ENDOXAN

Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide.

It has been used in the treatment of lymphoma and leukemia.

Its side effect, alopecia, has been used for defleecing sheep.

Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.

Cyclophosphamide for intravenous injection is indicated for the treatment of a number of malignancies, including: Hodgkin's disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, and breast carcinoma.

Cyclophosphamide oral capsules are additionally indicated for the treatment of minimal change nephrotic syndrome in pediatric patients who fail to adequately respond to (or are unable to tolerate) adrenocorticosteroid therapy.

Cyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer.

Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells.

They stop tumor growth by cross-linking guanine bases in DNA double-helix strands.

• directly attacking DNA.

This makes the strands unable to uncoil and separate.

As this is necessary in

DNA replication, the cells can no longer divide.

In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA.

Alkylating agents are cell cycle-nonspecific.

Alkylating agents work by three different mechanisms all of which achieve the same end result.

• disruption of DNA function and cell death.

After oral administration, peak concentrations occur at one hour.

and activation occurs at the liver. 75% of the drug is activated by cytochrome P450 isoforms, CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19.

CYP2B6 isoform is the enzyme with the highest 4-hydroxylase activity.

Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein.

Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration.

Hover over products below to view reaction partners Cyclophosphamide 4-Hydroxycyclophosphamide Aldophosphamide Phosphoramide Mustard Phosphoramide Aziridinium Acrolein Acrylic Acid Carboxyphosphamide Alcophosphamide Carboxyphosphamide Nornitrogen mustard 4-Ketocyclophosphamide Dechloroethyl cyclophosphamide Chloroacetaldehyde.

Cyclophosphamide is eliminated primarily in the form of metabolites. 10-20% is excreted unchanged in the urine and 4% is excreted in the bile following Intravenous administration.

Total body clearance = 63 ± 7.6 L/kg.

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Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea.

Cyclophosphamide for injection is contraindicated in patients who have a history of severe hypersensitivity reactions to cyclophosphamide, any of its metabolites, or to other components of the product.

Anaphylactic reactions including death have been reported with cyclophosphamide.

Cross-sensitivity with other alkylating agents can occur.

Cyclophosphamide for injection is contraindicated in patients with urinary outflow obstruction.

Hypersensitivity to cyclophosphamide

Urinary outflow obstruction.

During or immediately after cyclophosphamide for injection administration, administer adequate amounts of fluid to reduce the risk of urinary tract toxicity.

Adult and Pediatric Patients Intravenous: Initial course for patients with no hematologic deficiency: 40 mg per kg to 50 mg per kg in divided doses over to 5 days.

Other regimens include 10 mg per kg to 15 mg per kg given every to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

Oral: 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Minimal Change Nephrotic Syndrome in Pediatric Patients Oral: 2 mg per kg daily for to 12 weeks (maximum cumulative dose 168 mg per kg).

Treatment beyond 90 days increases the probability of sterility in males. 2.1 Important Administration Instructions During or immediately after the administration of cyclophosphamide for injection, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity.

Therefore, cyclophosphamide for injection should be administered in the morning. 2.2 Recommended Dosage for Malignant Diseases Adults and Pediatric Patients Intravenous Use When used as the only oncolytic drug therapy, the recommended dosage for the initial course of cyclophosphamide for injection for patients with no hematologic deficiency is 40 mg per kg to 50 mg per kg given intravenously in divided doses over a period of to 5 days.

Other intravenous regimens include 10 mg per kg to 15 mg per kg given every to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

The recommended dosage for oral cyclophosphamide is 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Adjust the dosage of cyclophosphamide for injection based on the specific regimen administered, response to treatment, myelosuppression or other adverse reactions, and patient risk factors. 2.3 Recommended Dosage for Minimal Change Nephrotic Syndrome in Pediatric Patients The recommended dosage is 2 mg per kg orally once daily for to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended.

Treatment beyond 90 days increases the probability of sterility in males. 2.4 Preparation, Handling and Administration Cyclophosphamide for injection is a hazardous drug.

Follow applicable special handling and disposal procedures.

Caution should be exercised when handling and preparing cyclophosphamide for injection.

