Capecitabine (capecitabine)
5 Fluoropyrimidines Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Capecitabine, a prodrug that has little pharmacologic activity until it is converted to fluorouracil (an antimetabolite) in tumor tissue, is an antineoplastic agent.
Capecitabine, a fluoropyrimidine carbamate, is an antineoplastic agent. Capecitabine is a prodrug of 5'-deoxy-5-fluorouridine (doxifuridine, 5'-DFUR) and has little pharmacologic activity until it is converted to fluorouracil, a fluorinated pyrimidine antagonist, in tumor tissue. Because capecitabine is converted to fluorouracil by enzymes that are expressed at higher concentrations in many tumors than in adjacent normal tissues or plasma, it is thought that high tumor concentrations of the active drug may be achieved with less systemic toxicity.
Fluorouracil is metabolized in both normal and tumor cells to 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). The main mechanism of fluorouracil is via the binding of the deoxyribonucleotide of the drug (FdUMP) and the folate cofactor (N5-10-methylenetetrahydrofolate) to thymidylate synthase (TS) to form a covalently bound ternary complex, which inhibits the formation of thymidylate from 2'-deoxyuridylate, thereby interfering with DNA synthesis. In addition, FUTP can be incorporated into RNA in place of uridine triphosphate (UTP), producing a fraudulent RNA and interfering with RNA processing and protein synthesis.
Capecitabine has been shown to be active in xenograft tumors that are resistant to fluorouracil indicating incomplete cross-resistance between the drugs.
Over a dosage range of 500-3500 mg/m2 daily, the pharmacokinetics of capecitabine and its metabolite, 5'-deoxy-5-fluorocytidine (5'-DFCR), were dose proportional and did not change over time. However, the manufacturer reports that increases in area under the concentration-time curves (AUCs) of metabolites 5'-DFUR and fluorouracil were greater than proportional to the increase in dose. Considerable interindividual variations (i.e., exceeding 85%) in peak plasma concentrations and AUCs have been reported following oral administration of capecitabine.
According to the manufacturer, peak plasma concentrations of capecitabine occur in about 1.5 hours, and peak plasma concentrations of fluorouracil, its active metabolite, occur at 2 hours.
Administration of capecitabine after a breakfast that is medium-rich in fat and carbohydrates resulted in decreases in the peak plasma concentration and AUC of capecitabine by 60 and 34%, respectively. The peak plasma concentration and AUC of fluorouracil were also decreased by 37 and 12%, respectively. The time to maximum concentration of both capecitabine and fluorouracil were delayed by 1.5 hours.
Plasma protein binding (mainly to albumin) of capecitabine and its metabolites is less than 60% and is not concentration dependent. Capecitabine is extensively metabolized in the liver and tumors. The plasma elimination half-life of capecitabine and fluorouracil is about 45 minutes.
In the liver, capecitabine is largely hydrolyzed to 5'-DFCR by carboxylesterase. 5'-DFCR subsequently is converted to another noncytotoxic intermediate, 5'-deoxy-5-fluorouridine (5'-DFUR), by cytidine deaminase. Hydrolysis of 5'-DFUR to the active drug fluorouracil is catalyzed by thymidine phosphorylase.
Once capecitabine is converted to the active drug fluorouracil, mainly in tumor tissue, fluorouracil is anabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), the active metabolites of the drug. Fluorouracil is catabolized to dihydrofluorouracil (FUH2), by dihydropyrimidine dehydrogenase. Dihydropyrimidinase cleaves the pyrimidine ring of FUH2, yielding 5-fluoro-ureido-propionic acid (FUPA), which is then cleaved by beta-ureido-propionase to form alpha-fluoro-beta-alanine (FBAL).
Capecitabine and its metabolites are excreted predominantly in urine (96%); fecal excretion is minimal (2.6%). Most of the capecitabine dose is excreted in urine as metabolites, principally FBAL, a catabolite of fluorouracil (57% of an administered dose); about 3% of an administered dose is excreted in urine as unchanged drug.
Following therapeutic doses of capecitabine, no clinically meaningful differences in the pharmacokinetics of 5'-DFUR, fluorouracil, or FBAL were observed based on sex and race; additionally, no clinically meaningful differences of 5'-DFUR and fluorouracil were observed based on age (range, 27--86 years). The exposure to FBAL increased by 15% following a 20% increase in age. Data from a study in Japanese and white patients receiving capecitabine 825 mg/m2 twice daily for 14 days showed differences in the pharmacokinetic disposition of capecitabine and its catabolite, FBAL.
Peak plasma concentration and the AUC of capecitabine were reduced by about 36 and 24%, respectively, and peak plasma concentration and AUC of FBAL were about 25 and 34% lower, respectively, in the Japanese patients than in the white patients. The clinical importance of these differences is not known. No clinically significant differences in the pharmacokinetics of 5'-DFCR, 5'-DFUR, or fluorouracil were observed.
USES: Capecitabine is used to treat certain types of cancer (such as breast, colon, rectal, stomach, esophageal, pancreatic cancer). It works by slowing or stopping the growth of cancer cells.
Generic name: capecitabine
Pronunciation: (KAP-e-SYE-ta-been)
Drug class: 5 Fluoropyrimidines
Therapeutic class: Antineoplastics
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Capecitabine
Indications
The following indications are listed for Capecitabine:
- Adenocarcinoma Of Pancreas
- Gastric Cancer
- Her2-Positive Adenocarcinoma Of Gastroesophageal Junction
- Lymph Node Positive Colorectal Carcinoma
- Malignant Esophageal Neoplasm
- Metastatic Breast Carcinoma
- Metastatic Colorectal Cancer
- Metastatic Her2-Positive Carcinoma Of Breast
Also known as: Advanced Breast Carcinoma, Esophageal Cancer, Esophagus Cancer, Gastric Malignancy, Her-2 Overexpressing Adenocarcinoma Of Gastroesophageal Junction, Her-2 Overexpressing Gastroesophageal Junction Adenocarcinoma, Her2-Positive Gastroesophageal Junction Adenocarcinoma, Malignancy Of Esophagus, Malignant Neoplasm Of Esophagus, Malignant Neoplasm Of Stomach, Malignant Tumor Of Esophagus, Malignant Tumor Of Stomach, Metastatic Breast Cancer, Metastatic Malignancy Of Breast, Metastatic Malignant Neoplasm Of Breast, Metastatic Malignant Tumor Of Breast, Pancreatic Adenocarcinoma, Stage Iii Colon Cancer.
Dosing
Monitor patients for adverse reactions during treatment with capecitabine and modify dosages as indicated in Table 1 below. When capecitabine is administered in combination with docetaxel, withhold both capecitabine and docetaxel until the requirements for resuming both agents are met. Refer to the prescribing information for docetaxel for additional dosing information.
Table 1. Recommended Capecitabine Dosage Modifications for Adverse Reactions
Severity Dosage Modification Resume at Same or Reduce Dose (Percent of Current Dose) Grade 2 toxicity First appearance Withhold therapy until 100% resolved to grade 0 or 1 Second appearance Withhold therapy until 75% resolved to grade 0 or 1 Third appearance Withhold therapy until 50% resolved to grade 0 or 1 Fourth appearance Permanently discontinue capecitabine Grade 3 toxicity First appearance Withhold therapy until 75% resolved to grade 0 or 1 Second appearance Withhold therapy until 50% resolved to grade 0 or 1 Third appearance Permanently discontinue capecitabine Grade 4 toxicity First appearance Permanently discontinue 50% capecitabine OR withhold until resolved to grade 0 or 1
If patients develop grade 3 or 4 hyperbilirubinemia during treatment with capecitabine, withhold treatment and resume once the event is grade 2 or less (i.e., bilirubin level below 3 times the upper limit of normal); use the percent of current dose column of Table 1 to determine the appropriate dose of capecitabine to resume therapy.
Capecitabine is administered orally. Capecitabine tablets should be swallowed whole with water within 30 minutes after the end of a meal. The recommended dose should be rounded to the nearest 150-mg dose so that whole tablets are administered. Capecitabine tablets should not be chewed, cut, or crushed. If a dose is missed or vomited, skip the missed/vomited dose and continue with the next scheduled dose.
Capecitabine tablets should be stored in tightly closed containers at 20-25degreesC; excursions are permitted to 15-30degreesC.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Capecitabine 150 Mg Tablet | Maintenance | Take 1,250 mg/m2 by oral route 2 times per day every 2 weeks of a 3 week cycle. |
| Capecitabine 500 Mg Tablet | Maintenance | Take 1,250 mg/m2 by oral route 2 times per day every 2 weeks of a 3 week cycle. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Capecitabine 150 Mg Tablet | Maintenance | Take 1,250 mg/m2 by oral route 2 times per day every 2 weeks of a 3 week cycle. |
| Capecitabine 500 Mg Tablet | Maintenance | Take 1,250 mg/m2 by oral route 2 times per day every 2 weeks of a 3 week cycle. |
Drug interactions
Capecitabine is not metabolized by cytochrome P-450 (CYP) isoenzymes. In vitro studies indicate that capecitabine and its metabolites do not inhibit CYP isoenzymes 1A2, CYP2A6, CYP3A4, CYP2C19, CYP2D6, or CYP2E1.
Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
Fluorouracil & Fluorouracil Prodrugs/Allopurinol
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: 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)
Fluorouracil & Fluorouracil Prodrugs/Brivudine
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: Brivudine is an irreversible inhibitor of dihydropyrimidine dehydrogenase, which catalyzes the rate-limiting step in the catabolism of fluorouracil.(1-5) Brivudine may decrease the clearance and increase the toxicity of fluorouracil.
CLINICAL EFFECTS: Concurrent use of brivudine with fluorouracil or fluorouracil prodrugs (e.g., capecitabine, tegafur) may result in elevated levels of fluorouracil and serious toxicity, including melenic diarrhea, mucositis, hand-foot syndrome, pancytopenia, and death.(1-5)
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: The use of fluorouracil or fluorouracil prodrugs is contraindicated during and for 4 weeks after therapy with brivudine. Treatment with brivudine can be started 24 hours after the last dose of fluorouracil or fluorouracil prodrug. If brivudine is coadministered with fluorouracil or fluorouracil prodrugs, immediate hospitalization is recommended and effective measures should be taken to reduce the toxicity of capecitabine, including prevention of systemic infections and dehydration.(1)
DISCUSSION: Brivudine inhibition of dihydropyrimidine dehydrogenase has been reported to cause a 5- to 15-fold increase in 5-fluorouracil (5-FU) concentrations.(2) In June 2012, the Spanish Agency of Medicines and Health Products (AEMPS) reported that 29 cases of concomitant use of a fluoropyrimidine and brivudine had occurred in Europe, with 23 of the cases resulting in death.(6) In September 2017, the AEMPS issued an update that an additional 7 fatalities had occurred since 2012 as a result of this drug combination.(7) In a case report, an 80-year-old woman with metastatic colon cancer on capecitabine was given brivudine for herpes zoster. She took two doses of brivudine prior to stopping therapy due to rash and mucositis. Nevertheless, two weeks later, she was hospitalized with skin lesions that progressed to Stevens-Johnson Syndrome, leukopenia, and thrombocytopenia. She developed septic shock and ultimately died.(2) Another two case reports describe similar patients with metastatic colon cancer who received combinations of brivudine with 5-FU. One patient had overlapping therapy for one day, and the other received 5-FU four days after stopping brivudine. Both developed mucositis, pancytopenia, and respiratory failure and died.(3,4) A 66-year-old woman with metastatic breast cancer took brivudine on the last 4 days of a chemotherapy cycle that included capecitabine. She was hospitalized for over 3 weeks with hand-foot syndrome, severe mucositis requiring parenteral nutrition, pancytopenia requiring filgrastim, platelet transfusion, and blood transfusion, and sepsis. She recovered from symptoms of hand-food syndrome and mucositis after about 6 weeks.(5)
Immunosuppressive; Immunomod/Cladribine Onc Inj (10 MG/5 ML)
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The UK and AU manufacturers of Litak state that concomitant use of other myelosuppressive medicinal products with cladribine is contraindicated.(1-2) The Israeli manufacturer of Litak states that cladribine should not be used concomitantly with other myelosuppressive medicinal products.(3)
DISCUSSION: The risk of severe myelotoxicity and long-lasting immunosuppression is increased in patients with a disease-related bone marrow infiltration or a previous myelosuppressive treatment.(1-3)
Immunosuppressives; Immunomodulators/Efalizumab; Natalizumab
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Natalizumab,(1-3) efalizumab,(4) immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of natalizumab(1-3) or efalizumab(4) with immunosuppressives or immunomodulators may result in an increased risk of infections, including progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).
PREDISPOSING FACTORS: Previous JCV infection, longer duration of natalizumab treatment - especially if greater than 2 years, and prior or concomitant treatment with immunosuppressant medication are all independent risk factors which increase the risk for PML.(1,5) The FDA has estimated PML incidence stratified by risk factors: If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment less than 25 months, incidence <1/1,000. If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment less than 25 months, incidence 2/1,000 If anti-JCV antibody positive, no prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 4/1,000 If anti-JCV antibody positive, history of prior immunosuppressant use and natalizumab treatment 25-48 months, incidence 11/1,000.
PATIENT MANAGEMENT: The US manufacturer of natalizumab states patients with Crohn's disease should not receive concurrent immunosuppressants, with the exception of limited overlap of corticosteroids, due to the increased risk for PML. For new natalizumab patients currently receiving chronic oral corticosteroids for Crohn's Disease, begin corticosteroid taper when therapeutic response to natalizumab has occurred. If corticosteroids cannot be discontinued within six months of starting natalizumab, discontinue natalizumab.(3) The US manufacturer of natalizumab states that natalizumab should not ordinarily be used in multiple sclerosis patients receiving immunosuppressants or immunomodulators due to the increased risk for PML. Immunosuppressives include, but are not limited to azathioprine, cyclophosphamide, cyclosporine, mercaptopurine, methotrexate, mitoxantrone, mycophenolate, and corticosteroids.(3,6) The UK manufacturer of natalizumab states that concurrent use with immunosuppressives or antineoplastic agents is contraindicated.(1) The Canadian manufacturer of natalizumab states that natalizumab should not be used with immunosuppressive or immunomodulatory agents.(2) The US manufacturer of certolizumab states that concurrent therapy with natalizumab is not recommended.(7)
DISCUSSION: Progressive multifocal leukoencephalopathy has been reported in patients receiving concurrent natalizumab were recently or concomitantly taking immunomodulators or immunosuppressants.(1-5,8,9) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(10)
Selected Immunosuppressants/Nadofaragene Firadenovec
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Nadofaragene firadenovec may contain low levels of replication-competent adenovirus.(1)
CLINICAL EFFECTS: Concurrent use of nadofaragene firadenovec in patients receiving immunosuppressive therapy may cause disseminated adenovirus infection.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Individuals who are immunosuppressed or immune-deficient should not receive nadofaragene firadenovec.(1)
DISCUSSION: Nadofaragene firadenovec is a non-replicating adenoviral vector-based gene therapy but may contain low levels of replication-competent adenovirus. Immunocompromised persons, including those receiving immunosuppressant therapy, may be at risk for disseminated adenovirus infection.(1)
Selected Immunosuppressants/Talimogene Laherparepvec
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: Talimogene laherparepvec is a live, attenuated herpes simplex virus.(1)
CLINICAL EFFECTS: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Talimogene laherparepvec is contraindicated in immunosuppressed patients.(1) The magnitude of immunocompromise and associated risks due to immunosuppressant drugs should be determined by a physician.
DISCUSSION: Concurrent use of talimogene laherparepvec in patients receiving immunosuppressive therapy may cause a life-threatening disseminated herpetic infection.(1)
Selected Immunosuppressive Agents/Live Vaccines; Live Bcg
SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.
MECHANISM OF ACTION: A variety of disease modifying agents suppress the immune system. Immunocompromised patients may be at increased risk for uninhibited replication after administration of live, attenuated vaccines or intravesicular BCG. Immune response to vaccines may be decreased during periods of immunocompromise.(1)
CLINICAL EFFECTS: The expected serum antibody response may not be obtained and/or the vaccine may result in illness.(1) After instillation of intravesicular BCG, immunosuppression may interfere with local immune response, or increase the severity of mycobacterial infection following inadvertent systemic exposure.(2)
PREDISPOSING FACTORS: Immunosuppressive diseases (e.g. hematologic malignancies, HIV disease), treatments (e.g. radiation) and drugs may all increase the magnitude of immunodeficiency.
