Cyclophosphamide (Page 3 of 5)

7 DRUG INTERACTIONS

Cyclophosphamide is a pro-drug that is activated by cytochrome P450s [see Clinical Pharmacology (12.3)].

An increase of the concentration of cytotoxic metabolites may occur with:

Protease inhibitors: Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen.

Combined or sequential use of cyclophosphamide and other agents with similar toxicities can potentiate toxicities.

Increased hematotoxicity and/or immunosuppression may result from a combined effect of cyclophosphamide and, for example:
ACE inhibitors: ACE inhibitors can cause leukopenia.
Natalizumab
Paclitaxel: Increased hematotoxicity has been reported when cyclophosphamide was administered after paclitaxel infusion.
Thiazide diuretics
Zidovudine
Increased cardiotoxicity may result from a combined effect of cyclophosphamide and, for example:
Anthracyclines
Cytarabine
Pentostatin
Radiation therapy of the cardiac region
Trastuzumab
Increased pulmonary toxicity may result from a combined effect of cyclophosphamide and, for example:
Amiodarone
G-CSF, GM-CSF (granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor): Reports suggest an increased risk of pulmonary toxicity in patients treated with cytotoxic chemotherapy that includes cyclophosphamide and G-CSF or GMCSF.
Increased nephrotoxicity may result from a combined effect of cyclophosphamide and, for example:
Amphotericin B
Indomethacin: Acute water intoxication has been reported with concomitant use of indomethacin
Increase in other toxicities:
Azathioprine: Increased risk of hepatotoxicity (liver necrosis)
Busulfan: Increased incidence of hepatic veno-occlusive disease and mucositis has been reported.
Protease inhibitors: Increased incidence of mucositis
Increased risk of hemorrhagic cystitis may result from a combined effect of cyclophosphamide and past or concomitant radiation treatment.

Etanercept: In patients with Wegener’s granulomatosis, the addition of etanercept to standard treatment, including cyclophosphamide, was associated with a higher incidence of non-cutaneous malignant solid tumors.

Metronidazole: Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. Causal association is unclear. In an animal study, the combination of cyclophosphamide with metronidazole was associated with increased cyclophosphamide toxicity.

Tamoxifen: Concomitant use of tamoxifen and chemotherapy may increase the risk of thromboembolic complications.

Coumarins: Both increased and decreased warfarin effect have been reported in patients receiving warfarin and cyclophosphamide.

Cyclosporine: Lower serum concentrations of cyclosporine have been observed in patients receiving a combination of cyclophosphamide and cyclosporine than in patients receiving only cyclosporine. This interaction may result in an increased incidence of graft-versus-host disease.

Depolarizing muscle relaxants: Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine). If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Capsules can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)]. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn [see Data]. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys [see Data]. Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Human Data

Malformations of the skeleton, palate, limbs and eyes as well as miscarriage have been reported after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis have been reported after exposure to cyclophosphamide.

Animal Data

Administration of cyclophosphamide to pregnant mice, rats, rabbits and monkeys during the period of organogenesis at doses at or below the dose in patients based on body surface area resulted in various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.

8.2 Lactation

Risk Summary

Cyclophosphamide is present in breast milk. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide. Because of the potential for serious adverse reactions in a breastfed child from Cyclophosphamide Capsules, advise lactating women not to breastfeed during the treatment and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of Cyclophosphamide Capsules [see Use in Specific Populations (8.1)].

Contraception

Females

Cyclophosphamide Capsules can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Capsules for up to 1 year after completion of therapy [see Use in Specific Populations (8.1)].

Males

Based on findings in genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Capsules and for 4 months after completion of therapy [see Use in Specific Populations (8.1) and Nonclinical Toxicology (13.1)].

Infertility

Females

Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age. Oligomenorrhea has also been reported in association with cyclophosphamide treatment.

Animal data suggest an increased risk of failed pregnancy and malformations may persist after discontinuation of cyclophosphamide as long as oocytes/follicles exist that were exposed to cyclophosphamide during any of their maturation phases. The exact duration of follicular development in humans is not known, but may be longer than 12 months [see Nonclinical Toxicology (13.1)].

Males

Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.

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