Consumer medicine information

Akynzeo

Netupitant; Palonosetron

BRAND INFORMATION

Brand name

Akynzeo

Active ingredient

Netupitant; Palonosetron

Schedule

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

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

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

What Akynzeo is used for

This medicine is used to prevent nausea (feeling sick) and vomiting caused by cancer chemotherapy in adult patients.

It is a combination medicine which contains two active ingredients. The active ingredients are called netupitant and palonosetron.

Netupitant belongs to a group of medicines called 'neurokinin-1 (NK1) receptor antagonists'.

Palonosetron belongs to a group of medicines called 'serotonin (5-HT3) receptor antagonists'.

Akynzeo works by blocking the actions of substances in your body and brain that are thought to cause nausea and vomiting.

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

This medicine is not addictive.

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

There is not enough information to recommend its use in children under the age of 18 years.

Before you take it

When you must not take it

Do not take this medicine if:

You are pregnant
You are allergic to any medicine containing palonosetron or netupitant
You are allergic to any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing or a tight feeling in your chest
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take Akynzeo if you have the rare hereditary problem of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency.

Do not take it after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

Before you start to take it

Your doctor must know about all of the following before you are given this medicine.

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

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

constipation
bowel obstruction
alterations in heart rhythm also known as QT prolongation
other heart problems
taking any medicines that may induce an abnormal heart rhythm such as amiodarone, nicardipine, quinidine, moxifloxacin, erythromycin, haloperidol, chlorpromazine, quetiapine, thioridazine, domperidone
liver disease
imbalance of certain minerals in your blood such as potassium and magnesium
an intolerance to fructose
peanut or soya allergy.

Tell your doctor if you are pregnant or plan to become pregnant. Do not take Akynzeo if you are pregnant or if you are a woman of childbearing potential not using contraception. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breastfeeding or planning to breast-feed. Do not breast feed if you are taking Akynzeo. It is not known whether Akynzeo passes into breast milk.

If you have not told your doctor about any of the above, tell him/ her before you start taking Akynzeo.

It is not recommended to take Akynzeo in the days following chemotherapy unless you are receiving another chemotherapy cycle.

Taking or being given other medicines

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

Akynzeo can affect other medicines both during and after treatment. These include:

dexamethasone, a steroid used for a variety of conditions
certain cancer chemotherapy medicines such as docetaxel, etoposide or cyclophosphamide
certain antibiotics such as erythromycin or moxifloxacin
midazolam, used as a sedative and to relieve anxiety
ketoconazole, used to treat fungal infections
rifampin, an antibiotic used to treat tuberculosis and other infections
heart medications such as amiodarone, quinidine and nicardipine
medicines normally used to treat certain mental and emotional conditions (antipsychotics) such as haloperidol, chlorpromazine, quetiapine and thioridazine
domperidone, a medicine normally used to treat nausea and vomiting, or certain other gastric problems
SSRIs (selective serotonin reuptake inhibitors) used to treat depression and/or anxiety including fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram
SNRIs (serotonin noradrenaline reuptake inhibitors) used to treat depression and/or anxiety including venlafaxine, duloxetine.

These medicines may be affected by Akynzeo or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take it

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The recommended dose is one capsule by mouth, one hour before you start your chemotherapy cycle.

How to take it

Swallow the capsule whole with a drink of water.

If you have trouble swallowing your capsule, tell your doctor.

When to take it

Take Akynzeo approximately one hour prior to starting your chemotherapy cycle.

Take it with or without food.

How long to take it

Akynzeo is a single dose given only on the day of chemotherapy treatment.

It is not recommended to take Akynzeo in the days following chemotherapy unless you are receiving another chemotherapy cycle.

If you forget to take it

If you forget to take your capsule, contact your doctor for instructions.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Akynzeo.

Do this even if there are no signs of discomfort or poisoning.

While you are taking it

Things you must do

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed.

Tell your doctor if you feel the medicine is not helping to prevent the nausea and vomiting.

If the medicine starts to upset you, tell your doctor.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not take it to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how Akynzeo affects you. Akynzeo may induce dizziness, somnolence or fatigue in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are taking Akynzeo.

