Cisplatin

Cisplatin is an inorganic platinum complex (cis-diamminedichloroplatinum(II)) whose cytotoxic effect resembles that of the alkylating agents. Its main activity is inhibition of DNA synthesis through cross-links within and between DNA strands; protein and RNA synthesis are inhibited to a lesser degree.

Mechanism of Action

• DNA binding: cisplatin attaches to DNA bases, with a preference for the N-7 position of guanine and adenine, and cross-links the strands. The strands can then no longer separate, so DNA replication and transcription cannot proceed and the cell dies.
• Cell-cycle independence: the activity does not appear to depend on a particular phase of the cell cycle.
• Further actions: the antitumour effect includes other activities, such as increasing the immunogenicity of the tumour. Cisplatin also has immunosuppressive, radiosensitising and antibacterial properties.

Pharmacokinetics

• Distribution: after intravenous administration, cisplatin spreads rapidly to all tissues but penetrates the central nervous system very little. The highest concentrations are reached in the liver, kidneys, bladder, muscle, skin, testes, prostate, pancreas and spleen, and platinum stays in tissues for as long as 180 days after the last dose. The volume of distribution at steady state is 11–12 L/m².
• Protein binding: about 90% of the platinum in plasma is bound to proteins (albumin, transferrin and gamma globulin). These platinum–protein complexes do not dissociate to a significant extent and are eliminated slowly.
• Elimination: the unbound, filterable platinum is cleared in two phases, with an initial half-life of 10–20 minutes and a terminal half-life of 32–53 minutes. For total platinum the half-life varies widely between individuals and studies; most studies report about 5 days or more.
• Excretion: elimination is mainly through the urine, which contains 27–43% of the dose in the first five days; platinum is also excreted in bile. Renal clearance of free platinum exceeds the glomerular filtration rate, which indicates that the kidney also secretes it actively.
• Special populations: the dose is reduced in kidney dysfunction or bone marrow depression (see Administration and Dosage).

Cisplatin can be used alone or in combination with other chemotherapy. The indications below follow the nationally authorised generic SmPC available for this page (Spain); the wording can differ slightly between member states.

• Testicular cancer: metastatic or advanced.
• Ovarian cancer: metastatic or advanced.
• Bladder carcinoma: metastatic or advanced.
• Head and neck cancer: metastatic or advanced squamous cell carcinoma of the head and neck.
• Lung cancer: metastatic or advanced non-small cell lung carcinoma, and metastatic or advanced small cell lung carcinoma.
• Cervical carcinoma: in combination with radiotherapy.

• Hypersensitivity to cisplatin, to other platinum-containing compounds or to any of the excipients.
• Kidney dysfunction (creatinine clearance below 60 mL/min), because cisplatin is nephrotoxic.
• Dehydration, because hydration before and after the dose is needed to prevent severe kidney dysfunction.
• Myelosuppression.
• Hearing impairment, because cisplatin is neurotoxic and in particular ototoxic.
• Neuropathy caused by cisplatin.
• Combination with the yellow fever vaccine.
• Breastfeeding: patients treated with cisplatin must not breastfeed.

Side effects depend on the dose and can be cumulative. The reactions reported most often (in more than 10% of patients) are blood-related (leucopenia, thrombocytopenia, anaemia), gastrointestinal (anorexia, nausea, vomiting, diarrhoea), hearing impairment, kidney-related (renal failure, nephrotoxicity, hyperuricaemia) and fever. Severe toxic effects on the kidneys, bone marrow and ears occur in up to a third of patients after a single dose; they are generally dose-related and cumulative, and effects have appeared months or years after administration.

The frequency groups below follow the SmPC table, which draws on clinical trials and post-marketing reports.

Very common (≥1/10): bone marrow failure, thrombocytopenia, leucopenia, anaemia; hyponatraemia; fever.

Common (≥1/100 to <1/10): sepsis; neurotoxicity; arrhythmia, bradycardia, tachycardia; phlebitis, venous thromboembolism; dyspnoea, pneumonia, respiratory failure; erythema, skin ulcer, localised oedema and pain (at the infusion site).

Uncommon (≥1/1,000 to <1/100): hypomagnesaemia; ototoxicity; abnormal sperm production and ovulation; gynaecomastia.

Rare (≥1/10,000 to <1/1,000): acute leukaemia; immunosuppression; hypercholesterolaemia; seizure, peripheral neuropathy, leukoencephalopathy, posterior reversible encephalopathy syndrome; retrobulbar optic neuritis; myocardial infarction, coronary artery disease; hypertension; stomatitis; raised blood albumin.

