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.

For patients whose pancreatic cancer has not been previously treated, ONIVYDE is used in combination with other cancer medicines, called oxaliplatin, 5-fluorouracil and leucovorin.
For patients previously treated by gemcitabine, ONIVYDE is used in combination with other cancer medicines, called 5-fluorouracil and leucovorin.

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
have chronic inflammatory bowel disease
have a bowel obstruction (a blockage that keeps food, liquid, gas, and stool from moving through the intestines in a normal way).

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 carbamazepine (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.

Before you start treatment with ONIVYDE pegylated liposomal, if you have been previously treated with a medicine called gemcitabine, your doctor will perform blood tests (or other medical examinations) to determine the best starting dose for you.

You will need to have (blood or other) tests during treatment so that your doctor can monitor your blood cells and assess how you are responding to the treatment. Your doctor may need to adjust the dose or your treatment.

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.

If your cancer has not been previously treated, after you have been given ONIVYDE you will be given three other medicines called: oxaliplatin, leucovorin and 5-fluorouracil.

If your cancer has been previously treated with a medicine called gemcitabine, after you have been given ONIVYDE you will be given two other medicines called: leucovorin and 5-fluorouracil.

The treatment will be repeated every two weeks.

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

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

Immune system

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

infections

fever, chills and signs of an infection (as this might require immediate treatment)

Gastro-intestinal

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

Infections

Increased risk of infections including severe infections
Fungal infection of the mouth
Infection related to the administration of the product into a vein
Whole body inflammation, caused by infection
Infection of the parts of the body that collect and pass out urine
Fever

Blood

Anaemia, which may make you weak and light-headed or may cause you to faint
Reduction in white blood cell numbers
Low platelets in your blood

Metabolism related

Loss of body fluid (dehydration)
Low blood sugar
Decrease in some salts (electrolytes) in the body

Gastro-intestinal

Diarrhoea (loose or watery and frequent stools)
Nausea and vomiting
Dry mouth
Difficulty in swallowing
Disease where stomach acid rises up into the oesophagus (gastroesophageal reflux disease)
Inflammation of the stomach and the gut (gastroenteritis)
Pain and inflammation of the bowel causing diarrhoea (enterocolitis), gas, swelling in belly
Indigestion
Constipation
Loss of appetite

Nervous system / psychiatric

Headache
Pain, numbness, burning and tingling in the arms and/or legs (peripheral neuropathy)
Numbness, tingling, pins and needles of the hands and/or feet (paraesthesia)
A syndrome called cholinergic syndrome with sweating, salivation and abdominal cramping
Sleeplessness
Toxicity altering the nervous system
Unpleasant and abnormal feeling when touched
Shaking
A change in the sense of taste

Eye

Blurry vision

Ear

Dizziness

Heart

Rapid heartbeat

Vascular

Low blood pressure
Blood clots
Swollen and/or inflamed veins in the low gut area

Respiratory

Hiccups
Inflammation of the nose and throat
Nosebleed
Voice impairment and shortness of breath

Skin

Hand foot syndrome - redness, swelling, and/or pain on the palms of the hands and/or the soles of the feet
Dry skin
Skin eruption
Darkened areas of skin (hyperpigmentation)
Itching
Sore mouth and lips
Unusual hair loss

Musculoskeletal

Muscular weakness, muscle pain, abnormal muscle contractions

Kidney related

Sudden problems with the kidney function

Test results

Increased or decreased liver enzymes in laboratory tests
Abnormal changes in blood protein levels in laboratory tests

General

Tiredness and generalised weakness
Weight loss
Abnormal fluid retention which results in swelling

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

This leaflet was prepared in March 2024.

Published by MIMS May 2024

BRAND INFORMATION

Brand name

Onivyde

Active ingredient

Irinotecan

Schedule

1 Name of Medicine

Nanoliposomal irinotecan as sucrosofate.

2 Qualitative and Quantitative Composition

Onivyde is a topoisomerase 1 inhibitor (irinotecan) encapsulated in lipid bilayer vesicles or liposomes, presented in solution as 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

Onivyde is indicated: in combination with oxaliplatin and 5-fluorouracil (5-FU) and leucovorin (LV) for the first-line treatment of metastatic pancreatic adenocarcinoma;
in combination with 5-FU and LV for the treatment of metastatic pancreatic adenocarcinoma after disease progression following 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.
For intravenous use only.

