Consumer medicine information

DBL Cisplatin Injection

Cisplatin

BRAND INFORMATION

Brand name

DBL Cisplatin Injection

Active ingredient

Cisplatin

Schedule

What is in this leaflet

This leaflet answers some common questions about DBL Cisplatin Injection. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given cisplatin against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What DBL Cisplatin Injection is used for

DBL Cisplatin Injection belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may also hear it referred to as a chemotherapy medicine.

This medicine is used to treat:

testicular cancer
ovarian cancer
bladder cancer
cancer of the head and neck

DBL Cisplatin Injection is a platinum-containing medicine and is used as an anticancer drug to interfere with the growth of cancer cells and eventually destroy them. Cancer cells are like normal cells which have changed so that they grow out of control in the body. Since the growth of normal body cells may also be affected by cisplatin, other effects may also occur (see Side Effects).

DBL Cisplatin Injection may be used alone or with other anticancer therapies.

DBL Cisplatin Injection has been chosen as your therapy, as the benefits of treatment are expected to be greater than the unwanted or side effects.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor’s prescription.

Before you are given DBL Cisplatin Injection

When you must not be given it

Do not use DBL Cisplatin Injection if you have an allergy to:

any medicine containing cisplatin
any other platinum-containing compounds
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

DBL Cisplatin Injection should not be given if:

you have kidney disorders
you have impaired hearing
you have a low blood count.

Do not use this medicine if you are pregnant. It may affect your developing baby if you are given it during pregnancy.

It is recommended that you and your doctor discuss your need for cisplatin treatment during pregnancy and the possible risks and benefits of using cisplatin during pregnancy.

Cisplatin may cause birth defects if you or your partner are being treated with it at the time of conception or, if cisplatin is given to females already pregnant.

Females: Tell your doctor or pharmacist if you are pregnant or intend to become pregnant. Avoid becoming pregnant by using effective birth control during your treatment with cisplatin and for at least 26 weeks after you stop treatment (at least 31 weeks if have kidney disease). You must tell your doctor immediately if you suspect you are pregnant.

Males: Tell your doctor or pharmacist if your partner intends to become pregnant while you are being given cisplatin, or shortly after you have stopped treatment. It is recommended that you use effective contraception while you are using cisplatin and for at least 14 weeks after you stop treatment (at least 19 weeks if you have kidney disease).

Cisplatin may have a prolonged effect on fertility in males and females. Your doctor should discuss this issue with you before you begin therapy with cisplatin.

Do not breast-feed if you are using this medicine. The active ingredient in DBL Cisplatin Injection passes into breast milk and there is a possibility that your baby may be affected. As the possible harmful effects to the infant are not known, breastfeeding is not recommended while you are receiving cisplatin.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you are given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or plan to become pregnant.

Tell your doctor if are breast-feeding or plan to breastfeed.

Tell your doctor if you have or have had any of the following medical conditions:

hearing problems
kidney problems
heart problems
anaemia or bone marrow depression
liver disease
low magnesium or calcium levels
any sort of infection, particularly herpes zoster infections (also known as shingles), chicken pox (now or recently), or if you have been in recent contact with someone who has chicken pox
a problem with blood clots forming in your blood vessels, such as painful inflammation of the veins (thrombophlebitis) or blockage of blood vessels in the legs (deep vein thrombosis or DVT), or lungs (pulmonary embolism).

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

If you have not told your doctor about any of the above, tell him/her before you are given DBL Cisplatin Injection.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and cisplatin may interfere with each other. These include:

antibiotics, such as aminoglycoside antibiotics used to treat infections
amphotericin B, used to treat fungal infections
water tablets, such as frusemide, used to treat fluid build up
lithium, used to treat bipolar disorder or schizophrenia
anticonvulsants, used to treat seizures
aspirin or anticoagulants, used to prevent blood clots
paclitaxel or ifosfamide, used to treat cancer
antigout medicines, used to prevent or treat gout.

These medicines may be affected by cisplatin or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor or pharmacist will advise you.

Do not have any immunisations (vaccinations) without your doctor’s approval while you are being treated with cisplatin. Cisplatin may lower your body’s resistance and there is a chance you may get the infection the immunisation is meant to prevent. In addition, other persons living in your household should not have any immunisations until they check with a doctor since there is a chance they could pass the infection the immunisation is meant to prevent to you.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while you are being given DBL Cisplatin Injection.

How DBL Cisplatin Injection is given

How much is given

The dose of cisplatin will be different for different patients.

Your doctor will decide what dose you will receive. This depends on the cancer being treated, your weight, physical condition and other factors, such as the results of your kidney and blood tests.

How it is given

DBL Cisplatin Injection should only be given by a doctor or nurse.

DBL Cisplatin Injection is given as a continuous slow infusion into a vein. A cycle of treatment may be given as a single dose in a day or as a number of doses over several days.