This medicine helps most people with control of nausea and vomiting associated with chemotherapy treatment, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

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

headache
constipation
general weakness
tiredness
generally feeling unwell
indigestion, heartburn, loss of appetite, bloating or stomach pain
vomiting
pain on urination

The above list includes the more common side effects of your medicine.

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

slow, fast or irregular heart beat
severe stomach pain
dizziness or feeling light headed

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

Tell your doctor immediately or go to the accident and emergency at your nearest hospital if any of the following happen:

swelling of the mouth, face, lips, tongue or throat, which may cause difficulty breathing or swallowing
raised, itchy rash on the skin

These may be signs of a serious allergic reaction. You may need urgent medical attention. These side effect are rare.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Storage

Keep the capsule in the blister pack until it is time to take it. If you take the capsule out of the blister it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 30°C.

Do not store Akynzeo or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

Ask your pharmacist what to do with any medicine that is left over or if the expiry date has passed.

Product description

What it looks like

The Akynzeo capsule is opaque with a white body and a caramel cap with "HE1" printed on the body.

Akynzeo capsules are supplied in an aluminium blister containing 1 capsule.

Ingredients

Active ingredient:
Akynzeo 300/500 - 300 mg netupitant and 500 micrograms palonosetron (as the hydrochloride) per capsule.

Inactive ingredients

microcrystalline cellulose
sucrose laurate
povidone
croscarmellose sodium
silicon dioxide
sodium stearylfumarate
magnesium stearate
glyceryl caprylate / caprate
glycerol
polyglyceryl-3-dioleate
purified water
butylated hydroxyanisole
gelatin
sorbitol special glycerin blend A-810
titanium dioxide (E171)
iron oxide yellow, iron oxide red (E172) and iron oxide black (E172)
shellac
propylene glycol (E1520)
ammonium hydroxide (E527).

Each Akynzeo hard capsule contains 7 mg of sorbitol.

Akynzeo contains sucrose. It may contain traces of lecithin derived from soya.

Akynzeo does not contain gluten, tartrazine or any other azo dyes.

Supplier

Akynzeo is supplied in Australia by:

Juniper Biologics Pty Ltd
Level 14 Suite 3A16 275 Alfred Street
North Sydney
NSW 2060
Australia

®Akynzeo is a registered trade mark of Helsinn Healthcare SA, Switzerland. Distributed under license of Helsinn Healthcare SA, Switzerland.

This leaflet was prepared in June 2022

Australian Registration Number
Akynzeo 300 mg/500 microgram capsule
AUST R 222237

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Akynzeo

Active ingredient

Netupitant; Palonosetron

Schedule

1 Name of Medicine

Netupitant, palonosetron (as hydrochloride).

2 Qualitative and Quantitative Composition

Each Akynzeo hard gelatin capsule contains three 100 mg netupitant (300 mg total) immediate release tablets and one 500 microgram palonosetron (as hydrochloride) soft capsule.
For the full list of excipients, see Section 6.1 List of Excipients.
300 mg/500 micrograms: AUST R 222237.

3 Pharmaceutical Form

Akynzeo is supplied as a hard, opaque, gelatin capsule with white body and caramel cap with "HE1" printed on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

Akynzeo is indicated in adult patients for:
prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy;
prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

4.2 Dose and Method of Administration

Method of administration.

One Akynzeo 300 mg/500 microgram capsule should be administered approximately one hour prior to the start of each chemotherapy cycle.
To be taken orally.
The hard capsule should be swallowed whole.
Akynzeo can be taken with or without food.
The concomitant use of dexamethasone is recommended.
The recommended oral dexamethasone dose should be reduced by approximately 50% when coadministered with Akynzeo (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Tables 3 and 5).

Elderly population.

No dosage adjustment is necessary for elderly patients.

Paediatric population.

The safety and efficacy of Akynzeo in children have not been established. No data are available.

Patients with renal impairment.

Dosage adjustment for Akynzeo is not considered necessary in patients with mild to moderate renal impairment. Use of Akynzeo in patients with severe renal impairment or end stage renal disease should be avoided (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment).

