Consumer medicine information

Cisplatin Accord

Cisplatin

BRAND INFORMATION

Brand name

Cisplatin Accord

Active ingredient

Cisplatin

Schedule

SUMMARY CMI

CISPLATIN ACCORD

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Cisplatin Accord?

Cisplatin Accord contains the active ingredient cisplatin. Cisplatin Accord is used for the treatment of ovarian cancer, cancer of the testes, cancer of the bladder, cancer of the head and neck.

For more information, see Section 1. Why am I using Cisplatin Accord? in the full CMI.

2. What should I know before I use Cisplatin Accord?

Do not use if you have ever had an allergic reaction to an any medicine containing cisplatin, carboplatin, other platinum-containing compounds, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Cisplatin Accord? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Cisplatin Accord and affect how it works.

See Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Cisplatin Accord?

Cisplatin Accord is an injection and will be given to you by your doctor or nurse.

More instructions can be found in Section 4. How do I use Cisplatin Accord? in the full CMI.

5. What should I know while using Cisplatin Accord?

Things you should do

Be sure to keep all your doctor's appointments.
You will have blood and other tests from time to time to check on your progress and detect any unwanted side effects.
Tell all the doctors, dentists, and pharmacists who are treating you that you are being given Cisplatin Accord.
If you are about to be started on any new medicine, tell your doctor or pharmacist that you are being given Cisplatin Accord.
If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given Cisplatin Accord.
If you become pregnant while taking this medicine, tell your doctor immediately

Driving or using machines

Be careful driving or operating machinery until you know how Cisplatin Accord affects you. This medicine may cause dizziness, light-headedness or problems with movement in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous. Be careful when drinking alcohol while you are taking this medicine. If you drink alcohol dizziness or light-headedness may be worse.

For more information, see Section 5. What should I know while using Cisplatin Accord? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Some of the common, serious and very serious side effects are included in full below in the CMI.

The very serious side effects are:

flushing, swelling of the face, wheezing, fast heartbeat, a rash, dizziness or feeling light-headed
fever and chills, sore throat, sweats or feel generally unwell
blurred vision, changes in colour or blindness
reduced urination, swelling of the feet or lower legs
bleeding, unusual bruising, bleeding gums, blood in the urine or stools, or pinpoint red spots
seizures, slurred speech and loss of taste and memory
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
irregular and/or rapid heartbeat
severe nausea or vomiting

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

CISPLATIN ACCORD

Active ingredient: cisplatin

Consumer Medicine Information (CMI)

This leaflet provides important information about using Cisplatin Accord. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Cisplatin Accord.

Where to find information in this leaflet:

1. Why am I using Cisplatin Accord?
2. What should I know before I use Cisplatin Accord?
3. What if I am taking other medicines?
4. How do I use Cisplatin Accord?
5. What should I know while using Cisplatin Accord?
6. Are there any side effects?
7. Product details

1. Why am I using Cisplatin Accord?

Cisplatin Accord contains the active ingredient cisplatin. Cisplatin belongs to a group of anticancer medicines known as the platinum complexes. Cisplatin works by preventing the growth of cancer cells and eventually destroying them.

Cisplatin Accord is used for the treatment of:

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

Your doctor, however, may prescribe Cisplatin Accord for another purpose.

2. What should I know before I use Cisplatin Accord?

Warnings

Do not use Cisplatin Accord if:

you are allergic to cisplatin, carboplatin, other medicines containing platinum or any of the ingredients listed at the end of this leaflet.
always check the ingredients to make sure you can use this medicine

Check with your doctor if you have or have had:

allergies to any other medicines, foods, preservatives or dyes.
kidney disease or poor kidney function
a low blood count, abnormal or heavy bleeding
hearing problems
any sort of infection (e.g. sinusitis), tooth abscess, etc.
abnormal or heavy bleeding
bleeding gums
unusual tiredness
severe nausea and vomiting
numbness or weakness of the arms and legs
dizziness or being light-headed, especially on standing up
problems with your sight
fits
muscle weakness
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)

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them.

See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

As with many medicines, Cisplatin Accord may harm your developing or breastfeeding baby.

Birth control should be used during 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 think you are pregnant.

Males: Tell your doctor or pharmacist if your partner intends to become pregnant while you are being give 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.