PATIENT MANAGEMENT: The Centers for Disease Control(CDC) Advisory Committee on Immunization Practices (ACIP) states that live-virus and live, attenuated vaccines should not be administered to patients who are immunocompromised. The magnitude of immunocompromise and associated risks should be determined by a physician.(1) For patients scheduled to receive chemotherapy, vaccination should ideally precede the initiation of chemotherapy by 14 days. Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy.(1) Patients who receive anti-B cell therapies should not receive live vaccines for at least 6 months after such therapies due to a prolonged duration of immunosuppression. An exception is the Zoster vaccine, which can be given at least 1 month after receipt of anti-B cell therapies.(1) The US manufacturer of abatacept states live vaccines should not be given during or for up to 3 months after discontinuation of abatacept.(2) The US manufacturer of live BCG for intravesicular treatment of bladder cancer states use is contraindicated in immunosuppressed patients.(3) The US manufacturer of daclizumab states live vaccines are not recommended during and for up to 4 months after discontinuation of treatment.(4) The US manufacturer of guselkumab states that live vaccines should be avoided during treatment with guselkumab.(5) The US manufacturer of inebilizumab-cdon states that live vaccines are not recommended during treatment and after discontinuation until B-cell repletion. Administer all live vaccinations at least 4 weeks prior to initiation of inebilizumab-cdon.(6) The US manufacturer of ocrelizumab states that live vaccines are not recommended during treatment and until B-cell repletion occurs after discontinuation of therapy. Administer all live vaccines at least 4 weeks prior to initiation of ocrelizumab.(7) The US manufacturer of ozanimod states that live vaccines should be avoided during and for up to 3 months after discontinuation of ozanimod.(8) The US manufacturer of siponimod states that live vaccines are not recommended during treatment and for up to 4 weeks after discontinuation of treatment.(9) The US manufacturer of ustekinumab states BCG vaccines should not be given in the year prior to, during, or the year after ustekinumab therapy.(10) The US manufacturer of satralizumab-mwge states that live vaccines are not recommended during treatment and should be administered at least four weeks prior to initiation of satralizumab-mwge.(11) The US manufacturer of ublituximab-xiiy states that live vaccines are not recommended during treatment and until B-cell recovery. Live vaccines should be administered at least 4 weeks prior to initiation of ublituximab-xiiy.(12) The US manufacturer of etrasimod states that live vaccines should be avoided during and for 5 weeks after treatment. Live vaccines should be administered at least 4 weeks prior to initiation of etrasimod.(13) The US manufacturer of emapalumab-lzsg states that live vaccines should not be administered to patients receiving emapalumab-lzsg and for at least 4 weeks after the last dose of emapalumab-lzsg. The safety of immunization with live vaccines during or following emapalumab-lzsg therapy has not been studied.(14) The US manufacturer of sibeprenlimab-szsi states live vaccines should not be given within 30 days prior to initiation or during treatment with sibeprenlimab-szsi.(15)
DISCUSSION: Killed or inactivated vaccines do not pose a danger to immunocompromised patients.(1) Patients with a history of leukemia who are in remission and have not received chemotherapy for at least 3 months are not considered to be immunocompromised.(1)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
Capecitabine/Proton Pump Inhibitors
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: The aqueous solubility of capecitabine is pH dependent. Higher gastric pH leads to lower solubility and altered tablet dissolution which may reduce capecitabine absorption.(1,2)
CLINICAL EFFECTS: Coadministration of proton pump inhibitors (PPIs) may reduce the bioavailability of capecitabine, leading to decreased systemic levels and effectiveness.(1,2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Coadministration of proton pump inhibitors with capecitabine may decrease bioavailability. When clinically appropriate, consider using H2 blockers or antacids.
DISCUSSION: A retrospective study in early stage colorectal cancer patients treated with adjuvant monotherapy capecitabine examined recurrence-free survival (RFS) and overall survival (OS) in 1335 patients with and without concurrent proton pump inhibitor (PPI) therapy. The PPI group was defined as a prescription for a PPI filled at any point in time during capecitabine treatment. Patients in the capecitabine with concurrent PPI group had a statistically significant decrease in 5-year RFS (74% v 83%; hazard ratio (HR) 1.89; 95% confidence interval (CI) 1.07-3.35; p=0.03) compared to capecitabine without PPI therapy. OS was not significantly different between groups (81% PPI v 78% non-PPI; HR 1.13; 95% CI 0.6-2.14; p=0.7). After adjusting for male gender, stage III colorectal cancer, advance age >68, poorer ECOG PS, there was a trend toward decreased RFS in PPI patients (HR 1.65; 95% CI 0.93-2.94; p=0.09).(1) An ad hoc analysis of the TRIO-013/LOCiC trial examined coadministration of PPI therapy, defined as 20% or more overlap between a PPI prescription and trial treatment duration with capecitabine and/or lapatinib, on progression-free survival (PFS) and overall survival (OS). The secondary analysis examined 545 patients in which 42% were on concurrent PPI therapy. Patients in the non-PPI group had an improved median PFS (5.7 v 4.2 months; HR 1.55; 95% CI 1.29-1.81; p<0.001) and median OS (11.3 v 9.2 months; HR 1.34; 95% CI 1.06-1.62; p=0.04) compared with PPI users. A multivariate analysis reviewed effects of PPIs on both PFS and OS with capecitabine alone and found effects of PPI use on both PFS and OS was still significant (HR 1.68; p<0.001 and HR 1.41; p=0.001, respectively).(2) In a study in 12 subjects, concomitant administration of capecitabine with aluminum-magnesium hydroxide containing antacid 20 mL increased area-under-curve (AUC) and concentration maximum (Cmax) by 16% and 35%, respectively.(3) Proton pump inhibitors linked to this monograph include: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole.
Fluorouracil & Fluorouracil Prodrug/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)
Fluorouracil & Fluorouracil Prodrugs/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) and fluorouracil prodrugs.(1-3) Fluorouracil prodrugs include capecitabine and tegafur.
CLINICAL EFFECTS: Folic acid, when used concurrently with 5-FU or fluorouracil prodrugs, has been shown to increase side effects of 5-FU.(1-3)
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 or folate analog-containing products should not be used concurrently with fluorouracil or fluorouracil prodrugs unless directed by the healthcare provider.(1-3) Fluorouracil prodrugs include capecitabine and tegafur.
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.(2) In a cohort study in 290 patients, the use of dietary supplements with folic acid during treatment compared to nonuse increased the risk of capecitabine toxicities (HR 1.81, 95%CI: 1.15,2.85). The detection of folic acid in plasma also increased the risk of capecitabine toxicities (HR 2.09, 95%CI: 1.24,3.52 and HR 2.31, 95%CI: 1.29,4.13 at diagnosis and during treatment, respectively).(4) In a cohort study of 9 patients, patients taking folate-containing supplements and higher serum folate levels had an increased risk of grade >=2 toxicity. The risk of grade >=2 toxicity increased by 9% for every increase in serum folate level by 10 nmol/L. Patients with grade >=2 toxicity had higher serum folate levels than patients with grade <= 1 toxicity (28 nmol/L [range, 13.2-45.4] vs. 20 nmol/L [range, 12.8-45.4]; p=0.001).(5) In two case reports, patients developed capecitabine toxicity while taking supplements containing folic acid 400-500 mcg.(6) 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.(7) There are two other reports of excessive fluorouracil toxicity in patients treated with folic acid.(8)
Fluorouracil & Fluorouracil Prodrugs/Hydantoins
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.
Fluorouracil & Prodrugs/Slt Anticoagulants (VIT K ANTAG)
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)
Immunosuppres;Immunomodul/Selected Multiple Sclerosis Agents
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ocrelizumab or ofatumumab in combination with immunosuppressives and immune-modulators all suppress the immune system.(1,2)
CLINICAL EFFECTS: Concurrent use of ocrelizumab or ofatumumab with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1,2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ocrelizumab US prescribing information states: - Ocrelizumab and other immune-modulating or immunosuppressive therapies, (including immunosuppressant doses of corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating ocrelizumab.(1) The ofatumumab US prescribing information states: - Ofatumumab and other immunosuppressive therapies (including systemic corticosteroids) may have the potential for increased immunosuppressive effects and increase the risk of infection. When switching between therapies, the duration and mechanism of action of each therapy should be considered due to the potential for additive immunosuppressive effects. Ofatumumab for MS therapy has not been studied in combination with other MS agents that suppress the immune system.(2)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1,2) In a retrospective cohort study of multiple sclerosis patients newly initiated on a disease-modifying therapy, use of high-efficacy agents (alemtuzumab, natalizumab, or ocrelizumab) resulted in the same risk of overall infections as moderate-efficacy agents, but there was an elevated risk of serious infections (adjusted hazard ratio [aHR] = 1.24, 95% confidence interval (CI) = 1.06-1.44) and UTIs (aHR = 1.21, 95% CI = 1.14-1.30).(3)
Immunosuppressives; Immunomodulators/Baricitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of baricitinib with other biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine or cyclosporine may result in additive or synergistic effects on the immune system.
CLINICAL EFFECTS: Concurrent use of baricitinib with other biologic DMARDs or potent immunosuppressants such as azathioprine or cyclosporine may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of baricitinib states that concurrent use of baricitinib with biologic DMARDs or potent immunosuppressants is not recommended.(1)
DISCUSSION: Most patients who developed serious infections while being treated with baricitinib were on concomitant immunosuppressants like methotrexate and corticosteroids. The combination of baricitinib with other biologic DMARDs has not been studied.(1)
Immunosuppressives; Immunomodulators/Cladribine Oral
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-2)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-2)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US prescribing information states: -Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of cladribine.(1) The cladribine Canadian prescribing information states: -Use of cladribine in immunocompromised patients is contraindicated because of a risk of additive effects on the immune system. Acute short-term therapy with corticosteroids can be administered during cladribine treatment.(2)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-2)
Immunosuppressives; Immunomodulators/Deuruxolitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Deuruxolitinib, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of deuruxolitinib and potent immunosuppressants may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of deuruxolitinib states that concurrent use of deuruxolitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1) If concurrent use cannot be avoided, patients should be monitored for signs and symptoms of infection. If a patient develops a serious or opportunistic infection, interrupt deuruxolitinib treatment until the infection is controlled.
DISCUSSION: Serious infections have been reported in patients receiving treatment with deuruxolitinib.(1)
Immunosuppressives; Immunomodulators/Etrasimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Etrasimod causes reversible sequestration of lymphocytes in lymphoid tissues, resulting in a mean 55% decrease in peripheral blood lymphocyte count at 52 weeks.(1) Other immunosuppressives and immune-modulators also suppress the immune system.
