1. Name of the medicinal product

Cisplatin Injection BP 10mg/10ml Taj Pharma
Cisplatin Injection BP 10mg/20ml Taj Pharma
Cisplatin Injection BP 50mg/50ml Taj Pharma
Cisplatin Injection BP 50mg/100ml Taj Pharma
Cisplatin Injection BP 100mg/100ml Taj Pharma
Cisplatin Injection BP 200mg/200ml Taj Pharma

2. Qualitative and quantitative composition

a) Cisplatin Injection BP 10mg/10ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….1mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

b) Cisplatin Injection BP 10mg/20ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….0.5mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

c) Cisplatin Injection BP 50mg/50ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….1mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

d) Cisplatin Injection BP 50mg/100ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….0.5mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

e)Cisplatin Injection BP 100mg/100ml? Taj Pharma
Each ml contains:
Cisplatin BP ……………….1mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

f) Cisplatin Injection BP 200mg/200ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….1mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

For the full list of?excipients, see section 6.1.

3. Pharmaceutical form

Cisplatin Taj Pharma solution for injection.

4.????? Clinical particulars

4.1 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.

4.2 Posology and method of administration

Posology

Adults and children:

The Cisplatin Taj Pharma dosage depends on the primary disease, the expected reaction, and on whether Cisplatin Taj Pharma 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 120mg/m²?body surface every 3 to 4 weeks; 15 to 20mg/m²/day for five days, every 3 to 4 weeks.

If Cisplatin Taj Pharma is used in?combination chemotherapy, the dose of Cisplatin Taj Pharma must be reduced. A typical dose is 20mg/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 80mg/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, see section 4.4.

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

Method of administration

Cisplatin Taj Pharma “Ebewe” 10mg/20ml Cisplatin Taj Pharma solution for injection is to be diluted before use (see section 6.6.).

The diluted solution should be administered only intravenously by injection (see below). For administration, any device containing aluminium that may come in contact with Cisplatin Taj Pharma (sets for intravenous injection, needles, catheters, syringes) must be avoided (see section 6.2.).

The Cisplatin Taj Pharma solution for injection prepared according to instructions (see section 6.6.) should be administered by intravenous injection 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 Taj Pharma. Hydration is necessary to cause sufficient diuresis during and after treatment with Cisplatin Taj Pharma. It is realised by intravenous injection 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 Taj Pharma:

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

Hydration?after?termination of the administration of Cisplatin Taj Pharma:

Intravenous injection of another 2 litres at a rate of 100 to 200ml per hour for a period of 6 to 12 hours.

Forced diuresis may be required should the urine secretion be less than 100 to 200ml/hour after hydration. Forced diuresis may be realised by intravenously administering 37.5g mannitol as a 10% solution (375ml 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 Taj Pharma dose is higher than 60mg/m²?of body surface.

It is necessary that the patient drinks large quantities of liquids for 24 hours after the Cisplatin Taj Pharma injection to ensure adequate urine secretion.

4.3 Contraindications

Hypersensitivity to the active substance or other platinum containing compounds, or to any of the excipients listed in section 6.1.

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 Taj Pharma is nephrotoxic and neurotoxic (in particular ototoxic). These toxicities may be cumulative if disorders of this type pre-exist.who are pregnant or breastfeeding (see section 4.6.)

in combination with yellow fever vaccine and phenytoin in prophylactic use (See section 4.5)

4.4 Special warnings and precautions for use

Cisplatin Taj Pharma reacts with metallic aluminum to form a black precipitate of platinum. All aluminum containing IV sets, needles, catheters and syringes should be avoided.

