CYCLOPHOSPHAMIDE

Cyclophosphamide Tablets are for oral use. Cyclophosphamide should only be used by clinicians experienced in the use of cancer chemotherapy. Cyclophosphamide should only be administered where there are facilities for regular monitoring of clinical, biochemical and haematological parameters before, during, and after administration and under the direction of a specialist oncology service.

Posology Dosage must be individualized. Doses and duration of treatment and/or treatment intervals depend on the therapeutic indication, the scheme of a combination therapy, the patient’s general state of health and organ function, and the results of laboratory monitoring (in particular, blood cell monitoring).

The dosage regimen used for most indications is 100 – 300 mg daily as a single or divided dose. This treatment should be continued until a clear remission or improvement is seen or be interrupted when the extent of leucopenia becomes unacceptable.

In combination with other cytostatics of similar toxicity, a dose reduction or extension of the therapy-free intervals may be necessary. Activation of cyclophosphamide requires hepatic metabolism; therefore, oral and intravenous administrations are preferred.

Use of hematopoiesis stimulating agents (colony-stimulating factors and erythropoiesis stimulating agents) may be considered to reduce the risk of myelosuppressive complications and/or help facilitate the delivery of the intended dosing.

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.

See Section

ADR frequency is based upon the following scale:

Very Common (≥1/10); Common (≥1/100 - <1/10), Uncommon (≥1/1,000 - <1/100), Rare (≥1/10,000 - <1/1,000), Very Rare (<1/10,000), Unknown (adverse reactions reported in the post-marketing experience) System Organ Class Preferred term Frequency Infections and infestations Infections1 Pneumonia2 Sepsis1 Septic shock Common Uncommon Uncommon Not Known Neoplasms benign, malignant and unspecified (incl cycts and polyps) Acute leukemia3 Myelodysplastic syndrome Secondary tumours Bladder cancer Tumour lysis syndrome Rare Rare Rare Rare Not known Blood and lymphatic system disorders Myelosuppression 4 Haemolytic uraemic syndrome Disseminated intravascular coagulation (DIC ) Lymphopenia Very common Very common Very rare Not known Immune system disorders Immunosuppression Anaphylactic/Anaphylactoid reaction Hypersensitivity reaction Very common Very rare Uncommon Endocrine disorders SIADH Rare Metabolism and nutrition disorders Anorexia Dehydration Hyponatraemia Fluid retention Blood glucose changes (increase or decrease) Uncommon Rare Very rare Very rare Not known Psychiatric disorders Confusion Very rare Nervous system disorders Dizziness Convulsion Neurotoxicity5 Encephalopathy Rare Very rare Unknown Unknown Eye disorders Conjunctivitis Eye Oedema Visual impairment Lacrimation increased Very Rare Very Rare Rare Not known Ear and labyrinth disorders Deafness Tinnitus Not known Not known Cardiac disorders Ventricular fibrillation Ventricular tachycardia Cardiogenic shock Pericardial effusion Myocardial infarction Cardiac failure Cardiomyopathy Myocarditis Pericarditis Electrocardiogram QT prolonged Arrhythmias6 Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known System Organ Class Preferred term Frequency Vascular disorders Flushing Pulmonary embolism Venous thrombosis Vasculitis Peripheral ischaemia Uncommon Not known Not known Not known Not known Respiratory, thoracic and mediastinal disorders Pulmonary veno-occlusive disease Acute respiratory distress syndrome (ARDS) Interstitial Lung Diseases7 Pulmonary hypertension Pulmonary oedema Bronchospasm Dyspnea Hypoxia Cough Nasal congestion Rhinorrhea Oropharyngeal pain Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Gastrointestinal disorders Enterocolitis haemorrhagic Acute pancreatitis Mucosal ulceration Stomatitis Diarrhoea Vomiting Constipation Nausea Gastrointestinal Haemorrhage Colitis Enteritis Cecitis Abdominal pain Parotid gland inflammation Very rare Very rare Very rare Very rare Very rare Very rare Very rare Very rare Unknown Unknown Unknown Unknown Unknown Unknown Hepatobiliary disorders Hepatic function abnormal Veno-occlusive disorder Hepatitis Cholestasis Hepatotoxicity8 Common Not known Not known Not known Not known 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 (including inflammatory itching) Erythema Urticaria Blisters Facial swelling Hyperhidrosis Very common Rare Rare Rare Very rare Very rare Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known System Organ Class Preferred term Frequency Musculoskeletal and connective tissue disorders Rhabdomyolysis Scleroderma Muscle spasms Myalgia Arthralgia Not known Not known Not known Not known Not known Renal and urinary disorders Cystitis Microhematuria Haemorrhagic cystitis Macrohematuria Suburethral bleeding Oedema of the bladder wall Interstitial inflammation, fibrosis, and sclerosis of bladder Renal failure Blood creatinine increased Renal tubular necrosis Renal tubular disorder Nephropathy toxic Hemorrhagic ureteritis Cystitis ulcerative Bladder contracture Nephrogenic diabetes insipidus Atypical urinary bladder epithelial cells Blood urea nitrogen increased Very common Very common Common Common Very rare Very rare Very rare Very rare Very rare Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Unknown Pregnancy, puerperium and perinatal conditions Premature labour Not known Reproductive system and breast disorders Impairment of spermatogenesis Ovulation disorder Amenorrhoea9 Azoospermia9 Oligospermia9 Infertility Ovarian Failure Oligomenorrhoea, Testicular atrophy Blood oestrogen decreased Blood gonadotrophin increased Common Uncommon Rare Rare Rare Unknown Unknown Unknown Unknown Unknown Unknown Congenital, familial and genetic disorders Intra-uterine death Fetal malformation Fetal growth retardation Fetal toxicity (including myelosuppression/gastroenteritis) Not known Not known Not known Not known General disorders and administration site conditions Fever Asthenia Mucosal inflammation Chest pain Headache Injection/infusion site reactions10 Multiorgan failure Oedema Influenza-like illness General physical deterioration Very common Common Common Rare Very Rare Not known Not known Not known Not known Not known System Organ Class Preferred term Frequency Investigations Blood lactate hydrogenase increased C-reactive protein increased Not known Not known 1 including other bacterial, fungal, viral, protozoal, parasitic, reactivation of latent infections, including viral hepatitis, tuberculosis, JC virus with progressive multifocal leucoencephalopathy (including fatal outcomes), Pneumocystis jiroveci, herpes zoster, Strongyloides 2 including fatal outcomes 3 including acute myeloid leukemia, acute promyelocytic leukemia 4 manifested as Bone marrow failure, Pancytopenia, Neutropaenia, Agranulocytosis, Granulocytopenia,Thrombocytopaenia (complicated by bleeding), Leukopenia, Anaemia 5 manifested as reversible posterior leukoencephalopathy syndrome, myelopathy, peripheral neuropathy, polyneuropathy,neuralgia, dysesthesia, […]

