4 Ml Cyclophosphamide 500 Mg/ml Injection

Intravenous

When used as the only oncolytic drug therapy, the initial course of Cyclophosphamide Injection for patients with no hematologic deficiency usually consists of 40 mg/kg to 50 mg/kg given intravenously in divided doses over a period of 2 to 5 days. Other intravenous regimens include 10 mg/kg to 15 mg/kg given every 7 to 10 days or 3 mg/kg to 5 mg/kg twice weekly.

Dosages may also be adjusted based on antitumor activity and/or leukopenia. The total leukocyte count may be used to manage dosage.

When Cyclophosphamide Injection is included in combined cytotoxic regimens, it may be necessary to reduce the dose of Cyclophosphamide Injection as well as that of the other drugs.

Cyclophosphamide Injection

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use Cyclophosphamide Injection vials if there are signs of particulate matter.

Cyclophosphamide Injection does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions. Use aseptic technique.

For Direct Intravenous Injection

Withdraw the prescribed dose of Cyclophosphamide Injection from the vial with a syringe and dilute with 0.9% Sodium Chloride Injection, USP to a concentration of 20 mg/mL of cyclophosphamide.

For Intravenous Infusion

Withdraw the prescribed dose of Cyclophosphamide Injection from the vial with a syringe and dilute Cyclophosphamide Injection to a concentration of 2 mg per mL with any of the following diluents: 

Antimicrobial prophylaxis may be indicated in certain cases of neutropenia at the discretion of the managing physician. In case of neutropenic fever, antibiotic therapy is indicated. Antimycotics and/or antivirals may also be indicated.

Monitoring of complete blood counts is essential during cyclophosphamide treatment so that the dose can be adjusted, if needed. Cyclophosphamide Injection should not be administered to patients with neutrophils ≤1,500/mm³ and platelets < 50,000/mm³. Cyclophosphamide Injection treatment may not be indicated, or should be interrupted, or the dose reduced, in patients who have or who develop a serious infection. G-CSF may be administered to reduce the risks of neutropenia complications associated with cyclophosphamide use. Primary and secondary prophylaxis with G-CSF should be considered in all patients considered to be at increased risk for neutropenia complications. The nadirs of the reduction in leukocyte count and thrombocyte count are usually reached in weeks 1 and 2 of treatment. Peripheral blood cell counts are expected to normalize after approximately 20 days. Bone marrow failure has been reported. Severe myelosuppression may be expected particularly in patients pretreated with and/or receiving concomitant chemotherapy and/or radiation therapy.

Before starting treatment, exclude or correct any urinary tract obstructions [see Contraindications (4)]. Urinary sediment should be checked regularly for the presence of erythrocytes and other signs of urotoxicity and/or nephrotoxicity. Cyclophosphamide Injection should be used with caution, if at all, in patients with active urinary tract infections. Aggressive hydration with forced diuresis and frequent bladder emptying can reduce the frequency and severity of bladder toxicity. Mesna has been used to prevent severe bladder toxicity.

Supraventricular arrhythmias (including atrial fibrillation and flutter) and ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia) have been reported after treatment with regimens that included cyclophosphamide.

The risk of cardiotoxicity may be increased with high doses of cyclophosphamide, in patients with advanced age, and in patients with previous radiation treatment to the cardiac region and/or previous or concomitant treatment with other cardiotoxic agents.

Particular caution is necessary in patients with risk factors for cardiotoxicity and in patients with preexisting cardiac disease.

Monitor patients with risk factors for cardiotoxicity and with pre-existing cardiac disease.

Monitor patients for signs and symptoms of pulmonary toxicity.

Each administration of Cyclophosphamide Injection at 50 mg per kg delivers 0.0448 g/kg of ethanol. For a 75 kg patient this would deliver 3.36 grams of ethanol [see Description (11)]. Other cyclophosphamide products may have a different amount of alcohol or no alcohol.

Advise pregnant women and females of reproductive potential of the potential risk to the fetus [see Use in Specific Populations (8.1)].  Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for up to 1 year after completion of therapy.  Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and for 4 months after completion of therapy [see Use in Specific Populations (8.3)].

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

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.

A higher incidence of non-cutaneous malignant solid tumors in patients with Wegener's granulomatosis occurred with the addition of etanercept to cyclophosphamide treatment.