Dosage.

First-line treatment of metastatic pancreatic adenocarcinoma.

Onivyde, oxaliplatin, LV and 5-FU (also known collectively as NALIRIFOX) should be administered sequentially. The recommended dose and regimen of Onivyde (regardless of UGT1A1 genomic status) is 50 mg/m² intravenously over 90 minutes, followed by oxaliplatin 60 mg/m² intravenously over 120 minutes, followed by LV 400 mg/m² intravenously over 30 minutes, followed by 5-FU 2,400 mg/m² intravenously over 46 hours, administered every 2 weeks until development of disease progression or unacceptable toxicity.

Treatment of metastatic pancreatic adenocarcinoma after prior gemcitabine-based therapy.

Onivyde, LV and 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 2,400 mg/m² intravenously over 46 hours, administered every 2 weeks until development of disease progression or unacceptable toxicity. For patients known to be homozygous for the UGT1A1*28 allele, consider a reduced Onivyde starting dose of 50 mg/m², with an increase to 70 mg/m² as tolerated in subsequent cycles (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 5.2 Pharmacokinetic Properties).

Premedication.

Administer a corticosteroid and an antiemetic 30 minutes prior to each Onivyde infusion.

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 using aseptic technique prior to administration.
Withdraw the appropriate volume of concentrate containing the required dose of Onivyde from the vial, and dilute to a final volume of 500 mL using either 5% w/v glucose solution for injection or 0.9% sodium chloride solution for injection. Mix diluted solution by gentle inversion.
Onivyde is for single use only - discard vials with any unused portion.
Use the diluted Onivyde solution as possible after dilution to minimise microbiological risk. Administer within 6 hours of dilution if stored at ambient temperature, or within 24 hours if stored in a refrigerator (2°C to 8°C). Allow diluted solution to come to room temperature prior to administration. Protect the diluted solution from light, and do not freeze it.
Infuse the diluted Onivyde solution intravenously over at least 90 minutes, through a 21 gauge (or smaller) needle. Do not use any in-line filters.
Take care to avoid extravasation and monitor the infusion site for signs of inflammation. Should extravasation occur, flush the site with normal saline and/or sterile water and apply ice.

Dose modifications.

First-line treatment of metastatic pancreatic adenocarcinoma.

Recommended dose modifications for Onivyde in combination with oxaliplatin and 5-FU and LV (NALIRIFOX regimen) in case of toxicity are summarised in Table 1.

Treatment of metastatic pancreatic adenocarcinoma after prior gemcitabine-based therapy.

Recommended dose modifications for Onivyde in combination with 5-FU and LV in case of toxicity are summarised in Table 2.

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

Interchangeability of formulation.

Onivyde is a liposome-encapsulated formulation of irinotecan (sucrosofate) with different pharmacokinetics and dosing to non-liposomal irinotecan (hydrochloride). They should not be interchanged.

Myelosuppression/neutropenia.

Myelosuppression with severe neutropenia is very common with Onivyde treatment, and life-threatening neutropenic sepsis (with or without a febrile response, i.e. febrile neutropenia) can occur.
In NAPOLI 3, Grade 3 and 4 neutropenia occurred in 26% of patients receiving Onivyde in combination with oxaliplatin, fluorouracil, and leucovorin (NALIRIFOX) and fatal neutropenic sepsis occurred in 0.3% of patients. In NAPOLI-1, Grade 3 and 4 neutropenia occurred in 20% of patients receiving Onivyde in combination with fluorouracil and leucovorin (Onivyde/FU/LV). Neutropenic sepsis occurred in 3% and fatal neutropenic sepsis in 0.8% (see Section 4.8 Adverse Effects (Undesirable Effects)).
Inform patients of the significance of fever. Assess full blood cell counts on Days 1 and 8 of every cycle and more frequently if clinically indicated. For patients at higher risk of severe myelosuppression (such as those with a history of abdominal radiation), monitor closely, and consider myeloid growth factors. Use concurrent Onivyde and irradiation with caution. Patients with severe bone marrow failure should not receive Onivyde.
Withhold Onivyde for absolute neutrophil count below 1.5 x 10⁹/L, any occurrence of febrile neutropenia, or platelet count below 100 x 10⁹/L. Febrile neutropenia (body temperature > 38°C and neutrophil count < 1.0 x 10⁹/L) should be urgently treated in the hospital with broad spectrum intravenous antibiotics. After recovery, depending on severity and number of recurrences of haematological events, resume at a reduced dose or discontinue (see Section 4.2 Dose and Method of Administration, Dose modifications).

