Cyclophosphamide

Registered South African indications:

• Chronic lymphocytic leukaemia
• Non-Hodgkin's lymphoma
• Plasmacytoma
• Neuroblastoma
• Primary and metastatic breast cancer
• Lupus nephritis
• Wegener's granulomatosis

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding
• Acute infections
• Bone-marrow aplasia
• Urinary tract infection
• Acute urothelial toxicity from cytotoxic chemotherapy or radiation therapy
• Urinary outflow obstruction
• Management of non-malignant disease, except for immunosuppression in life-threatening situations

Cautions

• Pregnancy
• Renal impairment
• Severe hepatic impairment
• Elderly
• Latent infections 
• Severe bone marrow suppression
• Severe immunosuppression
• Severe infection
• Leukocyte count < 2 500 cells/mm³
• Platelet count < 50 000 cells/mm³
• Urinary tract obstructions
• Active urinary tract infections
• Severe hemorrhagic cystitis
• High dose
• Previous radiation treatment of the cardiac region 
• Risk factors for cardiotoxicity 
• Preexisting cardiac disease
• Risk factors for the development of veno-occlusive liver disease 
• Childbearing potential
• Adrenal insufficiency
• Pulmonary fibrosis

Forms avail. in SA and covered in this monograph: tab, inj

Used for the treatment of

Chronic lymphocytic leukaemia
Non-Hodgkin's lymphoma
Plasmacytoma
Neuroblastoma
Primary and metabolic breast cancer
Lupus nephritis
Wegener's granulomatosis

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Consult specialist for dosages and regimens

Not approved for use in South Africa for children

Pregnancy

• Caution; positive evidence for risk
• There are very limited data from the use of cyclophosphamide in pregnant women. There are reports of serious multiple congenital aberrations after use during the first trimester. Animal studies have shown teratogenicity and other reproduction toxicity. Considering the data from human case reports, animal studies and the mechanism of action of cyclophosphamide, its use during pregnancy, in particular during the first trimester, is not recommended. In each individual case the potential benefit of the treatment should be weighed against the potential risk for the foetus 
• Women should not become pregnant during the treatment and for a period of 12 months following discontinuation of the therapy. Men should not father a child during the treatment and for a period of 6 months following discontinuation of the therapy. Sexually active women and men should use effective methods of contraception during these periods of time.*See additional prescribing points for fertility

Breastfeeding

• Contraindicated
• Cyclophosphamide is excreted into the breast milk and can cause neutropenia, thrombocytopenia, low haemoglobin, and diarrhoea in children. Cyclophosphamide is contraindicated during breastfeeding

Fertility

• Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes
• In women, cyclophosphamide may cause transient or permanent amenorrhoea, and in males treated with cyclophosphamide during pre-pubescence, oligospermia and azoospermia
• Men treated with cyclophosphamide may develop oligospermia or azoospermia
• Prior to the treatment of men with cyclophosphamide, they should be informed of the possibility of infertility to store and keep viable sperm collected before treatment
• Females treated with cyclophosphamide who have retained ovarian function after completing treatment are at increased risk of developing premature menopause

Renal Impairment

• Caution; no dose adjustment recommended
  Cyclophosphamide may be administered without dosage adjustment for oncology patients (mainly multiple myeloma) with different stages of renal impairment
  It is recommended to use the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, as a first-choice (preferred; if accessible) or eGFR to evaluate renal function estimation in oncology patients (International Myeloma Working Group (IMWG) Recommendations)

Hepatic Impairment

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended
  Serum bilirubin: 3.1-5 mg/100ml (0.053-0.086mmol/l): Reduce dose by 25%

Elderly 

• Caution; no dose adjustment recommended

Porphyria Information

• Possibly porphyrinogenic (PSP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Confusion
• Dizziness
• Convulsion
• Neurotoxicity
• Encephalopathy
• Headache
• Asthenia

Cardiovascular Disorders

• Ventricular fibrillation
• Ventricular tachycardia
• Cardiogenic shock
• Pericardial effusion
• Myocardial infarction
• Cardiac failure
• Cardiomyopathy
• Myocarditis
• Pericarditis
• Prolonged QT interval
• Arrhythmias
• Flushing
• Pulmonary embolism
• Venous thrombosis
• Vasculitis
• Peripheral ischaemia
• Chest pain

Respiratory Disorders

• Pneumonia
• Pulmonary veno-occlusive disease
• Acute respiratory distress syndrome 
• Interstitial lung diseases
• Pulmonary hypertension
• Pulmonary oedema
• Bronchospasm
• Dyspnea
• Hypoxia
• Cough
• Nasal congestion
• Rhinorrhea
• Oropharyngeal pain
• Pneumonitis

Gastrointestinal Disorders

• Enterocolitis haemorrhagic
• Acute pancreatitis
• Mucosal ulceration
• Stomatitis
• Diarrhoea
• Constipation
• Nausea and vomiting
• Gastrointestinal Haemorrhage
• Colitis
• Enteritis
• Cecitis
• Abdominal pain
• Parotid gland inflammation