CLINICAL EFFECTS: Concurrent use of etrasimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious and fatal infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications increases the risk of adverse effects.
PATIENT MANAGEMENT: The etrasimod US prescribing information states etrasimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Concomitant administration of these therapies with etrasimod should be avoided because of the risk of additive immune effects during therapy and in the weeks following administration. Etrasimod's effect on peripheral lymphocytes may persist for up to 5 weeks after discontinuation.(1) When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients treated with other sphingosine-1 phosphate receptor modulators.(1)
Immunosuppressives; Immunomodulators/Filgotinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic disease-modifying antirheumatic drugs (DMARDs), or other Janus kinase (JAK) inhibitors may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The UK manufacturer of filgotinib states that concurrent use of filgotinib with other immunosuppressants or immunomodulators including azathioprine, cyclosporine, tacrolimus, biologic DMARDs, or other JAK inhibitors is not recommended.(1)
DISCUSSION: Serious infections have been reported in patients receiving filgotinib. Caution should be used in patients with a higher incidence of serious infection, including elderly patients aged 75 years and older.(1)
Immunosuppressives; Immunomodulators/Fingolimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Fingolimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-3)
CLINICAL EFFECTS: Concurrent use of fingolimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1-3)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for fingolimod regarding this interaction differ between regulatory approving agencies. The fingolimod US prescribing information states: - Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.(1) The fingolimod Canadian prescribing information states: - Concurrent use with immunosuppressive or immunomodulatory agents is contraindicated due to the risk of additive immune system effects. However, co-administration of a short course of corticosteroids (up to 5 days) did not increase the overall rate of infection in patients participating Phase III clinical trials.(2) The fingolimod UK specific product characteristics states: - Fingolimod is contraindicated in patients currently receiving immunosuppressive therapies or those immunocompromised by prior therapies. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing the risk of disease activation.(3)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1-3)
Immunosuppressives; Immunomodulators/Inebilizumab
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Inebilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of inebilizumab with immunosuppressive or immunomodulating agents may result in myelosuppression including neutropenia resulting in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of inebilizumab states that the concurrent use of inebilizumab with immunosuppressive agents, including systemic corticosteroids, may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Inebilizumab has not been studied in combination with other immunosuppressants. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents. The most common infections reported by inebilizumab treated patients in the randomized and open-label clinical trial periods included urinary tract infections (20%), nasopharyngitis (13%), upper respiratory tract infections (8%), and influenza (7%). Although there been no cases of Hepatitis B virus reactivation or progressive multifocal leukoencephalopathy reported in patients taking inebilizumab, these infections have been observed in patients taking other B-cell-depleting antibodies.(1)
Immunosuppressives; Immunomodulators/Ozanimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ozanimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ozanimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ozanimod US prescribing information state this information regarding this interaction: -Ozanimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ozanimod after alemtuzumab is not recommended. However, ozanimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Ponesimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ponesimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ponesimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection, cryptococcal infection, or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The ponesimod US prescribing information states ponesimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with ponesimod after alemtuzumab is not recommended. However, ponesimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections, cryptococcal meningitis, disseminated cryptococcal infections, and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Ritlecitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ritlecitinib, immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of ritlecitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of ritlecitinib states that concurrent use of ritlecitinib with other JAK inhibitors, biologic immunomodulators, cyclosporine or other potent immunosuppressants is not recommended.(1)
DISCUSSION: Serious infections have been reported in patients receiving ritlecitinib. Reported infections included appendicitis, COVID-19 infection (including pneumonia), and sepsis. Reports of viral reactivation, including herpes virus reactivation was reported in clinical studies with ritlecitinib.(1)
Immunosuppressives; Immunomodulators/Siponimod
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Siponimod in combination with immunosuppressives and immune-modulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of siponimod with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections, such as disseminated herpetic infection or progressive multifocal leukoencephalopathy (PML), an opportunistic infection caused by the JC virus (JCV).(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The siponimod US prescribing information state this information regarding this interaction: -Siponimod has not been studied in combination with anti-neoplastic, immune-modulating, or immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune effects during therapy and in the week following administration. When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered in order to avoid unintended additive immunosuppressive effects. Initiating treatment with siponimod after alemtuzumab is not recommended. However, siponimod can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.(1)
DISCUSSION: Fatal disseminated herpes zoster and herpes simplex infections and cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients who previously received immunomodulators or immunosuppressants.(1)
Immunosuppressives; Immunomodulators/Tofacitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of tofacitinib and azathioprine, other biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressants may result in additive or synergistic effects on the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants use may increase the risk of serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Tofacitinib should not be used concurrently with azathioprine, other biologic DMARDs, or cyclosporine.(1) Patient should be monitored for decreases in lymphocytes and neutrophils. Therapy should be adjusted based on the indication. - For all indications: If absolute neutrophil count (ANC) or lymphocyte count is less than 500 cells/mm3, discontinue tofacitinib. - For rheumatoid arthritis or psoriatic arthritis and absolute neutrophil count (ANC) 500 to 1000 cells/mm3: interrupt dosing. When ANC is greater than 1000 cells/mm3, resume Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily. - For ulcerative colitis and ANC 500 to 1000 cells/mm3: -If taking Xeljanz 10 mg twice daily, decrease to 5 mg twice daily. When ANC is greater than 1000 cells/mm3, increase to 10 mg twice daily based on clinical response. -If taking Xeljanz 5 mg twice daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 5 mg twice daily. -If taking Xeljanz XR 22 mg once daily, decrease to 11 mg once daily. When ANC is greater than 1000 cells/mm3, increase to 22 mg once daily based on clinical response. -If taking Xeljanz XR 11 mg once daily, interrupt dosing. When ANC is greater than 1000 cells/mm3, resume 11 mg once daily. - For polyarticular course juvenile idiopathic arthritis (pcJIA) and ANC 500 to 1000 cells/mm3: interrupt dosing until ANC is greater than 1000 cells/mm3.(1)
DISCUSSION: Concurrent use of tofacitinib and azathioprine, other biologic DMARDs, or potent immunosuppressants may increase the risk of infection.(1) Serious infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. Some patients presented with disseminated disease and were often taking concomitant immunomodulating agents. In the ulcerative colitis population, a greater risk of serious infections was seen with a higher tofacitinib dose. In 7 placebo-controlled rheumatoid arthritis trials (0-3 months exposure), the overall frequency of infections was 20% in the tofacitinib 5 mg twice daily group and 22% in the tofacitinib 10 mg twice daily group compared to 18% in the placebo group. Serious infections were reported in 11 patients (1.7 events per 100 patient-years) with a rate difference between treatment groups of 1.1 (-0.4, 2.5) events per 100 patient-years for both tofacitinib 5 mg twice daily and 10 mg twice daily. During 0-12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient years) in the tofacitinib 5 mg twice daily group and 33 patients (2.7 events per 100 patient years) in the tofacitinib 10 mg twice daily group.(1)
Immunosuppressives; Immunomodulators/Upadacitinib
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Upadacitinib, immunosuppressives, and immunomodulators all suppress the immune system.
CLINICAL EFFECTS: Concurrent use of upadacitinib with immunosuppressives or immunomodulators may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of upadacitinib states that concurrent use of upadacitinib with immunosuppressives or immunomodulators is not recommended.
DISCUSSION: Serious infections have been reported in patients receiving upadacitinib. Reported infections included pneumonia, cellulitis, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, cryptococcosis. Reports of viral reactivation, including herpes virus reactivation and hepatitis B reactivation, were reported in clinical studies with upadacitinib.(1)
Myelosuppressives; Immunomodulators/Sodium Iodide I 131
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)
DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)
Selected Immunosuppressants/Leflunomide; Teriflunomide
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of leflunomide or teriflunomide and potent immunosuppressants may result in additive or synergistic effects on the immune system.(1,2) Leflunomide is a prodrug and is converted to its active metabolite teriflunomide.(1)
CLINICAL EFFECTS: Concurrent use of leflunomide or teriflunomide with immunosuppressants may result in an increased risk of serious infections, including opportunistic infections, especially Pneumocystis jiroveci pneumonia, tuberculosis (including extra-pulmonary tuberculosis), and aspergillosis.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: If leflunomide or teriflunomide is used concurrently with immunosuppressive agents, chronic CBC monitoring should be performed more frequently, every month instead of every 6 to 8 weeks. If bone marrow suppression or a serious infection occurs, leflunomide or teriflunomide should be stopped and rapid drug elimination procedure should be performed.(1,2)
DISCUSSION: Pancytopenia, agranulocytosis and thrombocytopenia have been reported in patients receiving leflunomide or teriflunomide alone, but most frequently in patients taking concurrent immunosuppressants.(1,2) Severe and potentially fatal infections, including sepsis, have been reported in patients receiving leflunomide or teriflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Tuberculosis has also been reported.(1,2)
Selected Myelosuppressive Agents/Clozapine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Clozapine and other myelosuppressive agents may be associated with neutropenia or agranulocytosis.(2)
CLINICAL EFFECTS: Moderate neutropenia, even if due to combination therapy, may require abrupt discontinuation of clozapine resulting in decompensation of the patient's psychiatric disorder (e.g. schizophrenia). The disease treated by the myelosuppressive agent may be compromised if myelosuppression requires dose reduction, delay, or discontinuation of the myelosuppressive agent. Undetected severe neutropenia or agranulocytosis may be fatal.