Severe diarrhoea.

Severe diarrhoea is very common with Onivyde treatment, and can have life-threatening sequelae such as dehydration, electrolyte imbalances, renal toxicity, inflammation and infection. Renal impairment and fatal acute renal failure have occurred (see Section 4.8 Adverse Effects (Undesirable Effects)). Onivyde must not be administered to patients with bowel obstruction or chronic inflammatory bowel disease.
Diarrhoea can occur early (onset within 24 hours of starting Onivyde) or late. Early diarrhoea is usually transient and may be accompanied by other cholinergic symptoms (see below). An individual patient may experience both early and late diarrhoea.
In NAPOLI 3, Grade 3 and 4 diarrhoea (early or late-onset) occurred in 20% of patients receiving Onivyde (as part of the NALIRIFOX regimen). In NAPOLI-1, Grade 3 or 4 diarrhoea occurred in 13% of patients receiving Onivyde (in combination with 5-FU/LV): 9% experienced late-onset and 3% experienced early-onset diarrhoea. Of patients receiving Onivyde+5-FU/LV in NAPOLI-1, 34% received loperamide for late-onset diarrhoea and 26% received atropine for early-onset diarrhea.
Inform patients of the potential for life-threatening sequelae, and the importance of immediate treatment at first sign of loose or frequent stools. To help avoid severe diarrhoea, patients should stop lactose-containing products, eat a low-fat diet and maintain hydration during treatment with Onivyde.
Withhold Onivyde for all Grade ≥ 2 diarrhoea. For early-onset diarrhoea of any severity, administer atropine (0.25 to 1 mg, intravenous or subcutaneous) unless contraindicated, and consider atropine prophylaxis. For late-onset diarrhoea of any severity, initiate loperamide (maximum cumulative daily dose 16 mg). Ensure patients have loperamide readily available to begin treatment as soon as symptoms are noticed. Cease loperamide when diarrhoea has not recurred for at least 12 consecutive hours, or if diarrhoea persists at 48 hours. Local institutional guidelines should be followed for the treatment of diarrhoea that does not improve with loperamide treatment within 24 to 48 hours, including monitoring and replacing fluid and electrolytes, consideration of antibiotic support (e.g. 7 days of oral fluoroquinolone) and potentially the use of diphenoxylate hydrochloride plus atropine sulfate or octreotide. After recovery, depending on severity and number of recurrences of diarrhoea, resume at a reduced dose or discontinue (see Section 4.2 Dose and Method of Administration, Dose modifications).

Cholinergic reactions.

Onivyde can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early-onset diarrhoea. Treat with atropine, as described above (for early-onset diarrhoea).
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.

Hypersensitivity and infusion-related reactions.

Onivyde can cause acute infusion reactions (including rash, urticaria, periorbital oedema or pruritus), and anaphylactic/anaphylactoid reactions and angioedema may occur. Onivyde should be discontinued in case of severe hypersensitivity reactions (see Section 4.2 Dose and Method of Administration).

Interstitial lung disease/pneumonitis.

Non-liposomal irinotecan (hydrochloride) can cause severe or fatal interstitial lung disease (ILD)/pneumonitis. Pneumonitis was reported in 0.3% of patients receiving Onivyde in combination with oxaliplatin and 5-FU/LV (NALIRIFOX) in NAPOLI-3. 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. 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.

Immunosuppression and live vaccines.

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

Thromboembolism.

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.

Poor performance status.

Onivyde has not been studied in patients with a Karnofsky performance status (KPS) score of < 70 (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Use in hepatic impairment.

Hyperbilirubinaemia is associated with lower SN-38 clearance, and higher risk of neutropenia (see Section 4.8 Adverse Effects (Undesirable Effects), Safety in specific populations; Section 5.2 Pharmacokinetic Properties). No dedicated hepatic impairment study has been conducted with Onivyde, and patients with elevated baseline serum bilirubin were excluded from Onivyde clinical trials.
Monitor blood counts regularly in patients with total bilirubin of 1.0-2.0 mg/dL. Use cautiously in patients with hepatic impairment (bilirubin > 2 times the upper limit of normal [ULN]; transaminases > 5 times ULN), with deficiency of bilirubin glucuronidation (such as Gilbert's syndrome), and those taking other hepatotoxic substances.

