Consumer medicine information

Irinotecan Accord

Irinotecan hydrochloride trihydrate

BRAND INFORMATION

Brand name

Irinotecan Accord

Active ingredient

Irinotecan hydrochloride trihydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Irinotecan Accord.

SUMMARY CMI

IRINOTECAN 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 Irinotecan Accord?

Irinotecan Accord contains the active ingredient irinotecan hydrochloride trihydrate. Irinotecan Accord is used to treat bowel cancer, which has spread to other parts of the body. Irinotecan Accord may be used once spread of cancer beyond the bowel is first diagnosed. At this time Irinotecan Accord will be given in combination with other anticancer medicines. Alternatively, Irinotecan Accord is used alone when the cancer has not responded or has returned after initial treatment.

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

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

Do not use if you have ever had an allergic reaction to irinotecan 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 Irinotecan Accord? in the full CMI.

3. What if I am taking other medicines?

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

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Irinotecan Accord?

Irinotecan 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 Irinotecan Accord? in the full CMI.

5. What should I know while using Irinotecan Accord?

Things you should do
  • Tell your doctor as soon as possible if diarrhoea occurs. Diarrhoea is a common side effect of Irinotecan Accord. If untreated, severe diarrhoea can be life-threatening
  • Remind any doctor, dentist or pharmacist you visit that you are using Irinotecan Accord.
  • Be sure to keep all your doctor's appointments so your progress can be checked.
  • Keep follow up appointments with your doctor. It is important to have your follow-up doses of Irinotecan Accord at the appropriate times to get the best effects from your treatments.
Driving or using machines
  • Irinotecan Accord may cause dizziness or visual disturbances which may occur within 24 hours following the administration of irinotecan 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 being given this medicine. If you drink alcohol, dizziness light-headedness and diarrhoea may be worse.

For more information, see Section 5. What should I know while using Irinotecan 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 more common side effects are included in full below in the CMI. Speak to your doctor if you have any of these common side effects and they worry you.

The very serious side effect are:

  • inability to control diarrhoea within 24 hours after taking loperamide
  • any signs of infection such as fever, chills, sore throat or cough, low back or side pain, painful or difficult urination
  • symptoms of dehydration, such as faintness, light-headedness or dizziness, increased thirst, wrinkling of the skin
  • inability to drink due to nausea or vomiting
  • signs of an allergic reaction, such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching, hives on the skin
  • unusual bleeding or bruising (such as bloody or black stools, blood in urine)
  • yellowing of the skin and/or eyes (these may be symptoms of a type of liver disease called jaundice)
  • chest pain
  • heart and blood vessels related side effects such as slowed heartbeat, fainting, blackout, blood clot, heart attack or stroke

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

IRINOTECAN ACCORD

Active ingredient: irinotecan hydrochloride trihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Irinotecan 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 Irinotecan Accord.

Where to find information in this leaflet:

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

1. Why am I using Irinotecan Accord?

Irinotecan Accord contains the active ingredient irinotecan hydrochloride trihydrate. Irinotecan belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines. These medicines are used to kill cancer cells.

Irinotecan Accord is used to treat bowel cancer, which has spread to other parts of the body. Irinotecan Accord may be used once spread of cancer beyond the bowel is first diagnosed. At this time Irinotecan Accord will be given in combination with other anticancer medicines. Alternatively, Irinotecan Accord is used alone when the cancer has not responded or has returned after initial treatment.

It is not known if Irinotecan Accord is safe and effective in the treatment of children.

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

Warnings

Do not use Irinotecan Accord if:

  • you are allergic to irinotecan or any of the ingredients listed at the end of this leaflet

Check with your doctor if you have or have had:

  • liver problems, including liver disease or raised enzymes
  • kidney disease or have difficulty urinating
  • problems with your heart or blood vessels
  • been treated with radiation therapy
  • diabetes
  • asthma
  • constipation or obstruction of the bowel
  • diarrhoea or have taken anti-diarrhoea medication within the last 24 hours
  • hereditary fructose intolerance
  • Crigler-Najjar syndrome or Gilbert's syndrome
  • are going to be vaccinated (have an injection to prevent a certain disease
  • an infection or high temperature
  • allergies to any other medicines, foods, preservatives or dyes

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

Pregnancy should be avoided if you or your partner is receiving Irinotecan Accord.

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

Females: Tell your doctor or pharmacist if you are pregnant or intend to become pregnant.

Avoid becoming pregnant by using effective contraception during treatment and up to 6 months after therapy.

Males: Tell your doctor or pharmacist if your partner intends to become pregnant while you are being given Irinotecan Accord, or shortly after you have stopped treatment with irinotecan.

It is recommended that you use effective contraception while you are using Irinotecan Accord and for at least 3 months after you stop treatment.

Do not breast-feed if you are taking this medicine.

Irinotecan passes into breast milk and there is a possibility that your baby may be affected.

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 may interfere with Irinotecan Accord and affect how it works or Irinotecan Accord may affect how they work.

  • laxatives (for constipation)
  • diuretics (medicines which make you pass urine more frequently e.g. for heart disease)
  • any medicine used to treat nausea or vomiting
  • dexamethasone (also called a glucocorticoid), which may be used to prevent nausea or vomiting, or to treat skin diseases, asthma, or other allergic disorders
  • anticonvulsants used to treat seizures
  • St John's Wort, a herbal medicine used to treat depression
  • ketoconazole used to treat fungal infections.
  • atazanavir, used to treat HIV-1 infection
  • prochlorperazine, used to treat nausea, vomiting and dizziness
  • suxamethonium or other medicines used as an anaesthetic
  • other medicines used to treat cancer

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

4. How do I use Irinotecan Accord?

How much to use

Irinotecan Accord is given to you as a slow injection into your vein (intravenously) by your doctor or nurse.

Your doctor will decide what dose you will receive. This depends on several factors including your height and weight, and whether or not other chemotherapy medicines are also being given.

Irinotecan may be given alone or in combination with other medicines to treat cancer.

Several treatment courses of irinotecan may be needed, depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled.

Ask your doctor if you want to know more about the dose of irinotecan you will be receiving

When to use Irinotecan Accord

It is very important that you continue to receive Irinotecan Accord for as long as your doctor prescribes it. Your doctor will decide how many cycles of treatment you need.

If you use too much Irinotecan Accord

It is unlikely that you will receive an overdose of Irinotecan Accord because a trained nurse or doctor will give it. If you think that you have been given too much Irinotecan 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 Irinotecan Accord?

Things you should do

Keep all appointments with your doctor and always discuss with your doctor any problems during or after treatment with Irinotecan Accord.

Tell your doctor as soon as possible if diarrhoea occurs. Diarrhoea is a common side effect of Irinotecan Accord. If untreated, severe diarrhoea can be life-threatening.

Your doctor will prescribe loperamide (a medicine to treat diarrhoea) for you to take in case you get diarrhoea after treatment. You should start taking loperamide, when you first have poorly formed or loose stools or bowel movements more frequent than you would normally expect.

You must tell your doctor if you cannot get diarrhoea under control within 24 hours after taking loperamide. You should not take loperamide for more than 48 hours.

Also tell your doctor if you develop a fever in addition to the diarrhoea. In these cases, your doctor may give you antibiotics. If the diarrhoea or fever persists you may become dehydrated and need to go to hospital for treatment.

