Consumer medicine information

Onivyde

Irinotecan

BRAND INFORMATION

Brand name

Onivyde

Active ingredient

Irinotecan

Schedule

SUMMARY CMI

ONIVYDE^®

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 ONIVYDE?

ONIVYDE is a nanoliposomal formulation of irinotecan which means that the active substance irinotecan is contained in tiny lipid (fatty) particles called nanoliposomes. ONIVYDE is used to treat Pancreatic Cancer.

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

2. What should I know before I use ONIVYDE?

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

3. What if I am taking other medicines?

Some medicines may interfere with ONIVYDE 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 ONIVYDE?

ONIVYDE must only be given by healthcare professionals trained in administering anticancer medicines.

Your doctor will decide upon the doses you will receive. This depends on your condition, body weight and other factors and other chemotherapy medicines you are being given. Several courses of ONIVYDE therapy may be needed depending on your response to treatment.

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

5. What should I know while using ONIVYDE?

Things you should do	Remind any doctor, dentist, pharmacist or nurse you visit that you are using ONIVYDE. Keep all appointments and discuss with your doctor or nurse any problems during or after treatment.
Things you should not do	Do not breastfeed if you are taking ONIVYDE Do not start taking any other medicines, prescription or not, without first telling your doctor
Driving or using machines	ONIVYDE has moderate influence on a person's ability to drive and use machines. During treatment you should observe caution when driving or using machines.
Looking after your medicine	Treatment will normally take place in a hospital because of the need for hospital facilities and skilled personnel. ONIVYDE is stored in a refrigerator (2-8°C) protected from light. It must not be frozen.

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

6. Are there any side effects?

Very common side effects include but are not limited to increased risk of severe infections, anaemia, and diarrhoea (loose or watery and frequent stools). Serious side effects include swelling under the skin (angioedema) and/or symptoms of possible anaphylactic/anaphylactoid reactions; fever, chills and signs of an infection; and persistent diarrhoea.

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

ONIVYDE^®

Active ingredient(s): Nanoliposomal irinotecan - irinotecan 4.3 mg/mL concentrate for solution for infusion

Consumer Medicine Information (CMI)

This leaflet provides important information about using ONIVYDE. 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 ONIVYDE.

Where to find information in this leaflet:

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

1. Why am I using ONIVYDE?

ONIVYDE is a nanoliposomal formulation of irinotecan which means that the active substance irinotecan is contained in tiny lipid (fatty) particles called nanoliposomes.

Irinotecan is an anticancer medicine that belongs to the group of 'topoisomerase inhibitors'. It blocks an enzyme called topoisomerase I, which is involved in the division of cell DNA. When the enzyme is blocked, the DNA strands break. This prevents the cancer cells from multiplying and growing, and they eventually die.

The nanoliposomes are expected to accumulate within the tumour and release the medicine slowly over time, thereby decreasing the rate at which the irinotecan is removed from the body and allowing it to act for longer duration.

ONIVYDE is used to treat Pancreatic Cancer.

This medicine belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

ONIVYDE works by killing cancer cells and stopping them from multiplying. It will be given in combination with other anticancer medicines.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

There is no evidence that it is addictive.

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

2. What should I know before I use ONIVYDE?

Warnings

Do not use ONIVYDE if:

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

Always check the ingredients to make sure you can use this medicine.

Tell your doctor before you are given ONIVYDE if you:

have any other medical conditions such as:
have or have had liver, kidney, lung or heart disease
have previously been treated with radiation therapy
have difficulty urinating
plan to have a vaccination as some vaccinations may not be given during chemotherapy

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.

Like most cytotoxic medicines ONIVYDE is not recommended for use during pregnancy. If there is any need to consider this medicine during your pregnancy, your doctor will discuss with you the benefits and risks of using it.

Prior to taking this medicine talk with your doctor about the possible risk with this medicine and the options that may preserve your ability to have children.

During treatment with ONIVYDE and for seven months after you cease treatment with ONIVYDE, you should choose a suitable effective birth control method to prevent pregnancy during this period. Males should use condoms during treatment with ONIVYDE and for 4 months thereafter.

Do not breastfeed if you are taking this medicine.

The active ingredient in ONIVYDE may pass into breast milk and there is a possibility that your baby may be affected.

The safety and effectiveness of ONIVYDE in children (under 18 years) has not been established.

If you are not sure whether you should be given this medicine, talk to your doctor.

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.

Tell your doctor, pharmacist or nurse if you are already having, or have recently had chemotherapy and/or radiotherapy or treatment with the antifungal medicine flucytosine.

Some medicines may interfere with ONIVYDE and affect how it works.

Medicines that may increase the effect of ONIVYDE include:

grapefruit juice
ketoconazole, itraconazole or voriconazole (medicines used to treat fungal infections)
clarithromycin (an antibiotic medicine used to treat bacterial infections)
indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, atazanavir (medicines against HIV infection)
telaprevir (a medicine used to treat a liver disease called hepatitis C)
nefazodone (a medicine used to treat depression, sad mood)
gemfibrozil (medicine used to treat high fat levels in the blood)

Medicines that may reduce the effect of ONIVYDE include:

phenytoin, phenobarbital or carbamazepin (medicines used to treat convulsions and falls)
rifampicin and rifabutin (medicines used to treat tuberculosis)
St. John's wort (a medicine used to treat depression and sad mood)

Other medicines to be careful of:

laxatives - as they may increase the chance of having diarrhoea with ONIVYDE
fluid pills for blood pressure - as they may increase the chance of dehydration due to vomiting or diarrhoea with ONIVYDE.

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

You may need to take different amounts of your medicines or you may need to use different medicines.

Your doctor, or pharmacist or nurse will have more information to be careful with or avoid while taking this medicine.

4. How do I use ONIVYDE?

How much to take / use

You should be treated with ONIVYDE by a doctor who is experienced in treating patients with cancer. Treatment will normally take place in a hospital because of the need for hospital facilities and skilled personnel.

It is likely that your doctor will give you one or more medicines before administering ONIVYDE, to help stop you vomiting or feeling sick after the treatment. You will probably also have blood tests before each treatment.

