4.1. Therapeutic indications

Cisplatin is intended for the treatment of:

- advanced or metastasised testicular cancer

- advanced or metastasised ovarian cancer

- advanced or metastasised bladder carcinoma

- advanced or metastasised squamous cell carcinoma of the head and neck

- advanced or metastasised non-small cell lung carcinoma

- advanced or metastasised small cell lung carcinoma

Cisplatin is indicated in the treatment of cervical carcinoma in combination with other chemotherapeutics or with radiotherapy.

Cisplatin can be used as monotherapy and in combination therapy.

4.2. Posology and method of administration

Posology

Adults and Paediatric population

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. To obtain optimum therapeutic results with minimum adverse effects, the dosage of cisplatin must be based on the clinical, renal and hematologic status of the patient. 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 area (BSA) 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 BSA or more once every 3 to 4 weeks.

For treatment of cervical cancer cisplatin is used in combination with radiotherapy or other chemotherapeutics. A typical dose is 40 mg/m2 BSA weekly for 6 weeks.

For warning and precautions to be considered prior to the start of the next treatment cycle (see section 4.4).

Method of administration

The cisplatin solution for infusion should be administered by intravenous infusion over a period of 6 to 8 hours. Cisplatin 1 mg/ml sterile concentrate is to be diluted before administration. For instructions for dilution of the product before administration see sections 4.4 and 6.6. Reconstitution as recommended results in a clear, colourless solution with no visible particles.

Hydration

Adequate hydration must be maintained from 2 to 12 hours prior to administration until minimum 6 hours after the administration of cisplatin. Hydration is necessary to ensure sufficient diuresis during and after treatment with cisplatin. It is realised by intravenous infusion of Sodium chloride solution 0.9%.

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 1 litre.

Hydration after termination of the administration of cisplatin:

Intravenous infusion of another 2 litres 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. Forced diuresis may be realised by intravenously administering a 10% mannitol solution (37.5 g mannitol in 375 ml water for injection), 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 BSA.

It is necessary that the patient drinks large quantities of liquids for 24 hours after the cisplatin infusion to ensure adequate urine secretion.

Although cisplatin is usually administered intravenously, the drug has also been given by intraperitoneal instillation to patients with intraperitoneal malignancies (e.g., ovarian tumours). Steep concentration gradients between intraperitoneal and plasma drug levels can be achieved by this route of administration.

For administration, any device containing aluminium that may come in contact with cisplatin (sets for intravenous infusion, needles, catheters, syringes) must be avoided.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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.

Patients receiving cisplatin should not breast-feed (see section 4.6).

Concurrent administration of yellow fever vaccine is contraindicated.

4.4. Special warnings and precautions for use

Cisplatin is a highly toxic drug with a relatively narrow therapeutic index, and a therapeutic effect is unlikely to occur without some evidence of toxicity. This cytostatic agent has a more marked toxicity than is usually found in antineoplastic chemotherapy.

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 must be avoided.

Before administering the solution to the patient, verify the clarity of the solution and the absence of particles.

Cisplatin 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.

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.

To maintain urine output and reduce renal toxicity it is recommended that cisplatin be administered as an intravenous infusion over 6 to 8 hours (see section 4.2). A urine output of 100 ml/hour or greater will tend to minimise cisplatin nephrotoxicity. This can be accomplished by pre-hydration with 2 litres of an appropriate intravenous solution, and similar post cisplatin treatment hydration (recommended 2,500 ml/m2BSA/24 hours). If vigorous hydration is insufficient to maintain adequate urinary output, an osmotic diuretic may be administered (e.g., 10% mannitol solution).

Repeat courses of cisplatin should not be given unless the level of serum creatinine is below 1.5 mg/100 ml or the blood urea nitrogen (BUN) is below 25 mg/100 ml.

Special care has to be taken when cisplatin-treated patients are given concomitant therapies with other potentially nephrotoxic drugs (see section 4.5).

Bone marrow function

Peripheral blood counts should be monitored frequently in patients receiving cisplatin. Although the hematologic toxicity is usually moderate and reversible, severe thrombocytopenia and leukopenia may occur. In patients who develop thrombocytopenia special precautions are recommended: care in performing invasive procedures; search for signs of bleeding or bruising; test of urine, stools and emesis for occult blood; avoiding aspirin and other NSAIDs. Patients who develop leukopenia should be observed carefully for signs of infection and might require antibiotic support and blood product transfusions (see section 4.8).