You may need to take antibiotics if there are changes in your blood tests indicating a lack of white blood cells. Symptoms of this may include frequent infections such as fever, severe chills, sore throat or mouth ulcers. If this persists, you may need to go to hospital for treatment. If you have severe stomach cramps, you may need to be treated with antibiotics.

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

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

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Keep all of your doctor's appointments so that:

  • your progress can be checked
  • you have your follow up doses of Irinotecan Accord.

Your doctor may want to check your blood pressure and do some blood and other tests from time to time to make sure the medicine is working and to prevent unwanted side effects. It is also important to have your follow-up doses of Irinotecan Accord at the appropriate times to get the best effects from your treatments.

Things you should not do

Do not take any laxatives without checking with your doctor.

Diarrhoea is a common side effect of irinotecan. Taking laxatives, even if you are constipated, may cause or worsen diarrhoea.

Do not start taking any other medicines, prescription or not, without first telling your doctor or pharmacist.

Precautions to take

This medicine can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. Avoid people who have infections to reduce your risk of infection or bleeding.

Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate.

Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.

Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.

Avoid contact sports or other situations where you may bruise or get injured.

Take precautions to protect other people while you are receiving chemotherapy and for one week after the treatment period. Your body breaks down irinotecan and uses it to fight cancer. The breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomit and semen.

Take the following precautions:

  • flushing the toilet twice to dispose of any body fluids and waste
  • wearing gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet
  • washing linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water
  • placing soiled disposable nappies and other pads in a plastic bag, seal and dispose into the garbage
  • use a barrier method such as a condom, for sexual intercourse

Make sure you know what to do if you experience nausea, vomiting or diarrhoea.

You may feel nauseous, and have vomiting, diarrhoea, and/or stomach cramping, during or after treatment with irinotecan. This can lead to dehydration. It is likely that your doctor will give you one or more medicines to help manage these side effects.

Driving or using machines

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

This medicine may cause dizziness or visual disturbances which may occur within 24 hours following the administration of irinotecan 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 being given this medicine. If you drink alcohol, dizziness light-headedness and diarrhoea may be worse.

Looking after your medicine

The hospital will store Irinotecan Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Irinotecan 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.

Common side effects

Common side effectsWhat to do
  • nausea
  • loss of appetite
  • weight loss
  • hair loss
  • constipation (remember do not take laxatives)
  • heartburn, indigestion, hiccups
  • bloating, excessive wind
  • sore mouth, mouth ulcers
  • difficulty sleeping
  • headache
Speak to your doctor if you have any of these common side effects and they worry you. They are usually mild and short-lived.

Serious side effects

Serious side effectsWhat to do
  • vomiting
  • abdominal cramping/pain
  • runny nose or eyes, increased salivation, sweating or flushing
  • shortness of breath when exercising, dizziness, looking pale and walking abnormally
  • unusual tiredness or weakness
  • swelling and redness along a vein
  • fluid retention that results in swelling.
  • fungal infections (e.g. thrush)
Call your doctor or nurse as soon as possible.

Very serious side effects

Very serious side effectsWhat to do
  • inability to control diarrhoea within 24 hours after taking loperamide
  • any signs of infection such as fever, chills, sore throat or cough, low back or side pain, painful or difficult urination
  • symptoms of dehydration, such as faintness, light-headedness or dizziness, increased thirst, wrinkling of the skin
  • inability to drink due to nausea or vomiting
  • signs of an allergic reaction, such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching, hives on the skin
  • unusual bleeding or bruising (such as bloody or black stools, blood in urine)
  • yellowing of the skin and/or eyes (these may be symptoms of a type of liver disease called jaundice)
  • chest pain
  • heart and blood vessels related side effects such as slowed heartbeat, fainting, blackout, blood clot, heart attack or stroke
Call your doctor straight away 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 Irinotecan Accord contains

Active ingredient
(main ingredient)		Irinotecan hydrochloride trihydrate
Other ingredients
(inactive ingredients)		Sorbitol
Lactic acid
Sodium hydroxide
Hydrochloric acid
Water for injections

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

What Irinotecan Accord looks like

Irinotecan Accord is a sterile, pale yellow, clear, aqueous solution. (40 mg/2 mL Aust R 209856, 100 mg/5 mL Aust R 209857, 300 mg/15 mL AUST R 316415, 500 mg/25 mL AUST R 316412)

Who distributes Irinotecan Accord

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

This leaflet was prepared in January 2023.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Irinotecan Accord

Active ingredient

Irinotecan hydrochloride trihydrate

Schedule

S4

 

1 Name of Medicine

Irinotecan hydrochloride trihydrate.

2 Qualitative and Quantitative Composition

Irinotecan Accord (irinotecan hydrochloride trihydrate) concentrated injection is available in 40 mg/2 mL, 100 mg/5 mL, 300 mg/15 mL and 500 mg/25 mL single dose vials.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Irinotecan hydrochloride concentrated injection is supplied as a sterile, pale yellow, clear, aqueous solution with pH 3.0 - 3.8. It is intended for dilution with 5% glucose injection or 0.9% sodium chloride injection prior to infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Irinotecan hydrochloride is indicated as a component of first-line therapy for patients with metastatic carcinoma of the colon or rectum. Irinotecan hydrochloride is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial therapy.

4.2 Dose and Method of Administration

It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms (see Section 4.4 Special Warnings and Precautions for Use).

Combination agent therapy.

Dosage regimens.

Irinotecan hydrochloride in combination with fluorouracil (5-FU) and leucovorin (LV).

Irinotecan hydrochloride should be administered as an intravenous infusion over 90 minutes (see Preparation of infusion solution). For all regimens, the dose of LV should be administered immediately after irinotecan hydrochloride, with the administration of 5-FU to follow immediately after the administration of LV. The recommended regimens are shown in Table 1.
Dose modification. Patients should be carefully monitored for toxicity and assessed prior to each treatment, especially during the first cycle of therapy. Doses of irinotecan hydrochloride and 5-FU should be modified as necessary to accommodate individual patient tolerance to treatment. Based on the recommended dose levels described in Table 1, subsequent doses should be adjusted as suggested in Table 2, which shows the recommended dose modifications for combination schedules. All dose modifications should be based on the worst preceding toxicity. Patients should be diarrhoea free (return to pre-treatment bowel function) without requiring antidiarrhoeal medications for at least 24 hours before receiving the next chemotherapy administration.
A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less, the granulocyte count has recovered to ≥ 1.5 x 109/L, the platelet count has recovered to ≥ 100 x 109/L and treatment-related diarrhoea is fully resolved. Treatment should be delayed for 1 to 2 weeks to allow recovery from treatment-related toxicity. If the patient has not recovered after a 2 week delay, consideration should be given to discontinuing therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of irinotecan hydrochloride/5-FU/LV may be continued indefinitely as long as patients continue to experience clinical benefit.

Single agent therapy.

Dosage regimens. Irinotecan hydrochloride should be administered as an intravenous infusion (see Preparation of infusion solution) over 90 minutes in a recommended weekly or once every 3 week dosage schedule as shown in Table 3.
A reduction in the starting dose by one level of irinotecan hydrochloride may be considered for patients with any of the following circumstances: over 65 years, prior pelvic/abdominal radiotherapy, performance status of 2 or moderately increased bilirubin levels (17 - 34 micromol/L).