PREDISPOSING FACTORS: Low white blood counts prior to initiation of the myelosuppressive agent may increase risk for clinically significant neutropenia.
PATIENT MANAGEMENT: If a patient stabilized on clozapine therapy requires treatment with a myelosuppressive agent, the clozapine prescriber should consult with prescriber of the myelosuppressive agent (e.g. oncologist) to discuss treatment and monitoring options.(2) More frequent absolute neutrophil count (ANC) monitoring or treatment alternatives secondary to neutropenic episodes may need to be considered. The U.S. Food and Drug Administration (FDA) recommends that prescribers monitor patients' ANC according to the monitoring frequencies described in the prescribing information. Severe neutropenia remains a serious, potentially fatal risk that is greatest in the first several months of clozapine treatment. ANC monitoring can help identify neutropenia early to allow for timely intervention.(1-2) Australia, Canada, and U.K.: Clozapine is only available through a restricted distribution system which requires documentation of the ANC prior to dispensing. For most clozapine patients, clozapine treatment must be interrupted for a suspected clozapine-induced ANC < 1000 cells/microliter. For patients with benign ethnic neutropenia (BEN), treatment must be interrupted for suspected clozapine-induced neutropenia < 500 cells/microliter.(2)
DISCUSSION: Concurrent use of clozapine and selected myelosuppressive agents may require more frequent ANC monitoring or consideration of treatment alternatives secondary to neutropenic episodes. Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(3-26)
Selected Myelosuppressive Agents/Deferiprone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of deferiprone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1)
CLINICAL EFFECTS: Concurrent use of deferiprone and myelosuppressive agents may result in severe neutropenia or agranulocytosis, which may be fatal.
PREDISPOSING FACTORS: Agranulocytosis may be less common in patients receiving deferiprone for thalassemia, and more common in patients treated for other systemic iron overload conditions (e.g. myelodysplastic syndromes, sickle cell disease).(2,3) Inadequate monitoring appears to increase the risk for severe outcomes. Manufacturer post market surveillance found that in all fatal cases of agranulocytosis reported between 1999 and 2005, data on weekly white blood count (WBC) monitoring was missing. In three fatal cases, deferiprone was continued for two to seven days after the detection of neutropenia or agranulocytosis.(2)
PATIENT MANAGEMENT: If possible, discontinue one of the drugs associated with risk for neutropenia or agranulocytosis. If alternative therapy is not available, documentation and adherence to the deferiprone monitoring protocol is essential. Baseline absolute neutrophil count (ANC) must be at least 1,500/uL prior to starting deferiprone. Monitor ANC weekly during therapy. If infection develops, interrupt deferiprone therapy and monitor ANC more frequently. If ANC is less than 1,500/uL but greater than 500/uL, discontinue deferiprone and any other drugs possibly associated with neutropenia. Initiate ANC and platelet counts daily until recovery (i.e. ANC at least 1,500/uL). If ANC is less than 500/uL, discontinue deferiprone, evaluate patient and hospitalize if appropriate. Do not resume deferiprone unless potential benefits outweigh potential risks.(1)
DISCUSSION: Drugs linked to this monograph have an FDA Boxed Warning for risk of neutropenia, agranulocytosis, or pancytopenia, or have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(1-25) In pooled clinical studies submitted to the FDA, 6.1% of deferiprone patients met criteria for neutropenia and 1.7% of patients developed agranulocytosis.(1) The time to onset of agranulocytosis was highly variable with a range of 65 days to 9.2 years (median, 161 days).(3)
Selected Myelosuppressive Agents/Dipyrone
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Concurrent use of dipyrone with other drugs known to be associated with neutropenia or agranulocytosis may increase the frequency or risk for severe toxicity.(1-29)
CLINICAL EFFECTS: Concurrent use of dipyrone with agents that cause bone marrow depression, including myelosuppressives, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding. Undetected severe neutropenia or agranulocytosis may be fatal.(1-29)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Concurrent use of dipyrone and myelosuppressive agents should be avoided. The European Medicines Agency states dipyrone is contraindicated in patients with a prior medical history of dipyrone-induced agranulocytosis (or from other pyrazolones/pyrazolidines), impaired bone marrow function or diseases of the hematopoietic system.(3) International labeling for dipyrone and methotrexate state that co-administration may increase the hematotoxicity of methotrexate, especially in elderly patients, and therefore should be avoided.(1-2) The European Medicines Agency advises if agranulocytosis is suspected with dipyrone, a complete blood count (including differential blood count) should be performed immediately, and treatment must be stopped while waiting for the results. If confirmed, treatment must not be reintroduced.(1-3)
DISCUSSION: A retrospective cohort study analyzed new users of dipyrone (n=444,972), non-steroidal anti-inflammatory drugs (n=3,814,367) which served as a reference cohort, and opioids-paracetamol (n=3,129,221) which was the negative control. During continuous treatment over a median of 37-40 days, 26 cases of hospitalized agranulocytosis occurred. With the assumption that agranulocytosis onset was 7 days prior to admission, the hazard ratio of agranulocytosis associated with dipyrone was 4.40 [0.90-21.57] compared to NSAIDs and 2.45 [0.68-8.83] compared to opioid-paracetamol. HR of neutropenia from dipyrone was 2.98 [1.57-5.65] compared to NSAIDs and not statistically significant compared to opioids-paracetamol. In a sensitivity analysis assuming that the onset of agranulocytosis was the date of hospitalization, the HR of dipyrone-induced agranulocytosis was 7.20 [95% confidence interval: 1.92-26.99] compared to NSAIDs and 3.31 [1.17-9.34] compared to opioids-paracetamol. Agranulocytosis was very rare but more than 4 times more common with dipyrone than other analgesics.(4) In a review of 1,448 reports of agranulocytosis attributed to dipyrone, patients with fatal outcomes were older and more often had also received methotrexate compared to those with non-fatal outcomes (odds ratio: 5.18; 95% confidence interval: 3.06-8.78).(5) Agents linked to this interaction generally have > 5% risk for neutropenia and/or warnings describing risk for myelosuppression in manufacturer prescribing information.(2,6-26)
Slt Immunosuppress; Immunomodulator/Ropeginterferon Alfa-2B
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Ropeginterferon alfa-2b and immunosuppressives both suppress the immune system.
CLINICAL EFFECTS: Concurrent use of ropeginterferon alfa-2b with immunosuppressives may result in an increased risk of serious infections.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concurrent use of myelosuppressive agents.(1-2) If concurrent use cannot be avoided, monitor for effects of excessive immunosuppression.
DISCUSSION: In clinical trials, 20% of patients experienced leukopenia. Interferon alfa products may cause fatal or life-threatening infections.(1-2)
Moderate Interaction: Assess the risk to the patient and take action as needed.
