Adult: Monotherapy or in combination with other antineoplastic agents: Dose and treatment duration or interval are individualised depending on the indication, scheme of combination therapy, or patient condition including the state of bone marrow. Low-dose therapy: 2-6 mg/kg weekly as a single dose. Moderate-dose therapy: 10-15 mg/kg weekly as a single dose. High-dose therapy: 20-40 mg/kg as a single dose every 10-20 days. Alternative dosing regimens: For daily therapy: 3-6 mg/kg (approx 120-240 mg/m2). For intermittent therapy: 10-15 mg/kg (approx 400-600 mg2) at intervals of 2-5 days. For high-dose intermittent therapy: 20-40 mg/kg (approx 800-1,600 mg/m2) at intervals of 21-28 days. Doses are given via very slow infusion or inj. Dose reduction, dosing interruption or discontinuation may be required according to patient haematological status. Dosage recommendations may vary among countries and individual products. Refer to detailed product or local treatment guidelines.
Intravenous Conditioning regimens for haematopoietic stem cell transplantation
Adult: In combination with busulfan or whole-body irradiation: 20-40 mg/kg (approx 800-1,600 mg/m2) at intervals of 21-28 days. Alternatively, 60 mg/kg for 2 days or 50 mg/kg for 4 days. Doses are given via very slow infusion or inj. If given with busulfan regimen, administer the 1st dose of cyclophosphamide at least 24 hours after the last dose of busulfan. Dose reduction, dosing interruption or discontinuation may be required according to patient haematological status. Dosage recommendations may vary among countries and individual products. Refer to detailed product or local treatment guidelines.
Adult: Monotherapy or in combination with other antineoplastic agents: Dose and treatment duration or interval are individualised depending on the indication, scheme of combination therapy, or patient condition including the state of bone marrow. Low dose therapy: 2-6 mg/kg weekly in divided doses. Alternatively, 100-300 mg daily as a single or in divided doses, or 1-5 mg/kg once daily. Dosage recommendations may vary among countries and individual products (refer to detailed product or local treatment guidelines).
Oral Minimal change nephrotic syndrome
Child: For biopsy-proven cases in patients who failed to adequately respond to or are intolerant to corticosteroid therapy: 2 mg/kg once daily for 8-12 weeks. Max cumulative dose: 168 mg/kg. Max treatment duration: 90 days.
Renal Impairment
Intravenous:
Severe: Dose adjustment may be necessary.
Hepatic Impairment
Intravenous:
Severe (serum bilirubin of 3.1-5 mg/100 mL): Dose adjustment may be necessary.
Administration
Should be taken on an empty stomach. Preferably taken on an empty stomach, but may be taken w/ meals to minimise GI irritation. Ensure adequate fluid intake. Swallow whole.
Reconstitution
Powder for inj: Reconstitute vials labelled as 200 mg, 500 mg, 1,000 mg, or 2,000 mg with 10 mL, 25 mL, 50 mL, or 100 mL of 0.9% NaCl solution (for direct IV inj or IV infusion) or sterile water for inj (for IV infusion), respectively, to prepare a concentration of 20 mg/mL. Shake vigorously to completely dissolve the powder. For IV infusion, further dilute the reconstituted solution in 5% dextrose in water (D5W), 0.45% NaCl, or dextrose 5% in normal saline (D5NS) to make at least 2 mg/mL concentration. Solution for inj: Dilute appropriate dose in 0.9% NaCl, 0.45% NaCl, D5W, or D5NS to yield a concentration of at least 20 mg/mL (for direct IV inj) or 2 mg/mL (for IV infusion).
Incompatibility
Solutions containing benzyl alcohol may decrease the stability of cyclophosphamide.
Contraindications
Acute infections, bone marrow aplasia, severely impaired bone marrow function, urinary outflow obstruction, UTI, drug- or radiation-induced acute urothelial toxicity. Pregnancy and lactation.
Special Precautions
Patient with severe immunosuppression, pre-existing cardiac disease, risk factors for cardiotoxicity (e.g. previous radiation treatment of the cardiac region, prior or concomitant therapy with other cardiotoxic drugs), predisposing factors for hepatic sinusoidal obstruction syndrome (SOS) such as pre-existing hepatic dysfunction, previous radiotherapy of the abdomen, and low performance status; adrenal insufficiency, acute porphyria, diabetes mellitus. Avoid use in patients with neutrophil count ≤1,500 cells/mm3, leucocyte count <2,500 cells/mm3, or platelet count <50,000 cells/mm3. Debilitated patients. Renal and hepatic impairment. Children and elderly.
