CISPLATIN VENUS PHARMA

Posology Adults and children:

The cisplatin dosage depends on the primary disease, the expected reaction, and on whether cisplatin is used for monotherapy or as a component of combination chemotherapy. The dosage directions are applicable for both adults and children.

For monotherapy, the following two dosage regimens are recommended: << Single dose of 50 to 120 mg/m2 body surface every 3 to 4 weeks; < 15 to 20 mg/m2/day for five days, every 3 to 4 weeks. If cisplatin is used in combination therapy, the dose of cisplatin must be reduced.

A typical dose is 20 mg/m2 or more once every 3 to 4 weeks. For treatment of cervical cancer cisplatin is used in combination with radiotherapy. A typical dose is 40 mg/m2 weekly for 6 weeks. 4). 3). ) should be administered by intravenous infusion over a period of 6 to 8 hours.

Adequate hydration must be maintained from 2 to 12 hours prior to administration until minimum 6 hours after the administration of cisplatin. Hydratation is necessary to cause sufficient diuresis during and after treatment with cisplatin.

9% and glucose solution 5% (1:1). Method of administration Cisplatin 1 mg/ml sterile concentrate is to be diluted before administration. 6. The diluted solution should be administered only intravenously by infusion (see below). For administration, any device containing aluminum that may come in contact with cisplatin (sets for intravenous infusion, needles, catheters, syringes) must be avoided.

Hydration prior to treatment with cisplatin:

Intravenous infusion of 100 to 200ml/hour for a period of 6 to 12 hours, with a total amount of at least 1litre.

Hydration after termination of the administration of cisplatin:

Intravenous infusion of another 2 liters at a rate of 100 to 200 ml per hour for a period of 6 to 12 hours. Forced diuresis may be required should the urine secretion be less than 100 to 200 ml/hour after hydration. 5g mannitol as a 10% solution (375 ml mannitol solution 10%), or by administration of a diuretic if the kidney functions are normal.

The administration of mannitol or a diuretic is also required when the administrated cisplatin dose is higher than 60 mg/m2 of body surface. It is necessary that the patient drinks large quantities of liquids for 24 hours after the cisplatin infusion to ensure adequate urine secretion.

The most frequently reported adverse events (>10%) of cisplatin were haematological (leukopenia, thrombocytopenia and anaemia), gastrointestinal (anorexia, nausea, vomiting and diarrhoea), ear disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, hyperuricemia) and fever.

Serious toxic effects on the kidneys, bone marrow and ears have been reported in up to about one third of patients given a single dose of cisplatin; the effects are generally dose-related and cumulative. Ototoxicity may be more severe in children.

Frequencies are defined using the following convention:

Very common (≤1/10); common (≤1/100 to <1/10); uncommon (≤1/1,000 to <1/100); rare (≤1/10,000 to ≤1/1,000); very rare (≤1/10,000), not known (cannot be estimated from the available data). Table of Adverse Drug Events Reported During Clinical or Postmarketing Experience (MedDRA terms).

System Organ Class Frequency MedDRA term Not known Infectiona Infections and infestations Common Sepsis Very common Bone marrow failure, thrombocytopenia, leukopenia, anaemia Blood and lymphatic system disorders Not known Coombs positive haemolytic anaemia Neoplasm benign, malignant, and unspecified Rare Acute leukaemia Immune system disorders Uncommon Anaphylactoidb reaction Endocrine disorders Not known Blood amylase increased, inappropriate antidiuretic hormone secretion Not known Dehydration, hypokalaemia, hypophosphatemia, hyperuricemia, hypocalcaemia, tetany Uncommon Hypomagnesaemia Metabolism and nutrition disorders Very common Hyponatraemia Not known Cerebrovascular accident, haemorrhagic stroke, ischaemic stroke ageusia, cerebral arteritis, Lhermitte's sign, myelopathy, autonomic neuropathy Nervous system disorders Rare Convulsion, neuropathy peripheral, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome Eye disorders Not known Vision blurred, colour blindness acquired, blindness cortical, optic neuritis, papilledema, retinal pigmentation Uncommon OtotoxicityEar and labyrinth disorders Not known Tinnitus, deafness Not known Cardiac disorder Common Arrhythmia, bradycardia, tachycardia Rare Myocardial infarction Cardiac disorders Very rare Cardiac arrest Common Venous thromboembolismVascular disorders Not known Thrombotic microangiopathy (haemolytic uremic syndrome), Raynaud's phenomenon Not known Vomiting, nausea, anorexia, hiccups, diarrhoea Gastrointestinal disorders Rare Stomatitis Hepatobiliary disorders Not known Hepatic enzymes increased, blood bilirubin increased Respiratory, thoracic and mediastinal disorders Not known Pulmonary embolism Skin and subcutaneous tissue disorders Not known Rash, alopecia Musculoskeletal, connective tissue and bone disorders Not known Muscle spasms Renal and urinary disorders Not known Renal failure acute, renal failurec , renal tubular disorder Reproductive system and breast disorders Uncommon Abnormal spermatogenesis General disorders and administration site condition Not known Pyrexia (very common), asthenia, malaise, injection site extravasationd a: Infectious complications have led to death in some patients.

This agent should only be administered under the direction of oncologists in specialist units under conditions permitting adequate monitoring and surveillance. Supportive equipment should be available to control anaphylactic reactions.

Cisplatin reacts with metallic aluminium to form a black precipitate of platinum. All aluminium containing IV sets, needles, catheters and syringes should be avoided. The solution for infusion should not be mixed with other drugs or additives.

Appropriate monitoring and management of the treatment and its complications are only possible if adequate diagnosis and exact treatment conditions are available. 1. Nephrotoxicity Cisplatin produces severe cumulative nephrotoxicity.

Which may be potentiated by aminoglycoside antibiotics. The serum creatinine, plasma urea or creatinine clearance and magnesium, sodium potassium, and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course.

Cisplatin should not be given more frequently than once every 3-4 weeks. A urine output of 100 mL/hour or greater will tend to minimize cisplatin nephrotoxicity. This can be accomplished by prehydration with 2 litres of an appropriate intravenous solution, and similar post cisplatin hydration (recommended 2,500 mL/m2/24 hours).

, mannitol). 2. Neuropathies Severe cases of neuropathies have been reported. These neuropathies may be irreversible and may manifest by paresthesia, areflexia and a proprioceptive loss and a vibration perception. A loss of motor function has also been reported.

A neurologic examination must be carried out at regular intervals. Neurotoxicity appears to be cumulative. Prior to each course, the absence of symptoms of peripheral neuropathy should be established. 3. Ototoxicity Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50mg/m2 and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000Hz).

1. Cisplatin may give allergic reactions in some patients. Use is contraindicated in those patients with a history of allergic reaction to cisplatin or other platinum containing compounds, or any component of the formulation. Cisplatin induces nephrotoxicity which is cumulative.

It is therefore contraindicated in patients with pre-existing renal impairment. Cisplatin has also been shown to be cumulatively neurotoxic (in particular ototoxic) and should not be given to patients with pre-existing hearing impairment.

Cisplatin is also contraindicated in myelosuppressed patients and those who are dehydrated. 6). Concurrent administration of yellow fever vaccine is contraindicated.