Cyclophosphamide (Page 4 of 6)
8 USE IN SPECIFIC POPULATIONS
Pregnancy Category D
Cyclophosphamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action and published reports of effects in pregnant patients or animals. Exposure to cyclophosphamide during pregnancy may cause fetal malformations, miscarriage, fetal growth retardation, and toxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.
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.
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.
8.3 Nursing Mothers
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 nursing infants from cyclophosphamide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Pre-pubescent girls treated with cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses. Ovarian fibrosis with apparently complete loss of germ cells after prolonged cyclophosphamide treatment in late pre-pubescence has been reported. Girls treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.
Pre-pubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia and increased gonadotropin secretion. Some degree of testicular atrophy may occur. Cyclophosphamide-induced azoospermia is reversible in some patients, though the reversibility may not occur for several years after cessation of therapy.
8.5 Geriatric Use
There is insufficient data from clinical studies of cyclophosphamide available for patients 65 years of age and older to determine whether they respond differently than younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac functioning, and of concomitant disease or other drug therapy.
8.6 Females and Males of Reproductive Potential
Pregnancy should be avoided during treatment with cyclophosphamide because of the risk of fetal harm [see Use in Specific Populations (8.1)].
Female patients of reproductive potential should use highly effective contraception during and for up to 1 year after completion of treatment.
Male patients who are sexually active with female partners who are or may become pregnant should use a condom during and for at least 4 months after treatment.
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)].
Men treated with cyclophosphamide may develop oligospermia or azoospermia which are normally associated with increased gonadotropin but normal testosterone secretion.
8.7 Use in Patients with Renal Impairment
In patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity [see Clinical Pharmacology (12.3)]. Monitor patients with severe renal impairment (CrCl =10 mL/min to 24 mL/min) for signs and symptoms of toxicity.
Cyclophosphamide and its metabolites are dialyzable although there are probably quantitative differences
depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered.
8.8 Use in Patients with Hepatic Impairment
Patients with severe hepatic impairment have reduced conversion of cyclophosphamide to the active 4-hydroxyl metabolite, potentially reducing efficacy [see Clinical Pharmacology (12.3)].
No specific antidote for cyclophosphamide is known.
Overdosage should be managed with supportive measures, including appropriate treatment for any concurrent infection, myelosuppression, or cardiac toxicity should it occur.
Serious consequences of overdosage include manifestations of dose dependent toxicities such as myelosuppression, urotoxicity, cardiotoxicity (including cardiac failure), veno-occlusive hepatic disease, and stomatitis [see Warnings and Precautions (5.1, 5.2, 5.3 and 5.6)].
Patients who received an overdose should be closely monitored for the development of toxicities, and hematologic toxicity in particular.
Cyclophosphamide and its metabolites are dialyzable. Therefore, rapid hemodialysis is indicated when treating any suicidal or accidental overdose or intoxication.
Cystitis prophylaxis with mesna may be helpful in preventing or limiting urotoxic effects with cyclophosphamide overdose.
Cyclophosphamide is a synthetic antineoplastic drug chemically related to the nitrogen mustards. The chemical name for cyclophosphamide is 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, and has the following structural formula:
Cyclophosphamide, USP is a white crystalline powder with the molecular formula C7 H15 Cl2 N2 O2 P•H2 O and a molecular weight of 279.1. Cyclophosphamide is soluble in water, saline, or ethanol.
Cyclophosphamide for Injection, USP is a sterile white powder available as 500 mg, 1 g, and 2 g strength vials.
- 500 mg vial contains 534.5 mg cyclophosphamide monohydrate equivalent to 500 mg cyclophosphamide, USP.
- 1 g vial contains 1069 mg cyclophosphamide monohydrate equivalent to 1 g cyclophosphamide, USP
- 2 g vial contains 2138 mg cyclophosphamide monohydrate equivalent to 2 g cyclophosphamide, USP
12 CLINICAL PHARMACOLOGY
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