How long it is given for

Several cycles of cisplatin therapy may be needed, depending on your response to treatment.

Treatment cycles may be repeated every three or four weeks. You will be treated in the clinic under close supervision of medical and nursing staff.

Adequate fluid intake is important so you may be given fluids intravenously before, during and after treatment.

If you are given too much (overdose)

As DBL Cisplatin Injection is administered under the care of a highly trained doctor, it is unlikely that you will receive an overdose. However, if you experience severe side effects tell your doctor immediately or go to the Accident and Emergency department of your nearest hospital.

Symptoms of a cisplatin overdose include the side effects listed below in the “Side Effects” section, but are usually of a more severe nature.

Ask your doctor, nurse or pharmacist if you have any concerns.

Your doctor has information on how to recognise and treat an overdose.

While you are being given DBL Cisplatin Injection

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given Cisplatin.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given this medicine.

Cisplatin therapy may delay healing and increase bleeding from the gums, so avoid any dental work if possible.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

It is important to have your follow-up cycles of cisplatin at the appropriate times to get the best effects from your treatments.

While you are being treated with cisplatin your doctor will monitor your condition and take blood for tests prior to each treatment cycle. Blood tests are carried out as cisplatin affects the body’s ability to produce blood cells. Three types of blood cells are checked before each treatment:

platelets, involved with the control of bleeding,
white blood cells, involved with fighting infection and
red blood cells, involved in moving oxygen around the body.

Low red cell counts may indicate that you may require a blood transfusion or your next dose of cisplatin may be delayed or varied.

Take the following precautions to reduce your risk of infection or bleeding:

Avoid people with infections. Check with your doctor immediately if you think you are getting an infection, or if you get a fever or chills, cough or hoarseness, lower back or side pain, or find it painful or difficult to urinate.
Check with your doctor immediately if you notice any unusual bleeding or bruising, black stools, blood in urine or stools or pinpoint red spots on your skin.
Be careful when using a regular toothbrush, dental floss or toothpick. Your doctor or nurse may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work done.
Be careful not to cut yourself when you are using sharp objects such as a safety razor or nail cutters.
Avoid contact sports or other situations where you may get bruised or injured.

Blood and urine tests are taken to check how well your kidneys are functioning. Your dosage of cisplatin may be delayed or varied depending on your kidney function.

Tell your doctor or pharmacist if you have any concerns about this.

Things to be careful of

Be careful driving or operating machinery until you know how cisplatin affects you. If you feel weak, dizzy or nauseated, avoid driving, smoking, operating machinery or taking other medicines unless your doctor tells you to.

Avoid drinking alcohol while you are being given this medicine. If you drink alcohol, dizziness or light-headedness may be worse.

Alcohol and aspirin should be avoided because of the risk of gastrointestinal bleeding.

Side effects

Check with your doctor, pharmacist or nurse as soon as possible if you have any problems or do not feel well while you are being given cisplatin, even if you do not think the problems are connected with the medicine or are not listed in this leaflet. Like other medicines, cisplatin may cause some side effects. Some of these side effects may be prevented or treated by therapy with other medicines. If side effects do occur, their severity usually depends on the dose of cisplatin you receive. Most are likely to be minor or temporary. However, some may be serious and need medical attention.

The effects of cisplatin may take some time to occur and therefore the side effects may be delayed. It is possible that the unwanted side effects may not occur until months after DBL Cisplatin Injection is given.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

nausea, vomiting, diarrhoea, constipation
loss of appetite, weight loss
pain or redness at site of injection
hair loss, especially of the scalp
headaches, dizziness, feeling tired or weak
mouth ulcers.

Tell your doctor as soon as possible if you notice any of the following:

hearing problems or ringing in the ears (tinnitus)
eye pain
bursts of pain that run down the back into the arms and legs
muscle spasms, weakness, aches or pains
abnormal paleness, or lack of colour of the skin.

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor, pharmacist or nurse immediately or go to Accident and Emergency at your nearest hospital:

signs of an allergic reaction (such as shortness of breath, wheezing or difficulty breathing; flushing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin; dizziness or light-headedness)
changes in the rhythm or rate of the heart beat, tightness or pain of the chest, neck, back or arms
signs of infection, such as fever, chills, sore throat, sweats or feeling generally unwell
severe nausea and vomiting
extreme weakness
signs of kidney failure (reduced urination, joint pain, swelling of feet or lower legs, pain in the lower back or side)
seizures, slurred speech and loss of memory, confusion
problems with movement or reduced reflexes, and leg weakness
shaking or tremors, foot spasms
muscle cramps or twitching
paralysis or numbness of the face, arm or leg, tingling or a loss of sensation in the hands or feet
unusual bleeding such as bleeding gums, blood in urine or stools, unusual bruising or pinpoint red spots on the skin
blurred vision, altered colour perception or blindness
decreased or loss of consciousness
yellowing of the skin, eyes or mouth, dark urine.