Use in renal impairment.

No dedicated pharmacokinetic study has been conducted in patients with renal impairment. Creatinine clearance was not found as a significant covariate on SN-38 clearance. There was insufficient data in patients with severe renal impairment (CLcr < 30 mL/min) to assess its effect on pharmacokinetics.

Use in the elderly.

Meaningful differences in clinical safety and efficacy were not detected in subgroup analyses based on age above or below 65 years (see Section 4.8 Adverse Effects (Undesirable Effects), Safety in specific populations).

Paediatric use.

The safety and efficacy of Onivyde in patients under the age of 18 years has not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Table 4, Table 6.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions with combination partner drugs.

In a population pharmacokinetic analysis, the pharmacokinetics of total irinotecan and total SN-38 were not altered by the co-administration of fluorouracil/leucovorin. In NAPOLI-3, irinotecan AUC decreased by 33% and SN-38 C_max increased by 23% following co-administration with oxaliplatin.

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.

CYP substrates.

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

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 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, breastfeeding 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.

The safety profile for Onivyde is based on adverse reactions data from two international, randomised, active-controlled, open-label studies (also see Section 5.1 Pharmacodynamic Properties, Clinical trials).
NAPOLI-1 (a study of Onivyde as an add-on to 5-FU and LV [Onivyde+5-FU/LV] for the treatment of metastatic pancreatic adenocarcinoma after progression on prior gemcitabine-based therapy).
117 patients in this study received Onivyde+5-FU/LV.
147 patients in this study received Onivyde as monotherapy (noting that the efficacy of Onivyde monotherapy has not been established).
NAPOLI-3 (a study of Onivyde in combination with oxaliplatin and 5-FU and LV [NALIRIFOX] for the first-line treatment of metastatic pancreatic adenocarcinoma) 370 patients in this study received Onivyde in the NALIRIFOX arm.

In combination with fluorouracil and leucovorin for treatment of metastatic pancreatic adenocarcinoma after progression on gemcitabine or gemcitabine-based therapy (NAPOLI-1).

The safety data described below are derived from patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based therapy who received any part of protocol-specified therapy in NAPOLI-1, an international, randomised, active-controlled, open-label trial. Protocol-specified therapy consisted of Onivyde 70 mg/m² with leucovorin 400 mg/m² and fluorouracil 2,400 mg/m² over 46 hours every 2 weeks (Onivyde/FU/LV; N=117), Onivyde 100 mg/m² every 3 weeks (N=147), or leucovorin 200 mg/m² and fluorouracil 2,000 mg/m² over 24 hours weekly for 4 weeks followed by 2 week rest (FU/LV; N=134) (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Serum bilirubin within the institutional normal range, albumin ≥ 3 g/dL, and Karnofsky Performance Status (KPS) ≥ 70 were required for study entry. The median duration of exposure was 9 weeks in the Onivyde/FU/LV arm, 9 weeks in the Onivyde monotherapy arm, and 6 weeks in the FU/LV arm.
The most common adverse reactions (≥ 20%) of Onivyde were diarrhoea, fatigue/asthenia, vomiting, nausea, decreased appetite, stomatitis, and pyrexia. The most common, severe laboratory abnormalities (≥ 10% Grade 3 or 4) were lymphopenia and neutropenia. The most common serious adverse reactions (≥ 2%) of Onivyde were diarrhoea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.
Adverse reactions led to permanent discontinuation of Onivyde in 11% of patients receiving Onivyde/FU/LV; the most frequent adverse reactions resulting in discontinuation of Onivyde were diarrhoea, vomiting, and sepsis. Dose reductions of Onivyde for adverse reactions occurred in 33% of patients receiving Onivyde/FU/LV; the most frequent adverse reactions requiring dose reductions were neutropenia, diarrhoea, nausea, and anaemia. Onivyde was withheld or delayed for adverse reactions in 62% of patients receiving Onivyde/FU/LV; the most frequent adverse reactions requiring interruption or delays were neutropenia, diarrhoea, fatigue, vomiting, and thrombocytopenia.
Table 3 and Table 4 summarise the adverse reactions and laboratory abnormalities that were more common with addition of Onivyde to treatment.

In combination with oxaliplatin, fluorouracil and leucovorin for first-line treatment of metastatic pancreatic adenocarcinoma (NAPOLI-3).