Patients with hepatic impairment.

No dosage adjustment is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score 5-8). Limited data exist in patients with severe hepatic impairment (Child-Pugh score ≥ 9). As use in patients with severe hepatic impairment may be associated with increased exposure to netupitant, Akynzeo should be used with caution in these patients.

4.3 Contraindications

Hypersensitivity to palonosetron or netupitant or to any of the excipients listed (see Section 6.1 List of Excipients).
Akynzeo is contraindicated during pregnancy.

4.4 Special Warnings and Precautions for Use

General.

Hypersensitivity reactions to palonosetron may occur in patients who have exhibited hypersensitivity to other selective 5HT₃ receptor antagonists.
Akynzeo should not be used to prevent or treat nausea and vomiting in the days following chemotherapy if not associated with another chemotherapy administration.

Constipation.

As palonosetron may increase large bowel transit time, patients with a history of constipation or signs of subacute intestinal obstruction should be monitored following administration.

QT prolongation.

A specific thorough ECG study conducted in adult male and female healthy volunteers on netupitant (200 and 600 mg) orally administered with palonosetron (0.5 and 1.5 mg) demonstrated that Akynzeo had no clinically important effects on ECG parameters. The ECG data analyses including a pharmacodynamic-pharmacokinetic (PD-PK) analysis showed no effects on cardiac repolarisation. However since Akynzeo contains a 5HT₃ receptor antagonist caution should be exercised in the concomitant use of Akynzeo with medicinal products that increase the QT interval or in patients who have or are likely to develop prolongation of the QT interval. These conditions include patients with a personal or family history of QT prolongation, electrolyte abnormalities, congestive heart failure, bradyarrhythmias, conduction disturbances and in patients taking antiarrhythmic agents or other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalaemia and hypomagnesemia should be corrected prior to Akynzeo administration.

Excipients.

Akynzeo contains sorbitol and sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicinal product. Akynzeo capsules may also contain a trace of lecithin derived from soya. Therefore, patients with known hypersensitivity to peanut or soya should be monitored closely for signs of an allergic reaction.

Serotonin syndrome.

There have been reports of serotonin syndrome with the use of 5HT₃ antagonists either alone or in combination with other serotonergic drugs including selective serotonin reuptake inhibitors (SSRI) and serotonin noradrenaline reuptake inhibitors (SNRIs).

Concomitant use of CYP3A4 substrates.

Netupitant is a moderate inhibitor of CYP3A4. It has a half-life of 88 hours so its inhibitory effect on CYP3A4 can last for over 4 days. Systemic exposure to chemotherapy agents and other medicines metabolised by CYP3A4 may increase when administered with or after Akynzeo. For example, exposure to docetaxel was shown to increase by 37% with concomitant use. Likewise, exposure to dexamethasone is clearly increased with concomitant use. Patients should be closely monitored for adverse reactions that may arise from this additional systemic exposure to relevant chemotherapies and other medicines. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for further details.

Women of childbearing potential/ contraception in females.

Women of childbearing potential should not be pregnant or become pregnant while on treatment with Akynzeo. A pregnancy test should be performed on all pre-menopausal women prior to treatment. Women of childbearing potential must use effective contraception during therapy and up to one month after treatment with this medicinal product.

Race.

Intravenous palonosetron pharmacokinetics was characterised in twenty four healthy Japanese subjects over the dose range of 3-90 microgram/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites; however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterised. The pharmacokinetics of netupitant has been characterised only in Caucasians.

Use in hepatic impairment.

Palonosetron.

Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects.

Netupitant.

Maximum concentrations and total exposure of netupitant were increased in subjects with mild (n = 8), moderate (n = 8), and severe (n = 2) hepatic impairment compared to matching healthy subjects, although there was pronounced individual variability in both hepatically impaired and healthy subjects. Exposure to netupitant (C_max, AUC_0-t and AUC_0-∞) compared to matching healthy subjects was 11%, 28% and 19% higher in mild and 70%, 88% and 143% higher in moderate hepatically impaired subjects, respectively. As such, no dosage adjustment of Akynzeo is necessary for patients with mild or moderate hepatic impairment (Child-Pugh score 5-8). Limited data exist in patients with severe hepatic impairment (Child-Pugh score ≥ 9). No dose adjustment is possible with Akynzeo, and considerably increased exposure to netupitant can be expected in severe hepatic impairment. Therefore Akynzeo should be used with caution in these patients.