To minimize the risk of dermal exposure, always wear gloves when handling vials containing cyclophosphamide for injection.

Cyclophosphamide for Injection Intravenous Administration

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not use cyclophosphamide vials if there are signs of melting.

Melted cyclophosphamide is a clear or yellowish viscous liquid usually found as a connected phase or in droplets in the affected vials.

Cyclophosphamide for injection does not contain any antimicrobial preservative and thus care must be taken to assure the sterility of prepared solutions.

Use aseptic technique.

Reconstitute cyclophosphamide for injection with 0.9% Sodium Chloride Injection, USP only, using the volumes listed below in Table 1.

Shake the vial vigorously to dissolve the drug completely.

Do not use Sterile Water for

Injection, USP because it results in a hypotonic solution and should not be injected directly.

Discard unused solution.

Table 1: Reconstitution for Direct Intravenous Injection Strength Volume of 0.9% Sodium Chloride Injection, USP Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL For Intravenous Infusion Reconstitution of Cyclophosphamide for Injection: Reconstitute cyclophosphamide for injection using 0.9% Sodium Chloride Injection, USP or Sterile Water for Injection, USP with the volume of diluent listed below in Table 2.

Add the diluent to the vial and shake the vial vigorously to dissolve the drug completely.

Table 2: Reconstitution in preparation for Intravenous Infusion Strength Volume of Diluent Cyclophosphamide Concentration 500 mg 25 mL 20 mg per mL 1 g 50 mL 2 g 100 mL Dilution of Reconstituted Cyclophosphamide for Injection: Further dilute the reconstituted cyclophosphamide for injection solution to a minimum concentration of 2 mg per mL with any of the following diluents: 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 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 Reconstituted and Diluted Cyclophosphamide Solution: If not used immediately, for microbiological integrity, cyclophosphamide solutions should be stored as described in Table 3: Table 3: Storage of Cyclophosphamide Solutions Diluent Storage Room Temperature Refrigerated Reconstituted Solution (Without Further Dilution) 0.9% Sodium Chloride Injection, USP up to 24 hrs Up to 6 days Sterile Water for Injection, USP Do not store; use immediately Diluted Solutions 1 0.45% Sodium Chloride Injection, USP up to 24 hrs up to 6 days 5% Dextrose Injection, USP up to 24 hrs up to 36 hrs 5% Dextrose and 0.9% Sodium Chloride Injection, USP up to 24 hrs up to 36 hrs 1 Storage time is the total time cyclophosphamide is in solution including the time it is reconstituted in 0.9% Sterile Sodium Chloride Injection, USP or Sterile Water for Injection, USP.

Liquid preparations of cyclophosphamide for oral administration may be prepared by dissolving cyclophosphamide for injection in Aromatic Elixir, National Formulary (NF).

Store preparations under refrigeration in glass containers and used within 14 days.

See the prescribing information for cyclophosphamide for oral use for additional dosage information.

Cyclophosphamide for

Injection, USP (lyophilized powder) is a sterile white cake containing cyclophosphamide and mannitol and is supplied in single dose vials.

Injection, USP NDC 39822-0250-1 500 mg per vial, carton of 1 NDC 39822-0255-1 1 g per vial, carton of 1 NDC 39822-0260-1 2 g per vial, carton of 1 Store vials at or below 25°C (77°F).

During transport or storage of cyclophosphamide vials, temperature influences can lead to melting of the active ingredient, cyclophosphamide.

Cyclophosphamide is a hazardous product.

Follow special handling and disposal procedures.

Based on its mechanism of action and published reports of effects in pregnant patients or animals, cyclophosphamide for injection can cause fetal harm when administered to a pregnant woman.

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.

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 miscarriage is 15%-20% of clinically recognized pregnancies.

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.

The safety and effectiveness of cyclophosphamide have been established in pediatric patients and information on this use is discussed throughout the labeling.

Pre-pubescent females who receive cyclophosphamide generally develop secondary sexual characteristics normally and have regular menses.

Ovarian fibrosis with apparently complete loss of germ cells after prolonged administration of cyclophosphamide in late pre-pubescence has been reported.

Females who received cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause.

Pre-pubescent males who receive 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.

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.