The safety of Onivyde in patients with metastatic pancreatic adenocarcinoma who had not previously received chemotherapy was evaluated in NAPOLI-3 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients received Onivyde 50 mg/m² in combination with oxaliplatin 60 mg/m², leucovorin 400 mg/m² and fluorouracil 2,400 mg/m² over 46 hours every 2 weeks (NALIRIFOX; N=383) or nab-paclitaxel 125 mg/m² over 35 minutes and gemcitabine 1,000 mg/m² over 30 minutes on Day 1, 8 and 15 of each 28-day cycle (Gem+NabP; N=387). The median duration of exposure to Onivyde in combination with oxaliplatin, fluorouracil, and leucovorin was 24 weeks (range: 0 to 101 weeks).
Serious adverse reactions occurred in 54% of patients who received Onivyde in combination with oxaliplatin, fluorouracil and leucovorin. Serious adverse reactions in ≥ 2% of patients included infections including COVID-19 (14%), diarrhoea (9%), vomiting (6%), nausea (4.9%), fatigue (3.8%), embolism (3.5%), gastrointestinal tract stenosis or obstruction (3.5%), haemorrhage (3%), abdominal pain (2.7%), cerebrovascular accident (2.7%), dehydration (2.7%), liver function test abnormalities (2.2%), and pyrexia (2.2%). Fatal adverse reactions occurred in 6% of patients who received Onivyde in combination with oxaliplatin, fluorouracil and leucovorin including cerebrovascular accident (1.1%), haemorrhage (0.5%), pneumonia (0.5%), sepsis (0.5%) and sudden death (0.5%).
Permanent discontinuation of Onivyde due to an adverse reaction occurred in 17% of patients. Adverse reactions which resulted in permanent discontinuation of Onivyde in ≥ 1% of patients included neutropenia, thrombocytopenia, diarrhoea, fatigue, infections and cerebrovascular accident.
Dosage reduction of Onivyde due to an adverse reaction occurred in 52% of patients. Adverse reactions which required dosage reduction in ≥ 1% of patients included anaemia, decreased appetite, diarrhoea, fatigue, febrile neutropenia, hypokalaemia, liver function test abnormalities, nausea, mucosal inflammation, neutropenia, peripheral neuropathy, vomiting, thrombocytopenia and weight decreased.
Dosage interruptions of Onivyde due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage interruption in ≥ 0.5% of patients included hypersensitivity and infusion related reaction.
The most common adverse reactions (≥ 20% with a difference between arms of ≥ 5% for all grades or ≥ 2% for Grades 3 or 4 compared to Gem+NabP) of Onivyde in combination with oxaliplatin, fluorouracil, and leucovorin were diarrhoea, fatigue, nausea, vomiting, decreased appetite, abdominal pain, mucosal inflammation, constipation and decreased weight. The most common laboratory abnormalities (≥ 10% Grade 3 or 4) were decreased neutrophils, decreased potassium, decreased lymphocyte and decreased haemoglobin.
Table 5 and Table 6 summarise the most common adverse reactions in the NAPOLI-3 study.

Description of selected adverse reactions.

Description and management advice for key adverse reactions is contained in Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.
Other clinically relevant adverse reactions that were described in clinical studies include:

Cholinergic reactions.

Onivyde can cause cholinergic reactions manifesting as rhinitis, increased salivation, flushing, bradycardia, miosis, lacrimation, diaphoresis, and intestinal hyperperistalsis with abdominal cramping and early onset diarrhoea. In NAPOLI-1, Grade 1 or 2 cholinergic symptoms other than early diarrhoea occurred in 12 (4.5%) Onivyde-treated patients. Six of these 12 patients received atropine and in 1 of the 6 patients, atropine was administered for cholinergic symptoms other than diarrhoea.

Infusion reactions.

Infusion reactions, consisting of rash, urticaria, periorbital oedema, or pruritus, occurring on the day of Onivyde administration were reported in 3% of patients receiving Onivyde or Onivyde/FU/LV in NAPOLI-1.

Safety in specific populations.

Exploratory exposure-response analyses suggest toxicity is proportional to exposure (see Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects). Populations with higher exposure may be at higher risk of toxicities.

Patients with hepatic impairment.