Patients with impaired hepatic function (single agent).

In patients with hepatic dysfunction, the following starting doses are recommended (see Table 4):
Dose modifications. Patients should be carefully monitored for toxicity and doses of irinotecan hydrochloride should be modified as necessary to accommodate individual patient tolerance to treatment. Based on recommended dose-levels described in Tables 3 and 4, subsequent doses of irinotecan hydrochloride should be adjusted as suggested in Table 5. All dose modifications should be based on the worst preceding toxicity.
A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less, the granulocyte count has recovered to ≥ 1.5 x 109/L, the platelet count has recovered to ≥ 100 x 109/L and treatment-related diarrhoea is fully resolved. Treatment may be delayed for 1 to 2 weeks to allow recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing irinotecan hydrochloride therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of irinotecan hydrochloride may be continued indefinitely as long as patients continue to experience clinical benefit.

Preparation and administration precautions.

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride concentrated injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride concentrated injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride concentrated injection contacts the mucous membranes, flush thoroughly with water.

Preparation of infusion solution.

Irinotecan hydrochloride concentrated injection is intended for single use in one patient only and any unused portion should be discarded.
Irinotecan hydrochloride concentrated injection must be diluted prior to infusion in 5% glucose injection or 0.9% sodium chloride injection to a final concentration range of 0.12 to 2.8 mg/mL. Other drugs should not be added to the infusion solution. Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit. Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe.
Irinotecan hydrochloride concentrated injection has been shown to be chemically and physically stable when diluted with infusion solutions (0.9% sodium chloride solution and 5% glucose solution) for up to 28 days when stored in low-density polyethylene (LDPE) or polyvinyl chloride (PVC) containers at 5°C or at 30°C/ambient humidity and protected from light. When exposed to light, chemical and physical stability is indicated for up to 3 days.
To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, hold at 2°C - 8°C for not more than 24 hours.
Do not freeze irinotecan hydrochloride concentrated injection or admixtures of irinotecan hydrochloride concentrated injection as this may result in precipitation of the drug.

4.3 Contraindications

Irinotecan hydrochloride is contraindicated in patients with a known hypersensitivity to the drug or its excipients. Irinotecan hydrochloride antigenicity has not been observed in clinical trials, but irinotecan hydrochloride antigenicity occurred in tests for passive cutaneous anaphylaxis in guinea pigs and rabbits, and in tests for active systemic anaphylaxis in guinea pigs. In these tests, both animal species produced antibodies against irinotecan hydrochloride, and some deaths occurred in guinea pigs sensitised to irinotecan hydrochloride.
Irinotecan hydrochloride is contraindicated in women who intend to become pregnant (see Section 4.6 Fertility, Pregnancy and Lactation; Section 5.3 Preclinical Safety Data).
Irinotecan hydrochloride is contraindicated in pregnancy and lactation (see Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Administration.

Irinotecan hydrochloride should be administered only under the supervision of a physician who is experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
Irinotecan will only be prescribed in the following cases after the expected benefits have been weighted against the possible therapeutic risks:
In patients presenting a risk factor, particularly those with a WHO performance status = 2.
In the few rare instances where patients are deemed unlikely to observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrheal treatment combined with high fluid intake at onset of delayed diarrhea). Strict hospital supervision is recommended for such patients.

Extravasation.

Irinotecan hydrochloride is administered by intravenous infusion. Care should be taken to avoid extravasation and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site with sterile water and application of ice are recommended.

Mayo Clinic regimen.

Except in a well-designed clinical study, irinotecan hydrochloride should not be used in combination with the "Mayo Clinic" regimen of 5-FU/LV (administration for 4-5 consecutive days every 4 weeks; see Table 9) because of reports of increased toxicity, including toxic deaths. Irinotecan hydrochloride should be used as recommended (see Section 4.2 Dose and Method of Administration).

Immunosuppressant effects/increased susceptibility to infections.

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents, including irinotecan hydrochloride, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving irinotecan hydrochloride. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Cardiovascular.

Thromboembolic events have been observed rarely in patients receiving irinotecan hydrochloride. The specific cause of these events has not been determined (see Section 4.8 Adverse Effects (Undesirable Effects), Cardiovascular).

Diarrhoea and its management.

Irinotecan hydrochloride can induce both an early and a late form of diarrhoea that appear to be mediated by different mechanisms. Both forms of diarrhoea may be severe.
Early diarrhoea (occurring during or shortly after infusion of irinotecan hydrochloride) is cholinergic in nature. It is usually transient and only infrequently is severe. It may be accompanied by symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, bradycardia and intestinal hyperperistalsis that can cause abdominal cramping. Administration of 0.25 to 1 mg of intravenous or subcutaneous atropine should be considered (unless clinically contraindicated) in patients experiencing cholinergic symptoms occurring during or shortly after infusion of irinotecan hydrochloride. Patients ≥ 65 years of age should be closely monitored due to a greater risk of early diarrhoea observed in this population.
Late diarrhoea (generally occurring more than 24 hours after administration of irinotecan hydrochloride) can be prolonged, may lead to dehydration, electrolyte imbalance or infection and can be life-threatening. Late diarrhoea should be treated promptly with loperamide. Patients should be instructed to have loperamide readily available and begin treatment at the first episode of poorly formed or loose stools or the earliest onset of bowel movements more frequent than normally expected for the patient. One dosage regimen for loperamide used in clinical trials consisted of 4 mg at the first onset of late diarrhoea and then 2 mg every 2 hours until the patient was diarrhoea-free for at least 12 hours. During the night, the patient may take 4 mg of loperamide every 4 hours. Loperamide is not recommended to be used for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours. Premedication with loperamide is not recommended.
Patients with diarrhoea should be carefully monitored and given fluid and electrolyte replacement if they become dehydrated and should be given antibiotics if they develop ileus, fever or severe neutropenia. After the first treatment, subsequent chemotherapy should be delayed until patients are diarrhoea-free (return to pre-treatment bowel function) for at least 24 hours without the need for antidiarrhoeal medication. If NCI grade 2, 3 or 4 diarrhoea occurs, subsequent doses of irinotecan hydrochloride should be reduced within the current cycle (see Section 4.2 Dose and Method of Administration).
In addition to antibiotic treatment, hospitalisation is recommended for management of the diarrhoea, in the following cases: diarrhoea associated with fever, severe diarrhoea (requiring intravenous hydration), patients with vomiting associated with delayed (i.e. late) diarrhoea and diarrhoea persisting beyond 48 hours following the initiation of high-dose loperamide therapy and in the few rare instances where patients are deemed unlikely to observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrhoeal treatment combined with high fluid intake at onset of delayed diarrhoea).

Haematology.

Irinotecan hydrochloride commonly causes neutropenia, leukopenia, and anaemia, any of which may be severe and therefore should not be used in patients with severe bone marrow failure (see Section 4.8 Adverse Effects (Undesirable Effects), Haematological). Serious thrombocytopenia is uncommon.

Neutropenia.