How much to take / use

Your doctor will decide upon the doses you will receive. This depends on your condition, body weight and other factors and other chemotherapy medicines you are being given.

When to take / use ONIVYDE

ONIVYDE must only be given by healthcare professionals trained in administering anticancer medicines.

ONIVYDE may be given in combination with other medicines.

Several courses of ONIVYDE therapy 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.

How ONIVYDE is administered

ONIVYDE is diluted with saline or dextrose and usually given as an infusion (drip) into a vein over 90 minutes and is followed by an infusion of other medicines.

You may receive premedication against nausea and vomiting. If you have experienced sweating, abdominal cramping and salivation together with early frequent and liquid stools in previous treatments with ONIVYDE, you may receive additional medicines before ONIVYDE to prevent or reduce this in the following treatment cycles.

Ask your doctor if you want more information about the dose of ONIVYDE and the other medicines you will be receiving and how they are given while you are being treated with ONIVYDE.

5. What should I know while using ONIVYDE?

Things you should do

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

Call your doctor straight away if you:

experience diarrhoea

Diarrhoea is a common side effect of ONIVYDE. 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 have more frequent bowel movements 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 Accident and Emergency at your nearest hospital for treatment.

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. 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 Accident and Emergency at your nearest hospital for treatment.

If you have severe stomach cramps you may need to be treated with antibiotics.

If you become pregnant while you are being treated with this medicine, tell your doctor immediately.

Talk to your doctor if you need more information about this.

Remind any doctor, dentist or pharmacist you visit that you are using ONIVYDE.

Things you should not do

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

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ONIVYDE affects you.

Looking after your medicine

ONIVYDE is stored in a refrigerator (2-8°C) protected from light.

It must not be frozen.

Keep it where young children cannot reach it.

When to discard your medicine (as relevant)

Do not use ONIVYDE after the expiry date which is printed on the label after the word 'EXP'.

The expiry date refers to the last day of that month.

6. Are there any side effects?

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are being given ONIVYDE.

ONIVYDE, like all other medicines, may cause unwanted side effects. Side effects are very common with anti-cancer medicines such as ONIVYDE and they may be serious. You may need medical treatment if you get some of the side effects.

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

Tell your doctor as soon as possible if you experience any side effects, including any effects not listed below.

Tell your doctor immediately if you get any of the following side effects:

Serious side effects

Serious side effects

What to do

swelling under the skin (angioedema) and/or symptoms of possible anaphylactic/anaphylactoid reactions such as sudden shortness of breath, flushing, headache, tightness in the chest or throat during the infusion or shortly after it. Severe allergic reactions may be life threatening. The infusion may need to be stopped and you may need to be treated or observed)
fever, chills and signs of an infection (as this might require immediate treatment)
severe persistent diarrhoea (liquid and frequent stools)

The above side effects may be serious. You may need urgent medical attention.

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor immediately if you get any of the following side effects:

Less serious side effects

Less serious side effects

What to do

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

Increased risk of infections including severe infections
Anaemia, which may make you weak and light-headed or may cause you to faint
Diarrhoea (loose or watery and frequent stools)
Nausea and vomiting
Sore mouth and lips
Loss of appetite and loss of weight
Loss of body fluid (dehydration)
Unusual hair loss
Tiredness
Dizziness
Fluid retention which results in swelling
Pain and swelling in the stomach or the gut area
Fever
Generalised weakness

Common side effects (may affect up to 1 in 10 people)

Fungal infection of the mouth
Infection related to the administration of the product into a vein
Inflammation of the stomach and the guts (gastroenteritis)
Whole body inflammation, caused by infection
Decrease in some salts (electrolytes) in the body
Low blood sugar
Sleeplessness
A change in the sense of taste
A syndrome called cholinergic syndrome with sweating, salivation and abdominal cramping
Low blood pressure
Blood clots
Voice impairment and shortness of breath
Swollen and/or inflamed veins in the low gut area
Increased or decreased liver enzymes in laboratory tests
Itching
Sudden problems with the kidney function
Abnormal fluid retention

Speak to your doctor if you have any of these less serious side effects and they worry you.

Tell your doctor, nurse 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 ONIVYDE contains

Active ingredient (main ingredient)	Irinotecan hydrochloride trihydrate. One vial contains 43 mg irinotecan (as sucrosofate salt).
Other ingredients (inactive ingredients)	distearoylphosphatidylcholine (DSPC) cholesterol sodium methoxy PEG-40-carbonyl-distearoyl-phosphatidylethanolamine (MPEG-2000-DSPE), 4 - (2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) sodium chloride sucrosofate; and water for injections.

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

What ONIVYDE looks like

ONIVYDE is a sterile white to slightly yellow opaque dispersion in a glass vial and needs to be diluted prior to using a needle no larger than 21 gauge.

ONIVYDE is registered on the Australian register of Therapeutic Goods (AUST R 263184).

Who distributes ONIVYDE

ONIVYDE is distributed in Australia by:

Servier Laboratories (Aust.) Pty Ltd
Level 4, Building 9,
588A Swan Street
Burnley Victoria 3121.

ONIVYDE is distributed in New Zealand by:

Servier Laboratories (NZ) Limited
Level 4, Zurich House
21 Queen Street
Auckland Central
Auckland 1010

ONIVYDE^® is a registered trademark of Ipsen Bioscience Inc. and is used under license.

This leaflet was prepared in January 2023.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Onivyde

Active ingredient

Irinotecan

Schedule

1 Name of Medicine

Nanoliposomal irinotecan as sucrosofate.

