IFOSFAMIDE

Ifosfamide should only be administered when 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 by physicians experienced with this drug.

Dosage must be individualised. 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 combination with other agents of similar toxicity, a dose reduction or extension of the therapy-free intervals may be necessary. Method of administration A guide to the dosage regimens used for most indications is given below: a) 8 - 12 g/m² equally fractionated as single daily doses over 3 - 5 days every 2 - 4 weeks.

b) 5 - 6 g/m² (maximum 10 g) given as a 24 hour infusion every 3 – 4 weeks. The frequency of dosage is determined by the degree of myelosuppression and the time taken to recover adequate bone marrow function. The usual number of courses given is 4, but up to 7 (6 by 24 hour infusion) courses have been given.

Re-treatment has been given following relapse. During or immediately after administration, adequate amounts of fluid should be ingested or infused to force diuresis in order to reduce the risk of urothelial toxicity. See Section

The adverse reactions and frequencies below are based on publications describing clinical experience with fractionated administration of ifosfamide as monotherapy with a total dose of 4 to 12 g/m2 per course.

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), Not known (adverse reactions reported in the post-marketing experience). System Organ Class (SOC) Adverse Reaction Frequency Category INFECTIONS AND INFESTATIONS Infections (including reactivation of latent infections) Sepsis (septic shock)* Common Not known NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYCTS AND POLYPS) Secondary tumors* (including Urinary tract carcinoma, Myelodysplastic syndrome, Acute leukaemia, Acute lymphocytic leukaemia, Lymphoma [Non-Hodgkin’s lymphoma], Sarcomas, Renal cell carcinoma, Thyroid cancer) Progressions of underlying malignancies* Not known Not known BLOOD AND LYMPHATIC SYSTEM DISORDERS Myelosuppression - Leukopenia - Thrombocytopenia* - Anaemia - Agranulocytosis Haematotoxicity* - Haemolytic anaemia - Methaemoglobinaemia Febrile bone marrow aplasia Disseminated intravascular coagulation Haemolytic uremic syndrome Neonatal anaemia Very common Very common Very common Not known Not known Not known Not known Not known Not known Not known Not known Not known IMMUNE SYSTEM DISORDERS Angioedema* Anaphylactic reaction Immunosuppression Urticaria Hypersensitivity reaction Not known Not known Not known Not known Not known System Organ Class (SOC) Adverse Reaction Frequency Category ENDOCRINE DISORDERS Syndrome of inappropriate antidiuretic hormone secretion (SIADH) Not known METABOLISM AND NUTRITION DISORDERS Decreased Appetite Tumor lysis syndrome Metabolic acidosis Hypokalaemia Hypocalcaemia Hypophosphataemia Hyperglycaemia Polydipsia Common Not known Not known Not known Not known Not known Not known Not known PSYCHIATRIC DISORDERS Mutism Mental status change (includine mania, paranoia, delusion, delirium, catatonia, amnesia, panic attack) Echolalia Perseveration Not known Not known Not known Not known NERVOUS SYSTEM DISORDERS Central nervous system toxicity - Encephalopathy - Faecal incontinence - Status epilepticus* (convulsive and nonconvulsive) - Movement disorder - Extrapyramidal disorder - Gait disturbance - Dysarthria Peripheral neuropathy - Hypoesthesia - Paresthesia Asterixis Neuralgia Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known EYE DISORDERS Visual impairment Conjunctivitis Eye irritation Not known Not known Not known EAR AND LABYRINTH DISORDERS Deafness Vertigo Tinnitus Not known Not known Not known System Organ Class (SOC) Adverse Reaction Frequency Category CARDIAC DISORDERS Cardiotoxicity* Arrythmia (including supraventricular and ventricular arrhythmia) Atrial fibrillation Premature atrial contractions Bradycardia Cardiac arrest* Myocardial infarction Cardiac failure* Myocardial haemorrhage Angina pectoris Cardiomyopathy* (including congestive cardiomyopathy) Electrocardiogram ST-segment abnormal Electrocardiogram T- wave inversion Electrocardiogram QRS complex abnormal Uncommon Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known VASCULAR DISORDERS Hypotension Pulmonary embolism Deep vein thrombosis Capillary leak syndrome Vasculitis Hypertension Flushing Uncommon Not known Not known Not known Not known Not known Not known RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS Respiratory failure* Acute respiratory distress syndrome* Pulmonary hypertension Interstitial lung disease* (as manifested by Pulmonary fibrosis) Pneumonitis* Pulmonary oedema* Pleural effusion Dyspnea Hypoxia Cough Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known GASTROINTESTINAL DISORDERS Nausea/Vomiting Diarrhoea Stomatitis Enterocolitis Pancreatitis Ileus Gastrointestinal haemorrhage Mucosal ulceration Constipation Abdominal pain Salivary hypersecretion Very common Uncommon Uncommon Not known Not known Not known Not known Not known Not known Not known Not known System Organ Class (SOC) Adverse Reaction Frequency Category HEPATOBILIARY DISORDERS Hepatotoxicity - Hepatic failure Veno-occlusive liver disease Portal vein thrombosis Cytolytic hepatitis Common Not known Not known Not known Not known SKIN AND SUBCUTANEOUS TISSUE DISORDERS Alopecia Dermatitis Papular rash Toxic epidermal necrolysis Stevens-Johnson syndrome Palmar-plantar erythrodysesthesia syndrome Radiation recall dermatitis Skin necrosis Facial swelling Rash Pruritus Erythema Skin hyperpigmentation Hyperhidrosis Nail disorder Very common Rare Rare Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS Rhabdomyolysis Osteomalacia Rickets Growth retardation Myalgia Arthralgia Muscle twitching Not known Not known Not known Not known Not known Not known Not known RENAL AND URINARY DISORDERS Haemorrhagic cystitis Haematuria Renal dysfunction* - Acute renal failure - Chronic renal failure - Aminoaciduria - Phosphaturia - Fanconi syndrome - Tubulointerstitial nephritis Renal structural damage Nephrogenic diabetes insipidus Polyuria Enuresis Feeling of residual urine Very common Very common Very common Very common Not known Not known Not known Not known Not known Not known Not known Not known Not known Not known System Organ Class (SOC) Adverse Reaction Frequency Category REPRODUCTIVE SYSTEM AND BREAST DISORDERS Infertility Ovarian failure Premature menopause Amenorrhea Ovulation disorder Azoospermia Oligospermia Not known Not known Not known Not known Not known Not known Not known CONGENITAL, FAMILIAL AND GENETIC DISORDERS Fetal growth retardation Not known GENERAL DISORDERS AND ADMINISTRATIVE SITE […]