Deaths due to sepsis following severe neutropenia have been reported in patients treated with irinotecan hydrochloride. Neutropenic complications should be managed promptly with antibiotic support. Therapy with irinotecan hydrochloride should be temporarily omitted if neutropenic fever occurs or if the absolute neutrophil count drops below 1.5 x 109/L. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥ 1.5 x 109/L. After the patient recovers, subsequent doses of irinotecan hydrochloride should be reduced depending upon the level of neutropenia observed (see Section 4.2 Dose and Method of Administration). Routine administration of a colony-stimulating factor (CSF) is not necessary but physicians may consider CSF use in individual patients experiencing problems related to neutropenia.

Hypersensitivity.

Hypersensitivity reactions including severe anaphylactic and anaphylactoid reactions have been observed.

Colitis/ileus.

Cases of colitis have been reported. In some cases, colitis was complicated by ulceration, bleeding, ileus and infection. Cases of ileus without preceding colitis have also been reported. Patients experiencing ileus should receive prompt antibiotic support.

Chronic inflammatory bowel disease and/or bowel obstruction.

Patients must not be treated with irinotecan hydrochloride until resolution of the bowel obstruction.

Patients with reduced UGT1A1 activity.

Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1), which mediates the conjugation of the active metabolite SN-38 (see Section 5.2 Pharmacokinetic Properties, Metabolism, Excretion), is encoded by the UGT1A1 gene. This gene is highly polymorphic resulting in variable metabolic capacities among individuals. One specific variation of the UGT1A1 gene includes a polymorphism in the promoter region known as the UGT1A1*28 variant allele. This variant and other congenital deficiencies in UGT1A1 expression (such as Crigler-Najjar and Gilbert's syndrome) are associated with reduced enzyme activity and increased systemic exposure to SN-38. Higher plasma concentrations of SN-38 are observed in individuals who are homozygous for the UGT1A1*28 allele (also referred to as UGT1A1 7/7 genotype) compared to patients who have one or two wild-type alleles.
Another specific polymorphism of UGT1A1 gene (that reduces the activity of this enzyme) is a missense mutation known as UGT1A1*6 variant.
Patients with UGT1A1*28 or *6 variants (especially if homozygous) are at increased risk of experiencing adverse events such as neutropenia and diarrhoea. A reduced irinotecan starting dose should be considered for homozygous patients. In addition, *28 and *6 homozygous and heterozygous patients should be closely monitored for neutropenia and diarrhoea.
The exact reduction in starting dose in this patient population has not been established and any subsequent dose modifications should be based on individual patient tolerance to treatment.
In order to identify patients at increased risk of experiencing neutropenia and diarrhoea, UGT1A1 genotyping can be useful. More in detail, UGT1A1*28 genotyping can be useful in Caucasians, Africans and Latinos, UGT1A1*6 in East Asians and combined UGT1A1*28 and *6 in Chinese and Japanese, since these are the populations in which these variants are more prevalent.

Use with caution in the following circumstances.

Patients at particular risk.

Physicians should exercise particular caution in monitoring the effects of irinotecan hydrochloride in patients with poor performance status, in elderly patients and in patients who have previously received pelvic/abdominal irradiation (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with poor performance status are at increased risk of irinotecan-related adverse events. In patients receiving either irinotecan hydrochloride/ 5-FU/LV or 5-FU/LV in clinical trials comparing these agents, higher rates of hospitalisation, neutropenic fever, thromboembolism, first-cycle treatment discontinuation and early deaths were observed in patients with a baseline performance status of 2 than in patients with a baseline performance of 0 or 1. Patients with performance status of 3 or 4 should not receive irinotecan hydrochloride.

Irradiation therapy.

Patients who have previously received pelvic/abdominal irradiation are at increased risk of severe myelosuppression following the administration of irinotecan hydrochloride. The concurrent administration with irradiation has not been adequately studied and is not recommended.

Cholinergic effects.

Irinotecan hydrochloride has cholinergic effects and should be used with caution in patients with asthma or cardiovascular diseases, and in patients with mechanical intestinal or urinary obstruction.

Respiratory.

Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan hydrochloride therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include pre-existing lung disease, use of pneumotoxic drugs, radiation therapy, and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.

Before administration.

Monitoring.

Careful monitoring of the white blood cell count with differential, haemoglobin and platelet count is recommended before each dose of irinotecan hydrochloride. Liver function should be monitored before initiation of treatment and monthly or as clinically indicated.

Nausea and vomiting.

Irinotecan hydrochloride is emetogenic. It is recommended that patients receive premedication with antiemetic agents. In clinical studies with the weekly dosage schedule, the majority of patients received 10 mg of dexamethasone given in conjunction with another type of antiemetic agent, such as a 5-HT3 blocker (e.g. ondansetron or granisetron). Antiemetic agents should be given on the day of treatment, starting at least 30 minutes before administration of irinotecan hydrochloride. Physicians should also consider providing patients with an antiemetic regimen (e.g. prochlorperazine) for subsequent use as needed. Patients with vomiting associated with delayed (i.e. late) diarrhoea should be hospitalised as soon as possible for treatment.

Advice for patients.

Patients should be advised of the expected toxic effects of irinotecan hydrochloride, particularly of gastrointestinal complications such as nausea, vomiting, abdominal cramping, diarrhoea and infection.
Patients should be advised to consult their physician if any of the following occur after treatment with irinotecan hydrochloride: diarrhoea for the first time; inability to control diarrhoea within 24 hours; vomiting; fever or evidence of infection; symptoms of dehydration, such as faintness, light-headedness or dizziness; bloody or black stools; inability to take fluids by mouth due to nausea or vomiting. Patients should also be alerted to the possibility of alopecia. Laxatives should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) and patients should contact their physician to discuss any laxative use.

Others.

Since this product contains sorbitol, it is unsuitable in hereditary fructose intolerance.

Use in hepatic impairment.

In patients with hyperbilirubinemia, the clearance of irinotecan is decreased and therefore the risk of haematotoxicity is increased (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).
The use of irinotecan hydrochloride in patients with a serum total bilirubin concentration of > 3.0 x institutional upper limit of normal (IULN) given as a single agent on the once every 3 weeks schedule has not been established. In clinical trials of the single agent weekly dosage schedule, patients with even modest elevations in total baseline serum bilirubin levels (17-34 micromol/L) had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 17 micromol/L (50% versus 18%; p < 0.001) (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations; Section 4.2 Dose and Method of Administration). Patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at greater risk of myelosuppression when receiving therapy with irinotecan hydrochloride.

Use in renal impairment.

Studies in patients with impaired renal function have not been conducted (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations). Therefore, caution should be undertaken in patients with impaired renal function. Irinotecan hydrochloride is not recommended for use in patients on dialysis.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations, Geriatric.

Paediatric use.

The safety and effectiveness of irinotecan hydrochloride in children have not been established.

Effects on laboratory tests.

There are no known interactions between irinotecan hydrochloride and laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

CYP3A4 and/or UGT1A1 inhibitors.

Irinotecan and its active metabolite SN-38 are metabolised via the human cytochrome P450 3A4 isoenzyme (CYP3A4) and uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) (see Section 5.2 Pharmacokinetic Properties, Metabolism, Excretion). Coadministration of irinotecan with inhibitors of CYP3A4 and/or UGT1A1 may result in increased systemic exposure to irinotecan and the active metabolite SN-38. Physicians should take this into consideration when administering irinotecan with these drugs.

Ketoconazole.