Central Nervous System function

Cisplatin is known to induce neurotoxicity which appears to be cumulative.

Severe cases of neuropathies have been reported. These neuropathies may be irreversible and may manifest by paraesthesia, areflexia and a proprioceptive loss and a loss of vibration perception. A loss of motor function has also been reported. A neurological examination must be carried out at regular intervals in patients receiving a cisplatin-containing treatment. Since neurotoxicity may result in irreversible damage, it is recommended to discontinue therapy with cisplatin when neurologic toxic signs or symptoms become apparent (see section 4.8).

Prior to each course, the absence of symptoms of peripheral neuropathy should be established.

Ototoxicity

Cisplatin may produce cumulative ototoxicity, which is more likely to occur with high-dose regimens. Audiometry should be performed prior to initiating therapy, and repeated audiograms should be performed when auditory symptoms occur, or clinical hearing changes become apparent. Clinically important deterioration of auditive function may require dosage modifications or discontinuation of therapy.

Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin 50 mg/m2, and is manifested by tinnitus and/or hearing loss in the high frequency range (4000 to 8000 Hz). Decreased ability to hear conversational tones may occur occasionally. Ototoxic effect may be more pronounced in children receiving cisplatin.

Cases of delayed-onset hearing loss have been reported in the paediatric population. Long term follow-up in this population is recommended.

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. Vestibular toxicity has also been reported (see section 4.8).

Close supervision must also be carried out with regard to ototoxicity, myelodepression and anaphylactic reactions (see section 4.8).

Allergic phenomena

Anaphylactic-like reactions to cisplatin have been reported. These reactions have occurred within minutes of administration to patients with prior exposure to cisplatin and have been alleviated by administration of adrenaline, steroids and antihistamines.

As with other platinum-based products, hypersensitivity reactions may occur, appearing in most cases during perfusion, and necessitating 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).

Hepatic function and haematological formula

The haematological formula and hepatic function must be monitored at regular intervals.

Carcinogenic potential

In humans, in rare cases the appearance of acute leukaemia has coincided with the use of cisplatin, which was in general associated with other leukaemogenic agents.

Cisplatin has been shown to be teratogenic, embryotoxic and carcinogenic in mice and rats.

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.

Gastrointestinal effects

Nausea and vomiting may be intense and require adequate antiemetic treatment.

Immunosuppressant effects/increased susceptibility to infections

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cisplatin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving cisplatin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Excipient information

Cisplatin 10 mg/10 ml (1 mg/ ml) concentrate for solution for infusion contains 35.4 mg of sodium in each 10 ml vial, equivalent to 1.8% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Cisplatin 50 mg/50 ml (1 mg/ ml) concentrate for solution for infusion contains 177 mg of sodium in each 50 ml vial, equivalent to 8.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Cisplatin 100 mg/ 100 ml (1 mg/ ml) concentrate for solution for infusion contains 354 mg of sodium in each 100 ml vial, equivalent to 17.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Cisplatin may be further prepared for administration with sodium-containing solutions (see section 6.6) and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

4.5. Interaction with other medicinal products and other forms of interaction

Cisplatin is mostly used in combination with antineoplastic drugs having similar cytotoxic effects. In these circumstances additive toxicity is likely to occur.

Other known drug interactions are reported below.

Nephrotoxic substances

Concomitant administration of nephrotoxic (e.g., cephalosporins, aminoglycosides, amphotericin B or contrast media) medicinal products will potentiate the toxic effect of cisplatin on the kidneys and is therefore not recommended. In addition, aminoglycoside antibiotics should not be administered within 1-2 weeks after treatment with cisplatin.

Renally excreted drugs

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 and/or sequential administration of ototoxic (e.g. aminoglycosides, loop diuretics) medicinal products will potentiate the toxic effect of cisplatin on auditory function, especially in the presence of renal impairment. Except for patients receiving doses of cisplatin exceeding 60 mg/m2 BSA, 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.

Oral anticoagulants

In the event of simultaneous use of oral anticoagulants such as coumarins/warfarin, it is advisable to regularly check the INR.

Antihistamines, phenothiazines and others

Simultaneous use of antihistamines, buclizine, cyclizine, loxapine, meclizine, phenothiazines, thioxanthenes or trimethobenzamines may mask ototoxicity symptoms (such as dizziness and tinnitus).

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.