2 Qualitative and Quantitative Composition

Onivyde is formulated with irinotecan hydrochloride trihydrate, a topoisomerase inhibitor, into a liposomal dispersion for intravenous use. The liposome is a small unilamellar lipid bilayer vesicle, approximately 110 nanometer in diameter, which encapsulates an aqueous space containing irinotecan in a gelated or precipitated state, as the sucrosofate (sucrose octasulfate) salt.
Each 10 mL vial contains 43 mg irinotecan (4.3 mg/mL) equivalent to 50 mg irinotecan hydrochloride trihydrate (5.0 mg/mL).
The liposome carriers are composed of 68.1 mg distearoylphosphatidylcholine (6.81 mg/mL); 22.2 mg cholesterol (2.22 mg/mL) and 1.2 mg Sodium methoxy PEG-40-carbonyl-distearoylphosphatidylethanolamine (0.12 mg/mL). The solution is buffered at pH 7.25.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

The concentrated injection is supplied as a sterile, white to slightly yellow opaque isotonic liposomal dispersion for intravenous use.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of metastatic adenocarcinoma of the pancreas, in combination with 5-fluorouracil and folinic acid (leucovorin) in adult patients who have been previously treated with gemcitabine-based therapy.

4.2 Dose and Method of Administration

Onivyde must only be prescribed and administered to patients by healthcare professionals experienced in the use of anti-cancer therapies.
Onivyde is not equivalent to non-liposomal irinotecan formulations and should not be interchanged.
Dilute Onivyde prior to administration.
Onivyde treatment should continue until the development of disease progression or unacceptable toxicity.
For intravenous use only.

Preparation of the solution and administration.

Onivyde is supplied as a sterile liposomal dispersion at a concentration of 4.3 mg/mL and must be diluted prior to administration using a needle not larger than 21 gauge. Dilute with 5% w/v glucose solution for injection or 0.9% sodium chloride solution for injection to prepare a solution of the appropriate dose of Onivyde diluted to a final volume of 500 mL. Mix diluted solution by gentle inversion.
Do not use any in-line filters.
Onivyde should be administered before LV followed by 5-FU. Onivyde must not be administered as a bolus injection or an undiluted solution.
Aseptic techniques must be followed during the preparation of the infusion. Onivyde is for single use only.
From a microbiological point of view, the product should be used as soon as possible after dilution, but may be stored at ambient temperature for up to 6 hours. The diluted solution for infusion can be stored in the refrigerator (2°C to 8°C) for no more than 24 hours prior to use. Protect diluted solution from light. Do not freeze diluted solution.
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 normal saline and/or sterile water and applications of ice are recommended.

Dosage.

Onivyde, LV and 5-fluorouracil (5-FU) should be administered sequentially. The recommended dose and regimen of Onivyde is 70 mg/m² intravenously over 90 minutes, followed by LV 400 mg/m² intravenously over 30 minutes, followed by 5-FU 2400 mg/m² intravenously over 46 hours, administered every 2 weeks.
A reduced starting dose should be considered of Onivyde 50 mg/m² for patients known to be homozygous for the UGT1A1*28 allele as they may have an increased risk for developing neutropenia based on experience with non-liposomal irinotecan therapy. In the clinical study evaluating Onivyde in combination with 5-FU and LV, patients homozygous for the UGT1A1*28 allele received a starting dose of 50 mg/m² and did not experience a greater incidence of Grade 3 or 4 neutropenia than those not homozygous.

Dosage adjustments.

Subsequent doses of Onivyde and 5-FU should be adjusted as suggested in Table 1. All dose modifications should be based on the worst preceding toxicity. LV dose does not require adjustment. For Grade 1 and 2 toxicities there are no dose modifications recommended. Dose adjustments, as summarised in Table 1, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia, or other Grade 3 or 4 toxicities judged to be related to Onivyde.
For patients who start treatment with 50 mg/m² Onivyde and do not dose escalate to 70 mg/m², the recommended first dose reduction is to 43 mg/m² and the second dose reduction is to 35 mg/m². Patients who require further dose reduction should discontinue treatment.
Patients who are known to be homozygous for UGT1A1*28 and without medicine related toxicities during the first cycle of therapy (reduced dose of 50 mg/m²) may have the dose of Onivyde increased to a total dose of 70 mg/m² in subsequent cycles based on individual patient tolerance.

Premedication.

It is recommended that patients receive pre-medication with standard doses of dexamethasone (or an equivalent corticosteroid) together with a 5-HT3 antagonist (or other anti-emetic) at least 30 minutes prior to Onivyde infusion.

Patients with hepatic impairment.

No dedicated hepatic impairment study has been conducted with Onivyde. Patients with hyperbilirubinaemia had higher concentrations for total SN-38 (see Section 5.2 Pharmacokinetic Properties) and therefore the risk of neutropenia is increased. Frequent monitoring of complete blood counts should be conducted in this patient population. The use of Onivyde should be avoided in patients with bilirubin > 34 micromol/L or aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 times upper limit of normal (ULN) or > 5 times ULN if liver metastasis is present, see Section 4.4 Special Warnings and Precautions for Use.

4.3 Contraindications

Onivyde is contraindicated in patients with hypersensitivity to irinotecan or to any of the excipients.

4.4 Special Warnings and Precautions for Use

General.

Onivyde is a nanoliposomal formulation of irinotecan with altered pharmacokinetic properties compared to non-liposomal irinotecan. The dose concentration and strength is different to non-liposomal irinotecans. Do not substitute for or with other irinotecan formulations.

Myelosuppression/ neutropenia.