Elevated bilirubin level is associated with lower SN‑38 clearance (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in specific populations). In clinical studies of non-liposomal irinotecan administered on a weekly dosage schedule, patients with modestly elevated baseline serum total bilirubin levels (1.0 to 2.0 mg/dL) had a significantly greater likelihood of experiencing first cycle Grade 3 or Grade 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL. Also see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment.

Female patients.

Exposure is higher in female patients than males (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in specific populations). In NAPOLI-3, 19% of males (36 out of 189) and 32% of females (55 out of 171) who received Onivyde had neutropenia adverse events of Grade ≥ 3. In NAPOLI-1, 30% of males (20 out of 66) and 24% of females (12 out of 50) who received Onivyde had neutropenia adverse events of Grade ≥ 3.

Asian population.

Population pharmacokinetic analysis showed decreased irinotecan and increased SN-38 exposure in the Asian population (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in specific populations).
In NAPOLI-1, 33 of the patients who received Onivyde in combination with 5-FU/LV were Asian (28%), and 52 of the patients who received Onivyde as monotherapy (not an approved usage) were Asian (35%). Grade 3 or 4 diarrhoea occurred in 3% and 15% of these patients, respectively, as well as in 17% and 24% of the complementary (non-Asian) subgroups. Laboratory results for the same groups showed Grade 3 or 4 neutropenia in 52% and 33% of patients who were Asian, and 7% of those who were not. Neutropenic sepsis occurred in 6% and 10% of patients who were Asian, and 2.4% and 2.1% of those who were not.
In NAPOLI 3, 20 of the patients who received Onivyde were Asian (5%). Amongst Asian patients and non-Asian patients, the respective rates of Grade 3 or 4 diarrhoea were 5% and 21%; rates of laboratory results showing Grade 3 or 4 neutropenia were 15% and 25%; and rates of neutropenic sepsis were 5% and 2.3%.

Patients with homozygous UGT1A1 activity.

Individuals who are homozygous for the UGT1A1*28 allele (also known as having a UGT1A1 7/7 or *28/*28 genotype) have an increased risk of toxicities, notably neutropenia, with non-liposomal irinotecan hydrochloride treatment. In NAPOLI-1, patients homozygous for the UGT1A1*28 allele (n=7) initiated Onivyde at a reduced dose of 50 mg/m² in combination with 5-FU/LV. Grade 3 or 4 neutropenia occurred in 2 (29%) of these patients and in 30 (27%) patients not homozygous for the UGT1A1*28 allele who initiated Onivyde (in combination with 5-FU/LV) at a dose of 70 mg/m². In NAPOLI 3, patients homozygous for the UGT1A1*28 allele (n=39) initiated Onivyde at the same starting dose (50 mg/m²) as patients not homozygous for the UGT1A1*28 allele. Rates of serious or severe (Grade ≥ 3) treatment-emergent adverse events and of dose reduction were similar regardless of presence of the UGT1A1*28/*28 genotype.

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

In NAPOLI-1, 5 of 8 underweight patients experienced Grade ≥ 3 adverse reaction, mostly myelosuppression, while 7 of the 8 patients required dose modification such as dose delay, dose reduction or dose discontinuation.
In NAPOLI-3, rates of Grade ≥ 3 adverse events occurred in 13 (87%) of 15 patients who were underweight and 309 (87%) of 355 patients who were not. Onivyde dose reduction was required in 10 (67%) underweight patients and 185 (52%) of those who were not. Adverse events that led to death occurred in 3 (20%) underweight patients and 19 (5%) of those who were not. Discontinuation due to adverse events occurred in 2 (13%) underweight patients and 117 (33%) of those who were not.

Prior Whipple procedure.

Amongst patients receiving Onivyde+5-FU/LV in NAPOLI-1, serious infections occurred in 9 (30%) of 29 patients with a prior Whipple procedure and 11 (13%) of 88 patients without a prior Whipple procedure. Amongst patients receiving NALIRIFOX in NAPOLI-3, serious infections occurred in 3 (20%) of 15 patients with a prior Whipple procedure and 50 (14%) of 370 patients without a prior Whipple procedure.

Elderly patients.