Cisplatin Taj Pharma 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 Taj Pharma causes severe cumulative nephrotoxicity. A urine output of 100ml/hour or greater will tend to minimize Cisplatin Taj Pharma nephrotoxicity. This can be accomplished by pre-hydration with 2 liters of an appropriate intravenous solution, and similar post Cisplatin Taj Pharma hydration (recommended 2,500ml/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 Taj Pharma 10mg/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 Taj Pharma. 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 Taj Pharma has been reported rarely. Ototoxicity may be enhanced with prior simultaneous cranial irradiation and may be related to peak plasma concentration of Cisplatin Taj Pharma. It is unclear whether Cisplatin Taj Pharma induced ototoxicity is reversible. Careful monitoring by audiometry should be performed prior to initiation of therapy and prior to subsequent doses of Cisplatin Taj Pharma. Vestibular toxicity has also been reported (see section 4.8 Undesirable effects).

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 (see section 4.3 Contraindications and section 4.8 Undesirable effects).

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 Taj Pharma, which was in general associated with other leukemogenic agents.

Cisplatin Taj Pharma is a bacterial mutagen and causes chromosome aberrations in cultures on animal cells. Carcinogenicity is possible but has not been demonstrated. Cisplatin Taj Pharma is teratogenic and embryotoxic in mice.

Injection site reactions

Injection site reactions may occur during the administration of Cisplatin Taj Pharma. Given the possibility of extravasation, it is recommended to closely monitor the injection site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.

Warning This cytostatic agent has a more marked toxicity than is usually found in antineoplastic chemotherapy. Renal toxicity, which is above-all cumulative, is severe and requires particular precautions during administration (see section 4.2 Posology and method of administration and section 4.8 Undesirable effects). Nausea and vomiting may be intense and require adequate antiemetic treatment. Close supervision must also be carried out with regard to ototoxicity, myelodepression and anaphylactic reactions (see section 4.8 Undesirable effects). Warning Preparation of the intravenous solution As with all other potentially toxic products, precautions are essential when handling the Cisplatin Taj Pharma 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 Taj Pharma 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.

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This medicinal product contains 35mg sodium per 20ml vial, equivalent to 1.75% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

This medicinal product contains 71mg 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 177mg 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 354mg sodium per 100ml vial, equivalent to 17.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

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 Taj Pharma on the kidneys. During or after treatment with Cisplatin Taj Pharma 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 Taj Pharma or in patients who have previously been given Cisplatin Taj Pharma.

Reduction of the blood’s lithium values was noticed in a few cases after treatment with Cisplatin Taj Pharma 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 Taj Pharma on auditory function. Except for patients receiving doses of Cisplatin Taj Pharma exceeding 60mg/m², whose urine secretion is less than 1000ml 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 Taj Pharma.

Attenuated live vaccines

Yellow fever vaccine is strictly contraindicated because of the risk of fatal systemic vaccinal disease (see section 4.3 Contraindications). In view of the risk of generalized illness, it is advisable to use an inactivated vaccine if available.

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 Taj Pharma.

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 Taj Pharma.

Paclitaxel

Treatment with Cisplatin Taj Pharma prior to an injection with paclitaxel may reduce the clearance of paclitaxel by 33% and therefore can intensify neurotoxicity.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Cisplatin Taj Pharma in pregnant women, but based on its pharmacological properties Cisplatin Taj Pharma is suspected to cause serious birth defects. Studies in animals have shown reproductive toxicity and transplacental carcinogenicity (see section 5.3.). Cisplatin Taj Pharma is contraindicated during the pregnancy period.

Breast-feeding

Cisplatin Taj Pharma 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 Taj Pharma.

Genetic consultation is recommended if the patient wishes to have children after ending the treatment. Since a treatment with Cisplatin Taj Pharma 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.

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4.7 Effects on ability to drive and use machines

Due to the possible side effects Cisplatin Taj Pharmahas 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.

4.8 Undesirable effects

Undesirable effects depend on the used dose and may have cumulative effects.

The most frequently reported?adverse events (>10%)?of Cisplatin Taj Pharma were haematological (leukopenia, thrombocytopenia and anaemia), gastrointestinal (anorexia, nausea, vomiting and diarrhoea), ear disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, hyperuricaemia) and fever.

Serious toxic effects on the kidneys, bone marrow and ears have been reported in up to about one third of patients given a single dose of Cisplatin Taj Pharma; the effects are generally dose-related and cumulative. Ototoxicity may be more severe in children.

