Cyclophosphamide

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.

• •Intravenous: Initial course for patients with no hematologic deficiency: 40 mg/kg to 50 mg/kg in divided doses over 2 to 5 days. Other 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.
• •See full prescribing information for instructions on preparation, handling, and administration. (
  2.3 Preparation, Handling and Administration

  Cyclophosphamide Injection is a hazardous drug.¹Follow applicable special handling and disposal procedures. Caution should be exercised when handling and preparing Cyclophosphamide Injection. To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide Injection.

  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

  Aseptically withdraw the prescribed dose from the vial. Dilute the prescribed dose of Cyclophosphamide Injection to a concentration of 20 mg per mL by using any of the following diluents:

  • •0.9% Sodium Chloride Injection, USP
  • •0.45% Sodium Chloride Injection, USP
  • •5% Dextrose Injection, USP
  • •5% Dextrose and 0.9% Sodium Chloride Injection, USP

  Do not use Sterile Water for Injection, USP because it results in a hypotonic solution and should not be injected directly.

  For Intravenous Infusion

  Aseptically withdraw the prescribed dose from the vial. Dilute the prescribed dose of Cyclophosphamide Injection to a concentration of 2 mg per mL by using any of the following diluents:

  • •0.9% Sodium Chloride Injection, USP
  • •0.45% Sodium Chloride Injection, USP
  • •5% Dextrose Injection, USP
  • •5% Dextrose and 0.9% Sodium Chloride Injection, USP

  To reduce the likelihood of adverse reactions that appear to be administration rate-dependent (e.g., facial swelling, headache, nasal congestion, scalp burning), Cyclophosphamide Injection should be injected or infused very slowly. Duration of the infusion also should be appropriate for the volume and type of carrier fluid to be infused.

  Storage of Diluted Cyclophosphamide Injection Solution:

  If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 1:

  Diluent

  Diluted solutions (20 mg/mL)

  0.9% Sodium Chloride Injection, USPup to 24 hrsup to 6 days0.45% Sodium Chloride Injection, USPup to 24 hrsup to 6 days5% Dextrose Injection, USPup to 24 hrsup to 6 days5% Dextrose and 0.9% Sodium Chloride Injection, USPup to 24 hrsup to 6 days

  Diluted Solutions (2 mg/mL)

  0.9% Sodium Chloride Injection, USPup to 24 hrsup to 6 days0.45% Sodium Chloride Injection, USPup to 24 hrsup to 6 days5% Dextrose Injection, USPup to 24 hrsup to 6 days5% Dextrose and 0.9% Sodium Chloride Injection, USPup to 24 hrsup to 6 days

  Table 1: Storage of Cyclophosphamide Injection Solutions

  	Storage
  Room Temperature	Refrigerated

  Storage of Undiluted Cyclophosphamide Injection Solution:

  After first use, store partially used multiple-dose vial in the original carton at 2°C to 8°C (36ºF to 46°F) for up to 28 days. Discard unused portion after 28 days.
  )

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

• •500 mg/2.5 mL (200 mg/mL)
• •1,000 mg/5 mL (200 mg/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, advise lactating women not to breastfeed during treatment with Cyclophosphamide Injection and for 1 week after the last dose.
  )
• •Renal Patients: Monitor for toxicity in patients with moderate and severe renal impairment. (
  8.6 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 (CLcr=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. Use of a consistent interval between cyclophosphamide administration and dialysis should be considered in patients requiring dialysis.
  ,
  12.3 Pharmacokinetics

  Pharmacokinetics are linear over the dose range used clinically.

  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 < 10mL/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 (t1/2) 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 (t½) is prolonged by 64%. Mean CL and t½ 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.
  )

• •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 (6.1)]

  .

  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/mm³and 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.
  )
• •Urinary Tract and Renal Toxicity - Hemorrhagic cystitis, pyelitis, ureteritis, and hematuria can occur. 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 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.
  )
• •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 pre- existing 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 - Have been reported in patients treated with cyclophosphamide-containing regimens. (
  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 0.166 g/kg of ethanol over 2 to 5 days. For a 75 kg patient this would deliver 12.45 grams of ethanol over 2 to 5 days

  [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 reproductive potential of the potential risk to a 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 a 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 (8.1, 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 (8.1)]

  .

  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.
  )