Cisplatin 50
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Cisplatin 50
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Cisplatin 50 mg
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for injection
Yellowish-white, freeze-dried cake in a vial.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Cisplatin has antitumor activity either as a single agent or in combination chemotherapy particularly in the treatment of testicular and metastatic ovarian tumours, also cervical tumours, lung carcinoma and bladder cancer.
4.2 Posology and method of administration
Posology
Cisplatin should be dissolved in water for injections such that the reconstituted solution contains 1 mg/ml of Cisplatin. This solution should then be diluted in 2 litres of 0.9% saline or a dextrose/saline solution (to which 37.5 g of mannitol may be added) and administration should be over a 6-8 hour period.
Adults and paediatric population Single agent therapy
The usual dose regimen given as a single agent is 50 - 120 mg/m2 by infusion once every 3 - 4 weeks or 15 - 20 mg/m2 by infusion daily for 5 consecutive days, every 3 -4 weeks.
Combination chemotherapy
Dosage may be adjusted if the drug is used in combination with other antitumor chemotherapy.
With multiple drug treatment schedules Cisplatin is usually given in doses 20 mg/m1 upwards every 3 - 4 weeks.
Dosage should be reduced for patients with renal impairment or depressed bone marrow function.
Pre-treatment hydration with 1 - 2 litres of fluid infused for 8 - 12 hours prior to the Cisplatin will initiate diuresis. Adequate subsequent hydration should maintain diuresis during the 24 hours following administration.
Aluminium containing equipment should not be used for administration of Cisplatin as it may interact with metal aluminium to form a black precipitate of platinum.
Method of administration Intravenous infusion.
4.3 Contraindications
Hypersensitivity to the active substance or other platinum containing compounds, or to any of the excipients listed in section 6.1.
Cisplatin is contraindicated in patients with myelosuppression, in patients who are dehydrated, and those with pre-existing renal impairment or hearing impairment due to the fact that cisplatin is nephrotoxic and neurotoxic (in particular ototoxic). These toxicities may be cumulative if disorders of this type pre-exist.
Patients receiving cisplatin should not breast-feed.
Concurrent administration of yellow fever vaccine is contraindicated
4.4 Special warnings and precautions for use
Cisplatin reacts with metallic aluminium to form a black precipitate of platinum. All aluminium containing IV sets, needles, catheters and syringes should be avoided.
Cisplatin must be administered under close supervision by a qualified doctor specialised in the use of chemotherapeutic agents.
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 causes severe cumulative nephrotoxicity. 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). If vigorous hydration is insufficient to maintain adequate urinary output, an osmotic diuretic may be administered (eg, mannitol).
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). Decreased ability to hear conversational tones may occur occasionally. Ototoxic effect may be more pronounced in children receiving cisplatin. Hearing loss can be unilateral or bilateral and tends to become more frequent and severe with repeated doses; however, deafness after initial dose of cisplatin has been reported rarely. Ototoxicity may be enhanced with prior simultaneous cranial irradiation and may be related to peak plasma concentration of cisplatin. It is unclear whether cisplatin induced ototoxicity is reversible. Careful monitoring by audiometry should be performed prior to initiation of therapy and prior to subsequent doses of cisplatin. Vestibular toxicity has also been reported (see section 4.8).
4. Allergic phenomena
As with other platinum-based products, hypersensitivity reactions appearing in most cases during perfusion may occur, and necessitate discontinuation of the perfusion and an appropriate symptomatic treatment. Cross reactions, sometimes fatal, have been reported with all the platinum compounds (see sections 4.3 and 4.8).
5. Hepatic function and haematological formula
The haematological formula and the hepatic function must be monitored at regular intervals.
6 Carcinogenic potential
In humans, in the rare cases the appearance of acute leukaemia has coincided with use of Cisplatin, which was in general associated with other leukaemogenic agents. Cisplatin is a bacterial mutagen and causes chromosome aberrations in cultures on animal cells. Carcinogenicity is possible but has not been demonstrated. Cisplatin is teratogenetic and embryo toxic in mice.
7. Injection site reactions
Injection site reactions may occur during the administration of cisplatin. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.
Warning
This cytostatic agent had a more marked toxicity than is usually found in
antineoplastic
chemotherapy.
Renal toxicity, which is above-all cumulative, is severe and requires particular precautions
during administration (see sections 4.2 and 4.8).
Nausea and vomiting may be intense and require adequate antiemetic treatment.
Close supervision must also be carried out with regard to ototoxicity, myelodepression and anaphylactic reactions (see section 4.8).
Preparation of the intravenous solution
Warning
As with all other potentially toxic products, precautions are essential when handling the Cisplatin solution. Skin lesions are possible in the event of accidental exposure to
the product. It is advisable to wear gloves. In the event the Cisplatin solution comes into contact with the skin or mucous membranes, wash the skin or mucous membranes vigorously with soap and water.
Conforming to the procedures appropriate for the manipulation and elimination of cytostatic agents is recommended.
Before administering the solution to the patient, verify the clarity of the solution and the absence of particles.