Irinotecan clearance is greatly reduced in patients receiving concomitant ketoconazole, leading to increased exposure to the active metabolite SN-38. Ketoconazole should be discontinued at least 1 week prior to starting irinotecan therapy and should not be administered during irinotecan therapy.

Atazanavir sulfate.

Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs.

CYP3A4 inducers.

Anticonvulsants.

Concomitant administration of CYP3A-inducing anticonvulsant drugs (e.g. carbamazepine, phenobarbital or phenytoin) leads to reduced exposure to SN-38. Consideration should be given to starting or substituting non-enzyme-inducing anticonvulsants at least one week prior to initiation of irinotecan therapy in patients requiring anticonvulsant treatment.

St. John's wort (Hypericum perforatum).

Exposure to the active metabolite SN-38 is reduced in patients taking concomitant St. John's wort. St. John's wort should be discontinued at least 1 week prior to the first cycle of irinotecan, and should not be administered during irinotecan therapy.

Other interactions.

Neuromuscular blocking agents.

Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Since irinotecan has anticholinesterase activity, drugs with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonised.

Antineoplastic agents.

The adverse effects of irinotecan hydrochloride, such as myelosuppression and diarrhoea, would be expected to be exacerbated by other antineoplastic agents having similar adverse effects.

Dexamethasone.

Lymphocytopenia has been reported in patients receiving irinotecan hydrochloride and it is possible that the administration of dexamethasone as antiemetic prophylaxis may have enhanced the likelihood of this effect. However, serious opportunistic infections have not been observed and no complications have specifically been attributed to the lymphocytopenia.
Hyperglycaemia has also been reported in patients receiving irinotecan hydrochloride. Usually this has been observed in patients with a history of diabetes mellitus or evidence of glucose intolerance prior to administration of irinotecan hydrochloride. It is probable that the administration of dexamethasone contributed to hyperglycaemia in some patients.

Prochlorperazine.

The incidence of akathisia in clinical trials of the single agent weekly dosage schedule was greater (8.5%, 4/47 patients) when prochlorperazine was administered on the same day as irinotecan hydrochloride than when these drugs were given on separate days (1.3%, 1/80 patients). However, the 8.5% incidence of akathisia is within the range reported for use of prochlorperazine when given as a premedication for other chemotherapies.

Laxatives.

It would be expected that the incidence or severity of diarrhoea would be worsened by laxative use during therapy with irinotecan hydrochloride, but this has not been studied.

Diuretics.

In view of the potential risk of dehydration secondary to vomiting and/or diarrhoea induced by irinotecan hydrochloride, the physician may wish to withhold diuretics during dosing with irinotecan hydrochloride and, certainly, during periods of active vomiting or diarrhoea.

Bevacizumab.

Results from a dedicated drug-drug interaction trial demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan hydrochloride in doses of up to 6 mg/kg/day to rats. Atrophy of male reproductive organs was observed after multiple daily irinotecan hydrochloride doses both in rodents at 20 mg/kg (AUC approximately the same value as in patients administered 125 mg/m2 weekly) and dogs at 0.4 mg/kg (AUC about 1/15th the value in patients administered 125 mg/m2 weekly).
(Category D)
Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human foetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
There are no adequate and well-controlled studies of irinotecan hydrochloride in pregnant women. Irinotecan hydrochloride may cause foetal harm when administered to a pregnant woman. Administration of 6 mg/kg/day intravenous irinotecan hydrochloride to rats (AUC about 0.2 times the corresponding values in patients administered 125 mg/m2) and rabbits (about one-half the recommended human weekly starting dose on a mg/m2 basis) during the period of organogenesis, is embryotoxic as characterised by increased post-implantation loss and decreased numbers of live foetuses. Irinotecan hydrochloride was teratogenic in rats at doses greater than 1.2 mg/kg/day (AUC about 1/40th the corresponding values in patients administered 125 mg/m2) and in rabbits at 6.0 mg/kg/day. Teratogenic effects included a variety of external, visceral, and skeletal abnormalities.
Women of childbearing potential should not be started on irinotecan until pregnancy is excluded. Pregnancy should be avoided if either partner is receiving irinotecan hydrochloride.
Due to the potential for genotoxicity, advise female patients of reproductive potential to use highly effective contraception during treatment and for 6 months after the last dose of irinotecan hydrochloride.
Due to the potential for genotoxicity, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of irinotecan hydrochloride.
If the patient becomes pregnant while receiving this drug, the patient should be informed about the potential hazard to the foetus.
 The available data are limited to one patient only. Irinotecan and its active metabolite SN-38 were measured in the milk of one lactating patient. The effect on newborn/infants is unknown. As many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended not to breastfeed when receiving therapy with irinotecan hydrochloride.
Radioactivity appeared in rat milk within 5 minutes of intravenous administration of radiolabelled irinotecan hydrochloride and was concentrated up to 65-fold at 4 hours after administration relative to plasma concentrations. Irinotecan hydrochloride has been shown to impair learning ability and cause a delay in postnatal development in rats.

4.7 Effects on Ability to Drive and Use Machines

The effect of irinotecan on the ability to drive or use machinery has not been evaluated.
However, patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of irinotecan hydrochloride, and advised not to drive or operate machinery if these symptoms occur.

4.8 Adverse Effects (Undesirable Effects)

Combination therapy.

In the two phase III studies, a total of 955 patients with metastatic colorectal cancer received irinotecan hydrochloride in combination with 5-FU/LV, 5-FU/LV alone, or irinotecan hydrochloride alone (see Table 10; Section 5.1 Pharmacodynamic Properties, Clinical trials). In these studies, 370 patients received irinotecan hydrochloride in combination with 5-FU/LV, 362 patients received 5-FU/LV alone, and 223 patients received irinotecan hydrochloride alone.
Fifty-nine (6.1%) patients died within 30 days of last study treatment: 27 (7.3%) received irinotecan hydrochloride in combination with 5-FU/LV, 19 (5.3%) received 5-FU/LV alone, and 13 (5.8%) received irinotecan hydrochloride alone. Deaths potentially related to treatment occurred in 3 (0.7%) patients who received irinotecan hydrochloride in combination with 5-FU/LV (2 neutropenic fever/sepsis, 1 treatment toxicity), 3 (0.7%) patients who received 5-FU/LV alone (1 neutropenic fever/sepsis, 1 CNS bleeding during thrombocytopenia, 1 unknown) and 2 (0.9%) patients who received irinotecan hydrochloride alone (2 neutropenic fever). Deaths within 60 days of study treatment were reported for 18 (4.9%) patients who received irinotecan hydrochloride in combination with 5-FU/LV, 18 (5.0%) patients who received 5-FU/LV alone and 15 (6.7%) patients who received irinotecan hydrochloride alone. Discontinuations due to adverse events were reported for 26 (7.0%) patients who received irinotecan hydrochloride in combination with 5-FU/LV, 15 (4.1%) patients who received 5-FU/LV alone, and 26 (11.7%) patients who received irinotecan hydrochloride alone.
Table 6 lists the grade 3 and 4 clinically relevant adverse events reported in the combination treatment arms of the two phase III studies.
The most clinically significant adverse events for patients receiving irinotecan hydrochloride-based therapy were diarrhoea, nausea, vomiting, neutropenia, and alopecia (complete hair loss = Grade 2). The most clinically significant adverse events for patients receiving 5-FU/LV therapy were diarrhoea, neutropenia, neutropenic fever, and mucositis. In Study 1, grade 4 neutropenia, neutropenic fever (defined as ≥ grade 2 fever and grade 4 neutropenia), and mucositis were observed less often with irinotecan hydrochloride/5-FU/LV than with administration of 5-FU/LV.

