Cyclophosphamide

CYCLOPHOSPHAMIDE- cyclophosphamide capsule
West-Ward Pharmaceuticals Corp.

1 INDICATIONS AND USAGE

1.1 Malignant Diseases

Cyclophosphamide Capsules are indicated for the treatment of:

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 Capsules, 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 Capsules are 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 Capsules for the treatment of nephrotic syndrome in adults or other renal disease has not been established.

2 DOSAGE AND ADMINISTRATION

2.1 Hydration and Important Administration Instructions

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

Cyclophosphamide Capsules should be swallowed whole. The capsules should not be opened, chewed, or crushed.

Cyclophosphamide Capsules is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 Exposure to broken capsules should be avoided. If contact with broken capsules occurs, wash hands immediately and thoroughly.

2.2 Recommended Dosage for Malignant Diseases

Adults and Pediatric Patients

The recommended dosage of Cyclophosphamide Capsules is in the range of 1 mg per kg to 5 mg per kg orally once daily for both initial and maintenance dosing.

Other regimens of intravenous and oral cyclophosphamide have been reported. Dosages should be adjusted based on evidence of antitumor activity, myelosuppression, or other severe adverse reactions [see WARNINGS and PRECAUTIONS (5) ].

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.

2.3 Recommended Dosage for Minimal Change Nephrotic Syndrome in Pediatric Patients

The recommended dosage of Cyclophosphamide Capsules is 2 mg per kg orally once daily for 8 to 12 weeks (maximum cumulative dose 168 mg per kg). Treatment beyond 90 days increases the probability of sterility in males [see USE IN SPECIFIC POPULATIONS (8.4)].

3 DOSAGE FORMS AND STRENGTHS

Capsules:

25 mg capsule for oral administration contains 25 mg of cyclophosphamide USP. It is a blue/blue opaque capsule with “54 006” printed in black ink on the cap and body, containing a white to off-white powder.
50 mg capsule for oral administration contains 50 mg of cyclophosphamide USP. It is a blue/blue opaque capsule with “54 881” printed in black ink on the cap and body, containing a white to off-white powder.

4 CONTRAINDICATIONS

Cyclophosphamide Capsules are contraindicated in patients with:

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.
In patients with urinary outflow obstruction [see WARNINGS AND PRECAUTIONS (5.2) ].

5 WARNINGS AND PRECAUTIONS

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/mm3 and 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.

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.

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.

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