Adverse Reactions
Significant: Myelosuppression (e.g. leucopenia, neutropenia, thrombocytopenia, anaemia), bone marrow failure, infections or reactivation of latent infections; renal toxicity (e.g. pyelitis, ureteritis, haematuria, renal tubular necrosis); cardiotoxicity such as myocarditis, myopericarditis, pericardial effusion (including cardiac tamponade), haemopericardium secondary to haemorrhagic myocarditis and myocardial necrosis, supraventricular arrhythmias (including atrial flutter and fibrillation), ventricular arrhythmias (including severe QT prolongation associated with ventricular tachyarrhythmia); hepatic SOS; pulmonary toxicity (e.g. pneumonitis, pulmonary fibrosis, pulmonary veno-occlusive disease, acute respiratory distress syndrome) which may lead to respiratory failure; secondary malignancies (e.g. myelodysplastic alterations, urinary tract or bladder cancer, acute leukaemias, lymphomas, thyroid cancer, sarcomas); may impair wound healing, alopecia, nausea and vomiting, stomatitis, sterility (in male and female). Eye disorders: Increased lacrimation. Rarely, blurred vision. Ear and labyrinth disorders: Deafness, impaired hearing. Gastrointestinal disorders: Diarrhoea, abdominal pain, gastrointestinal haemorrhage, colitis, enteritis, parotid gland inflammation. General disorders and administration site conditions: Asthenia, fever, mucosal inflammation, chills, malaise. Rarely, IV inj/infusion site reactions (e.g. pain, erythema, swelling). Hepatobiliary disorders: Abnormal hepatic function. Investigations: Increased BUN, blood lactate dehydrogenase, and C-reactive protein; decreased LVEF; ECG changes. Metabolism and nutrition disorders: Anorexia. Nervous system disorders: Neurotoxicity (e.g. peripheral neuropathy, neuralgia, polyneuropathy). Rarely, dizziness. Renal and urinary disorders: Cystitis ulcerative, nephrogenic diabetes insipidus, atypical urinary bladder epithelial cells. Reproductive system and breast disorders: Ovulation disorder, ovarian failure, oligomenorrhoea, testicular atrophy. Rarely, amenorrhoea (transient or permanent), oligospermia, azoospermia. Skin and subcutaneous tissue disorders: Rash, skin pigmentation, changes in nails. Vascular disorders: Flushing. Potentially Fatal: Anaphylactic reactions, severe immunosuppression which may lead to fatal infections (including pneumonia, sepsis and septic shock); urotoxicity (e.g. bladder ulceration, necrosis, fibrosis, contracture and secondary cancer), hyponatraemia associated with increased total body water, acute water intoxication, and syndrome that resembles syndrome of inappropriate secretion of antidiuretic hormone (SIADH), haemorrhagic cystitis; CHF, late onset of pneumonitis.
IM/Intraperitoneal/Intrapleural/IV/Parenteral/PO: D
Patient Counseling Information
This drug may cause dizziness or blurred vision, if affected, do not drive or operate machinery. Ensure adequate fluid intake and regular bladder emptying.
Monitoring Parameters
Verify pregnancy status prior to use in females of reproductive potential. Hepatitis B virus (HBV) screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen is recommended before or at the beginning of systemic anticancer therapy; treatment must not be delayed for screening/results. Obtain CBC with differential and platelets, BUN, urinalysis, serum electrolytes and serum creatinine. Urinary sediment must be checked periodically for the presence of erythrocytes. Monitor for signs or symptoms of pulmonary, cardiac, and hepatic toxicity, and haemorrhagic cystitis or other urinary or renal toxicity.
Overdosage
Symptoms: Myelosuppression, stomatitis, urotoxicity, hepatic SOS, and cardiotoxicity (including cardiac failure). Management: Supportive treatment. Consider haemodialysis in case of suicidal or accidental overdose or intoxication. May give mesna to prevent or limit urotoxic effects.