Single agent therapy.

Information on adverse reactions for irinotecan hydrochloride as single agent therapy is available from 304 patients with metastatic carcinoma of the colon or rectum treated in phase II trials with the once weekly dosage schedule, 316 patients treated with the once-every-3-week dosage schedule and over 1100 patients with a variety of tumour types treated in Japan. In general the types of toxicities observed were similar. 4.3% of patients treated with the weekly dosage schedule and 8% of patients treated with the once-every-3-week dosage schedule discontinued treatment with irinotecan hydrochloride because of medical events. Seventeen of the 304 patients treated with the weekly dosage schedule died within 30 days of the administration of irinotecan hydrochloride and in five cases (1.6%), the deaths were potentially drug-related. Eleven patients treated with irinotecan hydrochloride in the once-every-3-week dosage schedule died within 30 days of treatment and in three cases (1%), the deaths were potentially related to treatment with irinotecan hydrochloride. The main causes of the deaths potentially related to treatment were neutropenic infection, grade 4 diarrhoea and asthenia.
The frequency of the most common adverse events reported from the single agent second line studies is presented in Table 7. Additional information on adverse events follows the table, organised by body system category.

Gastrointestinal.

Nausea, vomiting and diarrhoea are common adverse events following treatment with irinotecan hydrochloride and can be severe. Among those patients treated at the 125 mg/m2 single agent weekly dose, the median duration of any grade of late diarrhoea was 3 days and for grade 3 or 4 late diarrhoea was 7 days. The frequency of grade 3 and 4 late diarrhoea was significantly greater in patients 65 years or older (39.8% versus 23.4%, p = 0.0025).
Abdominal pain and cramping are associated with early-onset diarrhoea (diarrhoea which occurs within 24 hours of drug administration). In studies it has been found that atropine is useful in ameliorating these events. Colonic ulceration, sometimes with gastrointestinal bleeding, ileus and infection, has been observed in association with administration of irinotecan hydrochloride.

Haematological.

Irinotecan hydrochloride commonly causes neutropenia, leucopenia (including lymphocytopenia) and anaemia. Serious thrombocytopenia is uncommon. In clinical studies with the single agent weekly dosage schedule, one death due to neutropenic sepsis without fever was judged to be potentially drug-related (0.3%, 1/304). Blood transfusions were given to 9.9% of patients. When evaluated in the trials of single agent weekly administration, the frequency of grade 3 or 4 neutropenia was significantly higher in patients who had received previous pelvic/abdominal irradiation (48.1% versus 24.1%, p = 0.0356). In these same studies, patients with total baseline serum bilirubin levels of 17 micromol/L or more also had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 17 micromol/L (50% versus 17.7%, p < 0.001).

Cholinergic symptoms.

Patients may have cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing and intestinal hyperperistalsis that can cause abdominal cramping and early diarrhoea. If these symptoms occur, they manifest during or shortly after drug infusion. They are thought to be related to the anticholinesterase activity of the irinotecan parent compound and are more likely to occur at higher doses. The timing of the symptoms is most consistent with the occurrence of peak irinotecan hydrochloride serum levels during parenteral administration.

Metabolic and nutritional.

The dehydration observed in 14.8% of patients in clinical studies was as a consequence of diarrhoea, nausea and vomiting.

Hepatic.

In the clinical studies evaluating the single agent weekly dosage schedule, NCI grade 3 or 4 liver enzyme abnormalities were observed in fewer than 10% of patients. These events typically occur in patients with known hepatic metastases. For the once-every-3-week dosage schedule, hepatic events, such as ascites and jaundice of NCI Grade 3/4 severity occurred in 8.5% of patients in one study and 8.7% of patients in another study.

Renal.

Increases in serum creatinine or blood urea nitrogen, generally attributable to complications of infection or to dehydration related to nausea, vomiting or diarrhoea have been observed. There have been cases of acute renal failure. Rare instances of renal dysfunction due to tumour lysis syndrome have also been reported.

Dermatological.

Alopecia has been reported during treatment with irinotecan hydrochloride. Rashes have also been reported but did not result in discontinuation of treatment.

Respiratory.

Severe pulmonary events are infrequent. Over half the patients with dyspnoea in the clinical studies evaluating the single agent weekly dosage schedule had lung metastases; the extent to which malignant pulmonary involvement or other pre-existing lung disease may have contributed to dyspnoea in these patients is unknown. For the once-every-3-week dosage schedule, respiratory events, such as dyspnoea and cough of NCI grade 3/4 severity occurred in 10.1% of patients in one study and 4.7% of patients in another study.
A potentially life-threatening pulmonary syndrome, consisting of dyspnoea, fever and a reticulonodular pattern on chest x-ray was observed in a small percentage of patients in early Japanese studies. The contribution of irinotecan hydrochloride to these preliminary events was difficult to assess because these patients also had lung tumours and some had pre-existing nonmalignant pulmonary disease. As a result of these observations, however, clinical studies in the USA enrolled few patients with compromised pulmonary function, significant ascites, or pleural effusions.

Neurological.

Insomnia and dizziness were observed in 19.4% and 14.8% respectively of patients studied in clinical trials of the single agent weekly dosage schedule but were not usually considered to be directly related to the administration of irinotecan hydrochloride. Dizziness may sometimes represent symptomatic evidence of orthostatic hypotension in patients with dehydration.

Cardiovascular.

Vasodilation (flushing) may occur during administration of irinotecan hydrochloride. Irinotecan hydrochloride has anti-cholinesterase activity. As such, there are possible cardiovascular effects due to its administration. These include sudden death, blackout and bradycardia. Patients should be monitored for cholinergic effects during administration of irinotecan hydrochloride, and atropine should be readily available for treatment of these effects. There were no cases of sudden death reported in the Phase II clinical studies of the single agent weekly dosage schedule involving 304 patients. In these studies, two patients (0.7%) suffered syncope and one patient (0.3%) suffered bradycardia.
Thromboembolic events including angina pectoris, arterial thrombosis, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, embolus lower extremity, heart arrest, myocardial infarct, myocardial ischaemia, peripheral vascular disorder, pulmonary embolus, sudden death, thrombophlebitis, thrombosis and vascular disorder have been observed rarely in patients receiving irinotecan hydrochloride. The specific cause of these events has not been determined.

Other.

Other NCI grade 3 or 4 drug-related adverse events observed in 1-10% of patients in clinical trials included mucositis, bilirubinaemia and hypovolaemia. In fewer than 1% of patients, NCI grade 3 or 4 rectal disorder, gastrointestinal monilia, hypokalaemia, hypomagnesaemia, increased GGTP, malaise, sepsis, urinary tract infection, breast pain and abnormal gait were observed.

Post-marketing surveillance.

Cardiac disorders.

Myocardial ischaemic events have been observed following irinotecan therapy predominantly in patients with underlying cardiac disease, other known risk factors for cardiac disease or previous cytotoxic chemotherapy.

Gastrointestinal disorders.