Complete blood cell count monitoring is recommended during Onivyde treatment. Patients should be aware of the risk of neutropenia and the significance of fever. The median time to nadir for ≥ Grade 3 neutropenia is 23 (range 8-104) days post first dose of treatment with Onivyde. Febrile neutropenia (body temperature > 38°C and neutrophil count ≤ 1,000 cells/mm³) should be urgently treated in the hospital with broad spectrum intravenous antibiotics. Onivyde should be withheld if neutropenic fever occurs or the absolute neutrophil count drops below 1500/mm³. Sepsis with neutropenic fever and consequent septic shock with fatal outcome has been observed in patients with metastatic pancreatic adenocarcinoma treated with Onivyde.
In patients who experienced severe haematological events, a dose reduction or treatment discontinuation is recommended; see Section 4.2 Dose and Method of Administration, Table 1.
History of prior abdominal radiation increases the risk of severe neutropenia and febrile neutropenia following Onivyde treatment. Close monitoring of blood counts is recommended, and the use of myeloid growth factors should be considered for patients with a history of abdominal radiation. Caution should be exercised in patients receiving concurrent administration of Onivyde with irradiation.
Compared to Caucasian patients, Asian patients have an increased risk of severe and febrile neutropenia following treatment with Onivyde+5-FU/LV, see Section 4.8 Adverse Effects (Undesirable Effects).
Death due to sepsis following neutropenia has been reported in patients treated with Onivyde. In the NAPOLI-1 study, neutropenic fever/ sepsis (defined as febrile neutropenia or neutropenic sepsis) occurred in 4 out of 117 patients (3.4%) receiving Onivyde plus 5-FU/LV. Routine administration of colony-stimulating factor (CSF) is not necessary, but physicians may consider CSF use in individual patients experiencing problems related to neutropenia.
The frequency of grade 3 or 4 neutropenia was higher in Asian patients (18 out of 33 [55%]) than in Caucasian patients (13 out of 73 [18%]) when treated with Onivyde+5FU/LV. Neutropenic fever/ sepsis was reported in 2 of 33 (6.1%) Asian patients versus 1 of 73 (1.4%) Caucasian patients.
Anaemia and thrombocytopenia have also been reported with Onivyde. Withhold treatment if platelet count is below 100 x 10⁹/L, see Section 4.2 Dose and Method of Administration.
Patients with baseline serum total bilirubin levels > 34 micromol/L were excluded from Onivyde clinical trials. Patients with deficient glucuronidation of bilirubin, such as those with Gilbert's syndrome, may be at greater risk of myelosuppression when receiving therapy with Onivyde. In patients who experience severe myelosuppression, a dose reduction or treatment discontinuation is recommended; see Section 4.2 Dose and Method of Administration, Table 1.

Immunosuppressant effects and vaccines.

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

Diarrhoea.

Diarrhoea can occur early (onset in ≤ 24 hours after starting Onivyde) or late (> 24 hours), see Section 4.8 Adverse Effects (Undesirable Effects). Diarrhoea is a very common adverse reaction leading to colitis, ileus, gastroenteritis, fatigue, dehydration, weight loss, renal toxicities, hyponatraemia, and hypokalaemia. Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhoea.
As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate antidiarrhoeal therapy must be initiated immediately.
Patients should have loperamide (or equivalent) readily available to begin treatment for late diarrhoea. Loperamide should be initiated at first occurrence of poorly formed or loose stools or at the earliest onset of bowel movements more frequent than normal. Loperamide should be given until patient is without diarrhoea for at least 12 hours. If diarrhoea persists while patient is on loperamide for more than 24 hours, consider adding oral antibiotic support (e.g. fluoroquinolone for 7 days) should be considered. Loperamide should not be used for more than 48 consecutive hours due to risk of paralytic ileus. If diarrhoea persists for more than 48 hours, stop loperamide, monitor and replace fluid electrolytes and continue antibiotic support until resolution of accompanying symptoms. Onivyde treatment should be delayed until diarrhoea resolves to ≤ Grade 1 (2-3 stools/day more than pre-treatment frequency). Onivyde must not be administered to patients with bowel obstruction, until it is resolved. Following Grade 3 or higher diarrhoea, the subsequent dose of Onivyde should be reduced, see Section 4.2 Dose and Method of Administration.
The frequency of diarrhoea was higher and more severe in Caucasian patients than in Asian patients (Grade 3 or higher diarrhoea 19% vs 3%, respectively) when treated with Onivyde+5FU/LV.
Patients should be made aware of the risk of delayed diarrhoea which can be debilitating and, on rare occasions, life threatening since persistent loose or watery stools can result in dehydration, electrolyte imbalance, colitis, gastrointestinal (GI) ulceration, infection or sepsis.

Cholinergic reactions.

Early onset diarrhoea may be accompanied by cholinergic symptoms such as rhinitis, increased salivation, flushing, diaphoresis, bradycardia, miosis and hyperperistalsis. Prophylactic or therapeutic treatment with atropine in patients experiencing early onset diarrhoea with cholinergic symptoms should be considered unless contraindicated.
Based on experience with non-liposomal irinotecan in patients with asthma, cardiovascular diseases or urinary obstruction, Onivyde should be used with caution in these patients.

Acute infusion and related reactions.

Infusion reactions primarily consisting of rash, urticaria, periorbital oedema or pruritus were reported in patients receiving Onivyde treatment. New events (all Grade 1 or Grade 2) occurred generally early during Onivyde treatment, with only 2 out of 10 patients noted with events after the fifth dose. Hypersensitivity reactions, including acute infusion reaction, anaphylactic reaction, anaphylactoid reaction and angioedema may occur. Onivyde should be discontinued in case of severe hypersensitivity reactions.

Prior Whipple procedure.

Patients with a history of a Whipple procedure have a higher risk of serious infections following Onivyde treatment in combination with 5 FU and leucovorin (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for signs of infections.

Risk of neutropenia in patients with homozygous UGT1A1 activity.

Individuals who are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) are at an increased risk for neutropenia from non-liposomal irinotecan. In the NAPOLI-1 study evaluating Onivyde + 5-FU/LV, the frequency of ≥ Grade 3 neutropenia in these patients who received a starting dose of 50 mg/m² [2 out of 7 patients (28.6%)] was similar to the frequency in patients not homozygous for the UGT1A1*28 allele who received a starting dose of Onivyde of 70 mg/m² [30 of 110 patients (27.3%)]. In patients who experience severe neutropenia, a dose reduction or treatment discontinuation is recommended, see Section 4.2 Dose and Method of Administration, Table 1.
Consider a reduced starting dose of Onivyde of 50 mg/m² for patients known to be homozygous for the UGT1A1*28 allele. Patients without medicine related toxicities during the first 2 weeks of therapy may have their dose of Onivyde increased to 70 mg/m² based on individual patient tolerance (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Performance status.

Clinical trials with Onivyde were conducted in patients with a performance status of KPS ≥ 70, see Section 5.1 Pharmacodynamic Properties, Clinical trials.