Metronidazole

Acute encephalopathy has been reported in a patient receiving cyclophosphamide and metronidazole. 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

If a patient has been treated with cyclophosphamide within 10 days of general anesthesia, alert the anesthesiologist.

Cyclophosphamide treatment causes a marked and persistent inhibition of cholinesterase activity. Prolonged apnea may occur with concurrent depolarizing muscle relaxants (e.g., succinylcholine).

Based on its mechanism of action and published reports of effects in pregnant patients or animals, Cyclophosphamide Injection 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 a 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.

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, advise lactating women not to breastfeed during treatment with Cyclophosphamide Injection and for 1 week after the last dose.

Pregnancy Testing

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

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with Cyclophosphamide Injection and 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 Injection 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.

The alcohol content of Cyclophosphamide Injection should be taken into account when given to pediatric patients [see Warnings and Precautions (5.7) ].

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.

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 Injection administration and dialysis should be considered.

The alcohol content of Cyclophosphamide Injection should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions (5.7)].

The active alkylating metabolites of cyclophosphamide interfere with the growth of susceptible rapidly proliferating malignant cells.

Distribution

Cyclophosphamide volume of distribution approximates total body water (30 to 50 L). Cyclophosphamide is approximately 20% protein bound, with no dose dependent changes.  Some metabolites are greater than 60% protein bound. 

Elimination

The cyclophosphamide elimination half-life ranges from 3 to 12 hours with total body clearance (CL) values of 4 to 5.6 L/h following IV administration. Cyclophosphamide appears to induce its own metabolism. This auto-induction results in an increase in the total clearance, increased formation of active 4-hydroxyl metabolites and shortened elimination half-life values following repeated administration at 12- to 24-hour interval. 

When cyclophosphamide was administered at 4.0 g/m² (approximately 2 times the approved recommended dosage) over a 90-minutes infusion, saturable elimination in parallel with first-order renal elimination describe the kinetics of the drug.

Metabolism

The liver is the major site of cyclophosphamide activation. Approximately 75% of the administered dose of cyclophosphamide is activated by hepatic microsomal cytochrome P450s including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with 2B6 displaying the highest 4-hydroxylase activity. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo further oxidation by aldehyde dehydrogenases to form the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide, respectively. Aldophosphamide can undergo β-elimination to form active metabolites phosphoramide mustard and acrolein. This spontaneous conversion can be catalyzed by albumin and other proteins. Less than 5% of cyclophosphamide may be directly detoxified by side chain oxidation, leading to the formation of inactive metabolites 2-dechloroethylcyclophosphamide. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide in patients.

Excretion

Cyclophosphamide is primarily excreted as metabolites. 10 to 20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration.

Specific Populations

Renal Impairment

Cyclophosphamide exposure increased as the renal function decreased following one-hour intravenous infusion to renally impaired patients. Mean dose-corrected cyclophosphamide AUC increased by 38% in the moderate renal group, (Creatinine clearance (CLcr of 25 to 50 mL/min), by 64% in the severe renal group (CLcr of 10 to 24 mL/min) and by 23% in the hemodialysis group (CLcr of < 10 mL/min) compared to the control group.

Cyclophosphamide is dialyzable.  Dialysis clearance calculated by arterial-venous difference and actual drug recovery in dialysate averaged 104 mL/min, which is in the range of the metabolic clearance of 95 mL/min for the drug. A mean of 37% of the administered dose of cyclophosphamide was removed during hemodialysis. The elimination half-life (t_1/2) was 3.3 hours in patients during hemodialysis, a 49% reduction of the 6.5 hours to the elimination half life reported in uremic patients.

Hepatic Impairment

Total body clearance (CL) of cyclophosphamide is decreased by 40% in patients with severe hepatic impairment and elimination half-life (t_1/2) is prolonged by 64%. Mean CL and t_1/2 were 45 ± 8.6 L/kg and 12.5 ± 1.0 hours respectively, in patients with severe hepatic impairment and 63 ± 7.6 L/kg and 7.6 ± 1.4 hours respectively in the control group.

Cyclophosphamide was mutagenic and clastogenic in multiple in vitro and in vivo genetic toxicology studies.

Cyclophosphamide is genotoxic in male and female germ cells. Animal data indicate that exposure of oocytes to cyclophosphamide during follicular development may result in a decreased rate of implantations and viable pregnancies, and in an increased risk of malformations. Male mice and rats treated with cyclophosphamide show alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females [see Use in Specific Populations (8.3)].