Fluorouracil & Fluorouracil Prodrugs/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)
Immunosuppressives; Immunomodulators/Cladribine Oncology Inj
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Cladribine in combination with immunosuppressives and immune-modulators all suppress the immune system.(1-4)
CLINICAL EFFECTS: Concurrent use of cladribine with immunosuppressive or immune-modulating agents may result in an increased risk of serious infections.(1-4)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: Recommendations for cladribine regarding this interaction differ between regulatory approving agencies. The cladribine US, UK, and Australian prescribing information state: -Caution should be exercised if cladribine injection is administered before, after, or in conjunction with other drugs known to cause immunosuppression or myelosuppression.(1-3) The cladribine Canadian prescribing information states: -Proceed carefully in patients with severe bone marrow impairment of any etiology since further suppression of bone marrow function should be anticipated.(4)
DISCUSSION: Severe bone marrow suppression, including neutropenia, anemia and thrombocytopenia, has been commonly observed in patients treated with cladribine injection, especially at high doses.(1-4)
Immunosuppressives; Immunomodulators/Covid-19 Vaccines
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Immunosuppressants and immunomodulators may prevent the immune system from properly responding to the COVID-19 vaccine.(1-3)
CLINICAL EFFECTS: Administration of a COVID-19 vaccine with immunosuppressants or immunomodulators may interfere with vaccine-induced immune response and impair the efficacy of the vaccine. However, patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted.(1-3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The Centers for Disease Control and Prevention (CDC),(1) Infectious Diseases Society of America (IDSA),(2) and the American College of Rheumatology (ACR)(3) have published guidances for COVID-19 vaccination in patients on immunosuppressants. The CDC states that all immunocompromised patients over 6 months of age should receive at least 1 dose of COVID-19 vaccine if eligible. See the CDC's Interim Clinical Considerations for Use of COVID-19 Vaccines for specific recommendations based on age, vaccination history, and vaccine manufacturer.(1) The CDC advises planning for vaccination at least 2 weeks before starting or resuming immunosuppressive therapy.(1) IDSA recommends timing COVID-19 vaccination at least 2 weeks before starting or at least 3 months after completing immunosuppressive therapy.(2) The ACR states that in general, immunosuppressants and immunomodulators should be held for 1-2 weeks after each vaccine dose.(3) Patients should be offered and given a COVID-19 vaccine even if the use and timing of immunosuppressive agents cannot be adjusted, though the immune response will likely be blunted. COVID-19 vaccines should not be delayed in patients taking immunosuppressive therapies.(1-2) See below for specific recommendations for certain agents. B-cell depleting agents, including rituximab: The CDC states that the utility of B-cell quantification to guide clinical care is not known and is not recommended. Patients who receive B-cell depleting therapy on a continuing basis should receive COVID-19 vaccines about 4 weeks before the next scheduled dose. For patients who received 1 or more doses of COVID-19 vaccine during treatment with B-cell-depleting therapies that were administered over a limited period (e.g., as part of a treatment regimen for certain malignancies), revaccination may be considered according to the current CDC recommendations for unvaccinated patients. The suggested interval to start revaccination is about 6 months after completion of the B-cell-depleting therapy.(1) IDSA recommends waiting for at least 3-6 months after the last infusion of B-cell depleting therapy before administering COVID-19 vaccines.(2) The ACR recommends consulting with the rheumatologist to determine optimal timing of COVID-19 vaccination. Measuring CD19 B cells may be considered to determine need for a booster vaccine dose. If B cell levels are not measured, a supplemental vaccine dose 2-4 weeks before the next scheduled dose of rituximab is recommended.(3) Recipients of hematopoietic cell transplant or CAR-T-cell therapy who received one or more doses of COVID-19 vaccine prior to or during treatment should undergo revaccination following the current CDC recommendations for unvaccinated patients. Revaccination should start at least 3 months (12 weeks) after transplant or CAR-T-cell therapy.(1,2) The CDC includes abatacept, cyclophosphamide, and TNF-alpha and cytokine inhibitors in their general recommendation to hold therapy for at least 2 weeks following vaccination (1) while the ACR provides different recommendations:(3) *Abatacept: - Subcutaneous abatacept should be withheld for 1-2 weeks after each vaccine dose, as disease activity allows. - For intravenous abatacept, time administration so that vaccination will occur 1 week before the next abatacept infusion. *Cyclophosphamide: When feasible, administer cyclophosphamide 1 week after each COVID-19 vaccine dose. *TNF-alpha inhibitors and cytokine inhibitors: The ACR was not able to reach consensus on whether to modify dosing or timing of these agents with COVID-19 vaccination.
DISCUSSION: IDSA recommendations are based on cohort and case control studies in immunocompromised patients that found low to modest vaccine effectiveness (37-61%) but lower risks of COVID-19 association hospitalization, COVID-19 related mortality, and critical illness.(2) The ACR convened a COVID-19 Vaccine Guidance Task Force to provide guidance on optimal use of COVID-19 vaccines in rheumatology patients. These recommendations are based on limited clinical evidence of COVID-19 vaccines in patients without rheumatic and musculoskeletal disorders and evidence of other vaccines in this patient population.(3) The ACR recommendation for rituximab is based on studies of humoral immunity following receipt of other vaccines. These studies have uncertain generalizability to vaccination against COVID-19, as it is unknown if efficacy is attributable to induction of host T cells versus B cell (antibody-based) immunity.(3) The ACR recommendation for mycophenolate is based on preexisting data of mycophenolate on non-COVID-19 vaccine immunogenicity. Emerging data suggests that mycophenolate may impair SARS-CoV-2 vaccine response in rheumatic and musculoskeletal disease and transplant patients.(3) The ACR recommendation for methotrexate is based on data from influenza vaccines and pneumococcal vaccines with methotrexate.(3) The ACR recommendation for JAK inhibitors is based on concerns related to the effects of JAK inhibitors on interferon signaling that may result in a diminished vaccine response.(3) The ACR recommendation for subcutaneous abatacept is based on several studies suggesting a negative effect of abatacept on vaccine immunogenicity. The first vaccine dose primes naive T cells, naive T cell priming is inhibited by CTLA-4, and abatacept is a CTLA-4Ig construct. CTLA-4 should not inhibit boosts of already primed T cells at the time of the second vaccine dose.(3)
Immunosuppressives; Immunomodulators/Sarilumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Sarilumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of sarilumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of sarilumab recommends caution because the concurrent use of sarilumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Sarilumab was studied as monotherapy and in combination with methotrexate or conventional disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis studies. Sarilumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by sarilumab treated patients in the clinical trial periods included pneumonia and cellulitis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving sarilumab. Cases of tuberculosis, candidiasis, and pneumocystis with sarilumab have been reported.(1)
Immunosuppressives; Immunomodulators/Tocilizumab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Tocilizumab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of tocilizumab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US manufacturer of tocilizumab recommends caution because the concurrent use of tocilizumab with immunosuppressive agents may increase the risk of infection. If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents.(1)
DISCUSSION: Tocilizumab was studied as monotherapy and in combination with methotrexate, non-biologic DMARDs or corticosteroids, depending on the indication. Tocilizumab has not been studied with biological DMARDs and concurrent use should be avoided. If concurrent therapy is warranted, consider the potential for increased immunosuppressive risks from both agents.(1) The most common infections reported by tocilizumab treated patients in the clinical trial periods included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving tocilizumab. Cases of tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis have been reported.(1)
Immunosuppressives; Immunomodulators/Ublituximab
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Ublituximab, immunosuppressives, and immunomodulators all suppress the immune system.(1)
CLINICAL EFFECTS: Concurrent use of ublituximab with immunosuppressive or immunomodulating agents may result in an increased risk for serious infections.(1)
PREDISPOSING FACTORS: Incomplete washout of previously prescribed immunosuppressive or immune-modulating medications.
PATIENT MANAGEMENT: The US manufacturer of ublituximab recommends caution because the concurrent use of ublituximab with immunomodulating or immunosuppressive agents, including immunosuppressant doses of corticosteroids, may increase the risk of infection.(1) If concurrent therapy is warranted, consider the risk of additive immune suppression and monitor based on prescribing information for both agents. When switching from agents with immune effects, the half-life and mechanism of action of these drugs must be taken into consideration in order to prevent additive immunosuppressive effects.(1)
DISCUSSION: The most common infections reported by ublituximab-treated patients in the clinical trial periods included upper respiratory tract infections and urinary tract infections. Serious, including life-threatening or fatal, bacterial and viral infections were observed in patients receiving ublituximab.(1) Serious and/or fatal bacterial, fungal, and new or reactivated viral infections have been associated with other anti-CD20 B-cell depleting therapies. There were no cases of progressive multifocal leukoencephalopathy (PML) reported during the clinical trials; however, there have been reports of PML during or following completion of other anti-CD20 B-cell depleting therapies.(1)
Immunosuppressives; Immunomodulators/Ustekinumab
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)
Contraindications
*History of severe hypersensitivity reactions to fluorouracil or capecitabine.
- Congenital long QT syndrome
- Dihydropyrimidine dehydrogenase deficiency
- Lactation
- 30 day risk period post-myocardial infarction
- Anemia
- Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
- Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
- Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
- Chronic kidney disease stage 5 (failure) GFr<15 ml/min
- Coronary artery disease
- Hyperbilirubinemia
- Infection
- Necrotizing enterocolitis
- Neutropenic disorder
- Pregnancy
- Severe dehydration
- Severe diarrhea
- Severe nausea
- Severe vomiting
- Stomatitis
- Thrombocytopenic disorder
- Cardiac arrhythmia
- Disease of liver
- Kidney disease with likely reduction in glomerular filtration rate (GFr)
- Palmar-plantar erythrodysesthesia
Adverse reactions
Adverse effects reported in >=30% of patients receiving capecitabine monotherapy for adjuvant treatment of colon cancer include palmar-plantar erythrodysesthesia syndrome, diarrhea, and nausea.
Adverse effects reported in >=30% of patients receiving capecitabine monotherapy for metastatic colorectal cancer include anemia, diarrhea, palmar-plantar erythrodysesthesia syndrome, hyperbilirubinemia, nausea, fatigue, and abdominal pain.
Adverse effects reported in >=30% of patients receiving capecitabine monotherapy for metastatic breast cancer include lymphopenia, anemia, diarrhea, hand-and-foot syndrome, nausea, fatigue, vomiting, and dermatitis.
Adverse effects reported in >=30% of patients receiving capecitabine in combination with docetaxel for metastatic breast cancer include lymphocytopenia, leukopenia, neutropenia, anemia, diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, nausea, alopecia, thrombocytopenia, vomiting, edema, and abdominal pain.