Hepatobiliary Disorders

• Abnormal hepatic function 
• Veno-occlusive disorder
• Hepatitis
• Cholestasis
• Hepatotoxicity

Genitourinary Disorders

• Cystitis
• Microhematuria
• Haemorrhagic cystitis
• Macrohematuria
• Suburethral bleeding
• Oedema of the bladder wall
• Interstitial inflammation, fibrosis, and sclerosis of bladder
• Renal failure
• Increased blood creatinine
• Renal tubular necrosis
• Renal tubular disorder
• Nephropathy toxic
• Hemorrhagic ureteritis
• Cystitis ulcerative
• Bladder contracture
• Nephrogenic diabetes insipidus
• Atypical urinary bladder epithelial cells
• Increased blood urea nitrogen 
• Premature labour
• Impairment of spermatogenesis
• Ovulation disorder
• Amenorrhoea
• Azoospermia
• Oligospermia
• Infertility
• Ovarian Failure
• Oligomenorrhoea
• Testicular atrophy
• Decreased blood oestrogen 
• Increased blood gonadotrophin 

Endocrine and Metabolic Disorders

• Syndrome of inappropriate antidiuretic hormone secretion
• Anorexia
• Dehydration
• Hyponatraemia
• Fluid retention
• Blood glucose changes

Musculoskeletal Disorders

• Rhabdomyolysis
• Scleroderma
• Muscle spasms
• Myalgia
• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Alopecia
• Rash
• Dermatitis
• Discoloration of the palms, fingernails, soles
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Erythema multiforme
• Palmar-plantar erythrodysaesthesia
• Radiation recall dermatitis
• Erythema in irradiated area
• Pruritus
• Erythema
• Urticaria
• Blisters
• Facial swelling
• Hyperhidrosis
• Mucosal inflammation
• Infusion site reactions

Immune, Blood and Lymphatic System Disorders

• Infections
• Oedema
• Sepsis
• Septic shock
• Acute leukemia
• Myelodysplastic syndrome
• Secondary tumours
• Bladder cancer
• Tumour lysis syndrome
• Myelosuppression
• Haemolytic uraemic syndrome
• Disseminated intravascular coagulation 
• Lymphopenia
• Immunosuppression
• Anaphylactic/Anaphylactoid reaction
• Hypersensitivity reaction
• Increased blood lactate hydrogenase 
• Increased C-reactive protein
• Fever
• Multiorgan failure
• Influenza-like illness
• General physical deterioration

Sensory Disorders

• Conjunctivitis
• Eye Oedema
• Visual impairment
• Increased lacrimation 
• Deafness
• Tinnitus

Others

• Intra-uterine death
• Fetal malformation
• Fetal growth retardation
• Fetal toxicity 

• Aprepitant
• Bupropion
• Busulfan
• Ciprofloxacin
• Chloramphenicol
• Fluconazole
• Itraconazole
• Prasugrel
• Sulfonamides
• Thiotepa
• Allopurinol
• Protease inhibitors
• Chloral hydrate
• Cimetidine
• Disulfiram
• Glyceraldehyde
• Inducers of human hepatic and extrahepatic microsomal enzymes
• Ondansetron
• Angiotensin-converting enzyme inhibitors
• Natalizumab
• Paclitaxel
• Thiazide diuretics
• Zidovudine
• Clozapine
• Anthracyclines
• Cytarabine
• Pentostatin
• Radiation therapy of the cardiac region
• Trastuzumab
• Amiodarone
• Granulocyte colony-stimulating factor (G-CSF)
• Granulocyte macrophage colony-stimulating factor (GM-CSF) 
• Azathioprine
• Busulfan
• Amphotericin B
• Indomethacin
• Alcohol
• Etanercept
• Metronidazole
• Tamoxifen
• Bupropion
• Coumarins
• Cyclosporine
• Depolarizing muscle relaxants
• Digoxin
• β-acetyldigoxin
• Vaccines
• Verapamil

• Full blood count with differential
• Renal function
• Electrolytes
• Urine amylase

Fertility

• Cyclophosphamide interferes with oogenesis and spermatogenesis. It may cause sterility in both sexes
• In women cyclophosphamide may cause transient or permanent amenorrhea, and in boys treated with cyclophosphamide during pre-pubescence, oligospermia or azoospermia
• Men treated with cyclophosphamide may develop oligospermia or azoospermia. Prior to treatment of men with cyclophosphamide, they should be informed of the possibility to store and keep viable sperm collected before treatment

Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent. Cyclophosphamide also possesses potent immunosuppressive activity. Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the liver.

Tablet 50mg

• Endoxan (Sanofi Aventis) originator
• Endoxan (Baxter Healthcare South Africa)

Injection (per vial) 500mg

• Endoxan (Sanofi Aventis) originator
• Endoxan  (Baxter Healthcare South Africa)

Injection (per vial) 1g

• Endoxan (Sanofi Aventis) originator
• Endoxan (Baxter Healthcare South Africa)