Irradiation therapy.

History of prior abdominal radiation increases the risk of severe neutropenia and febrile neutropenia following Onivyde treatment. Close monitoring of blood counts is recommended, and the use of myeloid growth factors should be considered for patients with a history of abdominal radiation. Caution should be exercised in patients receiving concurrent administration of Onivyde with irradiation.

Vascular disorders.

Onivyde has been associated with thromboembolic events such as pulmonary embolism, venous thrombosis and arterial thromboembolism. A thorough medical history should be obtained in order to identify patients with multiple risk factors in addition to the underlying neoplasm. Patients should be informed about the signs and symptoms of thromboembolism and advised to contact their physician or nurse immediately if any such signs or symptoms should occur.

Pulmonary toxicity.

Interstitial Lung Disease (ILD)-like events, including fatalities, have occurred in patients receiving non-liposomal irinotecan. No cases of ILD-like events have been reported with Onivyde therapy in clinical studies. Risk factors include pre-existing lung disease, use of pneumotoxic medicinal products, colony stimulating factors or having previously received radiation therapy. Patients with risk factors should be closely monitored for respiratory symptoms before and during Onivyde therapy. A reticulo-nodular pattern on chest X-ray was observed in a small percentage of patients enrolled in a clinical study with irinotecan. New or progressive dyspnoea, cough, and fever should prompt interruption of Onivyde treatment, pending diagnostic evaluation. Onivyde should be discontinued in patients with a confirmed diagnosis of ILD.

Use in hepatic impairment.

No dedicated hepatic impairment study has been conducted with Onivyde. Patients with hyperbilirubinaemia had higher concentrations for total SN 38 and therefore the risk of neutropenia is increased, see Section 5.2 Pharmacokinetic Properties. Frequent monitoring of complete blood counts should be conducted in this patient population. The use of Onivyde should be avoided in patients with bilirubin > 34 micromol/L, or aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 times upper limit of normal (ULN) or > 5 times ULN if liver metastasis is present.

Use in renal impairment.

No dedicated pharmacokinetic study has been conducted in patients with renal impairment. In a population pharmacokinetic analysis, mild-to-moderate renal impairment had no effect on the exposure of total SN-38 after adjusting for BSA. The analysis included 68 patients with moderate (CLcr 30-59 mL/min), 147 patients with mild (CLcr 60-89 mL/min) renal impairment, and 135 patients with normal renal function (CLcr > 90 mL/min). There was insufficient data in patients with severe renal impairment (CLcr < 30 mL/min) to assess its effect on pharmacokinetics.

Patients on controlled sodium diet.

Each mL of Onivyde contains 0.144 mmol sodium, which is 3.31 mg sodium. This fact should be taken into consideration by patients on a controlled sodium diet.

Paediatric use.

There is no relevant use of Onivyde in the paediatric population in the treatment of pancreatic cancer. The safety and efficacy of Onivyde in patients under the age of 18 years has not been established.

Use in the elderly.

Forty one percent (41%) of patients treated with Onivyde across the clinical program were ≥ 65 years. Overall, no major clinical differences in safety or efficacy were reported between patients ≥ 65 years and patients < 65 years, although a higher frequency of discontinuation (14.8% vs 7.9%) was noted in the former group treated with Onivyde+5-FU/LV in the NAPOLI-1 study and in some cases the adverse reactions did not resolve. Grade 3 or higher and serious treatment emergent adverse reactions were more frequent in patients < 65 years (84.1% and 50.8%) compared to patients ≥ 65 years (68.5% and 44.4%). Conversely, patients > 75 years (n = 12) experienced more frequent serious adverse reactions, dose delay, dose reduction and discontinuation compared to patients ≤ 75 years (n = 105) when treated with Onivyde+5-FU/LV in the pancreatic adenocarcinoma study.

Effects on laboratory tests.

No data are available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In vitro studies indicate that irinotecan, SN-38 and another metabolite aminopentane carboxylic acid (APC), do not inhibit cytochrome P-450 isozymes.

5-fluorouracil (5-FU) and leucovorin (LV).

Based on the population PK analysis, the pharmacokinetics of Onivyde are not altered by the co-administration of 5-FU/LV.

Strong CYP3A4 inducers.

Exposure to irinotecan and its active metabolite SN-38 is substantially reduced in patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or carbamazepine. The appropriate starting dose for patients taking these anticonvulsants or other strong inducers such as rifampicin and rifabutin and St. John's wort has not been defined. Consideration should be given to substituting non-enzyme inducing therapies at least 2 weeks prior to initiation of Onivyde therapy. Strong CYP3A4 inducers should not be administered with Onivyde unless there are no therapeutic alternatives.

Strong CYP3A4 or UGT1A1 inhibitors.

Patients receiving concomitant ketoconazole, a CYP3A4 and UGT1A1 inhibitor, have increased exposure to irinotecan and its active metabolite SN-38. Coadministration of Onivyde with other inhibitors of CYP3A4 (e.g. grapefruit juice, clarithromycin, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telaprevir, voriconazole) or UGT1A1 (e.g. atazanavir, gemfibrozil, indinavir may increase systemic exposure to irinotecan or SN-38). Strong CYP3A4 inhibitors should be discontinued at least 1 week prior to starting Onivyde therapy. Strong CYP3A4 or UGT1A1 inhibitors should not be administered with Onivyde unless there are no therapeutic alternatives.

Other interactions.

Neuromuscular blocking agents.

Interaction between Onivyde and neuromuscular blocking agents was not studied. Since irinotecan has anticholinesterase activity, the neuromuscular blocking effects of suxamethonium may be prolonged and the neuromuscular blockade of non-depolarising medicines may be antagonised.

Prochlorperazine.

Prochlorperazine is a CYP3A4 inhibitor that is used as an antiemetic, particularly for nausea and vomiting caused by chemotherapy. Therefore, co-administration of Onivyde with other inhibitors of CYP3A4 may increase systemic exposure of Onivyde.

Laxatives.

