4.1. Therapeutic indications
Cisplatin is indicated for the treatment of:
• advanced or metastasized testicular cancer
• advanced or metastasized ovarian cancer
• advanced or metastasized bladder carcinoma
• advanced or metastasized squamous cell carcinoma of the head and neck
• advanced or metastasized non small cell lung carcinoma
• advanced or metastasized small cell lung carcinoma
 cervical carcinoma in combination with other chemotherapeutics or with radiotherapy
Cisplatin can be used as monotherapy and in combination therapy.

Posology
Adults and children:
Cisplatin dosage depends on the primary disease, the expected reaction and on whether Cisplatin is used
for monotherapy or as a component of combination chemotherapy. The dosage directions are applicable
for both adults and children.
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 daily for five days, every 3 to 4 weeks
If Cisplatin is used in combination therapy, the dose of Cisplatin must be reduced. A typical dose is
20mg/m2 or more once every 3 to 4 weeks.
For treatment of cervical cancer, Cisplatin is used in combination with radiotherapy. A typical dose is
40mg/m2 weekly for 6 weeks.
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
(see Section 4.3).
The Cisplatin solution for infusion prepared according to instructions (see Section 6.6.) should be
administrated 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 realized by intravenous infusion of the following solution:
 Sodium Chloride 0.9%
 Mixture of Sodium Chloride 0.9% and Glucose 5% (1:1), (resulting final concentrations: Sodium
Chloride 0.45%, Glucose 2.5%)
 Sodium Chloride 0.9% and 1.875% Mannitol for injection
 Sodium Chloride 0.45%, Glucose 2.5% and 1.875% Mannitol for injection

Method of administration
Cisplatin 1mg/ml sterile concentrate is to be diluted before administration. For instructions for dilution of
the product before administration see section 6.6.
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.
Hydration prior to treatment with Cisplatin:
Intravenous infusion of 100 to 200ml per hour for a period of 6 to 12 hours, with a total amount of at least
1 litre.

Hydration after termination of the administration of Cisplatin:
Intravenous infusion of another 2 litres at a rate of 100 to 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 per hour after
hydration. Forced diuresis may be realized 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 Cisplatin administered dose is
higher than 60mg/m2 of body surface.
It is necessary that the patient drinks large quantities of liquids for 24 hours after Cisplatin infusion to
ensure an adequate urine secretion.

 hypersensitivity to the active substance (Cisplatin) or to any of the excipients listed in Section 6.1. Cisplatin may give allergic reactions in some patients. Use is contraindicated in those patients with a history of allergic reaction to Cisplatin or other platinum- containing compounds, or any component of the formulation  Cisplatin induces nephrotoxicity which is cumulative. It is therefore contraindicated in patients with pre-existing renal impairment  Cisplatin has also been shown to be cumulatively neurotoxic (in particular ototoxic) and should not be given to patients with pre-existing hearing impairment.  Cisplatin is also contraindicated in myelosuppressed patients and those who are dehydrated  patients receiving Cisplatin should not breastfeed (see Section 4.6)  Concurrent administration of yellow fever vaccine is contraindicated

This agent should only be administered under the direction of oncologists in specialist units under
conditions permitting adequate monitoring and surveillance. Supportive equipment should be available
to control anaphylactic reactions.
Cisplatin reacts with metallic Aluminium to form a black precipitate of Platinum. All Aluminum- containing
IV sets, needles, catheters and syringes should be avoided. (see Section 6.2).
The solution for infusion should not be mixed with other drugs or additives.
Appropriate monitoring and management of the treatment and its complications are only possible if
adequate diagnosis and exact treatment conditions are available.
1. Nephrotoxicity
Cisplatin produces severe cumulative nephrotoxicity. Which may be potentiated by aminoglycoside
antibiotics. The serum creatinine, plasma urea or creatinine clearance and magnesium, sodium potassium,
and calcium levels should be measured prior to initiating therapy, and prior to each subsequent course.

Cisplatin should not be given more frequently than once every 3-4 weeks. A urine output of 100ml/hour
or greater will tend to minimize Cisplatin nephrotoxicity. This can be accomplished by pre-hydration with
2 litres of an appropriate intravenous solution, and similar post Cisplatin hydration (recommended
2,500ml/m2/24 hours). If a vigorous hydration is insufficient to maintain adequate urinary output, an
osmotic diuretic may be administered (e.g., Mannitol).
2. Neuropathies
Severe cases of neuropathies have been reported.
These neuropathies may be irreversible and may manifest by paresthesia, areflexia, proprioceptive loss
and vibration perception. A loss of motor function has also been reported. A neurologic examination must
be carried out at regular intervals.
Neurotoxicity appears to be cumulative. Prior to each course, the absence of symptoms of peripheral
neuropathy should be established.
3. 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. (see Section 4.8).
4. Allergic phenomena
Anaphylactic-like reactions to Cisplatin have been reported. These reactions have occurred within minutes
of administration to patients with prior exposure to Cisplatin and have been alleviated by administration
of adrenaline, steroids and antihistamines.
As with other Platinum- based products, hypersensitivity reactions 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 Platinum compounds (see
Sections 4.8 and 4.3).
5. Hepatic function and haematological formula
Haematological formula and hepatic function must be monitored at regular intervals.
6. Carcinogenic potential
In humans, in rare cases, the appearance of acute leukaemia has coincided with use of Cisplatin, which
was in general associated with other leukaemogenic 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.