Use in renal impairment.

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure of palonosetron increased by approximately 28% in severe renal impairment relative to healthy subjects.
Renal excretion for netupitant is negligible. The pharmacokinetics and safety of netupitant has not been studied in patients with renal impairment or chronic kidney disease. Therefore, no dose adjustment for Akynzeo is necessary in patients with mild to moderate renal impairment. Use of Akynzeo in patients with severe renal impairment or endstage renal disease should be avoided.

Use in the elderly.

Population pharmacokinetic analysis and clinical safety and efficacy data for palonosetron did not reveal any differences between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). In healthy elderly subjects (> 65 years old) the mean AUC_0-∞ and C_max was 25% and 36% higher, respectively, for netupitant, and 37% and 10% higher, respectively, for palonosetron compared to those in healthy younger adults (22-45 years old). No dose adjustment is required for these patients.

Paediatric use.

The safety and efficacy of Akynzeo in children have not been established. No data are available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In humans, netupitant is eliminated mainly by hepatic metabolism mediated by CYP3A4 with a marginal renal excretion. At a dose of 300 mg in humans, netupitant is a substrate and moderate inhibitor of CYP3A4. Palonosetron is eliminated from the body through both renal excretion and metabolic pathways, with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CPY2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.
Based on the in vitro studies, netupitant and its metabolites are unlikely to have in vivo drug-drug interactions via inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at the clinical dose of 300 mg.
Netupitant and its metabolites, M1, M2 and M3, are not inducers of CYP1A2, CYP2C9, CYP2C19 and CYP3A4. When Akynzeo is used concomitantly with another CYP3A4 inhibitor, netupitant plasma concentrations could be elevated. When Akynzeo is used concomitantly with medications that induce CYP3A4 activity, netupitant plasma concentrations could be reduced and this may result in decreased efficacy of Akynzeo. Akynzeo can increase plasma concentrations of concomitantly administered medications that are metabolised via CYP3A4.

Interaction between netupitant and oral palonosetron.

No clinically relevant pharmacokinetic interactions have been observed between oral netupitant and oral palonosetron.

Interaction with CYP3A4 substrates.

Netupitant, a component of Akynzeo, is a moderate inhibitor of CYP3A4. Akynzeo should be used with caution in patients receiving concomitant medications that are primarily metabolised through CYP3A4. The plasma concentrations of CYP3A4 substrates can increase when coadministered with Akynzeo. Netupitant has a half-life of 88 hours. The inhibitory effect on CYP3A4 can last over 4 days.

Dexamethasone.

Dexamethasone doses should be reduced when given with Akynzeo (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Table 3). Coadministration of a single dose of netupitant (300 mg) with a dexamethasone regimen (20 mg on day 1, followed by 8 mg b.i.d. from day 2 to day 4) significantly increased the exposure to dexamethasone in a time and dose dependent manner. During the 4 day treatment period, increase of dexamethasone exposure, as expressed by the AUC, ranged from 1.7 to 2.4-fold with coadministration of 300 mg netupitant. Similarly, increase of C_max and C_min ranged from 1.1 to 1.7-fold and from 3.5 to 5.1-fold, respectively.

Interaction with chemotherapeutic agents (docetaxel, etoposide, cyclophosphamide).

The systemic exposure of chemotherapy agents metabolised by CYP3A4 can increase when administered with Akynzeo. Chemotherapy agents that are known to be metabolised by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, cyclophosphamide, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. Exposure to docetaxel and etoposide was increased 37% and 21%, respectively, when coadministered with Akynzeo. Caution and monitoring for chemotherapeutic related adverse reactions are advised in patients receiving chemotherapy agents metabolized primarily by CYP3A4. No consistent effect was seen with cyclophosphamide after netupitant coadministration.

Interaction with oral contraceptives.