3. What if I am taking other medicines?

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

Some medicines and Cisplatin Accord may interfere with each other.

other anticancer drugs, such as paclitaxel and ifosfamide
antibiotics, such as aminoglycoside antibiotics, used to treat infection
fluid tablets, such as loop diuretics, used to treat fluid build up
lithium, used to treat bipolar disorder or schizophrenia
anticonvulsants, used to treat seizures
anticoagulants, used to prevent blood clots

Do not have any immunisations (vaccinations) without your doctor's approval while you are being treated with cisplatin.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Cisplatin Accord.

4. How do I use Cisplatin Accord?

How much to use

Cisplatin Accord should only be administered by trained professionals, with appropriate handling, in a hospital or clinic environment.

Cisplatin Accord is for single use in one patient only. Any unused residue should be discarded.

Cisplatin Accord may be given as a single intravenous infusion or slow intravenous infusion.

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight, age, blood tests, how well your kidneys, liver and ears are working, and whether other medicines are being given at the same time.

Additional fluid is given before and after your dose of cisplatin. This is to make sure that you do not lose too much water and cause problems with your kidneys.

When to use Cisplatin Accord

It is very important that you continue to receive Cisplatin Accord for as long as your doctor prescribes it. Be sure to keep all your doctor's appointments.

If you use too much Cisplatin Accord

It is very unlikely that you will receive an overdose of Cisplatin Accord because a trained nurse or doctor will give it. If you think that you have been given too much Cisplatin Accord, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre (by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Cisplatin Accord?

Things you should do

Be sure to keep all your doctor's appointments.
You will have blood and other tests from time to time to check on your progress and detect any unwanted side effects.
Tell all the doctors, dentists, and pharmacists who are treating you that you are being given Cisplatin Accord.
If you are about to be started on any new medicine, tell your doctor or pharmacist that you are being given Cisplatin Accord.
If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given Cisplatin Accord.
If you become pregnant while taking this medicine, tell your doctor immediately

Driving or using machines

Be careful driving or operating machinery until you know how Cisplatin Accord affects you.

This medicine may cause dizziness, light-headedness or problems with movement in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine.

If you drink alcohol dizziness or light-headedness may be worse.

Looking after your medicine

The hospital will store Cisplatin Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Cisplatin Accord that may be left over.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

If you are over 65 years of age you may have an increased chance of getting side effects.

Common side effects

Common side effects	What to do
nausea or vomiting pain or redness at site of injection hair loss, especially of the scalp tiredness	Speak to your doctor if you have any of these common side effects and they worry you

Temporary loss of hair, particularly that on the scalp is a less common but upsetting side effect of cisplatin and occurs in a small number of patients (about 2 patients per 100 treated). The severity of hair loss will depend on the dose of cisplatin given. It is more common when other anticancer medicines are used together with cisplatin.

Serious side effects

Serious side effects	What to do
muscle aches or pains bursts of pain that run down the back into the arms and legs hearing loss or ringing in the ears (tinnitus).	Call your doctor as soon as possible

Very Serious side effects

Very Serious side effects

What to do

flushing, swelling of the face, wheezing, fast heartbeat, a rash, dizziness or feeling light-headed
fever and chills, sore throat, sweats or feel generally unwell
blurred vision, changes in colour or blindness
reduced urination, swelling of the feet or lower legs
bleeding, unusual bruising, bleeding gums, blood in the urine or stools, or pinpoint red spots
seizures, slurred speech and loss of taste and memory
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
irregular and/or rapid heartbeat
severe nausea or vomiting

Call your doctor immediately or go straight to the Emergency Department at your nearest hospital

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What Cisplatin Accord contains

Active ingredient (main ingredient)	cisplatin
Other ingredients (inactive ingredients)	Sodium chloride Sodium hydroxide Hydrochloric acid water for injections

Do not take this medicine if you are allergic to any of these ingredients.

Cisplatin Accord does not contain gluten, sucrose, lactose, tartrazine or any other azo dyes.

Cisplatin Accord is not addictive.

What Cisplatin Accord looks like

Cisplatin Accord is a is a clear colourless to pale yellow solution supplied in a vial in single packs.

(10 mg/10 mL: AUST R 286790, 25 mg/25 mL: AUST R 286793, 50 mg/50 mL: AUST R 286786, 100 mg/100 mL AUST R 286791).

Who distributes Cisplatin Accord

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

This leaflet was prepared in January 2022.