These may be serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After being given DBL Cisplatin Injection

Continue drinking plenty of fluids.

Your doctor will continue to monitor your medical condition before your next cycle of treatment.

Tell your doctor immediately if you have unwanted side effects which continue after your treatment has stopped.

Storage

DBL Cisplatin Injection should be stored in the pharmacy or ward at room temperature (between 15°C to 25°C) away from light and out of reach of children.

Product description

What it looks like

DBL Cisplatin Injection is a sterile, aqueous, preservative-free clear colourless to pale yellow solution in glass vials.

Ingredients

DBL Cisplatin Injection contains cisplatin as the active ingredient. Other ingredients include:

mannitol
sodium chloride
water for injections

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

DBL Cisplatin Injection is available in the following strengths and pack sizes:

50 mg/50 mL, 1 x 50 mL vial. AUST R 47275

100 mg/100mL, 1 x 100mL vial. AUST R 47276.

™ = Trademark

This leaflet was prepared in January 2023.

Published by MIMS March 2023

BRAND INFORMATION

Brand name

DBL Cisplatin Injection

Active ingredient

Cisplatin

Schedule

1 Name of Medicine

Cisplatin.

2 Qualitative and Quantitative Composition

Each mL of DBL Cisplatin Injection contains 1 mg cisplatin.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Solution for injection.
DBL Cisplatin Injection is a clear, colourless to pale yellow sterile solution of cisplatin 1 mg/mL, mannitol 1 mg/mL and sodium chloride 9 mg/mL in water for injections. The solution does not contain any preservative.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Cisplatin Injection is indicated for the palliative treatment of metastatic non-seminomatous germ cell carcinoma, advanced stage refractory ovarian carcinoma, advanced stage refractory bladder carcinoma and refractory squamous cell carcinoma of the head and neck. It may be used as a single agent or in combination with other chemotherapeutic agents. It may be employed, in appropriate circumstances, in addition to other modalities, e.g. radiotherapy or surgery.

4.2 Dose and Method of Administration

Dosage.

A variety of doses and schedules are used. To obtain optimum therapeutic results with minimum adverse effects, the dosage of cisplatin must be based on the clinical, renal and haematologic status of the patient.
The usual dose in adults and children when used as single agent therapy is 50-100 mg/m² as a single IV infusion every 3-4 weeks; or 15-20 mg/m² as a daily IV infusion for 5 days every 3-4 weeks.

Dosage adjustment.

Dosage should be reduced in patients with depressed bone marrow function.

Subsequent treatment with cisplatin.

A repeat course of cisplatin should not be given until:
the serum creatinine is below 140 micromol/L and/or the plasma urea is below 9 mmol/L; and
circulating blood elements are at an acceptable level (platelets at least 100,000/mm³, WBC at least 4000/mm³).
A base line audiogram should be taken and the patient monitored periodically for auditory deterioration (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Human studies show a high uptake of cisplatin in the liver. An elevated aspartate aminotransferase (AST) and alkaline phosphatase with clinical signs of liver toxicity has been reported in some cases. The adult dosage should be used with caution in patients with pre-existing hepatic dysfunction.

Renal impairment.

Cisplatin displays high tissue uptake in the kidneys, exhibits dose related and cumulative nephrotoxicity and is excreted mainly in the urine. In addition, the plasma elimination half-life of cisplatin is prolonged in renal failure.
Caution should be exercised in patients with pre-existing renal dysfunction. Cisplatin is contraindicated in patients with serum creatinine levels greater than 0.2 mmol/L. Repeat courses are not advised until serum creatinine is below 0.14 mmol/L and/or blood urea below 9 mmol/L.

Administration.

(a) Pretreatment hydration.

Patients should be adequately hydrated before and for 24 hours after administration of cisplatin to ensure good urinary output and minimise nephrotoxicity. Hydration may be achieved by IV infusion of 2 litres of either sodium chloride IV infusion 0.9% or glucose-saline (e.g. glucose 4% in one-fifth sodium chloride IV infusion 0.9%) over a 2 hour period. During the last 30 minutes of the pretreatment hydration or after the hydration, 375 mL of 10% mannitol injection may be administered via a side-arm drip.

(b) Preparation of cisplatin infusion.

DBL Cisplatin Injection should be added to 1 litre of sodium chloride IV infusion 0.9%.
Aluminium containing equipment should not be used for administration of cisplatin (see Section 6.2 Incompatibilities).

(c) Treatment.

Following prehydration, administer the cisplatin infusion over 1-2 hours. It has been proposed that a longer infusion time of 6-8 hours may decrease gastrointestinal and renal toxicities.
The IV flask should be covered to preclude light.

