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Cisplatin

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

CisplatinSynonyms: cis-DDP; CDDP; Cis-platinum; Cisplatin; Cisplatina; Cisplatino; Cisplatinum; Ciszplatin; DDP; NSC-119875; Peyrone’s Salt; Platinum Diamminodichloride; Sisplatiini
BAN: Cisplatin
USAN: Cisplatin
INN: Cisplatin [rINN (en)]
INN: Cisplatino [rINN (es)]
INN: Cisplatine [rINN (fr)]
INN: Cisplatinum [rINN (la)]
INN: Цисплатин [rINN (ru)]
Chemical name: cis-Diamminedichloroplatinum
Molecular formula: (NH3)2.PtCl2 =300.0
CAS: 15663-27-1
ATC code: L01XA01
Read code: y02m8

Pharmacopoeias. In China, Europe, International, Japan, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Cisplatin). A yellow powder or yellow or orange-yellow crystals. Slightly soluble in water; practically insoluble in alcohol; sparingly soluble in dimethylformamide. A 0.1% solution in sodium chloride 0.9% has a pH of 4.5 to 6.0 immediately after preparation. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Cisplatin). Store in airtight containers. Protect from light.

Incompatibility

Cisplatin is rapidly degraded in the presence of bisulfite or metabisulfite, and admixture with preparations containing these as preservatives may result in loss of activity. Sodium bicarbonate may also increase the loss of cisplatin from solution, and in some cases may cause precipitation. The stability of cisplatin when mixed with fluorouracil is reported to be limited, with 10% loss of cisplatin in 1.2 to 1.5 hours. Mixtures with etoposide in sodium chloride 0.9% injection formed a precipitate if mannitol and potassium chloride were present as additives, but not when the diluent was glucose 5% with sodium chloride 0.45%.

Turbidity has been reported within 4 hours of mixing 0.1% solutions of cisplatin and thiotepa in glucose 5%. Cisplatin exhibits variable incompatibility with paclitaxel, depending on the paclitaxel concentration and the temperature. Cisplatin reacts with aluminium causing loss of potency and precipitate formation. Needles, syringes, catheters or giving sets that contain aluminium should not be used for preparing or giving cisplatin.

Stability

Decomposition of cisplatin in aqueous solutions is primarily due to reversible substitution of water for chloride, and its stability is enhanced in sodium chloride solutions because of the excess of chloride ions available. A solution in sodium chloride 0.9% injection has been reported to lose 3% of the drug in less than one hour and to remain stable at this equilibrium value for 24 hours at room temperature. Stability is decreased if exposed to intense light, but the effect of normal lighting conditions is apparently smaller.

It has been recommended that admixtures of cisplatin with mannitol and magnesium sulfate (in glucose 5% with sodium chloride 0.45%) stored at room temperature in PVC bags should be used within 48 hours, but may be stored for 4 days at 4° or frozen and stored at -15° for up to 30 days. However, solutions containing 600 micrograms/mL or more of cisplatin precipitate out when refrigerated and are slow to redissolve.

Adverse Effects and Treatment

For a general outline see Antineoplastics.

Severe nausea and vomiting occur in most patients during treatment with cisplatin; nausea may persist for up to a week.

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. Damage to the renal tubules may be evident during the second week after a dose of cisplatin and renal function must return to normal before further cisplatin is given. Adequate hydration, and use of osmotic diuretics such as mannitol to increase urine volume and thus decrease the urinary concentration of platinum, can reduce the incidence of nephrotoxicity. Electrolyte disturbances, particularly hypomagnesaemia and hypocalcaemia, may occur, possibly as a result of renal tubular damage. Hyperuricaemia is also seen.

Bone-marrow depression may be severe with higher doses of cisplatin. Nadirs in platelet and leucocyte counts occur between days 18 and 23 and most patients recover by day 39; anaemia is common and may be partly related to decreased production of erythropoietin after renal damage.

Ototoxicity may be more severe in children. It can manifest as tinnitus, loss of hearing in the high frequency range, and occasionally deafness or vestibular tox-icity. Other neurological effects reported include peripheral neuropathies, loss of taste, and seizures. Ocular toxicities include optic neuritis, papilloedema, and cerebral blindness.

Anaphylactoid reactions and cardiac abnormalities have occurred. Injection site reactions, including localised oedema, pain, erythema, skin ulceration and phlebitis may occur. Extravasation may lead to tissue cellu-litis, fibrosis, and necrosis.