Infrequent cases of intestinal obstruction, ileus, megacolon or gastrointestinal haemorrhage, and rare cases of colitis, including typhlitis (ileocecal syndrome), ischaemic and ulcerative colitis have been reported. In some cases, colitis was complicated by ulceration, bleeding, ileus or infection. Cases of ileus without preceding colitis have also been reported. Rare cases of intestinal perforation have been reported.
Rare cases of symptomatic pancreatitis or asymptomatic elevated pancreatic enzymes have been observed.

Hypovolaemia.

There have been rare cases of renal impairment and acute renal failure, generally in patients who became infected and/or volume depleted from severe gastrointestinal toxicities. Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting, or sepsis.

Infections and infestations.

Bacterial, fungal and viral infections have been reported.

Immune system disorders.

Hypersensitivity reactions including severe anaphylactic or anaphylactoid reactions have also been reported.

Investigations.

Rare cases of hyponatremia mostly related with diarrhoea and vomiting have been reported. Increases in serum levels of transaminases (i.e. AST and ALT) in the absence of progressive liver metastasis; transient increase of amylase and occasionally transient increase of lipase have been very rarely reported.

Musculoskeletal and connective tissue disorders.

Early effects such as muscular contraction or cramps and paresthesia have been reported.

Nervous system disorders.

Speech disorders, generally transient in nature, have been reported in patients treated with irinotecan; in some cases, the event was attributed to the cholinergic syndrome observed during or shortly after infusion of irinotecan.

Respiratory, thoracic and mediastinal disorders.

Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Early effects such as dyspnoea have been reported (see Section 4.4 Special Warnings and Precautions for Use). Hiccups have also been reported.

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 http://www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

In humans, at single doses up to 750 mg/m2, adverse events were similar to those reported with the recommended dosage regimens. There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhoea. There is no known antidote for overdosage of irinotecan hydrochloride. Support respiratory and cardiovascular function. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) or the national Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Irinotecan hydrochloride injection is an antineoplastic agent of the topoisomerase I inhibitor class.
Irinotecan hydrochloride trihydrate is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I, which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan hydrochloride and its active metabolite SN-38 bind to the topoisomerase I - DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan hydrochloride is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I, DNA, and either irinotecan hydrochloride or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.
Irinotecan hydrochloride serves as a water-soluble precursor of the lipophilic metabolite SN-38, which is approximately 1000 times as potent as irinotecan hydrochloride as an inhibitor of topoisomerase I purified from human and rodent tumour cell lines. However, the precise contribution of SN-38 to the activity of irinotecan hydrochloride is unknown. Both irinotecan hydrochloride and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. An acidic pH promotes the formation of the lactone whereas a basic pH favours the hydroxy acid anion form.
Administration of irinotecan hydrochloride has resulted in antitumour activity in mice bearing cancers of rodent origin and human carcinoma xenografts of various histological types.
Irinotecan hydrochloride is a non-competitive inhibitor of acetylcholinesterase and a cholinergic syndrome is associated with its administration (see Section 4.8 Adverse Effects (Undesirable Effects)).

Clinical trials.

Irinotecan hydrochloride has been studied in clinical trials in combination with 5-FU and LV as a first line agent in metastatic colorectal cancer and as a single agent used after failure of initial therapy. Weekly and once every 3 weeks dosage schedules were studied using irinotecan hydrochloride as the single agent. Weekly and once every 2 week schedules were studied with irinotecan hydrochloride used in combination treatment. Patients with a WHO performance status of 3 or 4 have not been studied in clinical trials (see Table 8).
Combination therapy for first-line treatment of metastatic colorectal cancer. Two randomised, open-label, controlled, multinational, phase III clinical trials support the use of irinotecan hydrochloride as first-line treatment of patients with metastatic carcinoma of the colon or rectum. The dosing regimens of these studies are given in Table 9.
In both studies, concomitant medications such as antiemetics, atropine and loperamide were given to patients for prophylaxis and/or management of symptoms from treatment. In study 2, if late diarrhoea persisted for greater than 24 hours despite loperamide, a 7-day course of fluoroquinolone antibiotic prophylaxis was given. Treatment with oral fluoroquinolone was initiated in patients whose diarrhoea persisted for greater than 24 hours despite loperamide or if they developed a fever in addition to diarrhoea. Treatment with oral fluoroquinolone was also initiated in patients who developed an absolute neutrophil count (ANC) < 0.5 x 109/L, even in the absence of fever or diarrhoea. Patients also received treatment with intravenous antibiotics if they had persistent diarrhoea or fever or if ileus developed.
In both studies the combination of irinotecan hydrochloride/5-FU/LV therapy resulted in significant improvements in objective tumour response rate, time to tumour progression (TTP) and survival when compared with 5-FU/LV alone. These differences in survival were observed despite the use of post-study second-line therapy, including irinotecan-containing regimens in patients in the control arm. Patient characteristics and major efficacy results are shown in Table 10.
Improvement was noted when response rates and time to tumour progression were examined across all demographic and disease-related subgroups (as categorised by age, gender, ethnic origin, performance status, extent of organ involvement with cancer, time from diagnosis of cancer, prior adjuvant therapy, and baseline laboratory abnormalities), with irinotecan hydrochloride-based combination therapy relative to 5-FU/LV.
The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was used in both studies. While there was no statistical evidence that there were significant differences between irinotecan hydrochloride/5-FU/LV combination and 5-FU/LV alone with regard to Quality of Life (QOL) improvement, descriptive evidence suggested a general trend favouring QOL improvement or less-worsening in favour of the irinotecan hydrochloride combination regimen.
Single agent treatment in recurrent or progressive metastatic colorectal cancer after 5-FU based treatment.

Weekly dosage schedule.

Three multicentre, open-label, phase II studies, all utilising repeated cycles of once weekly treatment with irinotecan hydrochloride for 4 consecutive weeks, followed by a two week rest period were conducted in a total of 304 patients in the United States. These studies were designed to evaluate tumour response rate and toxicity with irinotecan hydrochloride in patients with metastatic colorectal cancer that recurred or progressed following a prior 5-FU based chemotherapeutic regimen. Starting doses of irinotecan hydrochloride in these trials were 100, 125 or 150 mg/m2 with 150 mg/m2 proving to be poorly tolerated due to unacceptably high rates of grade 4 late diarrhoea and febrile neutropenia. The results of the individual studies are shown in Table 11.
Of the 304 patients treated in the phase II studies, response rates to irinotecan hydrochloride were similar in males and females and among patients younger than 65 years. Rates were also similar in patients with cancer of the colon or cancer of the rectum, and in patients with single and multiple metastatic sites. Response rate was 18.5% in patients with a WHO performance status of 0 and 8.2% in patients with a performance status of 1 or 2.
The response rates with irinotecan hydrochloride were unaffected by whether or not patients had responded to prior 5-FU based treatment given for metastatic disease. Patients who had received previous irradiation to the pelvis also responded to irinotecan hydrochloride at approximately the same rate as those who had not previously received irradiation.
Overall, across the pivotal studies, stable disease was documented in 148 (48.7%) of the 304 patients in the intent to treat population and in 145 (55.6%) of the 261 patients in the evaluable population.
Consistent with the results in Study C, a somewhat greater percentage of patients who were treated with the 125 mg/m2 starting dose (53.4%; 103/193) than with the 100 mg/m2 starting dose (39.2%; 40/102) had stable disease during therapy.