The list is presented by system organ class, MedDRA preferred term, and frequency using the following frequency categories:

very common (? 1/10), common (? 1/100, < 1/10), uncommon (?1/1000, < 1/100), rare (? 1/10000, < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data).

Table of Adverse Drug Events reported during clinical or post-marketing experience (MedDRA terms)

Infections and infestations Common Sepsis Not known Infectiona Neoplasm benign, malignant, and unspecified Uncommon Acute leukemia Blood and lymphatic system disorders Very common Bone marrow failure, thrombocytopenia, leukopenia, anemia Not known Coombs positive hemolytic anemia Immune system disorders Uncommon Anaphylactoidb?reactions Endocrine disorders Not known Blood amylase increased, inappropriate antidiurectic hormone secretion Metabolism and nutrition disorders Very common Hyponatremia Uncommon Hypomagnesemia Not known Dehydration, hypokalemia, hypophosphatemia, hyperuricemia, hypocalcemia, tetany Nervous system disorders Rare Convulsion, neuropathy peripheral, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome Not known Cerebrovascular accident, hemorrhagic stroke, ischemic stroke, ageusia, cerebral arteritis, Lhermitte’s sign, myelopathy, autonomic neuropathy Eye disorders Not known Vision blurred, color 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 Vascular disorders Common Venous thromboembolism Not known Thrombotic microangiopathy (hemolytic uremic syndrome), Raynaud’s phenomenon Respiratory, thoracic and mediastinal disorders Not known Pulmonary embolism Gastrointestinal disorders Rare Stomatitis Not known Vomiting, nausea, anorexia, hiccups, diarrhea Hepatobiliary disorders Not known Hepatic enzymes increased, blood bilirubin increased Skin and subcutaneous tissue disorders Not known Rash, alopecia Musculoskeletal, connective tissue and bone disorders Not known Muscle spasms Renal and urinary disorders Not known Renal failure acute, renal failurec, renal tubular disorder Reproductive system and breast disorders Uncommon Abnormal spermatogenesis General disorders and administration site conditions Very common Pyrexia Not known Asthenia, malaise, injection site extravasationd

a: Infectious complications have led to death in some patients.

b: Symptoms reported for anaphylactoid reaction such as facial edema (PT-face oedema), wheezing, bronchospasm, tachycardia, and hypotension will be included in the parentheses for anaphylactoid reaction in the AE frequency table.

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

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

Reporting 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.

4.9 Overdose

CAUTION IS ESSENTIAL IN ORDER TO PREVENT AN INADVERTENT OVERDOSE.

An acute overdose of Cisplatin Taj Pharma 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 Taj Pharma overdose. Even if hemodialysis is initiated 4 hours after the overdose it has little effect on the elimination of Cisplatin Taj Pharma from the body due to a strong and rapid fixation of Cisplatin Taj Pharma to proteins.

1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents / Platinum compounds

Mechanism of action

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

Cisplatin Taj Pharma does not seem to be cell cycle specific.

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

5.2 Pharmacokinetic properties

Distribution

After intravenous administration, Cisplatin Taj Pharma is rapidly distributed among all tissues. Following Cisplatin Taj Pharma doses of 20 to 120mg/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 Taj Pharma is bounded with protein after two hours following the administration. This process may be irreversible. The protein-bounded part is not antineoplastic active. Cisplatin Taj Pharma is non-linearly pharmacokinetic. Cisplatin Taj Pharma 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 50-100mg/m²?of Cisplatin Taj Pharma. The following half-life period have been registered for humans:

t ? (distribution): 10-60 minutes

t ? (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 injection 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 Taj Pharma.

5.3 Preclinical safety data

Chronic toxicity:

Chronic toxicity models indicate kidney damage, bone marrow depression, gastro-intestine disorders and ototoxicity.

Mutagenity and carcinogenity:

Cisplatin Taj Pharma is mutagenic in numerous?in vitro?and?in vivo?tests (bacterial test systems and chromosome defects in animal cells and tissue cultures). Long term studies of Cisplatin Taj Pharma on mice and rats evidenced the carcinogenic effects.