Very rare (<1/10,000): thrombotic microangiopathy with haemolytic uraemic syndrome; anaphylactoid reaction (for example facial oedema, wheezing, bronchospasm, tachycardia); raised blood iron; convulsions; cardiac arrest.

Not known: infection (infectious complications have been fatal in some patients); haemolytic anaemia with a positive Coombs test; raised blood amylase; inappropriate antidiuretic hormone secretion; dehydration, hypokalaemia, hypophosphataemia, hyperuricaemia, tetany; haemorrhagic or ischaemic stroke, loss of taste (ageusia), cerebral arteritis, Lhermitte’s sign, myelopathy, autonomic neuropathy; blurred vision, colour vision disturbance, cortical blindness, optic neuritis, papilloedema, retinal pigmentation; tinnitus, deafness; cardiac disorder; Raynaud’s phenomenon; pulmonary embolism; vomiting, nausea, anorexia, hiccups, diarrhoea; rash, alopecia; muscle spasms; acute renal failure, renal failure (raised urea and creatinine, raised uric acid and/or reduced creatinine clearance), renal tubular disorder; asthenia, malaise, extravasation at the infusion site (local soft-tissue toxicity that can cause cellulitis, fibrosis and necrosis); raised liver enzymes and bilirubin.

In the SmPC table the gastrointestinal and kidney reactions are classed as frequency not known, although the safety summary names them among the reactions reported in more than 10% of patients. The most important serious reactions are cumulative kidney toxicity, bone marrow suppression, hearing loss, neuropathy, anaphylactic-type reactions and tissue damage after extravasation.

Many interactions concern medicines that also harm the kidneys or the ears, or that depend on the kidney for elimination.

• Nephrotoxic medicines (for example cephalosporins, aminoglycosides, amphotericin B, contrast media): they increase the toxic effects of cisplatin on the kidney.
• Ifosfamide: its kidney toxicity may be greater when it is used with cisplatin or after cisplatin; it increases protein excretion in the urine and can add to cisplatin-related hearing loss.
• Medicines cleared mainly by the kidney (for example bleomycin and methotrexate): their renal elimination may be reduced, so caution is advised during or after cisplatin treatment. Blood lithium levels fell in a few patients given cisplatin with bleomycin and etoposide, so lithium levels should be monitored.
• Ototoxic medicines (for example aminoglycosides, loop diuretics): they add to the toxic effect of cisplatin on hearing. Forced diuresis with loop diuretics should be avoided, because of possible kidney-tract injury and ototoxicity, except in patients given more than 60 mg/m² of cisplatin whose urine output is below 1,000 mL per 24 hours.
• Antihypertensives containing furosemide, hydralazine, diazoxide or propranolol: can intensify cisplatin nephrotoxicity.
• Gout medicines (allopurinol, colchicine, probenecid, sulfinpyrazone): their dose may need adjusting, because cisplatin raises serum uric acid.
• Vaccines: the yellow fever vaccine is strictly contraindicated because of the risk of fatal systemic vaccine disease, and an inactivated vaccine is recommended where one is available. No live virus vaccine should be given during the three months after the end of cisplatin treatment.
• Oral anticoagulants (coumarins such as warfarin): INR monitoring must be more frequent.
• Antihistamines, buclizine, cyclizine, loxapine, meclozine, phenothiazines, thioxanthenes and trimethobenzamides: may mask symptoms of ototoxicity such as dizziness and tinnitus.
• Anticonvulsants (for example phenytoin): plasma levels may fall to subtherapeutic levels, possibly through reduced absorption and/or increased metabolism; serum levels should be monitored and the dose adjusted as needed.
• Pyridoxine with altretamine: in a randomised study in advanced ovarian carcinoma, the response to therapy was adversely affected by concurrent pyridoxine and altretamine (hexamethylmelamine) given with cisplatin.
• Taxanes: cisplatin given before a paclitaxel infusion can reduce paclitaxel clearance by 33% and so intensify neurotoxicity. In a study in patients with metastatic or advanced tumours, docetaxel with cisplatin caused more severe neurotoxic effects (dose-related, sensory) than docetaxel alone at similar doses.
• Myelosuppressants and radiation: they increase the myelosuppressive activity of cisplatin.
• Bleomycin and vinblastine: the combination with cisplatin can lead to Raynaud’s phenomenon.
• Chelating agents such as penicillamine: may reduce the effectiveness of cisplatin.
• Ciclosporin: excessive immunosuppression with a risk of lymphoproliferation should be considered.
• Echinacea: DrugBank advises avoiding it.