(d) Post-treatment hydration.

Adequate hydration and urinary output must be maintained during the 24 hours following infusion. It has been suggested that IV hydration continue after treatment with the aim to administer 2 litres of sodium chloride IV infusion 0.9% or glucose-saline over a period of 6-12 hours.
The product and its admixtures contain no antimicrobial agent. In order to reduce microbiological hazards it is recommended that further dilution be effected immediately prior to use and infusion commenced as soon as practicable after preparation of the admixture. Infusion should be completed within 24 hours of preparation and the residue discarded.

Handling precautions.

As with all antineoplastic agents, trained personnel should prepare cisplatin injection. This should be performed in a designated area (preferably a cytotoxic laminar flow cabinet). Care should be taken to prevent inhaling particles and exposing the skin to cisplatin. Protective gown, mask, gloves and appropriate eye protection should be worn while handling cisplatin. In the event of contact with the eyes, wash with water or saline; where solution accidentally contacts skin or mucosa, the affected area should be immediately washed thoroughly with soap and water and in both cases seek medical advice. Seek immediate medical attention if the drug is ingested or inhaled. It is recommended that pregnant personnel not handle cytotoxic agents such as cisplatin.
Luer-Lock fitting syringes and giving sets to avoid leakage are recommended. Large bore needles are recommended to minimise pressure and possible formation of aerosols. Aerosols may also be reduced by using a venting needle during preparation.
Items used to prepare cisplatin, or articles associated with body waste should be disposed of by placing in a double sealed polythene bag, and incinerating at 1100°C.

Spills and disposal.

If spills occur, restrict access to the affected area. Wear two pairs of gloves (latex rubber), a respirator mask, a protective gown and safety glasses. Limit the spread of the spill by covering with a suitable material such as absorbent towel or adsorbent granules. Spills may also be treated with 5% sodium hypochlorite. Collect up absorbent/adsorbent material and other debris from spill and place in a leak proof plastic container and label accordingly.
Cleanse the remaining spill area with copious amounts of water.

4.3 Contraindications

Use of cisplatin is contraindicated in the following conditions:
Renal impairment (see Section 4.2 Dose and Method of Administration);
Hearing disorders (see Section 4.4 Special Warnings and Precautions for Use, Ototoxicity);
Bone marrow depression;
Generalised infections;
During pregnancy or lactation;
In patients with a history of hypersensitivity to cisplatin or platinum-containing compounds.

4.4 Special Warnings and Precautions for Use

Cisplatin is a highly toxic drug with a relatively narrow therapeutic index, and a therapeutic effect is unlikely to occur without some evidence of toxicity. Cisplatin should be administered only under constant supervision by physicians experienced in therapy with cytotoxic agents and only when potential benefits of cisplatin therapy outweigh the possible risks. Appropriate facilities should be available for adequate management of complications should they arise.
To minimise the risk of nephrotoxicity, hydrate before, during and after therapy (see Section 4.2 Dose and Method of Administration). Prior to initial therapy, then before subsequent doses, the following parameters should be monitored: renal function including glomerular filtration rate (GFR), blood urea nitrogen (BUN), serum creatinine and creatinine clearance; electrolytes (magnesium, sodium, potassium and calcium) to detect hypomagnesaemia or hypocalcaemia; auditory function; red blood cells, white blood cells and platelets; liver function and neurological status.

Ototoxicity.

Ototoxicity is cumulative and occurs mainly with high dose regimes. Tinnitus or occasional decreased ability to hear normal conversation are indications of ototoxicity which have been frequently observed. Abnormalities of audiometric testing are more common and hearing loss can be unilateral or bilateral; frequency and severity increase with repeated doses and may not be reversible, but mostly occur in the 4,000 - 8,000 Hz range.
Audiometric testing should be performed, if possible, prior to initiation of therapy, and at regular intervals thereafter, particularly if the clinical symptoms of tinnitus or hearing impairment occur. Radiotherapy may enhance ototoxicity. Clinically important deterioration of auditive function may require dosage modifications or discontinuation of therapy.

Myelosuppression.

This may occur in patients treated with cisplatin. Haematological toxicity is dose-related and cumulative. The nadirs in circulating platelets and leucocytes generally occur between days 18 - 23 (range 7.3 - 45) with most patients recovering by day 39 (range 13 - 62). Leucopenia and thrombocytopenia are more pronounced at doses greater than 50 mg/m².
Peripheral blood counts should be monitored frequently in patients receiving cisplatin. Although the haematologic toxicity is usually moderate and reversible, severe thrombocytopenia and leucopenia may occur. In patients who develop thrombocytopenia special precautions are recommended: care in performing invasive procedures; search for signs of bleeding or bruising; test of urine, stools and emesis for occult blood; avoiding aspirin and other NSAIDs. Patients who develop leucopenia should be observed carefully for signs of infection and might require antibiotic support and blood product transfusions.
Subsequent courses of cisplatin should not be instituted until platelets are present at levels greater than 100,000/mm³ and white cells greater than 4,000/mm³.