Reproductive toxicity:

Fertility: Gonadal suppression resulting in amenorrhoea or azoospermia may be irreversible and cause definitive infertility.

Studies in rats showed that exposure during pregnancy produces tumours in the adult offspring.

Pregnancy and lactation: Cisplatin Taj Pharma is embryotoxic and teratogenic for mice and rats, and defects have been reported for both species. Cisplatin Taj Pharma was found in the milk.

1. Pharmaceutical particulars

6.1 List of excipients

Sodium chloride, Hydrochloric acid,Water for injections.

6.2 Incompatibilities

Cisplatin Taj Pharma reacts with aluminium which results in production of a black platinum precipitate. Therefore any device containing aluminium that may come in contact with Cisplatin Taj Pharma (sets for intravenous injection, needles, catheters, syringes) must be avoided.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

The Cisplatin Taj Pharma 1mg/ml concentrate must not be diluted with glucose solution 5% alone or mannitol solution 5% alone, but only with the mixtures containing additionally sodium chloride as stated in section 6.6.

Antioxidants (such as sodium metabisulphite), bicarbonates (sodium bicarbonate), sulfates, fluorouracil and paclitaxel may inactivate Cisplatin Taj Pharma in injection systems.

6.3 Shelf life

Medicinal product as packaged for sale:

2 years

Solution for injection after dilution (see section 6.6):

Chemical and physical in-use stability has been demonstrated for?48?hours?at?2 to?8?C?when protected from light for solutions with a final Cisplatin Taj Pharma concentration of 0.1mg/ml after dilution of the Cisplatin Taj Pharma 10mg/20ml concentrate with one of the following solutions:

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

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8?C, unless reconstitution / dilution (etc) has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Medicinal product as packaged for sale:

Do not store above 25 ?C. Do not refrigerate or freeze. Keep the vial in the outer carton.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

Packs of 1, 5 or 10 vial(s) containing 10ml, 20ml, 50ml, 100ml or 200ml Cisplatin Taj Pharma solution for injection each.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Cisplatin Taj Pharma 1mg/ml Cisplatin Taj Pharma solution for injection is to be diluted before use. For preparation of solution for injection, any device containing aluminium that may come in contact with Cisplatin Taj Pharma (sets for intravenous injection, needles, catheters, syringes) must be avoided (see section 6.2.).

Preparation of solution for injection must take place in aseptic conditions.

For dilution of the concentrate, one of the following solutions should be used:

• sodium chloride solution 0.9%;
• mixture of sodium chloride solution 0.9% and glucose solution 5% (1:1) (resulting final concentrations: sodium chloride 0.45%, glucose 2.5%).
• Should hydration prior to the treatment with Cisplatin Taj Pharma be impossible, the concentrate may be diluted with:
• mixture of sodium chloride solution 0.9% and mannitol solution 5% (1:1) (resulting final concentrations: sodium chloride 0.45%, mannitol 2.5%).

Preparation of Cisplatin Taj Pharma solution for injection:

The required amount (dose) of the Cisplatin Taj Pharma concentrate 1mg/ml calculated according to the instructions in section 4.2. should be diluted in 1-2 litres of one of the above mentioned solutions.

The diluted solution should be administered only by intravenous injection (see section 4.2.). Only clear and colourless to yellowish solutions without visible particles should be used.

For single use only.

Cytotoxic agents should be prepared for administration only by personnel who have been trained in the safe handling of the preparation.

Refer to local cytotoxic handling guidelines.

As any other cytotoxic agent, Cisplatin Taj Pharma should be used with extreme caution: gloves, face masks and protective clothing are required and vital. Cisplatin Taj Pharma should be processed under a protective hood, if possible. Contact with skin and/or mucous membranes must be avoided. Pregnant hospital employees should not work with Cisplatin Taj Pharma.

Skin contact: Rinse with large quantities of water. Apply an ointment if you have a temporary burning feeling. (Note: Some persons are sensitive to platinum and may experience a skin reaction).