More Frequent
- Anemia
- Neutropenic disorder
- Palmar-plantar erythrodysesthesia
- Thrombocytopenic disorder
Less Frequent
- Chest pain
- Gastrointestinal hemorrhage
- Ileus
- Peripheral neuropathy
- Venous thrombosis
Rare or Very Rare
- Acute myocardial infarction
- Angina
- Angioedema
- Cardiac arrhythmia
- Cardiomyopathy
- Cholestatic hepatitis
- Dehydration
- Encephalopathy
- Esophageal ulcer
- Heart failure
- Hepatic failure
- Hepatic fibrosis
- Hepatitis
- Hyperbilirubinemia
- Hypertension
- Hypotension
- Idiopathic thrombocytopenic purpura
- Infection
- Jaundice
- Keratitis
- Leukoencephalopathy
- Myocardial ischemia
- Necrotizing enterocolitis
- Phlebitis
- Pneumonia
- Pulmonary thromboembolism
- Radiation recall syndrome
- Rectal bleeding
- Renal failure
- Severe diarrhea
- Stevens-johnson syndrome
- Subacute cutaneous lupus erythematosus
- Thrombophlebitis
- Toxic epidermal necrolysis
More Frequent
- Acute abdominal pain
- Anorexia
- Fatigue
- Myalgia
- Nausea
- Skin inflammation
- Stomatitis
- Vomiting
Less Frequent
- Alopecia
- Arthralgia
- Back pain
- Conjunctivitis
- Constipation
- Depression
- Dizziness
- Dyschromia
- Dysgeusia
- Dyspepsia
- Edema
- Erythema
- Fever
- Headache disorder
- Insomnia
- Lethargy
- Mood changes
- Nail disorders
- Ocular irritation
- Onycholysis
- Pruritus of skin
- Skin photosensitivity
- Skin rash
- Sore throat
- Upper abdominal pain
- Visual changes
- Weight loss
Rare or Very Rare
- Ataxia
- Cough
- Diarrhea
- Dyspnea
- Epistaxis
- Nasolacrimal duct stenosis
Precautions
No enhanced messaging available.
The manufacturer states that safety and efficacy of capecitabine in children younger than 18 years of age have not been established.
Based on its mechanism of action and animal findings, capecitabine can cause fetal harm when administered to a pregnant patient. (See Fetal/Neonatal Morbidity and Mortality under Cautions.) Advise pregnant patients of the potential risk to a fetus.
In lactating mice receiving a single dose of capecitabine, significant amounts of capecitabine metabolites were distributed into milk. It is not known whether capecitabine or its metabolites are distributed into human milk. The effects of the drug on nursing infants or on milk production are unknown. Because of the potential for serious adverse reactions to capecitabine in nursing infants, women should be advised to discontinue nursing during capecitabine therapy and for 1 week after discontinuance of therapy.
The manufacturer makes no specific dosage recommendations for geriatric patients.
In clinical trials of patients with colorectal cancer (N=7938), metastatic breast cancer (N=4536), gastric, esophageal, or gastrointestinal junction cancer (N=1951), or pancreatic cancer (N=364) who were treated with capecitabine, 33, 18, 26, and 47% of patients, respectively, were >=65 years of age. No differences in efficacy were noted in geriatric patients compared to younger patients in these trials. However, geriatric patients experienced increased GI toxicity from capecitabine. Deaths have been reported from severe enterocolitis, diarrhea, and dehydration in geriatric patients treated with weekly leucovorin and fluorouracil.
ICD codes
| Code | Type | Description |
|---|---|---|
| Adenocarcinoma of pancreas | ||
| C24.1 | ICD10CM | Malignant neoplasm of ampulla of vater |
| C25 | ICD10CM | Malignant neoplasm of pancreas |
| C25.0 | ICD10CM | Malignant neoplasm of head of pancreas |
| C25.1 | ICD10CM | Malignant neoplasm of body of pancreas |
| C25.2 | ICD10CM | Malignant neoplasm of tail of pancreas |
| C25.3 | ICD10CM | Malignant neoplasm of pancreatic duct |
| C25.7 | ICD10CM | Malignant neoplasm of other parts of pancreas |
| C25.8 | ICD10CM | Malignant neoplasm of overlapping sites of pancreas |
| C25.9 | ICD10CM | Malignant neoplasm of pancreas, unspecified |
| Gastric cancer | ||
| C16 | ICD10CM | Malignant neoplasm of stomach |
| C16.0 | ICD10CM | Malignant neoplasm of cardia |
| C16.1 | ICD10CM | Malignant neoplasm of fundus of stomach |
| C16.2 | ICD10CM | Malignant neoplasm of body of stomach |
| C16.3 | ICD10CM | Malignant neoplasm of pyloric antrum |
| C16.4 | ICD10CM | Malignant neoplasm of pylorus |
| C16.5 | ICD10CM | Malignant neoplasm of lesser curvature of stomach, unspecified |
| C16.6 | ICD10CM | Malignant neoplasm of greater curvature of stomach, unspecified |
| C16.8 | ICD10CM | Malignant neoplasm of overlapping sites of stomach |
| C16.9 | ICD10CM | Malignant neoplasm of stomach, unspecified |
| HEr2-positive adenocarcinoma of gastroesophageal junction | ||
| C16.0 | ICD10CM | Malignant neoplasm of cardia |
| Lymph node positive colorectal carcinoma | ||
| C18 | ICD10CM | Malignant neoplasm of colon |
| C18.0 | ICD10CM | Malignant neoplasm of cecum |
| C18.1 | ICD10CM | Malignant neoplasm of appendix |
| C18.2 | ICD10CM | Malignant neoplasm of ascending colon |
| C18.3 | ICD10CM | Malignant neoplasm of hepatic flexure |
| C18.4 | ICD10CM | Malignant neoplasm of transverse colon |
| C18.5 | ICD10CM | Malignant neoplasm of splenic flexure |
| C18.6 | ICD10CM | Malignant neoplasm of descending colon |
| C18.7 | ICD10CM | Malignant neoplasm of sigmoid colon |
| C18.8 | ICD10CM | Malignant neoplasm of overlapping sites of colon |
| C18.9 | ICD10CM | Malignant neoplasm of colon, unspecified |
| C19 | ICD10CM | Malignant neoplasm of rectosigmoid junction |
| C20 | ICD10CM | Malignant neoplasm of rectum |
| Malignant esophageal neoplasm | ||
| C15 | ICD10CM | Malignant neoplasm of esophagus |
| C15.3 | ICD10CM | Malignant neoplasm of upper third of esophagus |
| C15.4 | ICD10CM | Malignant neoplasm of middle third of esophagus |
| C15.5 | ICD10CM | Malignant neoplasm of lower third of esophagus |
| C15.8 | ICD10CM | Malignant neoplasm of overlapping sites of esophagus |
| C15.9 | ICD10CM | Malignant neoplasm of esophagus, unspecified |
| Metastatic breast carcinoma | ||
| C50 | ICD10CM | Malignant neoplasm of breast |
| C50.1 | ICD10CM | Malignant neoplasm of central portion of breast |
| C50.11 | ICD10CM | Malignant neoplasm of central portion of breast, female |
| C50.111 | ICD10CM | Malignant neoplasm of central portion of right female breast |
| C50.112 | ICD10CM | Malignant neoplasm of central portion of left female breast |
| C50.119 | ICD10CM | Malignant neoplasm of central portion of unspecified female breast |
| C50.12 | ICD10CM | Malignant neoplasm of central portion of breast, male |
| C50.121 | ICD10CM | Malignant neoplasm of central portion of right male breast |
| C50.122 | ICD10CM | Malignant neoplasm of central portion of left male breast |
| C50.129 | ICD10CM | Malignant neoplasm of central portion of unspecified male breast |
| C50.2 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast |
| C50.21 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast, female |
| C50.211 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right female breast |
| C50.212 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left female breast |
| C50.219 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified female breast |
| C50.22 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast, male |
| C50.221 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right male breast |
| C50.222 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left male breast |
| C50.229 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified male breast |
| C50.3 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast |
| C50.31 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast, female |
| C50.311 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right female breast |
| C50.312 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left female breast |
| C50.319 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified female breast |
| C50.32 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast, male |
| C50.321 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right male breast |
| C50.322 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left male breast |
| C50.329 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified male breast |
| C50.4 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast |
| C50.41 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast, female |
| C50.411 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right female breast |
| C50.412 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left female breast |
| C50.419 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified female breast |
| C50.42 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast, male |
| C50.421 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right male breast |
| C50.422 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left male breast |
| C50.429 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified male breast |
| C50.5 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast |
| C50.51 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast, female |
| C50.511 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right female breast |
| C50.512 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left female breast |
| C50.519 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified female breast |
| C50.52 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast, male |
| C50.521 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right male breast |
| C50.522 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left male breast |
| C50.529 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified male breast |
| C50.6 | ICD10CM | Malignant neoplasm of axillary tail of breast |