Akynzeo, when given with a single oral dose of 60 microgram ethinylestradiol and 300 microgram levonorgestrel had no significant effect on the AUC of ethinylestradiol and increased the AUC of levonorgestrel by 1.4-fold; clinical effects on the efficacy of hormonal contraception are unlikely. No relevant changes in netupitant and palonosetron pharmacokinetics were observed.

Erythromycin and midazolam.

Exposure to erythromycin and midazolam was increased approximately 1.3 and 2.4-fold, respectively, when each was coadministered with netupitant. The pharmacokinetic profile of netupitant was unaffected by the concomitant administration of either midazolam or erythromycin. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with Akynzeo.

Rifampicin.

Single dose Akynzeo was administered with rifampicin, a strong CYP3A4 inducer, following once daily administration of 600 mg rifampicin for 17 days. Pharmacokinetics of netupitant and palonosetron were compared to that after administration of Akynzeo alone. Coadministration of rifampicin decreased the mean C_max and AUC_0-∞ of netupitant by 62% and 82%, respectively, compared to those after Akynzeo alone. Coadministration of rifampicin decreased the mean C_max and AUC for palonosetron by 15% and 19%, respectively. Coadministration of a strong CYP3A4 inducer can therefore decrease the efficacy of Akynzeo.

Ketoconazole.

Single dose Akynzeo was administered with ketoconazole, a strong CYP3A4 inhibitor, following once daily administration of 400 mg ketoconazole for 12 days. Pharmacokinetics of netupitant and palonosetron were compared to that after administration of Akynzeo alone. Coadministration with ketoconazole increased mean C_max and AUC of netupitant by 25% and 140%, respectively, compared to those after administration of Akynzeo alone. The mean AUC and C_max of palonosetron were 10% and 15% higher, respectively, when coadministered with ketoconazole. No dosage adjustment is necessary for single dose administration of Akynzeo.

Interaction with warfarin, tolbutamide.

Akynzeo interactions with CYP2C9 substrates (e.g. warfarin, tolbutamide) are unlikely. In vitro studies using human liver microsomes indicate that palonosetron is not an inhibitor of CYP2C9 and netupitant is not a CYP2C9 inducer or inhibitor at clinically relevant concentrations.

Effect of other agents on the pharmacokinetics of Akynzeo.

Netupitant is mainly metabolised by CYP3A4; therefore, coadministration of Akynzeo with drugs that inhibit or induce CYP3A4 activity may influence plasma concentrations of netupitant. Consequently, concomitant administration of Akynzeo with strong CYP3A4 inhibitors (e.g. ketoconazole) or inducers (e.g. rifampicin) should be approached with caution.

Additional interactions with palonosetron.

There have been reports of serotonin syndrome following concomitant use of 5HT₃ antagonists and other serotonergic drugs (including SSRIs and SNRIs). A study in healthy volunteers involving single dose IV palonosetron (0.75 mg) and steady-state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.
In controlled clinical trials, Aloxi injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.
Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumour models.

Additional interactions with netupitant.

