Cyclophosphamide

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Cyclophosphamide Prescribing Information

Dosage and Administration (

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 2 to 5 days. Other intravenous regimens include 10 mg per kg to 15 mg per kg given every 7 to 10 days or 3 mg per kg to 5 mg per kg twice weekly.

Oral Use

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 [see Warnings and Precautions ].

2.4 Preparation, Handling, and Administration

Cyclophosphamide for Injection is a hazardous drug. Follow applicable special handling and disposal procedures 1. 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 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

Reconstitute Cyclophosphamide 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:

Reconstitute Cyclophosphamide 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. Discard unused solution.

Table 2: Reconstitution in preparation for Intravenous Infusion
Strength	Volume of Diluent	Cyclophosphamide Concentration
500 mg	25 mL
1 g	50 mL	20 mg per mL
2 g	100 mL

Dilution of Reconstituted Cyclophosphamide:

Further dilute the reconstituted Cyclophosphamide 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
Diluent	Room Temperature	Refrigerated
Reconstituted Solution ( Without Further Dilution )
0.9% Sodium Chloride Injection, USP	up to 24 hours	Up to 6 days
Sterile Water for Injection, USP	Do not store; use immediately
Diluted Solutions 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.
0.45% Sodium Chloride Injection, USP	up to 24 hours	up to 6 days
5% Dextrose Injection, USP	up to 24 hours	up to 36 hours
5% Dextrose and 0.9% Sodium Chloride Injection, USP	up to 24 hours	up to 36 hours

Reconstituted Solution for Oral Administration

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 use within 14 days. See the prescribing information for cyclophosphamide for oral use for additional dosage information.

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Warnings and Precautions, Embryo Fetal Toxicity (

5.7 Embryo-Fetal Toxicity

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

[see Use in Specific Populations , Clinical Pharmacology , and Nonclinical Toxicology ]

. 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 ]

. Advise females of reproductive potential to use effective contraception during treatment with Cyclophosphamide for 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 for Injection and for 4 months after completion of therapy

[see Use in Specific Populations ].

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Cyclophosphamide for Injection 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 for 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.
)
•
Minimal Change Nephrotic Syndrome in Pediatric Patients
: biopsy proven minimal change nephrotic syndrome patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy (
1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients
Cyclophosphamide for Injection is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatric patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.
Limitations of Use:

The safety and effectiveness of Cyclophosphamide for Injection for the treatment of nephrotic syndrome in adults or other renal disease has not been established.
)

Limitations of Use
:

The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established. (
1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients
Cyclophosphamide for Injection is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatric patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.
Limitations of Use:

The safety and effectiveness of Cyclophosphamide for Injection for the treatment of nephrotic syndrome in adults or other renal disease has not been established.
)

During or immediately after Cyclophosphamide for Injection administration, administer adequate amounts of fluid to reduce the risk of urinary tract toxicity (

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.

Malignant Diseases: Adult and Pediatric Patients

(

2.2 Recommended Dosage for Malignant Diseases

Adults and Pediatric Patients

Intravenous Use

Oral Use

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.

)

•Intravenous: Initial course for patients with no hematologic deficiency: 40 mg per kg to 50 mg per kg in divided doses over 2 to 5 days. Other regimens include 10 mg per kg to 15 mg per kg given every 7 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

(

2.3 Recommended Dosage for Minimal Change Nephrotic Syndrome in Pediatric Patients

The recommended dosage is 2 mg per kg orally once daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg) is recommended. Treatment beyond 90 days increases the probability of sterility in males

[see Use in Specific Populations ].

)

•Oral: 2 mg per kg daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males.
•Treatment beyond 90 days increases the probability of sterility in males. (
8.4 Pediatric Use
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.
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•
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 for Injection and for 1 week after the last dose.
)
•
Renal Impairment:
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, which may increase toxicity
[see Clinical Pharmacology ]
. Monitor patients with severe renal impairment (creatinine clearance (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. In patients requiring dialysis, consider using a consistent interval between cyclophosphamide administration and dialysis.
,
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 t^1/2following 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).
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Hypersensitivity
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.
Urinary Outflow Obstruction
Cyclophosphamide for Injection is contraindicated in patients with urinary outflow obstruction
[see Warnings and Precautions (
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 ].
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.
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