Anaemia.

Anaemia (decrease of greater than 2 g/dL haemoglobin) occurs in a significant number of patients, usually after several courses of treatment. Anaemia occurs at approximately the same frequency but generally with a later onset than leucopenia and thrombocytopenia. Transfusions of packed red cells may be necessary in severe cases.
Rarely, the drug has caused haemolytic anaemia; Coombs-positive results have been reported in a few of these cases. Further courses with cisplatin in sensitised individuals may cause increased haemolysis.
A high incidence of severe anaemia requiring transfusion of packed red cells has been observed in patients receiving combination chemotherapy including cisplatin.

Nausea and vomiting.

Marked nausea and vomiting occur in almost all patients treated with cisplatin and are occasionally so severe that dosage reduction or discontinuance of treatment is necessary.

Anaphylaxis.

Reactions, secondary to cisplatin therapy, have been occasionally reported in patients who were previously exposed to cisplatin. Patients who are at particular risk are those with a prior history or family history of atopy. Facial oedema, wheezing, tachycardia, hypotension and skin rashes of urticarial non-specific maculopapular type can occur within a few minutes of administration. Serious reactions seem to be controlled by IV adrenaline, corticosteroids or antihistamines.
Patients receiving cisplatin should be observed carefully for possible anaphylactic-like reactions, and the necessary supportive equipment and medication should be readily available to treat such reactions.

Cardiovascular toxicity.

Cisplatin has been found to be associated with cardiovascular toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients may experience clinically heterogeneous venous thromboembolic events, myocardial infarction, cerebrovascular accidents, thrombotic microangiopathy and cerebral arteritis. Cases of pulmonary embolism (including fatalities) have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hypomagnesaemia and hypocalcaemia.

Hypomagnesaemia occurs quite frequently with cisplatin administration, while hypocalcaemia occurs less frequently. The loss of magnesium seems to be associated with renal tubular damage which prevents resorption of this cation. Where both electrolytes are deficient, tetany may result. It does not appear to be dose related. Monitoring of electrolytes is necessary.

Neurotoxicity and seizures.

Cisplatin is known to induce neurotoxicity; therefore, neurologic examination is warranted in patients receiving a cisplatin-containing treatment. Peripheral neuropathy, postural hypotension, myasthenic syndromes, seizures and visual loss may occur with cisplatin treatment. This appears to be more common after prolonged treatment. Since neurotoxicity may result in irreversible damage, the development of clinically significant symptoms should generally contraindicate further cisplatin usage.

Immunosuppressant effects/increased susceptibility to infections.

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including cisplatin, may result in serious or fatal infections. Extreme caution should be used where patients have recently been exposed to infections, particularly chicken pox and herpes zoster. Vaccination with a live vaccine should be avoided in patients receiving cisplatin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Dental.

The bone marrow depressant effects of cisplatin may result in an increased incidence of microbial infection, delayed healing and gingival bleeding. Dental work should be avoided during cisplatin therapy.

Others.

As patients undergoing treatment with cisplatin are at an increased risk of bleeding, bruising and infection, it is recommended that extreme care be used when performing necessary invasive procedures.
Alcohol and aspirin should be avoided because of the risk of gastrointestinal bleeding.

Use in hepatic impairment.

Liver function should be monitored periodically.

Use in renal impairment.

Cisplatin is contraindicated in patients with renal impairment (see Section 4.3 Contraindications).
Cumulative and dose-related renal insufficiency is the major dose-limiting toxicity of cisplatin. The most commonly observed change in renal function has been a fall in glomerular filtration rate reflected by a rise in serum creatinine and a reduction in effective renal plasma flow.
Pre and post treatment hydration may reduce nephrotoxicity (see Section 4.2 Dose and Method of Administration).
Renal function must return to normal before further doses are given (see Section 4.2 Dose and Method of Administration).
Special care has to be taken when cisplatin-treated patients are given concomitant therapies with other potentially nephrotoxic drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

No data available.

Paediatric use.

Cisplatin can also be used in children. Cases of delayed-onset hearing loss have been reported in the paediatric population. Long-term follow-up in this population is recommended.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Cisplatin is mostly used in combination with antineoplastic drugs having similar cytotoxic effects. In these circumstances additive toxicity is likely to occur.
Other known drug interactions are reported below.

Nephrotoxic drugs.

Potentially nephrotoxic medicines, e.g. aminoglycoside antibiotics and loop diuretics when given concurrently or within 1-2 weeks after cisplatin administration, may potentiate the nephrotoxic effects of cisplatin. Concomitant use of other potentially nephrotoxic drugs (e.g. amphotericin B) is not recommended during cisplatin therapy.
The renal toxicity of ifosfamide may be greater when used with cisplatin or in patients who have previously been given cisplatin.