4. For prophylaxis of haemorrhagic cystitis, ifosfamide should be used in combination with mesna. Use in Patients with Renal Impairment In patients with renal impairment, particularly in those with severe renal impairment, decreased renal excretion may result in increased plasma levels of ifosfamide and its metabolites.

, neurotoxicity, nephrotoxicity, haematotoxicity) and should be considered when determining the dosage in such patients. 3. Ifosfamide and its metabolites are dialyzable. Use in Patients with Hepatic Impairment Hepatic impairment, particularly if severe, may be associated with decreased activation of ifosfamide.

This may alter the effectiveness of ifosfamide treatment.. Hepatic impairment may increase the formation of a metabolite that is believed to cause or contribute to nephrotoxicity. This should be considered when selecting the dose and interpreting response to the dose selected.

3. Use in Paediatric Patients In children, the dosage and administration should be determined by the tumour type, tumour stage, the general condition of the patient, any previous cytotoxic therapy, and whether chemotherapy or radiotherapy is to be administered concurrently.

Clinical trials have involved doses of: a) 5 g/m² over 24 hours b) 9 g/m² equally fractionated as single daily doses over 5 days c) 9 g/m² as a continuous infusion over 72 hours repeated at three weekly intervals. 2).

Administration:

Ifosfamide is inert until activated by enzymes in the liver. However, safe handling is required, and advice is included under Pharmaceutical Precautions. 5 ml of Water for Injections The resultant solution of 8% of ifosfamide should not be injected directly into the vein.

The solution may be: 1. 9% and injected directly into the vein, with the patient supine. 2. 9% over 30-120 mins. 3. injected directly into a fast-running infusion, 4. 9% and infused over 24 hours. Each litre should be given over eight hours.

3. Ifosfamide and its metabolites are dialyzable. Use in Patients with Hepatic Impairment Hepatic impairment, particularly if severe, may be associated with decreased activation of ifosfamide. This may alter the effectiveness of ifosfamide treatment..

Hepatic impairment may increase the formation of a metabolite that is believed to cause or contribute to nephrotoxicity. This should be considered when selecting the dose and interpreting response to the dose selected. 3. Use in Paediatric Patients In children, the dosage and administration should be determined by the tumour type, tumour stage, the general condition of the patient, any previous cytotoxic therapy, and whether chemotherapy or radiotherapy is to be administered concurrently.

Clinical trials have involved doses of: a) 5 g/m² over 24 hours b) 9 g/m² equally fractionated as single daily doses over 5 days c) 9 g/m² as a continuous infusion over 72 hours repeated at three weekly intervals. 2).

Administration:

Ifosfamide is inert until activated by enzymes in the liver. However, safe handling is required, and advice is included under Pharmaceutical Precautions. 5 ml of Water for Injections The resultant solution of 8% of ifosfamide should not be injected directly into the vein.

The solution may be: 1. 9% and injected directly into the vein, with the patient supine. 2. 9% over 30-120 mins. 3. injected directly into a fast-running infusion, 4. 9% and infused over 24 hours. Each litre should be given over eight hours.

3 for in-use requirements. Care should be taken that extravasation does not take place, however, should it occur local tissue damage is unlikely, and no specific measures need be taken. Repeated intravenous injections of large doses of Ifosfamide have resulted in local irritation.