Anticonvulsant agents

In patients receiving cisplatin and anticonvulsants, plasma levels of anticonvulsant agents (e.g. phenytoin) may be decreased and potentially become subtherapeutic. This is possibly as a result of decreased absorption and/or increased metabolism. In these patients, serum levels of anticonvulsants should be monitored and dosage adjustments made a necessary.

Antigout agents

Cisplatin may raise the concentration of blood uric acid. Thus, in patients concurrently receiving antigout agents such as allopurinol, colchicine, probenecid or sulfinpyrazone, dosage adjustment of these drugs may be necessary to control hyperuricemia and gout.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should use effective contraception during treatment with cisplatin and for at least 29 weeks (at least 7 months) following the last dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment with cisplatin and for at least 17 weeks (at least 4 months) after the last dose.

Pregnancy

Cisplatin may be toxic to the foetus when administered to a pregnant woman.

Cisplatin has been shown to be teratogenic, embryotoxic and carcinogenic in mice and rats (see section 5.3).

Cisplatin should not be used during pregnancy unless the clinician considers the risk in an individual patient to be clinically justified.

Breast-feeding

Cisplatin and its active metabolites have been identified in human milk of treated mothers. The effect of cisplatin on infants is unknown. Women should not breast-feed while undergoing treatment with cisplatin and for 4 weeks after the last dose of cisplatin. A decision must be made whether to discontinue breast-feeding or to discontinue cisplatin treatment taking into account the benefit of breast-feeding for the child and the benefit of treatment for the patient.

Fertility

Female

Based on non-clinical (see section 5.3) and clinical findings, female fertility may be compromised by treatment with cisplatin. Use of cisplatin has been associated with cumulative dose-dependent ovarian failure, premature menopause and reduced fertility.

Male

Cisplatin can affect male fertility. Impairment of spermatogenesis and azoospermia have been reported (see section 4.8). Although the impairment of spermatogenesis can be reversible, males undergoing cisplatin treatment should be warned about the possible adverse effects on male fertility.

Both men and women should seek advice on fertility preservation before treatment.

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

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. Cases of delayed-onset hearing loss have been reported in the paediatric population (see section 4.4). Delayed onset occurring months/years after administration has also been reported.

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

Adverse Event

Infections and infestations

Common

Sepsis

Not known

Infectiona

Neoplasm benign, malignant, and unspecified (including cysts and polyps)

Rare

Acute leukaemias

Not known

Myelodysplastic syndromese

Blood and lymphatic system disorders

Very common

Bone marrow failure, thrombocytopenia, leukopenia, anaemia

Not known

Coombs positive haemolytic anaemia, thrombotic microangiopathy (haemolytic uraemic syndrome)

Immune system disorders

Uncommon

Anaphylactoidb reaction

Not known

Anaphylactic reaction

Endocrine disorders

Not known

Blood amylase increased, inappropriate antidiuretic hormone secretion (SIADH)

Metabolism and nutrition disorders

Very common

Hyponatraemia

Uncommon

Hypomagnesaemia

Not known

Dehydration, hypokalaemia, hypophosphataemia, hyperuricaemia, hypocalcaemia, tetany

Nervous system disorders

Rare

Convulsion, peripheral neuropathies, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome

Not known

Cerebrovascular accident, haemorrhagic stroke, ageusia, cerebral arteritis, Lhermitte's sign, myelopathy, autonomic neuropathy

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

Cardiac disorders

Common

Arrhythmia, bradycardia, tachycardia

Rare

Myocardial infarction

Very rare

Cardiac arrest

Not known

Cardiac disorder, coronary artery disease, congestive heart failure

Vascular disorders

Common

Venous thromboembolism

Not known

Raynaud's phenomenon, postural hypotension

Respiratory, thoracic and mediastinal disorders

Not known

Pulmonary embolism, Pulmonary toxicityf

Gastrointestinal disorders

Rare

Stomatitis

Not known

Vomiting, nausea, anorexia, hiccups, diarrhoea

Hepatobiliary disorders

Not known

Hepatic enzymes increasedg, blood bilirubin increased

Skin and subcutaneous tissue disorders

Not known

Rash, alopecia

Musculoskeletal, connective tissue and bone disorders

Not known

Muscle spasms, myalgia

Renal and urinary disorders

Not known

Renal failure acute, renal failurec, renal tubular disorder

Reproductive system and breast disorders

Uncommon

Abnormal spermatogenesis

Not known

Azoospermia

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.

b: Symptoms include facial oedema, flushing, wheezing, bronchospasm, tachycardia, and hypotension.

c: Elevations in BUN and creatinine, serum uric acid, and/or decrease in creatinine clearance are subsumed under renal insufficiency/failure.

d: Local soft tissue toxicity including cellulitis, fibrosis, and necrosis (common) pain (common), oedema (common), phlebitis and erythema (common) as the result of extravasation.

e: Mostly when given in combination with potentially leukemogenic agents.

f: Pulmonary toxicity has been reported in patients treated with cisplatin in combination with bleomycin or 5-fluorouracil.

g: Mild and transient elevations of serum AST and ALT levels may occur infrequently.