| C50.61 | ICD10CM | Malignant neoplasm of axillary tail of breast, female |
| C50.611 | ICD10CM | Malignant neoplasm of axillary tail of right female breast |
| C50.612 | ICD10CM | Malignant neoplasm of axillary tail of left female breast |
| C50.619 | ICD10CM | Malignant neoplasm of axillary tail of unspecified female breast |
| C50.62 | ICD10CM | Malignant neoplasm of axillary tail of breast, male |
| C50.621 | ICD10CM | Malignant neoplasm of axillary tail of right male breast |
| C50.622 | ICD10CM | Malignant neoplasm of axillary tail of left male breast |
| C50.629 | ICD10CM | Malignant neoplasm of axillary tail of unspecified male breast |
| C50.8 | ICD10CM | Malignant neoplasm of overlapping sites of breast |
| C50.81 | ICD10CM | Malignant neoplasm of overlapping sites of breast, female |
| C50.811 | ICD10CM | Malignant neoplasm of overlapping sites of right female breast |
| C50.812 | ICD10CM | Malignant neoplasm of overlapping sites of left female breast |
| C50.819 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified female breast |
| C50.82 | ICD10CM | Malignant neoplasm of overlapping sites of breast, male |
| C50.821 | ICD10CM | Malignant neoplasm of overlapping sites of right male breast |
| C50.822 | ICD10CM | Malignant neoplasm of overlapping sites of left male breast |
| C50.829 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified male breast |
| C50.9 | ICD10CM | Malignant neoplasm of breast of unspecified site |
| C50.91 | ICD10CM | Malignant neoplasm of breast of unspecified site, female |
| C50.911 | ICD10CM | Malignant neoplasm of unspecified site of right female breast |
| C50.912 | ICD10CM | Malignant neoplasm of unspecified site of left female breast |
| C50.919 | ICD10CM | Malignant neoplasm of unspecified site of unspecified female breast |
| C50.92 | ICD10CM | Malignant neoplasm of breast of unspecified site, male |
| C50.921 | ICD10CM | Malignant neoplasm of unspecified site of right male breast |
| C50.922 | ICD10CM | Malignant neoplasm of unspecified site of left male breast |
| C50.929 | ICD10CM | Malignant neoplasm of unspecified site of unspecified male breast |
| C50.A | ICD10CM | Malignant inflammatory neoplasm of breast |
| C50.A0 | ICD10CM | Malignant inflammatory neoplasm of unspecified breast |
| C50.A1 | ICD10CM | Malignant inflammatory neoplasm of right breast |
| C50.A2 | ICD10CM | Malignant inflammatory neoplasm of left breast |
| Metastatic colorectal cancer | ||
| C18 | ICD10CM | Malignant neoplasm of colon |
| C18.0 | ICD10CM | Malignant neoplasm of cecum |
| C18.1 | ICD10CM | Malignant neoplasm of appendix |
| C18.2 | ICD10CM | Malignant neoplasm of ascending colon |
| C18.3 | ICD10CM | Malignant neoplasm of hepatic flexure |
| C18.4 | ICD10CM | Malignant neoplasm of transverse colon |
| C18.5 | ICD10CM | Malignant neoplasm of splenic flexure |
| C18.6 | ICD10CM | Malignant neoplasm of descending colon |
| C18.7 | ICD10CM | Malignant neoplasm of sigmoid colon |
| C18.8 | ICD10CM | Malignant neoplasm of overlapping sites of colon |
| C18.9 | ICD10CM | Malignant neoplasm of colon, unspecified |
| C19 | ICD10CM | Malignant neoplasm of rectosigmoid junction |
| C20 | ICD10CM | Malignant neoplasm of rectum |
| C21.8 | ICD10CM | Malignant neoplasm of overlapping sites of rectum, anus and anal canal |
| Metastatic HEr2-positive carcinoma of breast | ||
| C50 | ICD10CM | Malignant neoplasm of breast |
| C50.1 | ICD10CM | Malignant neoplasm of central portion of breast |
| C50.11 | ICD10CM | Malignant neoplasm of central portion of breast, female |
| C50.111 | ICD10CM | Malignant neoplasm of central portion of right female breast |
| C50.112 | ICD10CM | Malignant neoplasm of central portion of left female breast |
| C50.119 | ICD10CM | Malignant neoplasm of central portion of unspecified female breast |
| C50.12 | ICD10CM | Malignant neoplasm of central portion of breast, male |
| C50.121 | ICD10CM | Malignant neoplasm of central portion of right male breast |
| C50.122 | ICD10CM | Malignant neoplasm of central portion of left male breast |
| C50.129 | ICD10CM | Malignant neoplasm of central portion of unspecified male breast |
| C50.2 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast |
| C50.21 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast, female |
| C50.211 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right female breast |
| C50.212 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left female breast |
| C50.219 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified female breast |
| C50.22 | ICD10CM | Malignant neoplasm of upper-inner quadrant of breast, male |
| C50.221 | ICD10CM | Malignant neoplasm of upper-inner quadrant of right male breast |
| C50.222 | ICD10CM | Malignant neoplasm of upper-inner quadrant of left male breast |
| C50.229 | ICD10CM | Malignant neoplasm of upper-inner quadrant of unspecified male breast |
| C50.3 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast |
| C50.31 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast, female |
| C50.311 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right female breast |
| C50.312 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left female breast |
| C50.319 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified female breast |
| C50.32 | ICD10CM | Malignant neoplasm of lower-inner quadrant of breast, male |
| C50.321 | ICD10CM | Malignant neoplasm of lower-inner quadrant of right male breast |
| C50.322 | ICD10CM | Malignant neoplasm of lower-inner quadrant of left male breast |
| C50.329 | ICD10CM | Malignant neoplasm of lower-inner quadrant of unspecified male breast |
| C50.4 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast |
| C50.41 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast, female |
| C50.411 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right female breast |
| C50.412 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left female breast |
| C50.419 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified female breast |
| C50.42 | ICD10CM | Malignant neoplasm of upper-outer quadrant of breast, male |
| C50.421 | ICD10CM | Malignant neoplasm of upper-outer quadrant of right male breast |
| C50.422 | ICD10CM | Malignant neoplasm of upper-outer quadrant of left male breast |
| C50.429 | ICD10CM | Malignant neoplasm of upper-outer quadrant of unspecified male breast |
| C50.5 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast |
| C50.51 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast, female |
| C50.511 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right female breast |
| C50.512 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left female breast |
| C50.519 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified female breast |
| C50.52 | ICD10CM | Malignant neoplasm of lower-outer quadrant of breast, male |
| C50.521 | ICD10CM | Malignant neoplasm of lower-outer quadrant of right male breast |
| C50.522 | ICD10CM | Malignant neoplasm of lower-outer quadrant of left male breast |
| C50.529 | ICD10CM | Malignant neoplasm of lower-outer quadrant of unspecified male breast |
| C50.6 | ICD10CM | Malignant neoplasm of axillary tail of breast |
| C50.61 | ICD10CM | Malignant neoplasm of axillary tail of breast, female |
| C50.611 | ICD10CM | Malignant neoplasm of axillary tail of right female breast |
| C50.612 | ICD10CM | Malignant neoplasm of axillary tail of left female breast |
| C50.619 | ICD10CM | Malignant neoplasm of axillary tail of unspecified female breast |
| C50.62 | ICD10CM | Malignant neoplasm of axillary tail of breast, male |
| C50.621 | ICD10CM | Malignant neoplasm of axillary tail of right male breast |
| C50.622 | ICD10CM | Malignant neoplasm of axillary tail of left male breast |
| C50.629 | ICD10CM | Malignant neoplasm of axillary tail of unspecified male breast |
| C50.8 | ICD10CM | Malignant neoplasm of overlapping sites of breast |
| C50.81 | ICD10CM | Malignant neoplasm of overlapping sites of breast, female |
| C50.811 | ICD10CM | Malignant neoplasm of overlapping sites of right female breast |
| C50.812 | ICD10CM | Malignant neoplasm of overlapping sites of left female breast |
| C50.819 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified female breast |
| C50.82 | ICD10CM | Malignant neoplasm of overlapping sites of breast, male |
| C50.821 | ICD10CM | Malignant neoplasm of overlapping sites of right male breast |
| C50.822 | ICD10CM | Malignant neoplasm of overlapping sites of left male breast |
| C50.829 | ICD10CM | Malignant neoplasm of overlapping sites of unspecified male breast |
| C50.9 | ICD10CM | Malignant neoplasm of breast of unspecified site |
| C50.91 | ICD10CM | Malignant neoplasm of breast of unspecified site, female |
| C50.911 | ICD10CM | Malignant neoplasm of unspecified site of right female breast |
| C50.912 | ICD10CM | Malignant neoplasm of unspecified site of left female breast |
| C50.919 | ICD10CM | Malignant neoplasm of unspecified site of unspecified female breast |
| C50.92 | ICD10CM | Malignant neoplasm of breast of unspecified site, male |
| C50.921 | ICD10CM | Malignant neoplasm of unspecified site of right male breast |
| C50.922 | ICD10CM | Malignant neoplasm of unspecified site of left male breast |
| C50.929 | ICD10CM | Malignant neoplasm of unspecified site of unspecified male breast |
ICD code information from First Databank (FDB).
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Last reviewed · Source: First Databank (FDB) drug data
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