Published by MIMS April 2022

BRAND INFORMATION

Brand name

Cisplatin Accord

Active ingredient

Cisplatin

Schedule

1 Name of Medicine

Cisplatin.

2 Qualitative and Quantitative Composition

1 mL contains 1 mg cisplatin.
1 vial of 10 mL concentrated injection for infusion contains 10 mg cisplatin.
1 vial of 25 mL concentrated injection for infusion contains 25 mg cisplatin.
1 vial of 50 mL concentrated injection for infusion contains 50 mg cisplatin.
1 vial of 100 mL concentrated injection for infusion contains 100 mg cisplatin.
Cisplatin is a yellow to orange crystalline powder. It is slightly soluble in water, sparingly soluble in dimethylformamide and practically insoluble in ethanol (96 percent).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cisplatin Accord is a clear, colourless to pale yellow sterile, isotonic, preservative free concentrated injection for infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Cisplatin Accord may be used as a monotherapy or in combination with other chemotherapeutic agents in the treatment of:
Metastatic non-seminomatous germ cell carcinoma;
Advanced stage, refractory ovarian carcinoma;
Advanced stage, refractory bladder carcinoma;
Refractory squamous cell carcinoma of the head and neck.

4.2 Dose and Method of Administration

Cisplatin Accord contains no antimicrobial agent. The product is for single use in one patient only. Discard any residue.

Adults and children.

Monotherapy.

Typical doses and schedules are:
50-100 mg/m² as a single IV infusion every 3-4 weeks over 6-8 hours; or slow IV infusion of 15-20 mg/m²/day for 5 days, every 3-4 weeks.

Combination therapy.

Cisplatin is commonly used in combination therapy with the following cytotoxic agents:
treatment of testicular cancer: vinblastine, bleomycin, actinomycin D;
treatment of ovarian cancer: cyclophosphamide, doxorubicin, hexamethylmelamine, fluorouracil;
treatment of head and neck cancer: bleomycin, methotrexate.

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).

Impaired hepatic function.

Human studies show a high uptake of cisplatin in the liver.
Elevated aspartate aminotransferase (AST) and alkaline phosphatase with clinical signs of liver toxicity have been reported. Cisplatin should be used with caution in patients with pre-existing hepatic dysfunction.

Impaired renal function.

Cisplatin displays high tissue uptake in the kidneys and exhibits dose related and cumulative nephrotoxicity. It is excreted mainly in the urine. The plasma elimination half-life of cisplatin is prolonged and plasma levels are markedly elevated in renal function.
Caution should be exercised in patients with pre-existing renal dysfunction. Cisplatin is contraindicated in patients with serum creatinine levels greater than 200 micromol/L. Repeat courses are not advised until serum creatinine is below 140 micromol/L and/or blood urea below 9 mmol/L.

Administration.

Patients should be adequately hydrated before and for 24 hours following administration of cisplatin to ensure good urinary output and minimise nephrotoxicity.
1. Pre-treatment hydration: hydration may be achieved by intravenous infusion of 2 litres of 5% glucose in ½ to ⅓ normal saline infused over a 2-4 hour period.
2. Administration: cisplatin injection may be added to 1 litre of normal saline and infused over the desired time period.
Aluminium containing equipment should not be used for administration of cisplatin (see Section 6.2 Incompatibilities).
3. Post-treatment hydration: it is important to maintain adequate hydration and urinary output for 24 hours following the infusion.
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.

4.3 Contraindications

Cisplatin Accord is contraindicated in the following conditions:
Renal impairment;
Hearing disorders;
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.

Nephrotoxicity.

Cumulative and dose-related renal insufficiency is the major dose-limiting toxicity of cisplatin. The most commonly observed changes are a fall in GFR 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.

Myelosuppression.

Haematological toxicity is dose-related and cumulative. The lowest levels of circulating platelets and leucocytes generally occur between 18-23 days (range 7.3-45) with most patients recovering after 39 days (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 % 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.
A Coombs' positive haemolytic anaemia has been reported with cisplatin. 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.

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. Tinnitus is usually transient lasting from a few hours to a week after cessation of therapy. Hearing loss is usually unilateral or bilateral and occurs in the 4000 to 8000 Hz range. Frequency and severity of these hearing disorders increases with repeated doses and severe impairment may not be reversible.
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.