Platinum derivatives are potentially mutagenic and teratogenic, and there is some evidence they may be associated with the development of secondary leukaemias — see Carcinogenicity.

Effects on the blood

Cisplatin-induced anaemia appears to be disproportionate to the effects on other blood cells, and to correlate with renal tubular dysfunction. It may therefore be due to an erythropoietin deficiency state resulting from cisplatin-induced renal tubular damage. Haemolysis has also been reported.

THROMBOEMBOLISM

For discussion of thromboembolic events possibly associated with cisp latin-containing chemotherapy regimens see Effects on the Cardiovascular System.

Effects on the ears

Ototoxicity is a well-established adverse effect of cisplatin. It appears to be due to generation of reactive oxygen species that cause apoptosis of hair cells in the cochlea, and results in hearing loss, particularly at high frequencies. Risk factors include younger age, larger cumulative doses (one study identified doses above 60 mg/m as risk factors), pre-existing hearing loss or renal disease, and irradiation of the brain or base of the skull. Various substances including thiols, amifostine, ebselen, allopurinol, and salicylates have been investigated in animals for their protective effect against cisplatin-induced neurotoxicity but although some promising results have been seen, benefit is yet to be demonstrated in large clinical studies, and there is some concern about the risk of reducing the antineoplastic effect of cisplatin as well. However, a small study comparing cisplatin chemoradiation with or without sodium thiosulfate tentatively concluded that thiosulfate did seem to offer some protection against hearing loss.

Effects on electrolytes

Renal-magnesium wasting and, less commonly, symptomatic hypomagnesaemia occurs with cisplatin therapy. Adding magnesium to the pre- and posthydration fluids has been suggested. When hypocalcaemia is also present, tetany may result, although this has responded to electrolyte infusion without the need to interrupt chemotherapy. Cisplatin therapy may also be associated with significant hypokalaemia and hyponatraemia. See also Effects on the Kidneys, below.

Effects on the kidneys

Nephrotoxicity is a well-established adverse effect of cisplatin, may be dose-limiting, and can manifest as acute or chronic renal failure, polyuria, or chronic hypomagnesaemia. The mechanism appears to involve primarily damage to the proximal renal tubule; selective magnesium loss may be due to a specific membrane or transport system abnormality. Sulfhydryl metabolism and oxidative stress play a role in toxicity, and measures that reduce glutathione depletion and scavenge intracellular free oxygen radicals have been tried in an attempt to modulate nephrotoxicity. However, the primary measures for reducing renal damage have been aggressive hydration with chloride-containing solutions, and the use of mannitol (see also Prophylaxis, below). It has been suggested that cisplatin may mobilise lead accumulated in bone and cause temporary accumulation in the kidney, with concomitant toxicity, but this has been vigorously disputed.

See also under Effects on Electrolytes, above.

PROPHYLAXIS

Hydration with 1 to 2 litres of fluid before treatment, and infusion of cisplatin in a further 2 litres of infusion fluid containing an osmotic diuretic such as mannitol reduces the nephrotoxicity of cisplatin, but does not abolish it. Maintaining adequate hydration and urinary output post-treatment is also important. Giving cisplatin over 6 to 8 hours rather than 1 to 2 hours may also decrease renal toxicity. Sulfur-containing nucleophiles can inactivate cisplatin, and have therefore been investigated for their chemoprotective potential.

Amifostine is a prodrug that is selectively activated by normal tissue, and has been shown to protect normal tissue (principally the kidney) against the cytotoxicity of cisplatin without affecting antitumour activity (see Cytoprotection). Glutathione is a similar agent, which may be selectively taken up by kidney and neural tissue. Sodium thiosulfate does not show selective activation or uptake, and its use is therefore limited to situations where cisplatin is given locally (e.g. intraperitoneal) or directly (e.g. intra-arterial).

CisplatinEffects on the nervous system

The features of cisplatin-induced peripheral neuropathy are consistent with damage predominantly to sensory fibres, with numbness, tingling, and decreased vibratory sensation and deep tendon reflexes, progressing in severe cases to disabling sensory ataxia. The toxicity is dose-dependent, with symptoms usually appearing in patients who have received cumulative doses of 300 to 600 mg/m, although individuals vary in susceptibility. Neuropathy is reversible but recovery may take a year or more. The pathophysiology is unknown. Peripheral neuropathy can be a dose-limiting toxicity for cisplatin and agents such as Org-2766 (a corticotropin analogue) and amifostine have been investigated for their potential in protecting peripheral nerves.

Vitamin E has been reported to be effective in reducing peripheral neuropathy. Glutathione is also under investigation for the prevention of neurotoxicity. However, a systematic review considered that the evidence for most of the interventions intended to reduce cisplatin neurotoxicity was insufficient to demonstrate benefit. Autonomic neuropathy, with, in some cases, consequent orthostatic hypotension, has also been described after treatment with cisplatin-containing regimens. Apart from ototoxicity (see above), cisplatin has also been associated with central neurotoxicity, including focal encephalopathy, seizures, aphasia, confusion, agitation, and cortical blindness. It has been suggested that the mechanism of focal encephalopathy may be vascular, although this is uncertain.

Extravasation

For discussion of the management of extravasation, including methods to manage cisplatin extravasation, see under Treatment of the Adverse Effects of Antineoplastics.

Hypersensitivity

Anaphylactoid reactions to intravenous cisplatin generally appear within a few minutes of dosage and have manifested as facial oedema, wheezing, tachycardia, and hypotension. A high incidence of anaphylactoid reaction has also been seen after intravesical instillation in patients with bladder cancer, but intraperitoneal or intrapleural use does not seem to be associated with an enhanced risk of hypersensitivity, although anaphylactoid reactions have occurred when cisplatin is given intraperitoneally. Anaphylactoid symptoms and ischaemia of the hands accompanied severe exfoliative dermatitis in one patient on the second cycle of cisp latin-based chemotherapy; she had earlier experienced exfoliative dermatitis associated with carboplatin. Palmar-plantar erythrodysesthesia has also occurred.

Nausea and vomiting

For discussion of the management of chemotherapy-induced nausea and vomiting, see under Nausea and Vomiting.

Precautions

For reference to the precautions necessary with antineoplastics. Cisplatin is generally contra-indicated in patients with renal or hearing impairment, or bone-marrow depression. Renal and neurological function and hearing should be monitored during treatment, and regular blood counts performed. Electrolytes should be measured before starting therapy, and before each subsequent course. Adequate hydration and urinary output must be maintained before, and for 24 hours after, a dose.

Patients are recommended to use appropriate contraceptive measures during treatment and for 6 months after stopping treatment.

Breast feeding

Platinum concentrations in a patient receiving cisplatin were 0.9 micrograms/mL in breast milk and 0.8 micrograms/mL in plasma. Although most of the platinum in breast milk is probably protein-bound the authors considered that a mother should not breast feed while receiving cisplatin chemotherapy. However, in another report, cisplatin was unde-tectable in breast milk and the American Academy of Pediatrics considers its use to be compatible with breast feeding.

Handling and disposal

Methods for the destruction of cisplatin wastes by reduction with zinc powder under acidic conditions or by reaction with ditiocarb sodium have been described. Residue produced by the degradation of cisplatin by either method showed no mutagenicity in vitro.

Urine produced for up to 7 days after a dose of cisplatin should be handled wearing protective clothing.

Pregnancy

Cisplatin was given with etoposide and bleomycin to a pregnant woman at 26 weeks of gestation for carcinoma of uncertain primary origin. At 27 weeks of gestation, she developed profound neutropenia followed by septicaemia and went into premature labour. The infant developed profound leucopenia and neutropenia by day 3, which was attributed to chemotherapy given 6 days before delivery; prophylactic antibacterials including gentamicin were given. Hair loss at the age of 10 days was attributed to etoposide.

At 1 year of age, the child exhibited moderate bilateral sensorineural hearing loss; this was considered to be either due to cisplatin exposure in utero or to gentamicin use. However, there are other reports of cisplatin use during the second or third trimester of pregnancy with no subsequent apparent adverse effects on the infant. fn most cases, cisplatin had been given with cyclophosphamide, although in one instance it was given with paclitaxel. In one report, cisplatin-induced maternal ototoxicity led to it being replaced after 2 courses by carboplatin.

Radiotherapy

Enhanced ototoxicity has been reported in patients given cisplatin for brain tumours who also had cranial irradiation.

Interactions

For a general outline of antineoplastic drug interactions. Use with other myelosuppressive, nephrotoxic or ototoxic drugs may exacerbate the adverse effects of cisplatin. The effects of cisplatin on renal function may also affect the pharmacokinetics of other drugs excreted by the renal route.

Antibacterials

Although the use of cisplatin with other nephrotoxic or ototoxic drugs requires great caution, there is some evidence that aminoglycosides can be used in patients who have recently received cisplatin if appropriate supportive care is available.

Antineoplastics

The ototoxicity of cisplatin was reportedly enhanced by ifosfamide, a drug that is not ototoxic when given alone, although it does have nephrotoxic potential, making reports of increased nephrotoxic ity in patients who have received both unsurprising.

For a report of increased toxicity with etoposide. Cisplatin may reduce the clearance of paclitaxel.

Cardiovascular drugs

A patient whose renal function was unaffected by cisplatin alone developed nephrotoxicity when given cisplatin and antihypertensive therapy with furosemide, hydralazine, diazoxide, and propranolol Previous results in animals suggest that furosemide may aggravate cisplatin nephrotoxicity, while the other antihypertensives might have contributed to a transient fall in renal-blood flow with resultant increased renal-tubular cisplatin concentration.

Gastrointestinal drugs

For mention of 2 retrospective studies, one showing a decreased area under the plasma-concentration time curve of high-dose cisplatin with ondansetron and the other an increase.

Pharmacokinetics

After intravenous doses cisplatin disappears from the plasma in a biphasic manner and half-lives of 25 to 49 minutes and 3 to 4 days have been reported for total platinum. More than 90% of the platinum from a dose is protein bound within 2 to 4 hours; only the unbound fraction has significant antineoplastic activity. Cisplatin is concentrated in the liver, kidneys, and large and small intestines. Penetration into the CNS appears to be poor. Excretion is mainly in the urine but is incomplete and prolonged: up to about 50% of a dose has been reported to be excreted in urine over 5 days, and platinum may be detected in tissue for several months afterwards. The unbound fraction, which is more rapidly cleared, may be actively secreted by the renal tubules.

Cisplatin is well-absorbed on intraperitoneal use. Cisplatin may be distributed into breast milk (see Breast Feeding, above).

Uses and Administration

The antineoplastic cisplatin is a platinum-containing complex that may act similarly to the alkylating agents. Its antineoplastic actions are cell-cycle non-specific and are dependent upon its cis configuration; they appear to be related to its hydrolysis in the body to form reactive aquated species. Although it causes immuno-suppression, stimulation of the host immune response against the tumour has been suggested as contributing to cisplatin’s antineoplastic action.

Cisplatin is of value in the treatment of tumours of the testis, usually as a major component of combination chemotherapy regimens, and particularly with bleomycin and etoposide (BEP), or with bleomycin and a vinca alkaloid. It is also used in metastatic ovarian tumours, cervical tumours, lung cancer, advanced bladder cancer, and squamous cell carcinoma of the head and neck. It has been reported to be active against many other solid tumours, as indicated by the cross references given below.

Cisplatin is given by intravenous infiision in sodium chloride 0.9% or in a mixture of sodium chloride and glucose. In monotherapy, it is usually given as a single dose of 50 to 120 mg/m every 3 to 4 weeks. Alternatively, 15 to 20 mg/m is given daily for 5 days, every 3 to 4 weeks. Lower doses are generally used for combination chemotherapy regimens than for single agent therapy; 20 mg/m or more is given once every 3 to 4 weeks. A dose of 20 mg/m daily for 5 days every 3 to 4 weeks has been used in combination chemotherapy of testicular tumours.

Licensed product information recommends that cisplatin is given in 2 litres of chloride-containing infiision fluid. In practice, volumes of less than 2 litres have been used in expert centres. The infusion may be given over 1 to 2 hours, although licensed product information generally recommends a longer infusion time of 6 to 8 hours in order to reduce renal and gastrointestinal toxicities.

To aid diuresis and protect the kidneys, 37.5 g of mannitol (e.g. 375 mL of mannitol 10%) is usually added to the infusion or is infused separately immediately before cisplatin. In order to begin diuresis the patient is usually hydrated by the infusion of 1 to 2 litres of a suitable fluid over several hours before giving cisplatin. Adequate hydration must also be maintained for up to 24 hours after a dose. Renal, haematological, auditory, and neurological function should be monitored during therapy, and dosage adjusted accordingly.

Cisplatin has also been given by the intra-arterial and intraperitoneal routes, and by instillation into the bladder. It is being investigated as a liposomal formulation, and as a collagen-based injectable gel containing cisplatin and adrenaline (MPI-5010) to localise the effect. An oral formulation of cisplatin is also under investigation.

Various analogues of cisplatin have been developed or investigated including those with fewer adverse effects (e.g. carboplatin; nedaplatin), an altered spectrum of activity (oxaliplatin), or activity on oral dosage (satraplatin).

Administration

Various adjustments to the administration of cisplatin have been suggested in an attempt to improve effectiveness while reducing toxicity.

Hydration before and after a dose of cisplatin, together with the use of mannitol to promote diuresis, is now standard (see Uses and Administration, above). Higher doses of cisplatin (up to 200 mg/m per treatment cycle) have been successfully given by infusion in hypertonic sodium chloride, accompanied by intensive hydration. Sodium chloride 3% infusion solution has been used. However, while such a regimen may limit nephrotoxicity, other toxic effects, such as peripheral neuropathy, are not prevented; myelosuppression may be less if the total dose is given in 2 divided doses rather than divided over 5 days. High-dose cisplatin has been given once weekly; haematological toxicity may be dose-limiting with this regimen. Toxicity has been reported to be reduced when cisplatin was given by continuous intra-arterial or intravenous infusion.

It has also been suggested that giving cisplatin in the evening rather than the morning results in less damage to renal function, apparently because of circadian variations in urine production. However, another study found that morning, rather than evening, doses of cisplatin resulted in less renal damage. Noting the inconsistency with previous reports, the authors concluded that use of a prolonged hydration protocol and concomitant furosemide might have been responsible for these results (see also under Interactions, Cardiovascular Drugs, above). It was also found that morning dosage of cisplatin may be more emetogenic than evening dosage, although the use of prophylactic ondansetron before cisplatin reduced this apparent circadian effect on vomiting.

A suggested alternative way to increase the platinum dose without producing incapacitating toxicity has been the combination of cisplatin and carboplatin.

Various drugs have been investigated to reduce toxicity, including amifostine, glutathione, and thiosulfate, as discussed under Effects on the Kidneys, and Effects on the Nervous System, above.

A retrospective study of patients with bladder cancer found that calculation of creatinine clearance (CC) by mathematical formulas was inadequate in determining renal eligibility for treatment with cisplatin, especially in patients over 65 years of age; up to 44% of patients who were treated with cisplatin based on measured CC would have been deemed ineligible using mathematical calculations.

Malignant neoplasms

Cisplatin is used in the management of many solid malignancies, notably those of the bladder, cervix, lung, ovary, and testis, as discussed on site respectively. Other malignancies where cisplatin may be employed, as discussed in the introduction to this chapter, include non-Hodgkin’s lymphomas, tumours of brain, endometrium, oesophagus, stomach, and anus, head and neck, and thymus, neuroblastoma, and sarcoma of bone and soft tissue.

Preparations

British Pharmacopoeia 2008: Cisplatin Injection;

The United States Pharmacopeia 31, 2008: Cisplatin for Injection.

Proprietary Preparations

Argentina: Ciskebir; Elvecis; Platamine; Platino II; Platinol ; Sicatem;

Austria; Cishexal; Platinol; Platosin;

Belgium: Platinol; Platistine ; Platosin;

Brazil: Astaplatin ; Bioplatino; C-Platin; Cisplatex; Citoplax; Incel; Laxifos ; Platiran; Platistine; Tecnoplatin; Unistin;

Chile: Blastolem;

Czech Republic: Cisanplat ; Platidiam;

Denmark: Lederpiatin; Platinol;

Finland: Platinol;

France: Cisplatyl;

Germany; Cis-Gry; Platinex;

Greece: Cisplamol; Cisplatyl; Oncoplat; Platamine; Platinol; Platosin;

Hungary: Platidiam;

India: Cisplat; Cytoplatin; Kemoplat; Platin;

Indonesia: Platinox; Platosin;

Israel: Abiplatin;

Italy: Citoplatino; Platamine; Platinex; Pronto Platamine;

Japan: Platosin; Randa;

Malaysia: Platosin;

Mexico: Blastolem; Metalino ; Niyaplat ; Noveldexis; Platinol; Platistill; Tecnoplatin;

The Netherlands: Platosin;

Norway: Platinol; Platistin;

New Zealand: Platinol;

Philippines: Ciplexal; Cytosplat Docistin; Kemoplat; Platamine; Platinol; Platinoxan; Platosin;

Poland: Platidiam

Portugal: Faulplatin;

Russia: Blastolem; Platidiam

South Africa: Abiplatin; Platosin;

Spain: Neoplatin; Placis; Platistil ;

Sweden: Platinol;

Switzerland: Platiblastin-S; Platinol;

Thailand: Abiplatin; Blastolem; Kemoplat; Platinol; Platosin;

Turkey: Placis; Platosin-S;

United Kingdom (UK): Platinex ;

United States of America (US and USA): Platinol ;

Venezuela: Cytoplatin.

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