4.5 Interaction with other medicinal products and other forms of interaction Nephrotoxic substances:
Concomitant administration of nephrotoxic (e.g. cephalosporins, aminoglycosides, amphotericin B or contrast media) or ototoxic (e.g. aminoglycosides) medicinal products will potentiate the toxic effect of cisplatin on the kidneys. During or after treatment with cisplatin caution is advised with predominantly renal eliminated substances, e.g. cytostatic agents such as bleomycin and methotrexate, because of potentially reduced renal elimination.
The renal toxicity of ifosfamide may be greater when used with cisplatin or in patients who have previously been given cisplatin.
Reduction of the blood’s lithium values was noticed in a few cases after treatment with cisplatin combined with bleomycin and etoposide. It is therefore recommended to monitor the lithium values.
Ototoxic substances:
Concomitant administration of ototoxic (e.g. aminoglycosides, loop diuretics) medicinal products will potentiate the toxic effect of cisplatin on auditory function. Except for patients receiving doses of cisplatin exceeding 60 mg/m2, whose urine secretion is less than 1000 ml per 24 hours, no forced diuresis with loop diuretics should be applied in view of possible damage to the kidney tract and ototoxicity.
Ifosfamide may increase hearing loss due to cisplatin.
Weakened live vaccines:
Yellow fever vaccine is strictly contraindicated because of the risk of fatal systemic vaccinal disease (see section 4.3). In view of the risk of generalised illness, it is advisable to use an inactive vaccine if available.
Oral anticoagulants:
In the event of simultaneous use of oral anticoagulants, it is advisable regularly to check the INR.
Antihistamines, Phenothiazines and others:
Simultaneous use of antihistamines, buclizine, cyclizine, loxapine, meclozine, phenothiazines, thioxanthenes or trimethobenzamides may mask ototoxicity symptoms (such as dizziness and tinnitus).
Anticonvulsive substances:
Serum concentrations of anticonvulsive medicines may remain at sub therapeutic levels during treatment with cisplatin.
Pyroxidine + altretamine combination:
During a randomised study of the treatment of advanced ovarian cancer, the response time was unfavourably affected when pyridoxine was used in combination with altretamine (hexamethylmelamine) and Cisplatin.
Paclitaxel:
Treatment with cisplatin prior to an infusion with paclitaxel may reduce the clearance of paclitaxel by 33% and therefore can intensify neurotoxicity.
4.6 Fertility, pregnancy and lactation
Cisplatin may be toxic to the foetus when administered to a pregnant woman.
During treatment with Cisplatin and for a minimum of the following 6 months, appropriate measures must be taken to avoid pregnancy; this applies to patients of both sexes.
Genetic consultation is recommended if the patient wishes to have children after ending the treatment. Since a treatment with cisplatin may cause irreversible infertility, it is recommended that men, who wish to become fathers in the future, ask for advice regarding cryoconservation of their sperm prior to treatment.
Breast-feeding
Cisplatin is excreted in breast milk. Patients treated with cisplatin must not breastfeed.
4.7 Effects on ability to drive and use machines
No studies on the effects on ability to drive and use machines have been performed. Nevertheless, the profile of undesirable effects (like nephrotoxicity) may influence the ability to drive vehicles and use machinery.
4.8 Undesirable effects
Undesirable effects depend on the used dose and may have cumulative effects.
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, hyperuricaemia) 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 Post marketing
Experience (MedDRA terms)
|
System Organ Class |
Frequency |
MedDRA Term |
|
Infections and infestations |
Not known |
Infection3 |
|
Common |
Sepsis | |
|
Blood and lymphatic system disorders |
Very common |
Bone marrow failure, thrombocytopenia, leukopenia, anaemia |
|
Not known |
Coombs positive haemolytic anaemia | |
|
Neoplasm benign,malignant and unspecified |
Rare |
Acute leukaemia |
|
Immune system disorders |
Uncommon |
Anaphylactoid reactionb |
|
Endocrine disorders |
Not known |
Blood amylase increased, inappropriate antidiuretic hormone secretion |
|
Metabolism and nutrition disorders |
Not known |
Dehydration, hypokalaemia, hypophosphatemia, hyperuricaemia, hypocalcaemia, tetany |
|
Uncommon |
Hypomagne saemia | |
|
Very common |
Hyponatraemia | |
|
Nervous system disorders |
Not known |
Cerebrovascular accident, haemorrhagic stroke, ischaemic stroke ageusia, cerebral arteritis, Lhermitte’s sign, myelopathy, autonomic neuropathy |
|
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 |
|
Ear and labyrinth disorders |
Uncommon |
Ototoxicity |
|
Not known |
Tinnitus, deafness, audiogram abnormalities | |
|
Cardiac disorders |
Common |
Arrhythmia, bradycardia, tachycardia |
|
Rare |
Myocardial infarction | |
|
Very rare |
Cardiac arrest | |
|
Not known |
Cardiac disorder | |
|
Vascular disorders |
Common |
Venous thromboembolism |
|
Not known |
Thrombotic microangiopathy (haemolytic uraemic syndrome), Raynaud’s phenomenon | |
|
Gastrointestinal disorders |
Not known |
Vomiting, nausea, anorexia, hiccups, diarrhoea |
|
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 |
Not known |
Rash, alopecia |
|
disorders | ||
|
Musculoskeletal, connective tissue and bone disorders |
Not known |
Muscle spasms |
|
Renal and urinary disorders |
Not known |
Renal failure acute, renal failure0, renal tubular disorder |
|
Reproductive system and breast disorders |
Uncommon |
Abnormal spermatogenesis |
|
General disorders and administration site condition |
Very common |
Pyrexia |
|
Not known |
Asthenia, malaise, injection site extravasation01 |
a: Infectious complications have led to death in some patients.