Cisplatin may be given only under the supervision of a physician qualified in oncology with experience in cytotoxic chemotherapy. The 1 mg/mL concentrate must be diluted before use (see SmPC section 6.6) and is given only as an intravenous infusion of the diluted solution over 6 to 8 hours. Cisplatin reacts with aluminium to form a black platinum precipitate, so any equipment containing aluminium that could touch the solution (infusion sets, needles, catheters, syringes) must be avoided.

Recommended Dose

The dose depends on the main disease, the expected response and whether cisplatin is used alone or with other chemotherapy. The regimens apply to both adults and children.

• As a single agent (two regimens): a single dose of 50 to 120 mg/m² of body surface area every 3–4 weeks; or 15 to 20 mg/m² per day for 5 days, every 3–4 weeks.
• In combination chemotherapy: the cisplatin dose is reduced; a typical dose is 20 mg/m² or more once every 3–4 weeks.
• Cervical cancer: given with radiotherapy; a typical dose is 40 mg/m² per week for 6 weeks.

Hydration and Forced Diuresis

Adequate hydration is needed from 2 to 12 hours before the dose until at least 6 hours after it, so that enough urine is produced during and after treatment. It is given as an intravenous infusion of 0.9% sodium chloride solution or of a 1:1 mixture of 0.9% sodium chloride and 5% glucose solution.

• Before cisplatin: 100–200 mL/hour over 6 to 12 hours, a total of at least 1 litre.
• After cisplatin: a further 2 litres at 100–200 mL/hour over 6 to 12 hours.
• Forced diuresis: may be needed if urine output stays below 100–200 mL/hour after hydration. It is given as 37.5 g of mannitol intravenously (375 mL of a 10% solution) or, if kidney function is normal, as a diuretic. Mannitol or a diuretic is also needed whenever the cisplatin dose is above 60 mg/m².
• Fluids by mouth: the patient should drink large amounts of fluid for 24 hours after the infusion to keep urine output adequate.

Dose Adjustments and Retreatment

• In patients with kidney dysfunction or bone marrow depression the dose should be reduced appropriately. The SmPC also lists kidney impairment (creatinine clearance below 60 mL/min) and myelosuppression among the contraindications.
• Repeat treatment is delayed until kidney function, blood counts and hearing have returned to the values listed under Special Instructions.

Special Populations

• Children and adolescents: the dosing regimens apply to adults and children. Ototoxicity can be more severe in children, and late-onset hearing loss has been reported, so long-term follow-up is recommended.
• Elderly and hepatic impairment: no specific dose adjustment is stated; liver function is checked at regular intervals.
• Renal impairment: see above and Contraindications.

Supervision and Monitoring

Cisplatin is given only under the supervision of a physician qualified in oncology, where adequate diagnostic and treatment facilities are available. The SmPC describes it as a cytostatic with more marked toxicity than is usual in anti-cancer chemotherapy, and its toxicity can be increased by other medicines that harm the same organs.

Before, during and after each administration, the following are measured and then repeated every week for the whole treatment: kidney function, liver function, blood counts (red cells, white cells and platelets) and serum electrolytes (calcium, sodium, potassium, magnesium). Repeat treatment is delayed until:

• serum creatinine is below 130 µmol/L (1.5 mg/dL);
• urea is below 25 mg/dL;
• the white cell count is above 4,000/µL;
• platelets are above 100,000/µL;
• the audiogram is normal.

Nephrotoxicity

Cisplatin causes severe cumulative kidney toxicity. Forced diuresis, by hydration or by hydration plus a diuretic, before and after the dose lowers the risk, and a urine output of 100 mL/hour or more tends to minimise it. The warnings section recommends pre-hydration with 2 litres of a suitable intravenous solution and similar hydration after cisplatin (2,500 mL/m² over 24 hours); if hydration cannot produce or maintain adequate urine output, an osmotic diuretic such as mannitol is advisable. Raised uric acid levels (hyperuricaemia) and albumin disturbances may predispose to cisplatin nephrotoxicity.

Ototoxicity

Ototoxicity (tinnitus and/or loss of high-frequency hearing, 4,000 to 8,000 Hz) was seen in up to 31% of patients after a single 50 mg/m² dose, and hearing is occasionally reduced in the normal conversational range. The hearing loss can be on one or both sides and tends to become more frequent and more severe with repeated doses; deafness has rarely been reported after the first dose. It can be made worse by previous or simultaneous cranial irradiation, may be related to the peak plasma concentration, and it is unclear whether it is reversible. Ototoxicity can be more severe in children, and late-onset hearing loss has been reported in the paediatric population, so long-term follow-up is recommended. Audiometry is done before treatment and before every further cycle. Vestibular toxicity has also been reported.