7. 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.
WARNING
This cytostatic agent has 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 Sections 4.8 and 4.2).
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).
Preparation of the intravenous solution
Warning
As with all other potentially toxic products, precautions are essential when handling Cisplatin solution.
Skin lesions are possible in the event of accidental exposure to the product. It is advisable to wear gloves.
In the event that 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.
Before administering the solution to the patient, verify the clarity of the solution and the absence of any
particles.
This medicinal product contains 3.5mg sodium per ml, equivalent to 38.3% of the WHO recommended
maximum daily intake of 2g sodium for an adult.

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.
Renal toxicity of Ifosfamide may be greater when used with Cisplatin or in patients who have previously
been given Cisplatin.

Reduction of blood's Lithium value was noticed in a few cases after treatment with Cisplatin combined
with Bleomycin and Etoposide. It is therefore recommended to monitor Lithium value.
Ototoxic substances
Concomitant administration of ototoxic medicinal products (e.g. Aminoglycosides, loop diuretics) will
potentiate the toxic effect of Cisplatin on auditory function. Except for patients receiving doses of Cisplatin
exceeding 60mg/m2, whose urine secretion is less than 1,000ml 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.
Weakened live vaccines
Yellow fever vaccine is strictly contraindicated because of the risk of fatal systemic vaccine-associated
disease (see Section 4.3).
In view of the risk of generalized illness, it is advisable to use an inactive vaccine if available.
Oral anticoagulants
In the event of simultaneous use of oral anticoagulants, it is advisable to regularly check the INR.
Antihistamines, Phenothiazines and others
Simultaneous use of antihistamines, Buclizine, Cyclizine, Loxapine, Meclozine, Phenothiazines,
Thioxanthenes or Trimethobenzamides may mask the ototoxicity symptoms (such as dizziness and
tinnitus).
Anticonvulsive substances
Serum concentrations of anticonvulsive medicines may remain at sub-therapeutic levels during treatment
with Cisplatin.
Pyroxidine + Altretamine combination
During a randomized study of the treatment of advanced ovarian cancer, the response time was
unfavourably affected when Pyridoxine was used in combination with Altretamine
(Hexamethylmelamine) and Cisplatin.
Paclitaxel
Treatment with Cisplatin prior to an infusion with Paclitaxel may reduce the clearance of Paclitaxel by 33%
and therefore can intensify neurotoxicity.
Antiepileptics
In patients receiving Cisplatin and Phenytoin, the serum level of Phenytoin might be reduced. This is
probably due to reduced absorption and/or increased metabolism. In these patients, one should monitor
the levels of Phenytoin in plasma, and adjust the dose accordingly.

Pregnancy
Cisplatin may be toxic to the foetus when administered to a pregnant woman. Cisplatin should not be
used during pregnancy unless the clinician considers the risk in an individual patient to be clinically
justified.

During treatment with Cisplatin and for a minimum of the following 6 months, appropriate measures
must be taken to avoid pregnancy; this applies to patients of both sexes.
Breastfeeding
Cisplatin is excreted in breast milk. Patients treated with Cisplatin must not breastfeed.
Fertility
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
treatment.
Male and female patients have to use an effective contraception during and for at least 6 months after
the treatment with Cisplatin.

No studies on the effects on the ability to drive and use machines have been performed.
Nevertheless, the profile of undesirable effects (like nephrotoxicity) may influence the ability to drive
vehicles and use machinery.

The most frequently reported adverse events (>10%) of Cisplatin were haematological (leukopenia,
thrombocytopenia and anaemia), gastrointestinal (anorexia, nausea, vomiting and diarrhoea), ear
disorders (hearing impairment), renal disorders (renal failure, nephrotoxicity, 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; the effects are generally dose-related and cumulative.
Ototoxicity may be more severe in children.
Frequencies are defined using the following convention:
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data).

a: Infectious complications have led to death in some patients.
b: Symptoms reported for anaphylactoid reaction such as facial oedema (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 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 authorization of the medicinal product is important. It allows
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are
asked to report any suspected adverse reactions to The National Pharmacovigilance Centre (NPC).
To report any side effect(s) in Saudi Arabia, please contact:
The National Pharmacovigilance Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Ext: 2317-2356-2340
SFDA Call Centre: 19999
E-mail : npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa/

CAUTION IS ESSENTIAL IN ORDER TO PREVENT AN INADVERTANT 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 an overdose of Cisplatin. Even if haemodialysis is initiated 4
hours after the overdose, it has little effect on the elimination of Cisplatin from the body following a strong
and rapid fixation of Cisplatin to proteins.
Treatment in the event of an overdose consists of general support measures.