Once every 3 week dosage schedule.

Two phase III, multicentre, randomised studies were conducted with a three weekly dosage regimen in patients with metastatic colorectal cancer whose disease had recurred or progressed following 5-FU therapy (n = 535). Second-line irinotecan hydrochloride was compared with best supportive care in one study and with infusional 5-FU-based therapy in the second study. The primary endpoint in both studies was survival. Parameters of clinical benefit and quality of life were also assessed. The starting dose was 350 mg/m2 infused intravenously over 90 minutes to a maximum total dose of 700 mg. For patients 70 years or older and for patients with a WHO performance status of 2 the starting dose was reduced to 300 mg/m2. Antiemetics, atropine and loperamide were provided as supportive care and late diarrhoea persisting for greater than 24 hours despite loperamide was treated with a 7-day course of a fluoroquinolone antibiotic.
A significant survival advantage for irinotecan hydrochloride over best supportive care or infusional 5-FU-based therapy was demonstrated. When adjusted for baseline patient characteristics (e.g. performance status), survival among patients treated with irinotecan hydrochloride remained significantly longer than in the control populations (p = 0.001 for Study 1 and p = 0.017 for Study 2). Clinical benefit in Study 1, as measured by pain-free survival and survival without weight loss were significantly longer for patients treated with irinotecan hydrochloride than for patients in the best supportive care group (p, 0.01 and p, 0.05 respectively). The results are summarised in Table 12.
In the two phase III studies, quality of life was assessed using the European Organisation on Research and Treatment of Cancer (EORTC QLQ-C30) questionnaire. In Study 1, the global quality of life scores were significantly higher for patients treated with irinotecan hydrochloride than for those who received best supportive care (p = 0.0013). In Study 2, the global quality of life scores were similar for patients who received either irinotecan hydrochloride or infusional 5-FU.
Other studies. A Japanese open-label, uncontrolled, late phase II study in patients with non-small-cell lung cancer enrolled a total of 153 patients. In this study, pneumonitis occurred in 6.2% (9/146) of the patients. One patient died of interstitial pneumonitis. Irinotecan hydrochloride was given at a dose of 100 mg/m2 intravenously once weekly. Dosage adjustments were made according to toxicity and the duration of treatment was until disease progression or unacceptable toxicity occurred (with each patient to receive at least three doses).

5.2 Pharmacokinetic Properties

Absorption/distribution.

After intravenous infusion of irinotecan hydrochloride in humans with various cancers, irinotecan hydrochloride plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. In a study where irinotecan hydrochloride was administered at doses of 100-750 mg/m2 by 30-minute intravenous infusion every three weeks, the plasma terminal elimination half-life was 14.2 +/- 7.7 hours for irinotecan hydrochloride and 13.8 +/- 1.4 hours for SN-38.
Over the recommended dose range of 50 to 350 mg/m2, the area under the curve (AUC) of irinotecan hydrochloride increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90 minute infusion of irinotecan hydrochloride.
Pharmacokinetic parameters for irinotecan hydrochloride and SN-38 following a 90 minute infusion of irinotecan hydrochloride at dose levels of 125 and 340 mg/m2 determined in two clinical studies in patients with solid tumours are summarised in Table 13.
In vitro studies indicate that irinotecan hydrochloride exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan hydrochloride and SN-38 predominantly bind is albumin.

Metabolism.

The complete disposition of irinotecan hydrochloride has not been fully elucidated in humans. Irinotecan hydrochloride is subject to extensive metabolic conversion by various enzyme systems, including esterases to form the active metabolite SN-38, and uridine diphosphate-glucuronyl transferase 1A1 (UGT1A1) mediating glucuronidation of SN-38 to form the inactive metabolite SN-38 glucuronide (SN-38G). The metabolic conversion of irinotecan hydrochloride occurs primarily in the liver.
Irinotecan hydrochloride is oxidised by cytochrome P450 isozyme 3A4 (CYP3A4) to yield two relatively inactive metabolites, APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin) and the minor metabolite, NPC (7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin.

Excretion.

The urinary excretion of irinotecan hydrochloride was 11% to 20% of the administered dose; SN-38 < 1%; and SN-38 glucuronide 3%. The cumulative biliary and urinary excretion of irinotecan hydrochloride and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan hydrochloride in two patients ranged from approximately 25% (100 mg/m2) to 50% (300 mg/m2).

Pharmacokinetics in special populations.

Geriatric.

In studies where irinotecan hydrochloride was administered weekly, the terminal half-life of irinotecan hydrochloride was 6.0 hours in patients who were 65 years or older and 5.5 hours in patients younger than 65 years. Dose-normalised AUC0-24 for SN-38 in patients who were at least 65 years of age was 11% higher than in patients younger than 65 years. There are no kinetic data on the use of the once-every-three-weeks dosage schedule in elderly patients. A lower starting dose is recommended in patients 65 years and older based on clinical toxicity experienced with this dosage regimen (see Section 4.2 Dose and Method of Administration).

Hepatic insufficiency.

Irinotecan hydrochloride clearance is diminished in patients with hepatic dysfunction while relative exposure to the active metabolite SN-38 is increased. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in serum total bilirubin and transaminase concentrations (see Section 4.2 Dose and Method of Administration).

Renal insufficiency.

The influence of renal insufficiency on the pharmacokinetics of irinotecan hydrochloride has not been evaluated.

Pharmacokinetics in combination therapy.

In a phase I clinical study involving irinotecan hydrochloride, 5-FU and LV in 26 patients with solid tumours the disposition of irinotecan hydrochloride was not substantially altered when the drugs were co-administered. However, Cmax and AUC0-24 of SN-38, the active metabolite, were reduced (by 14% and 8%, respectively) when irinotecan hydrochloride was followed by 5-FU and LV administration compared with when irinotecan hydrochloride was given alone. Formal in vivo or in vitro drug interaction studies to evaluate the influence of irinotecan hydrochloride on the disposition of 5-FU and LV have not been conducted.

5.3 Preclinical Safety Data

Genotoxicity.

Irinotecan hydrochloride was clastogenic both in vitro (Chinese hamster ovary cells) and in vivo (micronucleus test in mice). Neither irinotecan hydrochloride nor SN-38 was mutagenic in the in vitro Ames assay.

Carcinogenicity.

Long-term carcinogenicity studies with irinotecan hydrochloride were not conducted. Rats were, however, administered intravenous doses of 2 mg/kg or 25 mg/kg irinotecan hydrochloride once per week for 13 weeks (AUC about 1.3 times the values of patients administered 125 mg/m2) and were then allowed to recover for 91 weeks. Under these conditions, there was a significant linear trend with dose for the incidence of combined uterine horn endometrial stromal polyps and endometrial stromal sarcomas.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sorbitol, lactic acid, sodium hydroxide, hydrochloric acid, water for injections.

6.2 Incompatibilities

Other drugs should not be added to the infusion solution.

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 freeze. Protect from light.

6.5 Nature and Contents of Container

Irinotecan Accord (irinotecan hydrochloride trihydrate) is available in the following strengths: 40 mg/2 mL, 100 mg/5 mL, 300 mg/15 mL and 500 mg/25 mL in type I amber glass vials in packs of 1.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

CAS-136572-09-3.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes