Grace Cisplatin

 

For the use only of a registered medical practitioner or a hospital or a laboratory

Rx

 

GRACE CISPLATIN

Cisplatin Injection BP 1mg/mL

 

COMPOSITION

For 10 mg/10 mL

Each mL contains:

Cisplatin Ph.Eur.    1mg

Water for Injection Ph.Eur.     q.s. Excipients q.s.

 

For 50 mg/50 mL

Each mL contains:

Cisplatin Ph.Eur.    1mg,

Water for Injection Ph.Eur.    q.s. Excipients q.s.

 

PHARMACEUTICAL FORM

Solution for injection

 

THERAPEUTIC INDICATIONS

     To be used as mono-therapy, or as part of an existing chemotherapy for advanced or metastatic tumours: testicular carcinoma (palliative and curative poly-chemotherapy) and ovary carcinoma (stages III and IV), and head and neck squamous-cell epithelioma (palliative therapy).

     In the treatment of small cell lung carcinoma.

     In the treatment of advanced non-small cell lung carcinoma.

 

POSOLOGYAND METHOD OFADMINISTRATION

Posology

Adults and children:

     The cisplatin dosage depends on the primary disease, the expected reaction, and on whether cisplatin is used for monotherapy or as a component of a combination chemotherapy. The dosage directions are applicable for both adults and children. For recommendations on the dosage applicable, based on the diagnosis and the clinical condition, the current medical literature should be consulted.

     For monotherapy, the following two dosage regimens are recommended:

     Single dose of 50 to 120 mg/m2 body surface 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 chemotherapy, the dose of cisplatin must be reduced. A typical dose is 20 mg/m2 or more once every 3 to 4 weeks unless in the combination therapy of small-cell and non-small-cell lung carcinoma, in which a typical dose of 80 mg/m2 is administered.

     Further dosage recommendations are to be based upon current medical insights, to be obtained from the literature or/and the appropriate working parties.

     For warnings and precautions to be considered prior to the start of the next treatment cycle.

     In patients with renal dysfunction or bone marrow depression, the dose should be reduced adequately.

 

Method of administration

     Cisplatin 1mg/ml concentrate for solution for infusion is to be diluted before use.

     The diluted solution should be administered only intravenously by infusion (see below). For administration, any device containing aluminium that may come in contact with cisplatin (sets for intravenous infusion, needles, catheters, syringes) must be avoided.

     The cisplatin solution for infusion prepared according to instructions should be administered by intravenous infusion over a period of 6 to 8 hours.

     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 cause sufficient diuresis during and after treatment with cisplatin. It  is realised by intravenous infusion of one of the following solutions:

sodium chloride solution 0.9%;

mixture of sodium chloride solution 0.9% and glucose solution 5% (1:1).

 

Hydration prior to treatment with cisplatin:

Intravenous infusion of 100 to 200ml/hour for a period of 6 to 12 hours.

 

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 37.5g mannitol as a 10% solution (375 ml mannitol solution 10%), 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 body surface.

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

 

CONTRAINDICATIONS

Hypersensitivity to the active substance or other platinum containing compounds, or to any of the excipients in dehydrated condition (pre- and post-hydration is required to prevent serious renal dysfunction); with myelosuppression; 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. who are pregnant or breastfeeding in combination with yellow fever vaccine and phenytoin in prophylactic use.

 

WARNINGS AND PRECAUTIONS

     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.

 

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 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).

 

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.

 

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.

 

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.

 

Hepatic function and hematological formula

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

 

Carcinogenic potential

     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

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.

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.

 

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.

     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.

 

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.

 

DRUG INTERACTIONS

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 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.

 

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.

 

Attenuated live vaccines

Yellow fever vaccine is strictly contraindicated because of the risk of fatal systemic vaccine. In view of the risk of generalized illness, it is advisable to use an inactivated 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.

 

Pyridoxine + altretamine combination

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.

 

Paclitaxel

Treatment with cisplatin prior to an infusion with paclitaxel may reduce the clearance of paclitaxel by 33% and therefore can intensify neurotoxicity.

 

FERTILITY PREGNANCYAND LACTATION

Pregnancy

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. Cisplatin is contraindicated during the pregnancy period.

 

Breast-feeding

Cisplatin is excreted in human milk. Breastfeeding during the therapy is contraindicated.

 

Fertility

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 CISPLATIN. 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.

 

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

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.

 

SIDE EFFECTS

Common adverse reactions are nephrotoxicity, peripheral neuropathy, nausea and vomiting myelosuppression, and ototoxicity. The following adverse reactions have been identified from clinical trials or post-marketing surveillance.

 

Blood and lymphatic system disorders: Coombs-positive hemolytic anemia. hemolytic uremic syndrome, thrombotic thrombocytopenic purpura.

 

Cardiovascular disorders: Venous thromboembolism, arterial thromboembolism, myocardial infarction, cerebrovascular accident, thrombotic microangiopathy, cerebral arteritis, pericardial effusion, cardiac failure, ventricular dysfunction, Raynaud’s phenomenon.

 

Eye disorders: Optic neuritis, papilledema, cortical blindness, blurred vision, color blindness, retinal pigmentation.

 

Gastrointestinal disorders: Nausea, vomiting, anorexia, diarrhea, stomatitis, gastrointestinal perforation, pancreatitis, hiccups.

 

General disorders: Asthenia, malaise.

 

Hepatobiliary disorders: Elevations of aminotransferases, lactate dehydrogenase, and bilirubin; hepatic failure.

 

Hypersensitivity: Anaphylaxis, facial edema, wheezing, tachycardia, and hypotension. Local Site Reactions: Tissue cellulitis, fibrosis, necrosis, pain, edema, and erythema Metabolism and nutrition disorders: Hypomagnesemia, often requiring magnesium supplementation; hyperuricemia, other electrolyte abnormalities (hypocalcemia, hyponatremia,hypokalemia, and hypophosphatemia), Syndrome of Inappropriate Antidiuretic Hormone Excretion (SIADH), dehydration, tumor lysis syndrome, increased serum amylase.

 

Musculoskeletal disorders: Muscle cramps (localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration).

 

Nervous system disorders: Peripheral neuropathy, Encephalopathy, loss of motor function, loss of taste, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, progressive multifocal leukoencephalopathy, seizures, Lhermitte’s sign, dorsal column myelopathy, autonomic neuropathy, seizures, involuntary skeletal muscle contractions, tetany (with hypocalcemia and hypomagnesemia).

 

Ototoxicity: Tinnitus, hearing loss, deafness, vestibular toxicity.

 

Renal and urinary disorders: Nephrotoxicity including renal failure, renal electrolyte wasting, azotemia, decreased creatinine clearance.

 

Respiratory disorders: pneumonitis/interstitial lung disease, pulmonary embolism.

Skin and subcutaneous tissue disorders: Alopecia, rash.

 

Overdose

CAUTION IS ESSENTIAL IN ORDER TO PREVENT AN INADVERTENT 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 a cisplatin overdose. Even if hemodialysis is initiated 4 hours after the overdose it has little effect on the elimination of cisplatin from the body due to a strong and rapid fixation of cisplatin to proteins.

 

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents / Platinum compounds ATC code: L01XA01

 

Mechanism of action

Cisplatin is an anorganic substance containing a heavy metal [cis diamminedichloroplatinum(II)]. This substance inhibits the DNA synthesis by realising transverse connections within and between the DNA strings. The protein and RNA synthesis is inhibited to a lesser extent.

 

Pharmacodynamic effects

     Although the primary activity of cisplatin seems to be the inhibition of DNA synthesis, the antineoplastic process includes other activities, such as enlargement of the tumour immunogenicity. Cisplatin’s oncolytic functions can be compared to the functions of alkylating substances. Cisplatin also offers immunosuppressive, radiosensitising and antibacterial features.

     Cisplatin does not seem to be cell cycle specific.

     The cytotoxic activities of cisplatin are caused by binding all DNA bases, with a preference for the N-7 position of guanine and adenosine.

 

Pharmacokinetic properties

Distribution

After intravenous administration, cisplatin is rapidly distributed among all tissues. Following cisplatin doses of 20 to 120 mg/m2, the concentrations of platinum are highest in liver, prostate and kidney, somewhat lower in bladder, muscles, testicle, pancreas and spleen and lowest in bowel, adrenal, heart, lung, cerebrum and cerebellum.

 

Biotransformation

Over 90% of the total plasma cisplatin is bounded with protein after two hours following the administration. This process may be irreversible. The protein-bounded part is not antineoplastic active. Cisplatin is non-linearly pharmacokinetic. Cisplatin is converted by a non-enzymatic process into one or more metabolites. Elimination from the plasma is realised in two phases after intravenous bolus injection of 50-100 mg/m2 of cisplatin. The following half-life period have been registered for humans:

t ½ (distribution): 10-60 minutes

t ½ (terminal): approximately 2-5 days

 

Elimination

The considerable protein binding of the total platinum contents results in an extended or incomplete excretion phase with cumulative urine secretion ranging from 27 to 45% of the administered dose in a period from 84 to 120 hours. An extended infusion results in the urine secretion of a larger part of the dose. The faecal secretion is minimal, and small amounts of platinum can be traced in the gallbladder and the large intestine. Dysfunctional kidneys increase the plasma half-life period, which may also increase theoretically in the presence of ascites caused by the highly protein binding activities of  cisplatin.

 

PHARMACEUTICAL PARTICULARS

List of excipients Sodium chloride

Water for injection

 

Shelf life: 2 years

 

Storage: Store in a cool & dry place below 30°C.

Protect from light & moisture

 

Nature and contents of container:

For 10 mg/10 mL

Cisplatin Injection 10 mg is supplied in a 10 mL Amber colored vials USP type-I with grey bromobutyl closures type-I Sealed with 20 mm flip off seals.

 

For 50 mg/50 mL

Cisplatin Injection 50 mg is supplied in a 50 mL Amber colored vials USP type-I with grey bromobutyl closures type-I Sealed with 20 mm flip off seals.

 

Manufactured by:

M/s Jodas Expoim Pvt. Ltd.

Plot No.55, Phase III, Biotech Park,

Karkapatla (V), Markook (M),

Siddipet (D)-502 279 ,

Telangana INDIA.

 

Product of:

Grace Biogen PtyLtd,

Sydney, Australia.