Based on in vitro studies, netupitant is an inhibitor of P-glycoprotein (P-gp). It cannot be excluded that this effect may be more marked, and then clinically relevant, in cancer patients, notably those having abnormal renal function. Therefore, caution is recommended when netupitant is combined with digoxin or with other P-gp substrates such as dabigatran or colchicine. In addition, metabolite M2 is a substrate for P-gp. Netupitant's potential for being a substrate for P-gp is unknown.
In vitro studies indicate that netupitant and its three major metabolites are unlikely to have in vivo drug-drug interactions with human efflux transporters BSEP, MRP2, and human uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1, and OCT2 at the clinical dose of 300 mg.
Based on in vitro studies, netupitant is an inhibitor of BCRP transporters. Caution is recommended when netupitant is combined with an oral substrate of glucuronidation isozyme UGT2B7 (e.g. zidovudine, valproic acid, morphine).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Palonosetron at oral doses of up to 60 mg/kg/day (> 30 times the human exposure after administration of Akynzeo based on plasma AUC) was found to have no effect on fertility and reproductive performance of male and female rats. Oral doses of 60 and 120 mg/kg/day given to male rats for 2 months prior to mating associated with complete infertility at the 120 mg/kg/day dose. Testicular degeneration was confirmed in a 3 month general toxicity study at oral doses of 60 and 120 mg/kg/day. An IV dose of up to 10 mg/kg/day (> 30 times the human exposure after administration of Akynzeo based on plasma AUC) had no effect on male fertility and reproductive performance.
Daily oral administration of up to 30 mg/kg netupitant in female (3 times the human AUC at the recommended human dose) and male rats had no effects on fertility or reproductive performance.
(Category D)
Palonosetron had no effect on fetal development at oral doses of up to 18 mg/kg/day in rats and 90 mg/kg/day in rabbits. At 60 and 120 mg/kg/day in rats, fetal weight was reduced. Palonosetron did not cause fetal abnormalities at these dose levels. However, palonosetron had toxic effects on the dams at 120 mg/kg in rats and 90 mg/kg/day in rabbits.
No effects on embryo-fetal development were observed following daily administration of netupitant in pregnant rats during the period of organogenesis at doses up to 3 times the human AUC at the recommended human dose. However, an increased incidence of positional fetal abnormalities of the limbs and paws. Fused sternebrae and supernumerary ribs were observed following daily administration of netupitant to rabbits at oral doses of 10 mg/kg/day and higher during the period of organogenesis. In a pilot study in rabbits, cleft palate, microphthalmia and aphakia were observed in foetuses following a maternal dose of 30 mg/kg/day. Exposure at the no observed adverse effect level was less than the anticipated human AUC.
There are no data from the use of palonosetron and netupitant in pregnant women. Animal studies are insufficient with respect to reproductive toxicity of the combination. Akynzeo is contraindicated in pregnancy.
It is not known whether palonosetron or netupitant are excreted in human milk. A risk to the newborn/infant cannot be excluded. Breastfeeding should be discontinued during treatment with Akynzeo and for one month after the last dose. Pre- and postnatal development study in rats with netupitant does not indicate direct or indirect harmful effects on F1 and F2 generations, after daily administration of netupitant up to 3 times the human AUC at the recommended human dose.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed with Akynzeo. Akynzeo may induce dizziness, somnolence or fatigue, therefore patients should use caution when driving or operating machines.

4.8 Adverse Effects (Undesirable Effects)

The safety profile of Akynzeo was evaluated in 1169 cancer patients, including 782 exposed to Akynzeo for at least 4 cycles and 321 exposed for at least 6 cycles, up to a maximum of 12 cycles of chemotherapy. All patients received a single oral dose of Akynzeo one hour prior to the start of each chemotherapy cycle. In all studies, dexamethasone was coadministered with Akynzeo (see Section 5.1 Pharmacodynamic Properties, Clinical trials, Tables 3, 5 and 7).
Adverse reactions, considered as drug related by the investigator, were reported in approximately 13% of patients treated with Akynzeo. Akynzeo was discontinued due to adverse reactions in 3.7% of patients. The adverse reaction profile was similar across all cycles. The following is a listing of the adverse reactions reported by ≥ 1% of patients treated with Akynzeo for one or more cycles. (See Table 1.)
The following uncommon (≥ 0.1% to < 1%) and rare (≥ 0.01% to < 0.1%) adverse reactions were reported as treatment related adverse events in at least two cancer patients receiving Akynzeo in chemotherapy induced nausea and vomiting studies. (See Table 2.)

Postmarketing experience.

There is no postmarketing data available at this time.

Reporting suspected adverse effects.

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

4.9 Overdose

No case of overdose has been reported and no specific information is available on the treatment of overdose with Akynzeo. Netupitant doses up to 600 mg and palonosetron doses up to 6 mg have been used in clinical studies without any safety concerns. In the unlikely event of overdose, Akynzeo should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of netupitant and palonosetron, emesis induced by a medicinal product may not be effective. Dialysis studies have not been performed, however, due to the large volume of distribution of palonosetron and netupitant, dialysis is unlikely to be an effective treatment for Akynzeo overdose.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antiemetics and antinauseants; serotonin (5HT₃) and neurokinin-1 (NK₁) receptor antagonists (see Section 5.1 Pharmacodynamic Properties, Mechanism of action).
ATC code: A04AA55 palonosetron, combinations (pending).