Ototoxic drugs.

Concurrent and/or sequential administration of potentially ototoxic medicines, e.g. aminoglycoside antibiotics and loop diuretics, may potentiate the ototoxic effects of cisplatin, especially in the presence of renal impairment.
Ifosfamide may increase hearing loss due to cisplatin.

Renally excreted drugs.

Literature data suggest that cisplatin may alter the renal elimination of bleomycin and methotrexate (possibly as a result of cisplatin-induced nephrotoxicity) and enhance their toxicity. Reduction of the lithium blood levels was noticed in a few cases after treatment with cisplatin combined with bleomycin and etoposide. It is therefore recommended to monitor the lithium values.

Antigout agents.

Cisplatin may raise the concentration of blood uric acid. Thus, in patients concurrently receiving antigout agents such as allopurinol, colchicine, probenecid or sulfinpyrazone, dosage adjustment of these drugs may be necessary to control hyperuricemia and gout.

Anticonvulsant agents.

Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy. In patients receiving cisplatin and phenytoin, serum concentrations of the latter may be decreased, possibly as a result of decreased absorption and/or increased metabolism. In these patients, serum levels of antiepileptics should be monitored and dosage adjustments made as necessary.

Anticoagulants.

It is advisable to check the international normalised ratio (INR) when oral anticoagulants such as coumarins/warfarin are used simultaneously with cisplatin.

Paclitaxel.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Female.

Based on non-clinical and clinical findings, female fertility may be compromised by treatment with cisplatin. Use of cisplatin has been associated with cumulative dose-dependent ovarian failure, premature menopause and reduced fertility. Non-clinical findings in mice treated with cisplatin (5 mg/kg intraperitoneally) showed that cisplatin caused direct damage to primordial follicle oocytes, leading to apoptosis, and ovarian depletion.

Male.

Cisplatin can affect male fertility. Impairment of spermatogenesis and azoospermia have been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Cisplatin caused testis damage and decreased sperm counts in mice, primarily through effects on differentiated spermatogonia. Although the impairment of spermatogenesis can be reversible, males undergoing cisplatin treatment should be warned about the possible adverse effects on male fertility.
Both men and women should seek advice on fertility preservation before treatment.
(Category D)¹
The safety of cisplatin in pregnancy has not been established. Cisplatin can cross the placental barrier. In mice and rats, cisplatin is teratogenic and embryotoxic. Studies in rodents have shown that exposure during pregnancy can cause tumours in adult offspring. Cisplatin may be toxic to the fetal urogenital tract. Therefore cisplatin is considered to be potentially harmful to the fetus when administered to a pregnant woman and its use in pregnant women is not recommended. Patients should be advised to avoid becoming pregnant.
If the patient becomes pregnant whilst receiving the drug she should be advised of the hazard to the fetus. Cisplatin should only be used if the potential benefits outweigh the risk of therapy.
Women of childbearing potential should use effective contraception during treatment with cisplatin and for at least 26 weeks following the last dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment with cisplatin and for at least 14 weeks after the last dose.
For patients with end-stage renal disease, the washout period of cisplatin will be longer (up to 7 weeks); effective contraception for men is advised for at least 19 weeks and for female patients, for at least 31 weeks after the last dose.
¹ Category D: Drugs which have caused, are suspected to caused or be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects.
Limited data from published literature report presence of cisplatin in human milk. Advise pregnant women not to breastfeed during treatment with cisplatin.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Ear and labyrinth disorders.

Unilateral or bilateral tinnitus and/or high frequency hearing loss (> 4000 Hz) has been observed in up to 31% of patients treated with cisplatin and is usually reversible. The damage to the hearing system appears to be dose related and cumulative, and it is reported more frequently in very young or very old patients. Auditory function should be monitored more closely during treatment.

Eye disorders.

Retinal toxicity manifests as blurred vision and altered colour perception. Optic neuritis, papilloedema and cortical blindness have been reported rarely following the administration of cisplatin. These events are usually reversible after drug withdrawal. Retinal pigmentation has also been reported.

Infections and infestations.

Infection (infectious complications have led to death), sepsis.

Blood and lymphatic system disorders.

Thrombotic microangiopathy (haemolytic uraemic syndrome), bone marrow failure, neutropenia, Coombs positive haemolytic anaemia.
Myelosuppression often occurs during cisplatin therapy. Mild bone marrow toxicity may occur with both leucopenia and thrombocytopenia. These effects are usually reversible after ceasing treatment. Cisplatin may also induce anaemia: this is not clearly dose related and is occasionally caused by haemolysis. Leucopenia and thrombocytopenia are dose-related and more pronounced at doses greater than 50 mg/m². Leucocyte and platelet nadirs generally occur between days 18 and 23 of treatment, with recovery in most patients by day 39. Anaemia occurs at approximately the same frequency.
There have been rare reports of acute myelogenous leukemias and myelodysplastic syndromes arising in patients who have been treated with cisplatin, mostly when given in combination with other potentially leukemogenic agents.

