Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Sandoz Ltd, Frimley Business Park, Frimley, Camberley, Surrey, GU16 7SR, UK
Cisplatin reacts with metallic aluminum to form a black precipitate of platinum. All aluminum containing IV sets, needles, catheters and syringes should be avoided.
Cisplatin must be administered under close supervision by a qualified doctor specialized 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.
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 pre-hydration with 2 liters 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).
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.
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 Undesirable effects).
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 section 4.3 Contraindications and section 4.8 Undesirable effects).
The hematological formula and the hepatic function must be monitored at regular intervals.
In humans, in rare cases the appearance of acute leukemia has coincided with use of cisplatin, which was in general associated with other leukemogenic 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 teratogenic and embryotoxic in mice.
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 has 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 section 4.2 Posology and method of administration and section 4.8 Undesirable effects).
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 Undesirable effects).
Warning:
Preparation of the intravenous solution:
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.
Administering the solution to the patient, verify the clarity of the solution and the absence of particles.
This medicinal product contains 35 mg sodium per 10ml vial, equivalent to 1.75% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains 71 mg sodium per 20ml vial, equivalent to 3.55% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains 177 mg sodium per 50ml vial, equivalent to 8.85% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
This medicinal product contains 354 mg sodium per 100ml vial, equivalent to 17.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
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 renally 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.
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.
Yellow fever vaccine is strictly contraindicated because of the risk of fatal systemic vaccinal disease (see section 4.3 Contraindications). In view of the risk of generalized illness, it is advisable to use an inactivated vaccine if available.
In the event of simultaneous use of oral anticoagulants, it is advisable regularly to check the INR.
Simultaneous use of antihistamines, buclizine, cyclizine, loxapine, meclozine, phenothiazines, thioxanthenes or trimethobenzamides may mask ototoxicity symptoms (such as dizziness and tinnitus).
Serum concentrations of anticonvulsive medicines may remain at sub-therapeutic levels during treatment with cisplatin.
During a randomized study of the treatment of advanced ovarian cancer, the response time was unfavorably affected when pyridoxine in combination with altretamine (hexamethylmelamine) and cisplatin.
Treatment with cisplatin prior to an infusion with paclitaxel may reduce the clearance of paclitaxel by 33% and therefore can intensify neurotoxicity.
There are no adequate data from the use of cisplatin in pregnant women, but based on its pharmacological properties Cisplatin is suspected to cause serious birth defects. Studies in animals have shown reproductive toxicity and transplacental carcinogenicity (see section 5.3.). Cisplatin is contraindicated during the pregnancy period.
Cisplatin is excreted in human milk. Breastfeeding during the therapy is contraindicated.
Both male and female patients must use effective contraceptive methods to prevent conception and/or reproduction during and for at least 6 months after treatment with ciplastin. 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 the treatment.
Due to the possible side effects cisplatinhas minor or moderate influence on the ability to drive and use machines. Patients who suffer from these effects (eg feeling sleepy or vomiting) must avoid driving and operating machinery.
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.
The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), and not known (cannot be estimated from the available data).
Common: Sepsis
Not known: Infectiona
Uncommon: Acute leukemia
Very common: Bone marrow failure, thrombocytopenia, leukopenia, anemia
Not known: Coombs positive hemolytic anemia
Uncommon: Anaphylactoidb reactions
Not known: Blood amylase increased, inappropriate antidiurectic hormone secretion
Very common: Hyponatremia
Uncommon: Hypomagnesemia
Not known: Dehydration, hypokalemia, hypophosphatemia, hyperuricemia, hypocalcemia, tetany
Rare: Convulsion, neuropathy peripheral, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome
Not known: Cerebrovascular accident, hemorrhagic stroke, ischemic stroke, ageusia, cerebral arteritis, Lhermitte’s sign, myelopathy, autonomic neuropathy
Not known: Vision blurred, color blindness acquired, blindness cortical, optic neuritis, papilledema, retinal pigmentation
Uncommon: Ototoxicity
Not known: Tinnitus, deafness
Common: Arrhythmia, bradycardia, tachycardia
Rare: Myocardial infarction
Very rare: Cardiac arrest
Not known: Cardiac disorder
Common: Venous thromboembolism
Not known: Thrombotic microangiopathy (hemolytic uremic syndrome), Raynaud’s phenomenon
Not known: Pulmonary embolism
Rare: Stomatitis
Not known: Vomiting, nausea, anorexia, hiccups, diarrhea
Not known: Hepatic enzymes increased, blood bilirubin increased
Not known: Rash, alopecia
Not known: Muscle spasms
Not known: Renal failure acute, renal failurec, renal tubular disorder
Uncommon: Abnormal spermatogenesis
Very common: Pyrexia
Not known: Asthenia, malaise, injection site extravasationd
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 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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in Google play or Apple App store.
Cisplatin reacts with aluminium which results in production of a black platinum precipitate. Therefore any device containing aluminium that may come in contact with cisplatin (sets for intravenous infusion, needles, catheters, syringes) must be avoided.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
The cisplatin 1 mg/ml concentrate must not be diluted with glucose solution 5% alone or mannitol solution 5% alone, but only with the mixtures containing additionally sodium chloride as stated in section 6.6.
Antioxidants (such as sodium metabisulphite), bicarbonates (sodium bicarbonate), sulfates, fluorouracil and paclitaxel may inactivate cisplatin in infusion systems.
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