In NAPOLI-1, 41% of patients who received Onivyde were at least 65 years of age and 12 patients (10%) were over 75 years of age. The overall toxicity profile of treatment with Onivyde+5-FU/LV was broadly similar between age groups. Rates of discontinuation due to adverse events amongst patients < 65 years and ≥ 65 years of age were 8% and 15%, respectively, but Grade 3 or higher and serious treatment emergent adverse reactions were more frequent in patients < 65 years (84% and 51%) compared to patients ≥ 65 years (69% and 44%). 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).
In NAPOLI-3, 50% of patients who received NALIRIFOX were at least 65 years of age and 7% were 75 years or older. The overall toxicity profile for NALIRIFOX was broadly similar between age groups of < 65 years, 65-75 years, and ≥ 75 years. Rates of discontinuation due to adverse events amongst these groups were 30%, 34% and 36%, respectively.

Postmarketing experience.

The following adverse reactions have been identified during post-approval use of Onivyde. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. See Table 7.

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

Pharmacotherapeutic group: Topoisomerase 1 (TOP1) inhibitors. ATC Code: L01CE02.

Mechanism of action.

The active ingredient in Onivyde is irinotecan: a water-soluble topoisomerase 1 inhibitor. Topoisomerase 1 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, leading to exposure time-dependent double-strand DNA damage and cell death. SN-38 is lipophilic and inhibits topoisomerase 1 approximately 1000-fold more potently than irinotecan.
Liposomal irinotecan (sucrosofate) has different pharmacokinetic properties to non-liposomal irinotecan hydrochloride (see Section 5.2 Pharmacokinetic Properties). Intravenous administration of both formulations to mice bearing human tumour xenografts resulted in similar systemic and tumour SN-38 exposures when liposomal irinotecan was given at a 5-fold lower dose than non-liposomal irinotecan hydrochloride.

Clinical trials.

NAPOLI-3: Onivyde in combination with oxaliplatin, 5-FU and LV for the first-line treatment of metastatic pancreatic adenocarcinoma.

The safety and efficacy of Onivyde in combination with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) was evaluated in NAPOLI-3, a randomised, multicentre, open-label, active-controlled study that included 770 patients with metastatic pancreatic adenocarcinoma who had not previously received chemotherapy in the metastatic setting. Randomisation was stratified by region, liver metastases and ECOG performance status. Patients were randomised (1:1) to the following treatment arms:
NALIRIFOX: Onivyde 50 mg/m² as an intravenous infusion over 90 minutes, followed by oxaliplatin 60 mg/m² as an intravenous infusion over 120 minutes, followed by leucovorin 400 mg/m² intravenously over 30 minutes, followed by 5-FU 2,400 mg/m² intravenously over 46 hours, administered every 2 weeks.
Gem+NabP: Nab-paclitaxel 125 mg/m² as an intravenous infusion over 35 minutes, followed by gemcitabine 1,000 mg/m² intravenously over 30 minutes on days 1, 8 and 15 of each 28-day cycle.
Patients homozygous for the UGT1A1*28 allele initiated Onivyde at the same dose (50 mg/m² Onivyde) and were closely monitored for safety. Tumour status assessments were conducted according to RECIST v1.1 at baseline and every 8 weeks thereafter. Treatment continued until RECIST-defined disease progression or unacceptable toxicity.
The primary efficacy endpoint was overall survival (OS). Investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were secondary efficacy endpoints.
Baseline demographics and patient characteristics were: median age of 65 years (range: 20-85); 50% age 65 or older; 56% male; 83% Caucasian; 5% Asian; 3% Black or African American; ECOG performance status was 0 or 1 in 43% and 57% of patients; 80% had liver metastases.
The efficacy results of NAPOLI-3 are summarised in Table 8, Figure 1 and Figure 2.

NAPOLI-1: Onivyde in combination with 5-FU and LV for the treatment of metastatic pancreatic adenocarcinoma after gemcitabine-based therapy.

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 (1:1:1) to the following treatment arms:
Onivyde plus 5-FU/ LV (n=117): Onivyde 70 mg/m² (based on irinotecan free base; equivalent to 80 mg/m² of irinotecan hydrochloride trihydrate) as an intravenous infusion over 90 minutes, followed by LV 400 mg/m² intravenously over 30 minutes, followed by 5-FU 2,400 mg/m² intravenously over 46 hours, every 2 weeks.
Onivyde monotherapy (n=151): 100 mg/m² as an intravenous infusion over 90 minutes every 3 weeks.
5-FU/LV (n=149): received LV 200 mg/m² intravenously over 30 minutes, followed by 5-FU 2,000 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 primary 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-FU/LV arm demonstrated improvement in overall survival and the other efficacy outcomes summarised in Table 9 and Figure 3. 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).