Drug Interactions
May cause delayed activation which alters cyclophosphamide efficacy with aprepitant, bupropion, busulfan, ciprofloxacin, chloramphenicol, fluconazole, itraconazole, CYP2B6 and CYP3A4 inhibitors (e.g. nevirapine, ritonavir), prasugrel, sulfonamides (e.g. sulfadiazine, sulfamethoxazole), and thiotepa. May increase concentration of cytotoxic metabolites with allopurinol, chloral hydrate, cimetidine, disulfiram, dabrafenib, CYP450 inducers (e.g. phenobarbital, phenytoin), and protease inhibitors. Decreased exposure with ondansetron. May result in enhanced haematotoxicity and/or immunosuppression with ACE inhibitors, natalizumab, paclitaxel, thiazide diuretics (e.g. hydrochlorothiazide), clozapine, and zidovudine. May cause increased cardiotoxicity with anthracyclines, cytarabine, pentostatin, and trastuzumab. May lead to enhanced pulmonary toxicity with amiodarone and granulocyte colony-stimulating factor or granulocyte macrophage colony-stimulating factor. Nephrotoxicity may be increased when concurrently given with amphotericin B and indometacin. Increased risk of hepatotoxicity (liver necrosis) with azathioprine. Increased incidence of hepatic SOS and mucositis with busulfan. Higher incidence of mucositis with saquinavir. Concomitant use with metronidazole may result in acute encephalopathy. May increase the risk of thromboembolic complications with tamoxifen. May increase or decrease the effects of warfarin. May decrease the serum concentrations of ciclosporin which may lead to increased incidence of graft-versus-host disease. May cause prolonged apnoea with depolarising muscle relaxants (e.g. suxamethonium). May impair the absorption of verapamil, digoxin and β-acetyldigoxin. May reduce the response to vaccines which may lead to vaccine-induced infection.
Food Interaction
Alcohol may enhance cyclophosphamide-induced nausea and vomiting.
Action
Description: Mechanism of Action: Cyclophosphamide is a prodrug antineoplastic agent. It is converted in the body to active alkylating metabolites that interfere with the growth of susceptible rapidly proliferating malignant cells through inhibition of cell division by cross-linking deoxyribonucleic acid (DNA) strands and reducing DNA synthesis. Additionally, it exerts a potent immunosuppressive effect. Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract. Bioavailability: >75%. Time to peak plasma concentration: Oral: Approx 1 hour; IV: 2-3 hours (metabolites). Distribution: Widely distributed in the tissues. Crosses the placenta and blood-brain barrier; enters breast milk. Volume of distribution: 30-50 L (approximates total body water). Plasma protein binding: Approx 20% (cyclophosphamide); >60% (some metabolites). Metabolism: Metabolised in the liver by various CYP450 isoenzymes (particularly CYP2B6) to form initial active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, which both undergo further metabolism. Aldophosphamide may undergo non-enzymatic conversion into phosphoramide mustard (active metabolite) and acrolein (associated with bladder toxicity). Excretion: Via urine (10-20% as unchanged drug); faeces (4%). Elimination half-life: 4-8 hours.
Chemical Structure
Cyclophosphamide Source: National Center for Biotechnology Information. PubChem Database. Cyclophosphamide, CID=2907, https://pubchem.ncbi.nlm.nih.gov/compound/Cyclophosphamide (accessed on Jan. 22, 2020)
Storage
Tab/cap: Store between 20-25°C. Powder for inj: Store unopened vials below 25°C. Reconstituted solutions in 0.9% NaCl may be stored for up to 24 hours between 2-8°C. Diluted solutions for infusion in 0.45% NaCl, D5W or D5NS are stable at room temperature for up to 24 hours. Solution for inj: Store unopened vials between 2-8°C. Diluted solutions for infusion (either 20 mg/mL or 2 mg/mL concentration) may be stored at room temperature for up to 24 hours and between 2-8°C for up to 6 days. Storage and stability recommendations may vary among individual products or between countries (refer to specific local product guidelines). This is a cytotoxic drug. Follow applicable procedures for receiving, handling, administration, and disposal.
L01AA01 - cyclophosphamide ; Belongs to the class of alkylating agents, nitrogen mustard analogues. Used in the treatment of cancer.
References
Anon. Cyclophosphamide. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 16/11/2021.Anon. Cyclophosphamide. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/08/2021.Buckingham R (ed). Cyclophosphamide. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/08/2021.Cyclophosphamide 1,000 mg Powder for Solution for Injection or Infusion (Sandoz Limited). MHRA. https://products.mhra.gov.uk. Accessed 05/08/2021.Cyclophosphamide Capsule (Cipla USA Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 05/08/2021.Cyclophosphamide Injection, Powder for Solution (BluePoint Laboratories). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 05/08/2021.Cyclophosphamide Injection, Solution (Athenex Pharmaceutical Division, LLC.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 05/08/2021.Cyclophosphamide Tablet (Baxter Healthcare Corporation). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 05/08/2021.Cyclophosphamide Tablets 50 mg (Baxter Healthcare Ltd). MHRA. https://products.mhra.gov.uk. Accessed 05/08/2021.Endoxan Powder for Solution for IV Injection; Sugar-Coated Tablet (Baxter Healthcare [Malaysia] Sdn. Bhd.). National Pharmaceutical Regulatory Agency - Ministry of Health Malaysia. https://www.npra.gov.my. Accessed 05/08/2021.Joint Formulary Committee. Cyclophosphamide. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/08/2021.
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