CYCLOPHOSPHAMIDE

CYCLOPHOSPHAMIDE- cyclophosphamide capsule
STI Pharma LLC

1 INDICATIONS AND USAGE

1.1 Malignant Diseases

Cyclophosphamide is 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, 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 pediatric 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 for Malignant Diseases

Adults and Pediatric Patients

Oral 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 Handling and Administration

Handle and dispose of cyclophosphamide in a manner consistent with other cytotoxic drugs.1 Caution should be exercised when handling cyclophosphamide containers and capsules. To minimize the risk of dermal exposure, always wear gloves when handling cyclophosphamide containers and capsules. To prevent inadvertent exposure to the active substance, the cyclophosphamide capsules should be swallowed whole. The capsules should not be opened, chewed, or crushed. Exposure to broken capsules should be avoided. If contact with broken capsules occurs, wash hands immediately and thoroughly.

3 DOSAGE FORMS AND STRENGTHS

Each 25 mg capsule for oral administration contains 25 mg of cyclophosphamide USP. It is a blue/blue opaque capsule with “STI 021” printed in black ink on the cap and body, containing a white to off-white powder.

Each 50 mg capsule for oral administration contains 50 mg of cyclophosphamide USP. It is a blue/blue opaque capsule with “STI 022” printed in black ink on the cap and body, containing a white to off-white powder.

4 CONTRAINDICATIONS

  • Hypersensitivity

Cyclophosphamide is contraindicated in patients who have a history of severe hypersensitivity reactions to it, any of its metabolites, or to other components of the product. Anaphylactic reactions including death have been reported with cyclophosphamide. Possible cross-sensitivity with other alkylating agents can occur.

  • Urinary Outflow Obstruction

Cyclophosphamide is contraindicated 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/mm 3 and platelets <50,000/mm 3. 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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