Interaction between Onivyde and laxatives was not studied; however, it would be expected that the incidence and/or severity of diarrhoea would be worsened by laxative use during therapy with Onivyde.

Diuretics.

In view of the potential risk of dehydration secondary to vomiting and/or diarrhoea induced by Onivyde, consideration should be given to withholding diuretics during dosing with Onivyde, particularly during periods of active vomiting or diarrhoea.

Antineoplastic agents (including flucytosine as a prodrug for 5-fluorouracil).

Adverse effects of irinotecan, such as myelosuppression, may be exacerbated by other antineoplastic agents having a similar adverse-effect profile.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no clinical data on fertility. Effects of liposome encapsulated irinotecan on fertility have not been assessed in animal studies. Prior to starting the administration of Onivyde pegylated liposomal consider advising patients on the preservation of gametes.
Atrophy of male and female reproductive organs was observed in rats and/or dogs receiving irinotecan liposome injection every 3 weeks at doses equal to or greater than 75 and 21 mg/kg, respectively (approximately 52 and 6 times the clinical exposure to irinotecan and 195 and 0.3 times to the active metabolite SN-38, at the clinical Onivyde dose of 70 mg/m², based on AUC).
No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of un-encapsulated 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 and dogs at 0.4 mg/kg.
(Category D)
There are no adequate data on the use of Onivyde in pregnant women. Onivyde can cause harm to the foetus when administered to the pregnant woman as the active ingredient irinotecan has been shown to be embryotoxic and teratogenic in animals.
Based on results from animal studies and the mechanism of action of irinotecan, Onivyde should not be used during pregnancy unless clearly necessary. If Onivyde is used during pregnancy or if the patient becomes pregnant while receiving therapy, the patient should be informed about the potential hazard to the foetus.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving Onivyde therapy. Women should use effective contraception during Onivyde treatment and 7 months thereafter. Males should be advised not to father children while receiving Onivyde. Males should use condoms during Onivyde treatment and 4 months thereafter.
Intravenous administration of 6 mg/kg/day irinotecan hydrochloride to rats and rabbits 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 and in rabbits at 6.0 mg/kg/day. Teratogenic effects included a variety of external, visceral, and skeletal abnormalities.
It is unknown whether Onivyde/or its metabolites are excreted into human milk. Because of the potential for serious adverse reactions in nursing infants from Onivyde, breast-feeding should be discontinued when receiving therapy with Onivyde.
In lactating rats, radioactivity appeared in milk within 5 minutes of intravenous administration of radiolabelled irinotecan hydrochloride and was concentrated up to 65-fold at 4 hours relative to plasma concentrations. Irinotecan hydrochloride administered to rat dams for the period following organogenesis through weaning at doses of 6.0 mg/kg/day caused decreased learning ability and decreased female body weights in the offspring.

4.7 Effects on Ability to Drive and Use Machines

Onivyde has moderate influence on a person's ability to drive and use machines. During treatment patients should observe caution when driving or using machines.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

Summary of the safety profile.

In a clinical trial, 147 patients with metastatic adenocarcinoma of the pancreas received Onivyde as monotherapy (100 mg/m²) and 117 received Onivyde (70 mg/m²) in combination with 5-FU/LV.
The most common adverse reactions (incidence ≥ 20%) seen with Onivyde in combination with 5-FU and LV were: diarrhoea, nausea, vomiting, decreased appetite, neutropenia, fatigue, anaemia, stomatitis and pyrexia. The most common serious adverse reactions (≥ 2%) of Onivyde therapy were diarrhoea, vomiting, febrile neutropenia, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia. The rates of adverse events leading to permanent discontinuation were 11% for the Onivyde+5-FU/LV arm and 12% for the monotherapy arm. The most frequently reported adverse reactions leading to discontinuation were infection and diarrhoea for Onivyde+5 FU/LV arm, and vomiting and diarrhoea for the monotherapy arm. Table 2 reports adverse events reported in the clinical trial at a frequency of 10% or more.

The adverse reactions described in this section are derived from study data and postmarketing experience of Onivyde. The adverse reactions that may occur during treatment with Onivyde are summarised and are presented by system organ class and frequency category (Table 3). Within each system organ class and frequency category, adverse reactions are presented in order of decreasing seriousness. Frequencies categories used for adverse reactions are: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000)* and not known (cannot be estimated from the available data.

Post-marketing surveillance.

The most frequently reported events in order of decreasing frequency are diarrhoea, infusion reactions, vomiting, nausea, abdominal pain, fatigue, and neutropenia.

Description of selected adverse reactions.

Myelosuppression.

Myelosuppression (leukopenia, neutropenia, anaemia and thrombocytopenia) was more common in the Onivyde+5-FU/LV arm compared to the 5-FU/LV control arm.

Neutropenia/ leukopenia.

Neutropenia/ leukopenia was the most notable important haematological toxicity. Grade 3 or higher neutropenia occurred more frequently in patients treated with Onivyde+5-FU/LV (27.4%) compared to patients treated with 5 FU/LV (1.5%). Neutropenic fever/ sepsis was infrequent, but appeared more frequently in the Onivyde+5-FU/LV combination arm: in 4 patients (3.4%) and in 1 patient (0.7%) in the 5 FU/LV control arm.

Anaemia.

Grade 3 or higher anaemia occurred in 10.3% of patients treated with Onivyde+5-FU/LV and in 6.7% of patients treated with 5 FU/LV.

Thrombocytopenia.

Grade 3 or higher thrombocytopenia occurred in 2.6% of patients treated with Onivyde+5-FU/LV and none (0%) in patients treated with 5-FU/LV.

Diarrhoea and related adverse reactions.