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.

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 nonspecific 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)).

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.

Other.

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.

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

Nephrotoxic drugs.

Potentially nephrotoxic drugs such as 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 drugs such as 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.
Cisplatin interacts with aluminium to form a black precipitate. Needles, syringes, catheters or IV administration sets that contain aluminium should not be used for the administration of cisplatin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Female.

Based on non-clinical (see Section 5.3 Preclinical Safety Data) 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), Reproductive system and breast disorders). Although the impairment of spermatogenesis can be reversible, males undergoing cisplatin treatment should be warned about the possible adverse effects on male fertility.
Cisplatin caused testis damage and decreased sperm counts in mice, primarily through effects on differentiated spermatogonia. 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 (at clinically relevant doses) and in both species, deformities have been reported. 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 foetus. Cisplatin should only be used if the potential benefits outweigh the risk of therapy.

Women of childbearing potential/contraception in males and females.

Women of childbearing potential should use effective contraception during treatment with cisplatin and for at least 7 months 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 4 months after the last dose.
¹Category 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.
Cisplatin and its active metabolites have been identified in human milk of treated mothers. Advise pregnant women not to breastfeed during treatment with cisplatin and for 1 month following last dose of treatment or to discontinue treatment, taking into account the importance of the drug to the mother.

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)

Gastrointestinal disorders.

Stomatitis, vomiting, nausea, anorexia, hiccups, diarrhoea.
Cisplatin induces severe nausea and vomiting in almost all patients. Severe nausea and vomiting usually begin 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.

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 first be noted during the second week after a dose and is manifested by an increase in serum creatinine, BUN, serum uric acid and/or 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 doses can increase the severity and duration of renal impairment and may produce irreversible renal insufficiency (sometimes fatal). Renal failure has been reported following intraperitoneal instillation of the drug.

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 such as 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 with IV adrenaline, corticosteroids and/or antihistamines.

Ear and labyrinth disorders.

Unilateral or bilateral tinnitus and/or hearing loss in high frequencies (> 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.

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.

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.

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 fluorouracil.

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.

Reproductive system and breast disorders.

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

Metabolism and nutrition disorders.

Cisplatin may cause dehydration in patients. Cisplatin may also cause serious electrolyte disturbances, mainly represented by hypomagnesaemia, hypocalcaemia, and hypokalaemia, and associated with renal tubular dysfunction. Hypomagnesaemia and/or hypocalcaemia 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 hyperuricaemia, hyponatremia 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.

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 adverse reactions.

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 https://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. It appears to produce intra- and interstrand cross links which modify DNA structure and inhibit DNA synthesis. In addition, and to a lesser extent, cisplatin inhibits protein and RNA synthesis. It does not appear to be phase-specific in the cell cycle.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Distribution.

Cisplatin seems to concentrate in the liver, kidneys, small intestine and testes.
More than 90% of platinum containing species remaining in the blood are bound (possibly irreversibly) to plasma proteins.
It does not cross the blood brain barrier so does not penetrate the cerebrospinal fluid (CSF) to any great extent. CSF levels of cisplatin are low although significant amounts can be detected in intracerebral tumours. Animal studies show good uptake into ovarian and uterine tissue.
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. Excretion is predominantly renal. About 15-25% of a dose is rapidly excreted, mainly as intact drug, in the first 2-4 hours and 20-80% in the first 24 hours. The remainder represents drug bound to tissues or plasma proteins.
Studies aiming at determining plasma elimination half-life of total platinum have shown a very large interindividual and interstudy variation. Most studies reported a half-life of total plasma platinum post cisplatin treatment of approximately 5 days or longer.

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

Sodium chloride, hydrochloric acid, sodium hydroxide, 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 below 25°C. Do not refrigerate or freeze. Protect from light.
If a precipitate has formed because of exposure to low temperatures, redissolve by storing at the recommended storage conditions until a clear solution is obtained.

6.5 Nature and Contents of Container

Cisplatin Accord is available in four strengths: 10 mg/10 mL, 25 mg/25 mL, 50 mg/50 mL and 100 mg/100 mL, in Type I amber glass vials in packs of 1.
Not all presentations may be marketed.

6.6 Special Precautions for 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.
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. Cleanse the remaining spill area with copious amounts of water.

6.7 Physicochemical Properties

Chemical structure.

CAS number.

15663-27-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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