In the event of spillage, operators should put on gloves and mop up the spilled material with a sponge kept in the area for that purpose. Rinse the area twice with water. Put all solutions and sponges into a plastic bag and seal it. In the case of spillage all items coming into contact with Cisplatin Taj Pharma should be handled and disposed in accordance to local cytotoxic guidelines.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Cisplatin Injection BP 10mg/10ml, 10mg/20ml, 50mg/50ml, 100mg/100ml and 200mg/200ml Taj Pharma

Package leaflet: Information for the user

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it
• If you have further questions, ask your doctor, pharmacist or
• This medicine has been prescribed for you Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist or This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Cisplatin Taj Pharma Injection is and what it is used for
2. What you need to know before you use Cisplatin Taj Pharma Injection
3. How to use Cisplatin Taj Pharma Injection
4. Possible side effects
5. How to store Cisplatin Taj Pharma Injection
6. Contents of the pack and other information

1. What Cisplatin Taj Pharma Injection is and what it is used for

Cisplatin Taj Pharma forms part of a group of medicines called cytostatics, which are used in the treatment of cancer. Cisplatin Taj Pharma can be used alone but more commonly Cisplatin Taj Pharma is used in combination with other cytostatics.

What is it used for?

Cisplatin Taj Pharma can destroy cells in your body that may cause certain types of cancer (tumour of testis, tumour of ovary, tumour of the bladder, head and neck epithelial tumour, lung cancer and for cervical cancer in combination with radiotherapy).

Your doctor will be able to provide you with more information.

2. What you need to know before you use Cisplatin Taj Pharma Injection

Do not take Cisplatin Taj Pharma if:

• you are allergic to Cisplatin Taj Pharma or to any of the other ingredients of this medicine (listed in section 6
• you are allergic (hypersensitive) to any other medicine that contains platina compounds
• you have kidney problems (renal dysfunction)
• you suffer from dehydration
• you suffer from severe suppression of bone marrow functionality, symptoms may be: extreme tiredness, easy bruising or bleeding, occurrence of infections
• your hearing is impaired
• you suffer from nervous disorders caused by Cisplatin Taj Pharma
• you are breast-feeding
• combined with live vaccines, including yellow fever
• combined with phenytoin in prophylactic use (see ?Other medicines and Cisplaitn? below).

Warnings and precautions

Your doctor will carry out tests in order to determine the levels of calcium, sodium, potassium and magnesium in your blood, as well as to check your blood picture and your liver and kidney functionality and neurological function.

• Cisplatin Taj Pharma should only be administered under the strict supervision of a specialist doctor experienced in administrating
• Your hearing will be tested prior to each treatment with
• If you suffer from a nervous disorder not caused by
• If you have had radiation therapy to your head
• If you suffer from an infection. Please consult your
• If you intend to have children (see Pregnancy, breast-feeding and fertility
• Tell your doctor if the above applies to you before this medicine is
• With spillage of Cisplatin Taj Pharma the contaminated skin must immediately be washed with water and soap. If Cisplatin Taj Pharma is injected outside the blood vessels the administration must be stopped immediately. Infiltration of Cisplatin Taj Pharma in the skin can result in tissue damage (cellulitis, fibrosis and necrosis).

Please consult your doctor, even if these statements were applicable to you at any time in the past.

Other medicines and Cisplatin Taj Pharma

Please note that these statements may also apply to products used some time ago or at some time in the future. Tell your doctor or pharmacist if you are taking, or have recently taken, or might take any other medicine ?

• Simultaneous use of medicines that inhibit the bone marrow function or radiation can potentiate the adverse effects of Cisplatin Taj Pharma on the bone
• Cisplatin Taj Pharma toxicity may increase when administered simultaneously with other cytostatics (medicine for cancer treatment), such as bleomycin and
• Agents to treat high blood pressure (antihypertensives containing furosemide, hydralazine, diazoxide, and propranolol) may increase the toxic effect of Cisplatin Taj Pharma on kidneys.
• Cisplatin Taj Pharma toxicity may severely affect the kidneys when administered simultaneously with agents that may cause side effects in the kidneys, such as those for the prevention/ treatment of certain infections (antibiotics: cephalosporins, aminoglycosides, and/or amphotericin B) and contrast
• Cisplatin Taj Pharma toxicity may affect hearing faculties when administered simultaneously with agents that may have a side effect on hearing faculties, such as
• If you use agents to treat gout during your treatment with Cisplatin Taj Pharma, then the dosage of such agents may need to be adjusted (e.g. allopurinol, colchicine, probenecid and/or sulfinpyrazone).
• Administration of drugs that elevate your rate of bodily urine excretion (loop diuretics) combined with Cisplatin Taj Pharma (Cisplatin Taj Pharma dose: more than 60mg/m?, urine secretion: less than 1000ml per 24 hours) may result in toxic effects on kidneys and
• The first signs of hearing damage (dizziness and/or tinnitus) may remain hidden when – during your treatment with Cisplatin Taj Pharma – you are also being administered agents to treat hypersensitivity (antihistamines, such as buclizine, cyclizine, loxapine, meclozine, phenothiazines, thioxanthenes and/or trimethobenzamides).
• Cisplatin Taj Pharma given in combination with ifosphamide may result in hearing
• The effects of treatment with Cisplatin Taj Pharma can be reduced through simultaneous administration of pyridoxine and hexamethylmelamine.
• Cisplatin Taj Pharma given in combination with bleomycin and vinblastine may result in paleness or blue coloration of the fingers and/or toes (Raynaud?s phenomenon).
• Administration of Cisplatin Taj Pharma prior to treatment with paclitaxel or in combination with docetaxel may result in severe nerve
• The combined use of Cisplatin Taj Pharma with bleomycin and etoposide may decrease lithium levels in the Therefore, lithium levels should be checked on a regular basis.
• Cisplatin Taj Pharma reduces the effects of phenytoin on the treatment of
• Penicillamine may reduce the effectiveness of
• Cisplatin Taj Pharma may have an adverse impact on the effectivity of agents preventing coagulation (anticoagulants). Therefore, coagulation should be checked more often during combined
• Concomitant use of Cisplatin Taj Pharma with ciclosporin can weaken the immune system, with the risk of increased production of white blood cells (lymphocytes)
• You should not receive any vaccinations containing live viruses within three months after the end of treatment with
• When undergoing treatment with Cisplatin Taj Pharma, you should not receive yellow fever vaccinations (also see ?Do not take Cisplatin Taj Pharma?).

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Cisplatin Taj Pharma must not be used during pregnancy unless clearly indicated by your doctor.

You must use effective contraception during and at least 6 months after treatment with Cisplatin Taj Pharma. You must not breastfeed while you are treated with Cisplatin Taj Pharma.

Male patients treated with Cisplatin Taj Pharma are advised not to father a child during treatment and for up to 6 months after treatment. Further, men are advised to seek counseling on sperm preservation before starting treatment.

Driving and using machines

Cisplatin Taj Pharma may cause side effects such as feeling sleepy and/or vomiting. If you suffer from either of these conditions, then you should not operate any machines that require your full attention.

Cisplatin Taj Pharma injection contains sodium

Cisplatin Taj Pharma contains 3.5mg sodium perml. This should be considered if you have to keep to a low sodium diet.

3. How to use Cisplatin Taj Pharma Injection

Dosage and method of administration

Cisplatin Taj Pharma should only be given by a specialist in cancer treatment.

The concentrate is diluted with a sodium chloride solution that contains glucose. Cisplatin Taj Pharma is only given by injection into a vein (an intravenous infusion).

Supportive equipment should be available to control anaphylactic reactions. Cisplatin Taj Pharma should not come into contact with any materials that contain aluminium.

The recommended dosage of Cisplatin Taj Pharma depends on your well-being, the anticipated effects of the treatment, and whether or not Cisplatin Taj Pharma is given on its own (monotherapy) or in combination with other agents (combination chemotherapy).