Diarrhoea is a very common ADR leading to colitis, ileus, gastroenteritis, fatigue, dehydration, weight loss, renal toxicities, hyponatraemia, hypokalaemia. Renal impairment and acute renal failure have been identified, usually in patients who became volume depleted from severe vomiting and/or diarrhoea. In the clinical study, Grade 3 or higher diarrhoea occurred in 15 out of 117 patients (12.8%) receiving Onivyde+5-FU/LV. For patients experiencing late diarrhoea, the median time to late diarrhoea onset was 8 days from the previous dose of Onivyde.
Early onset diarrhoea, typically appearing ≤ 24 hours after dose administration, can occur and is usually transient. Early onset diarrhoea may also be accompanied by cholinergic symptoms that can include rhinitis, increased salivation, flushing, diaphoresis, bradycardia, miosis and hyperperistalsis that can induce abdominal cramping. In the clinical study, early diarrhoea onset occurred in 35 patients (29.9%) and cholinergic events occurred in 4 patients (3.4%) receiving Onivyde+5-FU/LV.

Infusion reaction.

Acute infusion reaction was reported in 8 of 117 patients (6.8%) in the Onivyde+5-FU/LV arm, 3 of 147 patients (2.0%) in the Onivyde monotherapy arm, and 8 of 134 patients (6.0%) in the 5-FU/LV arm.

Other special populations.

Asian population.

Compared to Caucasians, Asian patients were observed with a lower incidence of diarrhoea [14 (19.2%) out of 73 Caucasians had a ≥ Grade 3 diarrhoea, and 1 out of 33 (3.3%) Asians had a ≥ Grade 3 diarrhoea], but a higher incidence and higher severity of neutropenia. In patients receiving Onivyde+5 FU/LV, the incidence of ≥ Grade 3 neutropenia was higher among Asian patients [18 of 33 (55%)] compared to White patients [13 of 73 (18%)]. Neutropenic fever/ neutropenic sepsis was reported in 6% of Asian patients compared to 1% of White patients. This is consistent with the population pharmacokinetic analysis that showed a lower exposure to irinotecan and a higher exposure to its active metabolite SN 38 in Asians than in Caucasians.

Patients with homozygous UGT1A1 activity.

Individuals who are 7/7 homozygous for the UGT1A1*28 allele are at increased risk for neutropenia from non-liposomal irinotecan. In the clinical study evaluating Onivyde+5 FU/LV, of the frequency of ≥ Grade 3 or 4 neutropenia in these patients (2 of 7 (28.6%)) was similar to the frequency in patients not homozygous for the UGT1A1*28 allele who received a starting dose of 70 mg/m² [30 of 110 (27.3%)].

Underweight patients (body mass index < 18.5 kg/m²).

In the clinical study evaluating Onivyde+5-FU/LV, 5 of 8 underweight patients experienced grade 3 or higher adverse reaction, mostly myelosuppression, while 7 of the 8 patients required dose modification such as dose delay, dose reduction or dose discontinuation.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre telephone: 13 11 26 (Australia).
In clinical trials, Onivyde was administered at doses up to 210 mg/m² to patients with various cancers. The adverse reactions in these patients were similar to those reported with the recommended dosage and regimen.
There have been reports of overdosage with non-liposomal irinotecan at doses up to approximately twice the recommended therapeutic dose of irinotecan, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhoea.
There is no known antidote for overdose of Onivyde. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The active ingredient in Onivyde is irinotecan which is encapsulated in long-circulating liposomes. The medicine product liposome is a small unilamellar lipid bilayer vesicle, approximately 110 nanometer in diameter, which encapsulates an aqueous space which contains irinotecan in a gelated or precipitated state, as sucrosofate salt. Onivyde has been shown to extend circulation of irinotecan and prolong the duration of active therapy at the site of tumour cells to inhibit tumour growth.
Irinotecan 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 and its active metabolite SN-38 bind reversibly to the topoisomerase I-DNA complex and prevent re-ligation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan 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 or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks.
Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumour cell lines.

Clinical trials.

The efficacy of Onivyde was evaluated in the NAPOLI-1 study, a three-arm, randomised, open label trial in 417 patients with metastatic pancreatic adenocarcinoma who had documented disease progression after gemcitabine-based therapy. Key eligibility criteria were Karnofsky Performance Status (KPS) ≥ 70, normal bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the ULN for patients with liver metastasis and albumin ≥ 30 g/L. Patients were randomised to receive Onivyde plus 5-fluorouracil (5-FU) / LV (N = 117), Onivyde monotherapy (N = 151), or 5-fluorouracil / LV (N = 149). Patients randomized to Onivyde plus 5-FU/LV received Onivyde 70 mg/m² as an intravenous infusion over 90 minutes, followed by LV 400 mg/m² intravenously over 30 minutes, followed by 5-FU 2400 mg/m² intravenously over 46 hours, every 2 weeks. The Onivyde dose of 70 mg/m² is based on irinotecan free base (equivalent to 80 mg/m² of irinotecan as the hydrochloride trihydrate). Patients randomised to Onivyde monotherapy received 100 mg/m² as an intravenous infusion over 90 minutes every 3 weeks. Patients randomized to 5-FU/LV received LV 200 mg/m² intravenously over 30 minutes, followed by 5-FU 2000 mg/m² intravenously over 24 hours, administered on days 1, 8, 15 and 22 of a 6 week cycle. Patients homozygous for the UGT1A1*28 allele initiated Onivyde treatment at a reduced dose (50 mg/m² Onivyde plus 5-FU/LV or 70 mg/m² Onivyde monotherapy), see Section 4.2 Dose and Method of Administration. Treatment continued until disease progression or unacceptable toxicity.
Patients enrolled in the NAPOLI-1 study had a median age of 63 years (range 31-87 years) with 46% ≥ 65 years of age; 57% were men; 61% were White and 33% were Asian. Mean baseline albumin level was 39.6 g/L, and baseline KPS was 90-100 in 55% of patients. Disease characteristics included 68% of patients with liver metastasis and 31% with lung metastasis; 12% of patients had no prior lines of metastatic therapy, 56% of patients had 1 prior line of metastatic therapy, 32% of patients had 2 or more prior lines of metastatic therapy. For the treated population, the median relative dose intensity for Onivyde was 88% in the Onivyde+5FU/LV arm.
The major efficacy measure was overall survival (OS). Additional outcome measures included progression-free survival (PFS) and objective response rate (ORR). Assessments were conducted at baseline and every 6 weeks thereafter. Comparison of the Onivyde+5FU/LV arm to the 5-FUl/LV arm demonstrated improvement in overall survival and the other efficacy outcomes summarised in Table 4 and Figure 1. Comparison of the Onivyde monotherapy arm to the 5-FU/LV control arm did not demonstrate evidence of an improvement in overall survival compared to the 5-FU/LV control arm (hazard ratio = 0.99, log rank two-sided p-value = 0.9416).

A treatment effect on overall survival was consistently observed with Onivyde+5FU/LV in prospective analyses of stratification factor subgroups with a sufficient number of subjects.

5.2 Pharmacokinetic Properties

Absorption.

Liposome encapsulation can substantially affect a medicine's functional properties relative to those of the non-liposomal irinotecan.
The plasma pharmacokinetics of Onivyde was evaluated from pooled data of 95 patients with solid tumours. Patients received Onivyde as monotherapy or as part of combination therapy at doses between 50 to 155 mg/m². The pharmacokinetic parameters of total (both liposomal and non-liposomal) irinotecan and SN-38, following the administration of Onivyde at 70 mg/m² are presented in Table 5.

Over the dose range of 50 to 155 mg/m², the maximum total concentration of both irinotecan and SN-38 increased linearly with dose. The AUC of total irinotecan increased linearly with dose; the AUC of SN-38 increased less than proportionally with dose. The half-lives of both total irinotecan and SN-38 do not change with dose.
In a pooled analysis from 353 patients, higher plasma SN-38 C_max was associated with increased likelihood of experiencing neutropenia, and higher plasma total irinotecan C_max was associated with increased likelihood of experiencing diarrhoea.
In the clinical trial demonstrating effectiveness of Onivyde, higher plasma exposures of total irinotecan and SN-38 for patients in the Onivyde+5-FU/folinic acid (leucovorin [LV]) treatment arm were associated with longer overall survival (OS) and progression-free survival (PFS) (and lower hazard ratios) and higher overall response rate (ORR).

Distribution.

Direct measurement of liposomal irinotecan shows that 95% of irinotecan remains liposome-encapsulated during circulation. Non-liposomal irinotecan displays a large volume of distribution (range: 110-234 L/m²). The volume of distribution of Onivyde 70 mg/m² was 2.2 L/m², which suggests that Onivyde is largely confined to vascular fluid.
The plasma protein binding of Onivyde is negligible (< 0.44% of total irinotecan in Onivyde). The plasma protein binding of non-liposomal irinotecan is moderate (30% to 68%) and SN-38 is highly bound to human plasma proteins (approximately 95%).

Metabolism.

Irinotecan released from liposome encapsulation follows a similar metabolic pathway as reported with non-liposomal irinotecan.
The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Based on the results of the population PK analysis, patients homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype) had similar SN-38 exposure.

Excretion.

The disposition of Onivyde and non-liposomal irinotecan has not been fully elucidated in humans. The urinary excretion of non-liposomal irinotecan is 11% to 20%; SN-38, < 1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m²) to 50% (300 mg/m²).
A mass balance study in Sprague-Dawley rats, using liposomal encapsulated ¹⁴C-irinotecan, showed that once irinotecan was released from the liposomes, it followed the same elimination pathway as non-liposomal irinotecan. Faecal excretion was the major route of excretion in rats, accounting for approximately 80% of the total radioactivity dose of liposomal encapsulated ¹⁴C-irinotecan over 168 hours.

5.3 Preclinical Safety Data

Genotoxicity.

No studies to assess the genotoxic potential have been performed with Onivyde. Irinotecan and SN-38 were genotoxic in vitro in the chromosomal aberration test in Chinese hamster ovary cells, and irinotecan in the in vivo micronucleus test in mice. Irinotecan or SN-38 was not mutagenic in the Ames assay.

Carcinogenicity.

Carcinogenicity studies with Onivyde were not conducted. For irinotecan, in rats treated once a week for 13 weeks at 12 or 150 mg/m² followed by a 91-week recovery period, 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

The concentrated injection contains HEPES (buffer), sodium chloride (isotonicity reagent), distearoylphosphatidylcholine, cholesterol, sodium methoxy PEG-40-carbonyl-distearoylphosphatidylethanolamine, sucrosofate (drug entrapment agent) and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 in a refrigerator (2°C to 8°C).
Do not freeze.
Protect from light.
Contains no antimicrobial preservative.

6.5 Nature and Contents of Container

Container type.

Onivyde concentrated solution for injection is packed in a 10 mL vial (type I glass) with a 20 mm, grey chlorobutyl stopper and a 20 mm aluminium seal with a flip-off cap, containing irinotecan sucrosofate equivalent to 43 mg irinotecan or 50 mg irinotecan hydrochloride trihydrate, encapsulated in liposomes, as a dispersion.
Onivyde is for single use in one patient only.

Pack size.

1 vial.

6.6 Special Precautions for Disposal

Onivyde is a cytotoxic medicine and caution should be exercised in handling it. The use of gloves, goggles and protective clothing when handling or administering Onivyde is recommended. If the solution contacts the skin, the skin should be washed immediately and thoroughly with soap and water. If the solution contacts mucous membranes, they should be flushed thoroughly with water. Pregnant staff should not handle Onivyde considering the cytotoxic nature of the agent.

6.7 Physicochemical Properties

The active component of Onivyde is irinotecan hydrochloride which has the chemical name (4S)-4, 11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1H-pyrano[3', 4':6, 7]indolizino[1, 2-b]quinoline-3, 14(4H, 12H) dione hydrochloride trihydrate. Irinotecan hydrochloride has the molecular formula: C₃₃H₃₈N₄O₆.HCl.3H₂O (MW= 677.19).
Irinotecan hydrochloride is a semisynthetic derivative of camptothecin, an alkaloid extracted from plants such as Camptotheca acuminata. It is a pale yellow to yellow crystalline powder and is slightly soluble in water and organic solvents.

Chemical structure.

CAS number.

136572-09-3.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine (S4).

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