(RS)-Cyclophosphamide

Uses

Malignant Diseases:

(RS)-Cyclophosphamide is used 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 myelogenousand 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

(RS)-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:

(RS)-Cyclophosphamide is used 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.

(RS)-Cyclophosphamide is also used to associated treatment for these conditions: Acute Lymphoblastic Leukaemias (ALL), Acute Myelocytic Leukemia, Adenocarcinoma of the Ovaries, Autoimmune Hemolytic Anemia, Breast Cancer, Burkitt's Lymphoma, Chronic Lymphocytic Leukaemia (CLL), Chronic Myeloid Leukemia (CML), Disseminated Neuroblastoma, Ewing's Sarcoma, Granulomatosis With Polyangiitis, Juvenile Idiopathic Arthritis (JIA), Lung Cancers, Lymphoma, Hodgkins, Minimal Change Nephrotic Syndrome (MCNS), Multiple Myeloma (MM), Myasthenia Gravis, Nephritis, Lupus, Non-Hodgkin's Lymphoma (NHL), Ovarian germ cell tumour, Pheochromocytomas, Retinoblastoma, Rhabdomyosarcomas, Uveitis, Waldenström's Macroglobulinemia (WM), Advanced Alibert-Bazin syndrome, Histiocytic lymphoma, Metastatic gestational trophoblastic tumor, Mixed-cell type lymphoma, Recurrent Pericarditis, Refractory Small cell lung cancer, Refractory immune thrombocytopenia, Relapsed Wilm's tumor, Conditioning regimens for allogeneic stem cell transplantation therapy

How (RS)-Cyclophosphamide works

Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations.

Dosage

(RS)-Cyclophosphamide dosage

Intravenous (Adult)-

Malignancies:

• Low dose regimen: 2-6 mg/kg wkly as a single dose;
• Moderate dose regimen: 10-15 mg/kg wkly as a single dose;
• High dose regimen: 20-40 mg/kg as a single dose every 10-20 days.

Alternatively,

• 80-300 mg/m2daily as a single dose, or
• 300-600 mg/m2wkly as a single dose, or
• 600-1,500 mg/m2as a single dose or
• Short infusion at 10- to 20-day intervals.

Oral(Child)-

Nephrotic syndrome:

• 2 mg/kg daily for 8-12 wk.
• Max cumulative dose: 168 mg/kg.
• Max duration: 90 days.

Oral(Adult)-

Malignancies:

• Low dose regimen: 2-6 mg/kg wkly in divided dose.
• Alternatively, 100-300 mg daily in divided doses, or
• 50-250 mg/m2daily or 80-300 mg/m2daily in divided doses.

Should be taken on an empty stomach. Preferably taken on an empty stomach, but may be taken with meals to minimise GI irritation. Ensure adequate fluid intake. Swallow whole.

Reconstitute with 25 mL for a 500 mg vial, 50 mL for a 1,000 mg vial or 100 mL for a 2,000 mg vial to a concentration of 20 mg/mL using NaCl 0.9% for direct IV push, or NaCl 0.9% or sterile water for inj for IV infusion. Gently swirl to mix. For IV infusion, dilute further with dextrose 5% in water, NaCl 0.45% or dextrose 5% and NaCl 0.9% inj to a minimum concentration of 2 mg/mL.

Side Effects

Alopecia, skin and nails hyperpigmentation, nausea and vomiting, mucositis, inappropriate antidiuretic hormone secretion, carbohydrate metabolism disturbances, gonadal suppression, interstitial pulmonary fibrosis.

Toxicity

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

Precaution

Patient with DM, severe immunosuppression, acute porphyria, pre-existing CV disease or those at risk for cardiotoxicity. Renal and hepatic impairment. Lactation.

Interaction

Increased risk of cardiotoxicity with doxorubicin or other cardiotoxic drugs. May increase incidence of mucositis with protease inhibitors. May increase haematotoxicity and/or immunosuppression with ACE inhibitors, natalizumab, paclitaxel, thiazide diuretics, zidovudine. May increase pulmonary toxicity with amiodarone. May increase nephrotoxicity with amphotericin B. May result to acute water intoxication with indometacin. May increase risk of hepatotoxicity with azathioprine. May increase incidence of hepatic veno-occlusive disease and mucositis with busulfan. May increase risk of haemorrhagic cystitis with previous or concomitant radiotherapy. May result to acute encephalopathy with metronidazole. May increase risk of thromboembolic complications. May alter the effect of warfarin. May increase immunosuppressive effect of ciclosporin. May result to prolonged apnoea with depolarising muscle relaxants (e.g. suxamethonium).

Food Interaction

• Drink plenty of fluids. Drink 2 to 3 liters of fluids a day.
• Take with food. Food reduces irritation.

(RS)-Cyclophosphamide Drug Interaction

Moderate: pegfilgrastim, pegfilgrastimMinor: doxorubicin, doxorubicin, ondansetron, ondansetronUnknown: sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, diphenhydramine, diphenhydramine, sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprim, pregabalin, pregabalin, acetaminophen, acetaminophen, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

(RS)-Cyclophosphamide Disease Interaction

Major: myelosuppression, urinary tract obstructionModerate: cardiac disease/cardiotoxicity, hepatic dysfunction, pulmonary impairment, renal dysfunction

Volume of Distribution

30-50 L

Elimination Route

After oral administration, peak concentrations occur at one hour.

Half Life

3-12 hours

Clearance

Total body clearance = 63 ± 7.6 L/kg.

Elimination Route

(RS)-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 IV administration.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Patient with bone marrow aplasia, urinary outflow obstruction, UTI, acute infection, drug- or radiation-induced urothelial toxicity. Pregnancy.

Acute Overdose

Symptoms: Urotoxicity, myelosuppression, cardiotoxicity (including cardiac failure), stomatitis, veno-occlusive hepatic disease.

Management: Supportive treatment. May consider haemodialysis. Cystitis prophylaxis with mesna may be useful for urotoxicity.

Storage Condition

Store at or below 25°C.

Innovators Monograph

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