Blood and lymphatic system disorders

Myelosuppression often occurs during cisplatin therapy but is mostly mild to moderate and reversible at the usual doses. However, leukopenia and thrombocytopenia are dose-related, and may become clinically relevant in patients receiving high doses of cisplatin or in patients who have received prior myelosuppressive treatments. White blood cells and platelet nadirs generally occur after about 2 weeks, but levels return to pre-treatment values in most patients within 4 weeks. Cisplatin may also induce anaemia: this is not clearly dose-related and is occasionally caused by haemolysis.

Metabolism and nutrition disorders

Cisplatin may also cause serious electrolyte disturbances, mainly represented by hypomagnesemia, hypocalcaemia, and hypokalaemia, and associated with renal tubular dysfunction. Hypomagnesemia and/or hypocalcaemia may become symptomatic, with muscle irritability or cramps, clonus, tremor, carpopedal spasm, and/or tetany. Other reported toxicities are hyperuricemia, hyponatremia and syndrome of inappropriate antidiuretic hormone (SIADH).

Nervous system disorders

Peripheral neuropathies occur infrequently with usual doses of the drug. These are generally sensory in nature (e.g. paraesthesia of the upper and lower extremities) but can also include motor difficulties, reduced reflexes and leg weakness. Autonomic neuropathy, seizures, slurred speech, loss of taste and memory loss have also been reported. These neuropathies usually appear after prolonged therapy but have also developed after a single drug dose. Peripheral neuropathy may be irreversible in some patients; however, it has been partially or completely reversible in others following discontinuance of cisplatin therapy.

Eye disorders

Optic neuritis, papilledema, and cortical blindness are usually reversible after drug withdrawal.

Ear and labyrinth disorders

Unilateral or bilateral tinnitus, with or without hearing loss is usually reversible. The damage to the hearing system appears to be dose-related and cumulative, and it is reported more frequently in very young and very old patients.

Gastrointestinal disorders

Nausea and vomiting occur in the majority of cisplatin-treated patients, usually starting within 1 hour of treatment and lasting up to 24 hours or longer. These side effects are only partially relieved by standard antiemetics. The severity of these symptoms may be reduced by dividing the total dose per cycle into smaller doses given once daily for five days. Reported toxicity includes gingival platinum line.

Renal and urinary disorders

Acute renal toxicity, which was highly frequent in the past and represented the major dose-limiting toxicity of cisplatin, has been greatly reduced by the use of 6 to 8-hour infusions as well as by concomitant intravenous hydration and forced diuresis. Cumulative toxicity, however, remains a problem and may be severe. Renal impairment, which is associated with tubular damage, may be first noted during the second week after a dose and is manifested by an increase in serum creatinine, BUN, serum uric acid and/or a decrease in creatinine clearance. Renal insufficiency is generally mild to moderate and reversible at the usual doses of the drug (recovery occurring as a rule within 2-4 weeks); however, high or repeated cisplatin doses can increase the severity and duration of renal impairment and may produce irreversible renal insufficiency (sometimes fatal). Renal failure has been reported also following intraperitoneal instillation of the drug.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

CAUTION IS ESSENTIAL IN ORDER TO PREVENT AN INADVERTENT OVERDOSE.

An acute overdose of cisplatin may result in an enhancement of its expected toxic effects such as renal failure, liver failure, severe neurosensorial toxicities (deafness), ocular toxicity (including detachment of the retina), significant myelosuppression, untreatable nausea and vomiting and/or neuritis. Death may also occur.

There is no specific antidote in the event of an over dosage of cisplatin. Haemodialysis is only effective, even then partially, up to 3 hours after administration because of the rapid and extensive binding of platinum to plasma proteins. If haemodialysis is initiated 4 hours after the overdose it has little effect on the elimination of cisplatin from the body due to rapid and extensive binding of platinum to plasma proteins.

Treatment in the event of an overdose consists of general support measures.