Neuropathy

Severe neuropathies have been reported. They may be irreversible and show as paraesthesia, loss of reflexes, and loss of proprioception and of the sense of vibration; loss of motor function has also been described. A neurological examination is repeated at regular intervals, and special care is needed in patients with peripheral neuropathy that was not caused by cisplatin.

Hypersensitivity Reactions

As with other platinum products, hypersensitivity (anaphylactic) reactions can occur, in most cases during the infusion. The infusion is stopped and appropriate symptomatic treatment (antihistamines, adrenaline and/or glucocorticoids) is given. Cross-reactions, sometimes fatal, have been reported with all platinum compounds.

Nausea, Vomiting and Fluid Loss

Severe nausea and vomiting may occur and need antiemetic treatment. Nausea, vomiting and diarrhoea often follow the dose and usually settle within 24 hours, although milder nausea and anorexia can continue for up to seven days. A preventive antiemetic can help, and fluid lost through vomiting and diarrhoea must be replaced.

Bone Marrow and Liver

Myelosuppression and anaphylactic reactions must be watched closely. Liver function and the blood count are checked at regular intervals.

Extravasation and Infusion-Site Reactions

Reactions can occur at the infusion site, so the site is watched closely for infiltration during administration. No treatment for extravasation reactions is known. If extravasation occurs, the infusion is stopped at once, the needle is left in place, the extravasated fluid is aspirated from the tissue and the area is rinsed with 0.9% sodium chloride solution. Special care is needed in patients with acute bacterial or viral infections.

Carcinogenic Potential

Acute leukaemia has rarely been seen in people treated with cisplatin, usually when it was given with other agents that can cause leukaemia. Cisplatin is mutagenic in bacteria and causes chromosomal changes in animal cell cultures; carcinogenicity is possible but has not been shown. It is teratogenic and embryotoxic in mice.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: cisplatin should not be used unless there is no safer alternative treatment, the treatment cannot be delayed until after the pregnancy, and the benefit–risk assessment for the individual patient supports its use. Data in pregnant women are absent or insufficient, but its pharmacological properties lead to the suspicion that it causes serious birth defects.
• Contraception: women of childbearing potential should use effective contraception during treatment and for at least 29 weeks (at least 7 months) after the last dose. Men with female partners of childbearing potential should do so during treatment and for at least 17 weeks (at least 4 months) after the last dose. The warnings section of the same SmPC gives at least 6 months for both sexes.
• Breastfeeding: patients treated with cisplatin must not breastfeed.
• Fertility: in women, cisplatin has been linked to ovarian failure that depends on the cumulative dose, premature menopause and reduced fertility. In men, impaired sperm production and absence of sperm (azoospermia) have been reported; the impairment may be reversible. Men and women should seek advice on preserving fertility before treatment.

Sodium Content

Each 50 mL vial contains 177 mg of sodium (8.9% of the maximum daily intake of 2 g recommended by the WHO for an adult), and each 100 mL vial contains 354 mg (17.7%).

Effect on Driving

No studies on the ability to drive and use machines have been done. Side effects such as kidney toxicity may have a slight to moderate influence, and patients who have side effects such as drowsiness or vomiting should avoid driving and using machines.

Store the vials below 25 °C; do not refrigerate or freeze. Keep the vial in its outer carton to protect it from light. Do not use the solution if it is not clear or if an insoluble precipitate has formed. Diluted solutions are protected from light and are not refrigerated or frozen (see Shelf Life). No cold chain is needed, but the vials must not be chilled or frozen during transport and storage.

The concentrate is supplied in 50 mL or 100 mL type I glass vials with a latex-free chlorobutyl rubber stopper, an aluminium cap and a plastic flip-off top; not all pack sizes may be marketed.

Unopened 50 mL and 100 mL vials: 2 years. After dilution in the infusion fluids described in SmPC section 6.6, the solution remains stable for 24 hours at room temperature (20–25 °C) and must be protected from light; diluted solutions must not be refrigerated or frozen. From a microbiological point of view the diluted solution should be used immediately; otherwise storage time and conditions before use are the responsibility of the user, and dilution should take place under controlled and validated aseptic conditions.

Prescription only (Rx). Cisplatin may be given only under the supervision of a physician qualified in oncology with experience in chemotherapy. The concentrate is diluted and infused intravenously over 6 to 8 hours together with hydration, so it is supplied to the hospital or clinic that administers it. It is stored at room temperature (below 25 °C) and is not sent chilled or frozen.