Prospective subgroup analyses based on stratification factors did not identify a differential treatment effect on OS.

Pharmacodynamic effects.

NAPOLI-3: Onivyde in combination with oxaliplatin, 5-FU and LV for the first-line treatment of metastatic pancreatic adenocarcinoma.

An exploratory exposure-safety analysis of NAPOLI-3 data suggested that the risk of Grade ≥ 3 diarrhoea or neutropenia increases with increasing exposures of both irinotecan and SN-38.

NAPOLI-1: Onivyde in combination with 5-FU and LV for the treatment of metastatic pancreatic adenocarcinoma after gemcitabine-based therapy.

An exploratory exposure-safety analysis of pooled data from 353 patients who received Onivyde either as monotherapy or in combination with 5-FU/LV in NAPOLI-1, suggested that 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. Exploratory exposure-efficacy analyses suggested a positive correlation.

5.2 Pharmacokinetic Properties

Onivyde (liposome-encapsulated irinotecan as sucrosofate) has different pharmacokinetics to non-liposomal irinotecan hydrochloride.

Absorption.

The plasma pharmacokinetics of total (liposomal and non-liposomal) irinotecan and total SN-38 were evaluated in patients with cancer who received Onivyde (as monotherapy or as part of combination therapy) at doses between 35 mg/m² and 155 mg/m². The pharmacokinetic parameters of total irinotecan and total SN-38, following the administration of Onivyde at 70 mg/m² as a single agent or as part of combination chemotherapy, and at 50 mg/m² in the NALIRIFOX regimen, are presented in Table 10.

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.

Distribution.

Direct measurement of liposomal irinotecan shows that 95% of irinotecan remains liposome-encapsulated during circulation, and the ratios between total and encapsulated forms did not change with time from 0 to 170 hours post-dose. The mean volume of distribution of Onivyde is 4 L (obtained from population pharmacokinetic analysis).
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.

The metabolism of liposomal irinotecan has not been evaluated. Irinotecan is subject to extensive metabolic conversion by various enzyme systems, including carboxylesterases to form the active metabolite SN-38, and UGT1A1 mediating glucuronidation of SN-38 to form the inactive glucuronide metabolite SN-38G. Irinotecan can also undergo CYP3A4-mediated oxidative metabolism to several inactive oxidation products, one of which can be hydrolysed by carboxylesterase to release SN-38. In the population PK analysis of liposomal irinotecan, UGT1A1*28 7/7 homozygous status (10.6%) had no effect on SN-38 clearance compared with patients not homozygous for UGT1A1*28 7/7.

Excretion.

The disposition of Onivyde has not been elucidated in humans. Following administration of non-liposomal irinotecan hydrochloride, the urinary excretion of 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 hydrochloride 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.

Pharmacokinetics in specific populations.

Age, sex, ethnicity, renal and hepatic impairment.

The population pharmacokinetic analyses suggest that age (20 to 87 years) and BSA (1.15 to 2.88 m²) had no clinically meaningful effect on the exposure of irinotecan and SN-38 after administration of Onivyde.
Irinotecan and SN-38 AUC in female patients were 28% and 32% higher, respectively, than those in male patients. Irinotecan AUC in patients of Asian ethnicity was 32% lower than that in non-Asian patients, but SN-38 C_max was 7% higher in Asian than non-Asian patients. The exposures of irinotecan and SN-38 in patients with mild or moderate renal impairment were comparable to patients with normal renal function after adjusting for BSA. The exposures of irinotecan and SN-38 in patients with mild hepatic impairment (based on NCI score) were comparable to patients with normal hepatic function. There was insufficient data in patients with severe renal impairment (CLcr < 30 mL/min) or in patients with moderate and severe hepatic impairment to assess their effects on the exposures of irinotecan and SN-38. Increased AST/ALT had no effect on irinotecan clearance; however, increased bilirubin level was associated with lower SN‑38 clearance. SN-38 AUC was increased by 32% in patients with bilirubin level of 1.14 mg/dL (95th of the overall population) compared with that of median bilirubin level of 0.44 mg/dL. No data are available in patients with bilirubin > 2.8 mg/dL.

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.
Note for patients on a controlled sodium diet: each mL of Onivyde contains 0.144 mmol sodium, which is 3.31 mg sodium.

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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