Pharmacotherapeutic group: Other antineoplastic agents, Platinum compounds
ATC code: L01XA01
Cisplatin has biochemical properties similar to those of bifunctional alkylating agents. The drug inhibits
DNA-synthesis by producing intrastrand and interstrand cross- links in DNA. Protein and RNA synthesis
are also inhibited to a lesser extent.
Although the principal mechanism of action of Cisplatin appears to be inhibition of DNA synthesis, other
mechanisms, including enhancement of tumour immunogenicity may be involved in its antineoplastic
activity. Cisplatin also has immunosuppressive, radiosensitizing, and antimicrobial properties. Cisplatin
does not appear to be cell-cycle specific.

Absorption
There is good uptake of Cisplatin by the kidneys, liver and intestine. More than 90% of Platinumcontaining
species remaining in the blood are bound (possibly irreversibly) to plasma proteins.
Penetration into the CSF is poor although significant amounts of Cisplatin can be detected in
intracerebral tumours.
Distribution
The clearance of total Platinum from plasma is rapid during the first four hours after intravenous
administration, but then proceeds more slowly because of covalent binding to serum proteins. Levels of
unbound Platinum fall with a half-life of 20 minutes to 1 hour depending on the rate of drug infusion.
Elimination
The elimination of intact drug and various platinum- containing biotransformation products is via the
urine. About 15-25% of administered Platinum is rapidly excreted in the first 2-4 hours after
administration of Cisplatin. This early excretion is mostly of intact Cisplatin. In the first 24 hours after
administration, 20-80% is excreted, the remainder representing drug bound to tissues or plasma
protein.

Cisplatin has been shown to be mutagenic. It may also have an antifertility effect. Other antineoplastic
substances have been shown to be carcinogenic and this possibility should be borne in mind in longterm
use of Cisplatin.

Sodium chloride
Sodium hydroxide (for pH adjustment)
Hydrochloric acid (for pH adjustment)
Water for injection

Do not bring in contact with Aluminium. Cisplatin reacts with metal Aluminium to form a black precipitate
of Platinum. All Aluminium-containing IV sets, needles, catheters and syringes should be avoided.
Cisplatin decomposes with solution in media with low Chloride content; the Chloride concentration should
at least be equivalent to 0.45% of Sodium Chloride.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
Antioxidants (such as Sodium Metabisulphite), Bicarbonates (Sodium Bicarbonate), Sulfates, Fluorouracil
and Paclitaxel may inactivate Cisplatin in infusion systems.
Cisplatin should only be used with those diluents specified in Section 6.6.

24 months

Keep this medicine out of sight and reach of children.
Do not store above 30°C.
Do not refrigerate or freeze.
Keep vial in the outer carton in order to protect from light.
Do not use this medicine after the expiry date which is stated on the pack. The expiry date refers to the
last day of that month.
This product is a concentrate and must be diluted before use.
For storage conditions of the diluted medicinal product, see Section 6.3.

Tinplat 1mg/ml concentrate for Solution for Infusion is filled in Type-I amber glass vial sealed with rubber
stopper and Aluminium flip-off cap.
Pack sizes:
1 × 10ml vial (10mg/10ml)
1 X 25ml vial (25mg/25ml)
1 × 50ml vial (50mg/50ml)
1 × 100ml vial (100mg/100ml)
Not all pack sizes may be marketed.

Preparation and handling of the product
Like with all antineoplastic products, caution is needed with the processing of Cisplatin.
This medicinal product must be diluted before use. Dilution should take place under aseptic conditions by
trained personnel in an area specifically intended for this. Protective gloves should be worn for this.
Precautions should be taken to avoid contact with the skin and mucous membranes. If skin contact did

occur anyway, the skin should be washed with soap and water immediately. With skin contact, tingling,
burns and redness have been observed. In case of contact with the mucous membranes they should be
copiously rinsed with water. After inhalation dyspnoea, pain in the chest, throat irritation and nausea
have been reported.
Pregnant women must avoid contact with cytostatic drugs.
Bodily waste matter and vomit should be disposed with care.
If the solution is cloudy or a deposit that does not dissolve is noticed, the bottle should be discarded.
A damaged bottle must be regarded and treated with the same precautions as contaminated waste.
Contaminated waste must be stored in waste containers specifically marked for this.
See Section “Disposal”.
Preparation of the intravenous administration
Take quantity of the solution that is needed from the bottle and dilute with at least 1 litre of the following
solutions:
 Sodium Chloride 0.9%
 Mixture of Sodium Chloride 0.9% and Glucose 5% (1:1), (resulting final concentrations: Sodium
Chloride 0.45%, Glucose 2.5%)
 Sodium Chloride 0.9% and 1.875% Mannitol for injection
 Sodium Chloride 0.45%, Glucose 2.5% and 1.875% Mannitol for injection
Always look at the injection before use. If the solution is not clear or an un-dissolvable precipitate is
formed the solution must not be used. Only a clear solution, free from particles should be administered.
DO NOT bring in contact with injection material that contains Aluminium.
DO NOT administer undiluted.
With respect to microbiological, chemical and physical stability with use of the undiluted solutions (see
Section 6.3).
Disposal
All materials that have been used for the preparation and administration or which have been in contact
with Cisplatin in any way must be disposed of according to local cytotoxic guidelines. Medicines should
not be disposed of via wastewater or household waste.