Cyclophosphamide

Cyclophosphamide is an alkylating drug indicated for treatment of adults and pediatric patients with:

• Malignant Diseases:
  malignant lymphomas: Hodgkin's disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma. (
  1.1 Malignant Diseases

  Cyclophosphamide Injection is indicated for the treatment of adult and pediatric patients with:

  • malignant lymphomas (Stages III and IV of the Ann Arbor staging system), Hodgkin's disease, lymphocytic lymphoma (nodular or diffuse), mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma
  • multiple myeloma
  • leukemias: chronic lymphocytic leukemia, chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis), acute myelogenous and monocytic leukemia, acute lymphoblastic (stem-cell) leukemia (cyclophosphamide given during remission is effective in prolonging its duration)
  • mycosis fungoides (advanced disease)
  • neuroblastoma (disseminated disease)
  • adenocarcinoma of the ovary
  • retinoblastoma
  • carcinoma of the breast

  Cyclophosphamide, although effective alone in susceptible malignancies, is more frequently used concurrently or sequentially with other antineoplastic drugs.
  )

Cyclophosphamide Injection is a 200 mg/mL sterile clear colorless ready to dilute solution in a multiple-dose vial available in the following presentations:

• 500 mg/2.5 mL
• 1 g/5 mL
• 2 g/10 mL

• Lactation: Advise not to breastfeed. (
  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 Injection, advise lactating women not to breastfeed during the treatment and for 1 week after the last dose.
  )
• Renal Impairements: Monitor for toxicity in patients with moderate and severe renal impairment. (
  8.3 Females and Males of Reproductive Potential

  Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ].

  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 females 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.
  ,
  12.3 Pharmacokinetics

  Cyclophosphamide is a prodrug. Cyclophosphamide pharmacokinetics are linear over the approved recommended dose range.

  Distribution

  The volume of distribution of cyclophosphamide is 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 elimination half-life (t½) of cyclophosphamide ranges from 3 to 12 hours, and clearance (CL) ranges from 4 to 5.6 L/h.

  When cyclophosphamide was administered at 4 g/m²(approximately 2 times the approved recommended dosage) over a 90-minute infusion, concentration-time data demonstrate saturable elimination in parallel with first-order renal elimination.

  Metabolism

  Cyclophosphamide is metabolized by cytochrome P450s including CYP2A6, 2B6, 3A, 2C9, and 2C19. Cyclophosphamide is activated to form 4-hydroxycyclophosphamide, which is in equilibrium with its ring-open tautomer aldophosphamide. 4-hydroxycyclophosphamide and aldophosphamide can undergo 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. At high doses, the fraction of parent compound cleared by 4-hydroxylation is reduced resulting in non-linear elimination of cyclophosphamide.

  Cyclophosphamide appears to induce its own metabolism. This auto-induction results in an increase in CL, increased formation of active 4-hydroxycyclophosphamide and shortened t½ following multiple doses administered at 12-to 24-hour interval.

  Excretion

  Cyclophosphamide and its metabolites are eliminated by hepatic and renal pathways. Cyclophosphamide is primarily excreted as metabolites. Ten to 20% is excreted unchanged in the urine. A small percentage of cyclophosphamide may be eliminated unchanged in bile.

  Specific Populations

  Renal Impairment

  Following one-hour intravenous infusion, cyclophosphamide AUC increased by 38% in patients with CLcr of 25 to 50 mL/min, by 77% in patients with CLcr of 10 to 24 mL/min and by 23% in the hemodialysis group (CLcr of < 10 mL/min) compared to the control group (CLcr≥ 80 mL/min). Cyclophosphamide is dialyzable. Dialysis clearance averaged 104 mL/min, which is similar to the metabolic clearance of 95 mL/min for cyclophosphamide. A mean of 37% of the administered dose of cyclophosphamide was removed during a 4-hour hemodialysis period. The t½ was 3.3 hours in patients during hemodialysis, a 49% reduction compared to t½ of 6.5 hours in uremic patients.

  Hepatic Impairment

  Cyclophosphamide CL is decreased by 40% (45 ± 8.6 L/kg) and t½ is prolonged by 64% (12.5 ± 1 hours) in patients with hepatic impairment with a mean bilirubin 3.5 mg/dL and mean AST 90 IU/L compared to patients with normal hepatic function (mean bilirubin 0.5 mg/dL, mean AST 10 IU/L).
  )

•  Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections - Severe immunosuppression may lead to serious and sometimes fatal infections. Close hematological monitoring is required. (
  5.1 Myelosuppression, Immunosuppression, Bone Marrow Failure and Infections

  Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated

  [see Adverse Reactions (6.2)].