Mechanism of action.

Netupitant is a selective high affinity antagonist of human substance P/neurokinin-1 (NK₁) receptors. Palonosetron is a selective serotonin subtype 3 (5HT₃) receptor antagonist with a strong binding affinity for this receptor. Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5HT₃ receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5HT₃ receptors located on vagal afferents to initiate the vomiting reflex. The development of acute emesis is known to depend on 5-hydroxytryptamine serotonin (5HT) and the 5HT₃ receptor has been demonstrated to selectively participate in the emetic response. Delayed emesis has been largely associated with the activation of tachykinin family neurokinin-1 (NK₁) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant and palonosetron can contribute to the inhibition of substance P mediated response. In vitro studies have demonstrated that while palonosetron does not bind to the NK₁ receptor, it does inhibit cisplatin induced substance P enhancement of NK₁ signalling, in a dose dependent manner.

Pharmacodynamic effects.

NK₁ receptor occupancy.

The receptor occupancy for the chemotherapy induced nausea and vomiting (CINV) dosing regimen of netupitant has been determined in a human positron emission tomography (PET) study with three single doses tested (100 mg, 300 mg and 450 mg, 2 subjects per dose). Netupitant was shown to cross the blood brain barrier with a high occupancy of brain NK₁ receptors. All doses achieved a relatively long duration of blockade of the NK₁ receptor. NK₁ receptor occupancy in striatum at 6, 24, 48, 72 and 96 hours after administration of 300 mg netupitant was 92.5%, 86.5%, 85.0%, 78.0% and 76.0%, respectively.

Clinical trials.

Oral administration of Akynzeo in combination with dexamethasone has been shown to prevent acute and delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in two separate pivotal studies.

Highly emetogenic chemotherapy (HEC) study.

In a multicenter, randomised, parallel, double blind, controlled clinical study of 694 patients (study 1), the efficacy and safety of single doses of oral netupitant in combination with oral palonosetron, were compared with a single oral dose of palonosetron in cancer patients receiving a chemotherapy regimen that included cisplatin (median dose = 75 mg/m²). Lung and respiratory tract, head and neck, and ovarian cancers were the most frequent cancer types; approximately half of the enrolled patients had metastatic disease.
The primary efficacy analysis included 135 patients who received a single oral dose of netupitant 300 mg plus palonosetron 500 microgram, and 136 patients who received oral palonosetron 500 microgram alone.
The treatment regimens for the oral netupitant 300 mg plus palonosetron 500 microgram and the palonosetron 500 microgram arms are defined in Table 3.

Of the 135 patients who received netupitant 300 mg plus palonosetron 500 microgram, 43% were women, and all patients were White. The age ranged from 19 to 77 years, with a mean age of 53 years. During the study 86% of the 135 treated patients in the netupitant 300 mg plus palonosetron 500 microgram arm received a concomitant chemotherapeutic agent in addition to protocol mandated cisplatin. The most common chemotherapeutic agents and the proportion of patients exposed were cyclophosphamide (34%), fluorouracil (24%), etoposide (21%) and doxorubicin (16%).
The primary efficacy endpoint was complete response (CR) rate (defined as no emetic episodes, no rescue medication) within 120 hours (overall phase) after the start of the highly emetogenic chemotherapy administration.
Major secondary efficacy endpoints included:
CR for the 0-24 hour interval (acute phase) and for the 25-120 hour interval (delayed phase);
complete protection (defined as no emesis, no rescue therapy, no significant nausea) for the overall, acute and delayed phases;
no emesis for the overall, acute and delayed phases;
no significant nausea (maximum VAS < 25 mm) and no nausea (maximum VAS < 5 mm) for the overall, acute and delayed phases.
A summary of the key results from this study is shown in Table 4.
The proportion of patients with CR in the overall phase was 13.2% (95% CI: 4.4 to 21.9%) higher (p-value = 0.004) in the netupitant 300 mg plus palonosetron 500 microgram group (89.6%) than in the palonosetron group (76.5%). In the acute phase, the proportion of patients with CR was 8.8% higher (p-value = 0.007) in the netupitant 300 mg plus palonosetron 500 microgram group (98.5%) than in the palonosetron group (89.7%). In the delayed phase, the proportion of patients with CR was 10.2% higher (p-value = 0.018) in the netupitant 300 mg plus palonosetron 500 microgram group (90.4%) than in the palonosetron group (80.1%).