b: Symptoms reported for anaphylactoid reaction such as facial edema (PT-face oedema), wheezing, bronchospasm, tachycardia, and hypotension will be included in the parentheses for anaphylactoid reaction in the AE frequency table.
c: Elevations in BUN and creatinine, serum uric acid, and/or a decrease in creatinine clearance are subsumed under renal insufficiency/failure.
d: Local soft tissue toxicity including tissue cellulitis, fibrosis, and necrosis (common) pain (common), oedema (common) and erythema (common) as the result of extravasation.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
An acute overdose of Cisplatin may result in renal failure, liver failure, deafness, ocular toxicity (including detachment of the retina), significant myelosuppression, untreatable nausea and vomiting and/or neuritis. An overdose may be fatal.
There is no specific antidote in the event of an overdose of Cisplatin. Even if haemodialysis is initiated 4 hours after the overdose it has little effect on the elimination of cisplatin from the body following a strong and rapid fixation of Cisplatin to proteins.
Treatment in the event of an overdose consist of general support measures.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC Code: L01XA01
In vitro studies indicate that DNA is the principal target molecule of cis-platinum. The basis for the selectivity of the cis-isomer may reside in its ability to react in a specifically defined configuration with DNA.
Modification of the DNA template results in the selective inhibition of DNA synthesis.
The drug is cell cycle non-specific.
5.2 Pharmacokinetic properties
A biphasic plasma-decay pattern occurs in man after bolus administration. The initial plasma half-life in man is 25 - 49 minutes and the terminal half-life 3 - 4 days. In addition, a third excretory phase with a longer half-life may be postulated from the high plasma platinum concentration found after 21 days. During the terminal phase more than 90% of the drug is bound to plasma proteins.
The urinary elimination of the drug is incomplete: the 5-day recovery of platinum in the urine being only 27 to 45%.
Studies in man measuring free platinum species have shown a mean terminal half-life of 48 minutes after bolus injection, which probably corresponds to the initial half-life (25 - 49 minutes) seen when total platinum is monitored and reflects the distribution of the drug. Urinary excretion of filterable platinum was greater after 6 hours infusion (75%) than after a 15 minute injection (40%) of the same dose of cis-platinum.
Diuresis induced by high-volume hydration or mannitol infusion was associated with a reduction in the concentration of platinum excreted in the urine. The reduced concentration of platinum caused by the high urine volume may play a role in renal protection.
5.3 Preclinical safety data
No further preclinical safety data are available.
6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients
Sodium chloride Mannitol
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years
6.4 Special precautions for storage
The unopened vials should be stored below <25 °C. Store in original container to protect from light.
The reconstituted solution must not be cooled or refrigerated, as cooling may result in precipitation. It should be kept below <25 °C and store in original container to protect from light, also during intravenous infusion. Any unused solution should be discarded.
6.5 Nature and contents of container
Colourless glass vials (Type II) with bromobutyl rubber stoppers and aluminium snap-caps.
6.6 Special precautions for disposal
Cisplatin powder should be dissolved in sterile Water for Injections such that the reconstituted solution contains 1mg/ml of Cisplatin. The reconstituted solution should be diluted in 2 litres of 0.9% saline or a dextrose/saline solution (to which 37.5g of mannitol may be added).
Personnel should be trained in good technique for reconstitution and handling. Pregnant staff should be excluded from working with Cisplatin.
Care should be taken to prevent inhaling particles and exposing the skin to Cisplatin. Adequate protective clothing should be worn, such as PVC gloves, safety glasses, disposable gowns and masks.
In the event of contact with eyes, wash with water or saline. If the skin comes into contact with the drug wash thoroughly with water and in both cases seek medical advice. Seek immediate medical attention if the drug is ingested or inhaled.
All used materials, needles, syringes, vials and other items which have come into contact with cytotoxic drugs should be incinerated. Contaminated surfaces should be washed with copious amounts of water.
7 MARKETING AUTHORISATION HOLDER
Pharmacia Limited Ramsgate Road Sandwich CT13 9NJ UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 00032/0334
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
25 March 2002 / 22 February 2006
10 DATE OF REVISION OF THE TEXT
03/11/2016
Neuropathies
Severe cases of neuropathies have been reported.
These neuropathies may be irreversible and may manifest by paraesthesia, areflexia and a proprioceptive loss and a sensation of vibrations. A loss of motor function has also been reported. A neurologic examination must be carried out at regular intervals.