Immune system disorders.

Anaphylactic and anaphylactic-like reactions, consisting principally of flushing, facial oedema, wheezing, tachycardia and hypotension have been reported in patients previously exposed to cisplatin. The reactions usually occur within a few minutes of cisplatin administration and may be controlled by IV adrenaline, corticosteroids and/or antihistamines.

Metabolism and nutritional disorders.

Cisplatin may cause dehydration in patients. Cisplatin may also cause serious electrolyte disturbances, mainly represented by hypomagnesemia, hypocalcemia, and hypokalemia, and associated with renal tubular dysfunction. Hypomagnesemia and/or hypocalcemia may become symptomatic, with muscle irritability or cramps, clonus, tremor, carpopedal spasm, and/or tetany. Hypomagnesaemia and hypocalcaemia may develop during cisplatin therapy or following discontinuance of the drug. Other reported toxicities are hyperuricemia, hyponatremia, hypophosphataemia and syndrome of inappropriate antidiuretic hormone (SIADH). Hyperuricaemia may occur in patients receiving cisplatin, principally as a result of drug-induced nephrotoxicity. Hyperuricaemia is more pronounced with doses greater than 50 mg/m², with peak levels occurring between 3-5 days after administration of the drug. Allopurinol may be used to reduce serum uric acid levels. Regular monitoring of serum electrolyte levels and replacement where necessary are advisable.

Nervous system disorders.

Convulsion, leukoencephalopathy, reversible posterior leukoencephalopathy syndrome, haemorrhagic stroke, ischaemic stroke, ageusia, cerebral arteritis, myelopathy.
Peripheral neuropathies occur infrequently with usual doses of the drug. They are generally sensory in nature (e.g. paraesthesia of the upper and lower extremities), but can also include motor difficulties, reduced or absent reflexes and leg weakness. Autonomic neuropathy, seizures, slurred speech, loss of taste and memory loss have also been reported. These neuropathies usually appear after prolonged therapy, but have also developed after a single drug dose. Areflexia and loss of proprioception and vibratory sensation may be seen, especially if cisplatin is given at higher doses or more frequently than recommended. In some patients they may be irreversible however, they have been partially or completely reversible in others following discontinuance of cisplatin therapy. Cerebrovascular accident has been reported in patients treated with cisplatin. Lhermitte's sign has been reported.

Cardiac disorders.

Cardiovascular abnormalities (coronary disease, congestive heart failure, postural hypotension, thrombotic microangiopathy, arrhythmia, bradycardia, tachycardia, cardiac arrest, cardiac disorder etc.)

Vascular disorders.

Raynaud's phenomenon.
Venous thromboembolism: A significant increase in the risk of venous thromboembolic events has been reported in patients with advanced solid tumours and treated with cisplatin compared with non-cisplatin-based chemotherapy.
Vascular toxicity coincident with the use of cisplatin in combination with other antineoplastic agents have been reported rarely. The events are clinically heterogeneous and may include myocardial infarction, cerebrovascular accident (haemorrhagic and ischaemic stroke), thrombotic microangiopathy (haemolytic uremic syndrome) or cerebral arteritis. Various mechanisms have been proposed for these vascular complications.

Respiratory, thoracic and mediastinal disorders.

Pulmonary embolism.
Pulmonary toxicity has been reported in patients treated with cisplatin in combination with bleomycin or 5-fluorouracil.

Gastrointestinal disorders.

Stomatitis, vomiting, nausea, anorexia, hiccups, diarrhoea.
Cisplatin induces severe nausea and vomiting in almost all patients. Severe nausea and vomiting usually begin within 1-4 hours after treatment and may persist for up to a week after treatment. These side effects are only partially relieved by standard antiemetics. The severity of these symptoms may be reduced by dividing the total dose per cycle into smaller doses given once daily for five days. Reported toxicity includes gingival platinum line.

Hepatobiliary disorders.

Mild and transient elevations of serum AST and ALT levels may occur infrequently. Liver damage has also been infrequently reported.

Skin and subcutaneous tissue disorders.

Mild alopecia. Rarely, urticarial or maculopapular skin rashes have also been observed.

Musculoskeletal and connective tissue disorders.

Myalgia, muscle spasms.

Renal and urinary disorders.