Cisplatin Taj Pharma (monotherapy):

The following dosages are recommended:

• A single dosage of 50 to 120mg/m? body surface, every 3 to 4
• 15 to 20mg/m? per day over a 5-day period, every 3 to 4 weeks

Cisplatin Taj Pharma in combination with other chemotherapeutical agents (combination chemotherapy):

• 20mg/m? or more, once every 3 to 4

For treatment of cervical cancer Cisplatin Taj Pharma is used in combination with radiotherapy. A typical dose is 40mg/m? weekly for 6 weeks.

In order to avoid, or reduce, kidney problems, you are advised to drink copious amounts of water for a period of 24 hours following treatment with Cisplatin Taj Pharma.

If you take more Cisplatin Taj Pharma than you should

Your doctor will ensure that the correct dose for your condition is given. In case of overdose, you may experience increased side effects. Your doctor may give you symptomatic treatment for these side effects. If you think you received too much Cisplatin Taj Pharma, immediately contact your doctor.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them

If you experience any side effect it is important that you inform your doctor before your next treatment.

Tell your doctor immediately, if you notice any of the following:

• persistent or severe diarrhoea or vomiting
• stomatitis/mucositis (sore lips or mouth ulcer)
• swelling of the face, lips mouth or throat
• unexplained respiratory symptoms such as non-productive cough, difficulty in breathing or crackles
• difficulty in swallowing
• numbness or tingling in your fingers or toes
• extreme tiredness
• abnormal bruising or bleeding
• signs of infection, such as sore throat and high temperature
• sensation of discomfort close to or at the injection site during the

The following side effects may occur:

Very common (may affect more than 1 in 10 people)

Blood and lymphatic system: suppression of the bone marrow characterised by a severe decrease of white blood cells, which makes infections more likely (leukopenia), reduction in blood platelets, which increases the risk of bruising and bleeding (thrombocytopenia), as well as reduction in red blood cells, which can make the skin pale and cause weakness or breathlessness (anaemia).

Nutrition and metabolism: reduced level of electrolytes (sodium)

Gastrointestinal tract: loss of appetite (anorexia), nausea, vomiting, diarrhoea.

Kidneys and urinary tracts: excessive uric acid levels (hyperuricaemia) in the blood (e.g. gout).

General symptoms: fever.

Common (may affect up to 1 in 10 people) Infections: blood-poisoning (sepsis).

Heart: arrhythmia, including reduced heartbeat (bradycardia), accelerated heartbeat (tachycardia).

Blood vessels: inflammation of a vein (phlebitis) at injection site.

Respiratory disorders: difficulty of breathing (dyspnoea), inflammation of the lungs (pneumonia) and respiratory failure.

Uncommon (may affect up to 1 in 100 people)

Immune system: hypersensitivity reactions, including rash, eczema with severe itching and lump formation (urticaria), redness and inflammation of the skin (erythema) or itching (pruritus), (anaphylactoid reactions) with symptoms such as swelling of the face and fever, low blood pressure (hypotension), accelerated heartbeat (tachycardia), breathing difficulties (dyspnoea), distress as a result of muscle cramps in the airways (bronchospasms) Hearing: damage to the ear (ototoxicity)

Nutrition and metabolism: reduced level of electrolytes (Magnesium)

Gastrointestinal tract: metallic setting on the gums.

Skin: loss of hair (alopecia).

Reproductive system and breasts: dysfunctional spermatogenesis and ovulation, and painful breast growth in men (gynaecomastia).

Rare (may affect up to 1 in 1,000 people)

Immune system: severe hypersensitivity (anaphylactic reactions) with low blood pressure (hypotension), accelerated heartbeat (tachycardia), breathing difficulties (dyspnoea), distress as a result of muscle cramps in the airways (bronchospasms), swelling of the face and fever; suppression of the immune system (immunosuppression).