  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 should not be administered to patients with neutrophils ≤1,500/mm³and platelets < 50,000/mm³. Cyclophosphamide 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.
  )
•  Urinary Tract and Renal Toxicity - Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur.Urotoxicity can be fatal. Exclude or correct any urinary tract obstructions prior to treatment. (
  5.2 Urinary Tract and Renal Toxicity

  Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria have been reported with cyclophosphamide. Medical and/or surgical supportive treatment may be required to treat protracted cases of severe hemorrhagic cystitis. Discontinue cyclophosphamide therapy in case of severe hemorrhagic cystitis. Urotoxicity (bladder ulceration, necrosis, fibrosis, contracture and secondary cancer) may require interruption of cyclophosphamide treatment or cystectomy. Urotoxicity can be fatal. Urotoxicity can occur with short-term or long-term use of cyclophosphamide.

  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 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.
  )
•   Cardiotoxicity - Myocarditis, myopericarditis, pericardial effusion, arrhythmias and congestive heart failure, which may be fatal, have been reported. Monitor patients, especially those with risk factors for cardio toxicity or pre-existing cardiac disease. (
  5.3 Cardiotoxicity

  Myocarditis, myopericarditis, pericardial effusion including cardiac tamponade, and congestive heart failure, which may be fatal, have been reported with cyclophosphamide therapy.

  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.
  )
•  Pulmonary Toxicity - Pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease leading to respiratory failure may occur. Monitor patients for signs and symptoms of pulmonary toxicity. (
  5.4 Pulmonary Toxicity

  Pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease and other forms of pulmonary toxicity leading to respiratory failure have been reported during and following treatment with cyclophosphamide. Late onset pneumonitis (greater than 6 months after start of cyclophosphamide) appears to be associated with increased mortality. Pneumonitis may develop years after treatment with cyclophosphamide.

  Monitor patients for signs and symptoms of pulmonary toxicity.
  )
•  Secondary Malignancies (
  5.5 Secondary Malignancies

  Cyclophosphamide is genotoxic

  [see Nonclinical Toxicology (13.1)].

  Secondary malignancies (urinary tract cancer, myelodysplasia, acute leukemias, lymphomas, thyroid cancer, and sarcomas) have been reported in patients treated with cyclophosphamide-containing regimens. The risk of bladder cancer may be reduced by prevention of hemorrhagic cystitis.
  )
•  Veno-occlusive Liver Disease - Fatal outcome can occur. (
  5.6 Veno-occlusive Liver Disease

  Veno-occlusive liver disease (VOD) including fatal outcome has been reported in patients receiving cyclophosphamide-containing regimens. A cytoreductive regimen in preparation for bone marrow transplantation that consists of cyclophosphamide in combination with whole-body irradiation, busulfan, or other agents has been identified as a major risk factor. VOD has also been reported to develop gradually in patients receiving long-term low-dose immunosuppressive doses of cyclophosphamide. Other risk factors predisposing to the development of VOD include preexisting disturbances of hepatic function, previous radiation therapy of the abdomen, and a low performance status.
  )
•  Alcohol Content - The alcohol content in a dose of Cyclophosphamide Injection may affect the central nervous system. This may include impairment of a patient's ability to drive or use machines immediately after infusion. (
  5.7 Alcohol Content

  The alcohol content in a dose of Cyclophosphamide Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Cyclophosphamide Injection on the ability to drive or use machines immediately after the infusion. Each administration of Cyclophosphamide Injection at 50 mg per kg delivers 0.155 g/kg of ethanol.  For a 75 kg patient this would deliver 11.625 grams of ethanol

  [see Description (11)]

  .  Other cyclophosphamide products may have a different amount of alcohol or no alcohol.
  )
•  Embryo-Fetal Toxicity - Can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception. (
  5.8 Embryo-Fetal Toxicity

  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 Use in Specific Populations (8.1), Clinical Pharmacology (12.1)and Nonclinical Toxicology (13.1)]

  . Exposure to cyclophosphamide during pregnancy may cause birth defects, miscarriage, fetal growth retardation, and fetotoxic effects in the newborn. Cyclophosphamide is teratogenic and embryo-fetal toxic in mice, rats, rabbits and monkeys.

  Advise pregnant women and females of reproductive potential of the potential risk to the fetus

  [see Use in Specific Populations (8.1)]

  . Verify the pregnancy status of females of reproductive potential prior to initiation of Cyclophosphamide Injection. 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 (8.1, 8.3)].
  ,
  8.1 Pregnancy

  Risk Summary

  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 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.
  ,
  8.3 Females and Males of Reproductive Potential

  Cyclophosphamide Injection can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ].

  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 females 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.
  )