4. Patients with Hepatic Impairment Severe hepatic impairment may be associated with decreased activation of cyclophosphamide. This may alter the effectiveness of cyclophosphamide treatment and should be considered when selecting the dose and interpreting response to the dose selected.

Patients with Renal Impairment In patients with renal impairment, particularly in patients with severe renal impairment, decreased renal excretion may result in increased plasma levels of cyclophosphamide and its metabolites. This may result in increased toxicity and should be considered when determining the dosage in such patients.

Cyclophosphamide and its metabolites are dialyzable, although there may be differences in clearance depending upon the dialysis system being used. In patients requiring dialysis, use of a consistent interval between cyclophosphamide administration and dialysis should be considered.

4. Elderly In elderly patients, monitoring for toxicities and the need for dose adjustment should reflect the higher frequency of decreased hepatic, renal, cardiac, or other organ function, and concomitant diseases or other drug therapy in this population.

Children No specific information. Children have received Cyclophosphamide. No adverse reactions specific to this group have been reported. Method of Administration Cyclophosphamide Tablets should be swallowed with sufficient fluid without chewing.

The tablets are coated and should not be divided before use. 3 Contraindications Cyclophosphamide is contra-indicated in patients with: • hypersensitivity to cyclophosphamide or to any of its metabolites. • acute infections, • bone-marrow aplasia, • urinary tract infection • acute urothelial toxicity from cytotoxic chemotherapy or radiation therapy • Urinary outflow obstruction.

Cyclophosphamide should not be used in the management of non-malignant disease, except for immunosuppression in life-threatening situations. Cyclophosphamide is contra-indicated during pregnancy. 6. 4 Special warnings and precautions for use WARNINGS Anaphylactic Reactions, Cross-sensitivity with Other Alkylating Agents Anaphylactic reactions including those with fatal outcomes have been reported in association with cyclophosphamide.

Cyclophosphamide is contra-indicated in patients with: • hypersensitivity to cyclophosphamide or to any of its metabolites. • acute infections, • bone-marrow aplasia, • urinary tract infection • acute urothelial toxicity from cytotoxic chemotherapy or radiation therapy • Urinary outflow obstruction.

Cyclophosphamide should not be used in the management of non-malignant disease, except for immunosuppression in life-threatening situations. Cyclophosphamide is contra-indicated during pregnancy. 6.