Cyclophosphamide

CYCLOPHOSPHAMIDE- cyclophosphamide injection, powder, for solution
Civica, Inc.

1 INDICATIONS AND USAGE

1.1 Malignant Diseases

Cyclophosphamide is indicated for the treatment of:

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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

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multiple myeloma

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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)

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mycosis fungoides (advanced disease)

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neuroblastoma (disseminated disease)

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adenocarcinoma of the ovary

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retinoblastoma

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carcinoma of the breast

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

1.2 Minimal Change Nephrotic Syndrome in Pediatric Patients

Cyclophosphamide is indicated for the treatment of biopsy proven minimal change nephrotic syndrome in pediatrics patients who failed to adequately respond to or are unable to tolerate adrenocorticosteroid therapy.

Limitations of Use:
The safety and effectiveness for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

2 DOSAGE AND ADMINISTRATION

During or immediately after the administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urinary tract toxicity. Therefore, cyclophosphamide should be administered in the morning.

2.1 Dosing of Malignant Diseases

Adults and Pediatric Patients

Intravenous
When used as the only oncolytic drug therapy, the initial course of cyclophosphamide for patients with no hematologic deficiency usually consists of 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.

OralOral cyclophosphamide dosing is usually in the range of 1 mg per kg per day to 5 mg per kg per day for both initial and maintenance dosing.

Many other regimens of intravenous and oral cyclophosphamide have been reported. Dosages must be adjusted in accord with evidence of antitumor activity and/or leukopenia. The total leukocyte count is a good, objective guide for regulating dosage.

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

2.2 Dosing for Minimal Change Nephrotic Syndrome in Pediatric Patients

An oral dose of 2 mg per kg 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 (8.4)].

2.3 Preparation, Handling and Administration

Handle and dispose of cyclophosphamide in a manner consistent with other cytotoxic drugs.1 Caution should be exercised when handling and preparing Cyclophosphamide for Injection, USP. To minimize the risk of dermal exposure, always wear gloves when handling vials containing Cyclophosphamide for Injection, USP.

Cyclophosphamide for Injection, USP

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. Add the diluent to the vial and 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.

Table 1: Reconstitution for Direct Intravenous Injection

Strength	Volume of 0.9% Sodium Chloride	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.

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:

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5% Dextrose Injection, USP

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5% Dextrose and 0.9% Sodium Chloride Injection, USP

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0.45% 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

* 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.
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 *
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

Use of 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). Such preparations should be stored under refrigeration in glass containers and used within 14 days.