Acute renal toxicity, which was highly frequent in the past and represented the major dose-limiting toxicity of cisplatin, has been greatly reduced by the use of 6 to 8-hour infusions as well as by concomitant intravenous hydration and forced diuresis. Cumulative toxicity, however, remains a problem and may be severe. Renal impairment, which is associated with tubular damage, may be first noted during the second week after a dose and is manifested by an increase in serum creatinine, BUN, serum uric acid and/or a decrease in creatinine clearance. Renal insufficiency is generally mild to moderate and reversible at the usual doses of the drug (recovery occurring as a rule within 2-4 weeks); however, high or repeated cisplatin doses can increase the severity and duration of renal impairment and may produce irreversible renal insufficiency (sometimes fatal). Renal failure has been reported also following intraperitoneal instillation of the drug.

Reproductive system and breast disorders.

Impairment of spermatogenesis and azoospermia have been reported (see Section 4.6 Fertility, Pregnancy and Lactation).

General disorders and administration site conditions.

Pyrexia, asthenia, malaise. Local effects such as pain, oedema, erythema, phlebitis, tissue cellulitis, fibrosis, and skin necrosis (following extravasation of the drug) may also occur. Extravasation may result from infusion of solutions greater than 0.5 mg/mL cisplatin.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Acute overdosage with cisplatin may result in an enhancement of its expected toxic effects (e.g. kidney failure, severe myelosuppression, intractable nausea and vomiting, severe neurosensorial toxicities, liver failure etc.). Death may also occur. No proven antidotes are known for cisplatin overdosage. Haemodialysis is only effective, even then partially, up to 3 hours after administration because of the rapid and extensive binding of platinum to plasma proteins. Signs and symptoms of overdosage should be managed with supportive measures. Patients should be monitored for 3 to 4 weeks in case of delayed toxicity. See Section 4.8 Adverse Effects (Undesirable Effects) for possible complications.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Class.

Antineoplastic agent.

Mechanism of action.

Cisplatin is a platinum compound of which only the cis-isomer is active and has biochemical properties similar to those of bifunctional alkylating agents. The drug inhibits DNA synthesis by producing intrastrand and interstrand crosslinks in DNA. Protein and RNA synthesis are also inhibited to a lesser extent. Cisplatin does not appear to be cell cycle specific.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Distribution.

There is good uptake of cisplatin by the kidneys, liver and intestine.
More than 90% of platinum containing species remaining in the blood are bound (possibly irreversibly) to plasma proteins.
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.

Excretion.

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.

5.3 Preclinical Safety Data

Genotoxicity.

Cisplatin has been shown to be genotoxic in vitro, in bacterial gene mutation assays, gene mutation assays in yeast (Saccharomyces cerevisiae D7) and mammalian cells (mouse lymphoma cells and Chinese hamster cells), in vitro chromosome aberration assays (in Chinese hamster cells and in human lymphocytes), in vitro DNA repair assays (Saccharomyces cerevisiae D7 and v79 Chinese hamster cells) and in vivo in a chromosome aberration assay in mouse bone marrow cells. Based on these studies, cisplatin is considered to present a genotoxic risk to humans.

Carcinogenicity.

No formal carcinogenicity studies were performed. In a transplacental carcinogenicity study, a single IP injection of cisplatin (7.5 mg/kg) to pregnant mice on day 17 of gestation initiated and/or induced thymic lymphomas, lung tumours and proliferative kidney lesions in offsprings at week 25. In another transplacental carcinogenicity study, pregnant rats were given a single IP injection of cisplatin (5 mg/kg) on day 18 of gestation resulted in significantly higher incidences (20/82 in treatment vs 3/75 in control) of hepatocellular adenoma in offspring rats at 79 weeks. Therefore, cisplatin has a high carcinogenic potential in mice and rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, sodium chloride, water for injections.

6.2 Incompatibilities

Cisplatin may interact with aluminium to form a black precipitate. Needles, syringes, catheters or IV administration sets that contain aluminium parts which may come in contact with cisplatin should not be used for preparation or administration of the drug. The stability of cisplatin is adversely affected by the presence of bisulphite, metabisulphite, sodium bicarbonate and fluorouracil.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store between 15°C-25°C. Do not refrigerate. Do not freeze. Protect from light. Single use only. Discard unused portion.

Stability.

Cisplatin 0.15 mg/mL in sodium chloride IV infusion 0.9% is chemically stable for 24 hours when stored at room temperature and protected from light.

6.5 Nature and Contents of Container

DBL Cisplatin Injection is available as followed.

Strength and pack size.

50 mg/50 mL: 1 x 50 mL vial.
100 mg/100 mL: 1 x 100 mL vial.

6.6 Special Precautions for Disposal

Cytotoxic waste should be regarded as hazardous or toxic and clearly labelled 'Cytotoxic waste for incineration at 1100°C'. Waste material should be incinerated at 1100°C for at least 1 second.

6.7 Physicochemical Properties

Chemical structure.

CAS number.

15663-27-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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