Nervous system: loss of certain types of brain function, including brain dysfunction characterised by spasms and reduced levels of consciousness (encephalopathy), peripheral neuropathy of the sensory nerves (bilateral, sensory neuropathy), characterised by tickling, itching or tingling without cause and sometimes characterised by a loss of taste, touch, sight, sudden shooting pains from the neck through the back into the legs when bending forwards, attacks (seizures)..

Hearing: unable to hold normal conversation, loss of hearing (in particular among children and elderly patients).

Heart: increased blood pressure levels, coronary artery disease and heart attacks.

Liver and bile: reduced albumin (protein) levels in blood

Gastrointestinal tract: inflammation of mucous membranes of the mouth (stomatitis)

General: Cisplatin Taj Pharma, like other similar medicines, increases the risk of leukaemia (acute leukaemia).

Very rare (may affect up to 1 in 10,000 people)

Nutrition and metabolism: increased iron levels in the blood.

Heart: heart (cardiac) arrest.

Not known (frequency cannot be estimated from the available data)

Infections: Infection

Blood and lymphatic system:, haemolytic anaemia

Hormones: insufficient production of the vasopressin hormone in the brain (SIADH), blood amylase (enzyme) increased.

Nutrition and metabolism: reduced level of electrolytes (calcium, phosphate, potassium) in the blood with muscle cramping and/or changes in an electrocardiogram (ECG). Excessive cholesterol levels in the blood.

Nervous system: spinal disease, brain dysfunction (confusion, slurred speech, sometimes blindness, memory loss, and paralysis); stroke, loss of taste (ageusia), as well as closure of the carotid artery.

General symptoms: weakness (asthenia), malaise, dehydration, swelling (oedema), pain,redness and inflammation of the skin (erythema, skin ulcer)at the area of injection

Kidneys and urinary tracts: kidney dysfunction, such as failure to produce urine (anuria) and urine poisoning of the blood (uraemia)

Musculoskeletal: muscle spasms

Skin and dermis: hair loss, rash

Liver and bile: liver dysfunction, liver enzymes increased, bilirubin increased.

Gastrointestinal tract: loss of appetite (anorexia), nausea, vomiting, diarrhoea, hiccups.

Blood vessels: blood flow dysfunction, e.g. in the brain, but also in the fingers and toes (Raynaud?s syndrome), Thrombotic microangiopathy combined with haemolytic uraemic syndrome.

Heart: cardiac disorder

Hearing and balance function: loss of hearing combined with tinnitus (ringing in ears)

Eyes: Blurred vision, difficulties in colour perception and eye movement dysfunction. swelling (papilloedema), inflammation of the eye nerve combined with pain and reduced nerve function (optic neuritis), blindness as a result of brain dysfunction.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.

5. How to store Cisplatin Taj Pharma Injection

Keep this medicine out of sight and reach of children.

Keep the vial in the outer carton (to avoid exposure of Cisplatin Taj Pharma to light).

Concentrate for solution for infusion 1mg/ml

Keep container in the outer carton in order to protect from light. Do not refrigerate or freeze.

Do not use this medicine after the expiry date which is stated on the vial and the outer carton after ?exp?. The expiry date refers to the last day of that month. Do not use this medicine if you notice visible signs of deterioration.

All materials that have been used for the preparation and administration, or which have been in contact with Cisplatin Taj Pharma in any way, must be disposed of according to local cytotoxic guidelines

If you find the solution cloudy or a deposit that does not dissolve is noticed, the bottle should be discarded.

6. Contents of the pack and other information

What Cisplatin Taj Pharma Injection contains:

a) Cisplatin Injection BP 10mg/10ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….1mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

b) Cisplatin Injection BP 10mg/20ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….0.5mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

c) Cisplatin Injection BP 50mg/50ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….1mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

d) Cisplatin Injection BP 50mg/100ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….0.5mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

e)Cisplatin Injection BP 100mg/100ml? Taj Pharma
Each ml contains:
Cisplatin BP ……………….1mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

f) Cisplatin Injection BP 200mg/200ml Taj Pharma
Each ml contains:
Cisplatin BP ……………….1mg
Water for Injection……… Q.S
Excipients: ………………..Q.S

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).