50.429	Malignant neoplasm of upper-outer quadrant of unspecified male breast
C50.5	Malignant neoplasm of lower-outer quadrant of breast
C50.51	Malignant neoplasm of lower-outer quadrant of breast, female
C50.511	Malignant neoplasm of lower-outer quadrant of right female breast
C50.512	Malignant neoplasm of lower-outer quadrant of left female breast
C50.519	Malignant neoplasm of lower-outer quadrant of unspecified female breast
C50.52	Malignant neoplasm of lower-outer quadrant of breast, male
C50.521	Malignant neoplasm of lower-outer quadrant of right male breast
C50.522	Malignant neoplasm of lower-outer quadrant of left male breast
C50.529	Malignant neoplasm of lower-outer quadrant of unspecified male breast
C50.6	Malignant neoplasm of axillary tail of breast
C50.61	Malignant neoplasm of axillary tail of breast, female
C50.611	Malignant neoplasm of axillary tail of right female breast
C50.612	Malignant neoplasm of axillary tail of left female breast
C50.619	Malignant neoplasm of axillary tail of unspecified female breast
C50.62	Malignant neoplasm of axillary tail of breast, male
C50.621	Malignant neoplasm of axillary tail of right male breast
C50.622	Malignant neoplasm of axillary tail of left male breast
C50.629	Malignant neoplasm of axillary tail of unspecified male breast
C50.8	Malignant neoplasm of overlapping sites of breast
C50.81	Malignant neoplasm of overlapping sites of breast, female
C50.811	Malignant neoplasm of overlapping sites of right female breast
C50.812	Malignant neoplasm of overlapping sites of left female breast
C50.819	Malignant neoplasm of overlapping sites of unspecified female breast
C50.82	Malignant neoplasm of overlapping sites of breast, male
C50.821	Malignant neoplasm of overlapping sites of right male breast
C50.822	Malignant neoplasm of overlapping sites of left male breast
C50.829	Malignant neoplasm of overlapping sites of unspecified male breast
C50.9	Malignant neoplasm of breast of unspecified site
C50.91	Malignant neoplasm of breast of unspecified site, female
C50.911	Malignant neoplasm of unspecified site of right female breast
C50.912	Malignant neoplasm of unspecified site of left female breast
C50.919	Malignant neoplasm of unspecified site of unspecified female breast
C50.92	Malignant neoplasm of breast of unspecified site, male
C50.921	Malignant neoplasm of unspecified site of right male breast
C50.922	Malignant neoplasm of unspecified site of left male breast
C50.929	Malignant neoplasm of unspecified site of unspecified male breast
C50.A	Malignant inflammatory neoplasm of breast
C50.A0	Malignant inflammatory neoplasm of unspecified breast
C50.A1	Malignant inflammatory neoplasm of right breast
C50.A2	Malignant inflammatory neoplasm of left breast
Metastatic colorectal cancer
C18	Malignant neoplasm of colon
C18.0	Malignant neoplasm of cecum
C18.1	Malignant neoplasm of appendix
C18.2	Malignant neoplasm of ascending colon
C18.3	Malignant neoplasm of hepatic flexure
C18.4	Malignant neoplasm of transverse colon
C18.5	Malignant neoplasm of splenic flexure
C18.6	Malignant neoplasm of descending colon
C18.7	Malignant neoplasm of sigmoid colon
C18.8	Malignant neoplasm of overlapping sites of colon
C18.9	Malignant neoplasm of colon, unspecified
C19	Malignant neoplasm of rectosigmoid junction
C20	Malignant neoplasm of rectum
C21.8	Malignant neoplasm of overlapping sites of rectum, anus and anal canal