Moderately emetogenic chemotherapy (MEC)¹ study.

In a multicentre, randomised, parallel, double blind, active controlled, superiority study, the efficacy and safety of a single oral dose of Akynzeo was compared with a single oral dose of palonosetron 500 microgram in cancer patients scheduled to receive the first cycle of an anthracycline and cyclophosphamide regimen for the treatment of a solid malignant tumor.
Almost all patients (97%) had breast cancer, which was metastatic in 16% of cases.
¹ At the time of the study, anthracycline-cyclophosphamide containing chemotherapy regimens were considered to be moderately emetogenic. Recent guidelines have updated these regimens to highly emetogenic.
All patients received a single oral dose of dexamethasone.
The treatment regimens for the Akynzeo and the palonosetron 500 microgram PO arms are displayed in Table 5.

After completion of cycle 1, patients had the option to participate in a multiple cycle extension, receiving the same treatment as assigned in cycle 1. There was no prespecified limit of the number of repeat consecutive cycles for any patient. A total of 1450 patients (Akynzeo n = 725; palonosetron n = 725) actually received study medication: of these, 1438 patients (98.8%) completed cycle 1 and 1286 patients (88.4%) continued treatment in the multiple cycle extension. A total of 907 patients (62.3%) completed the multiple cycle extension up to a maximum of eight treatment cycles.
Of the 725 patients who received Akynzeo study medication, 711 (98%) were women; 79% were White, 14% Asian, 6% Hispanic, and < 1% were Black or other. Age ranged from 22 to 79 years, with a median age of 54 years. A total of 724 patients (99.9%) were treated with cyclophosphamide. All patients were additionally treated with either doxorubicin (68.0%) or epirubicin (32.0%).
During the first cycle, 32% of the 725 patients treated with Akynzeo received a concomitant chemotherapeutic agent in addition to protocol mandated regimens, with the most common chemotherapeutic being fluorouracil (28.3%) and docetaxel (2.6%).
The primary efficacy endpoint was the CR rate in the delayed phase, 25-120 hours after the start of the chemotherapy administration. Major secondary efficacy endpoints included:
CR for the acute and the overall phase;
complete protection (defined as no emesis, no rescue therapy, no significant nausea) for the delayed, the acute and the overall phase;
no emesis for the delayed, the acute and the overall phase;
no significant nausea (maximum VAS < 25 mm) and no nausea (maximum VAS < 5 mm) for the delayed, the acute and the overall phase.
A summary of the key results from study 2 is shown in Table 6.

Complete response.

The primary efficacy analysis was conducted in 1449 randomised patients who received the chemotherapy regimen and the study treatment. The proportion of patients with CR in the delayed phase was 7.4% (95% CI: 2.9 to 11.9%) higher (p-value = 0.001) in the Akynzeo group (76.9%) than in the palonosetron group (69.5%). In the acute phase, the proportion of patients with CR was 3.4% higher (p-value = 0.047) in the Akynzeo group (88.4%) than in the palonosetron group (85.0%). In the overall phase, the proportion of patients with CR was 7.7% higher (p-value = 0.001) in the Akynzeo group (74.3%) than in the palonosetron group (66.6%).

Multiple cycles.

Patients continued into the multiple cycle extension for up to 7 additional cycles of chemotherapy. The proportion of patients with complete response and no significant nausea in the delayed phase by treatment group at each cycle (cycles 2 to 6) is displayed in Figure 1. A limited number of patients received treatment beyond cycle 6. During all cycles the CR rate and the proportion of patients with no significant nausea rates in the delayed phase were higher for Akynzeo than for palonosetron PO. Antiemetic activity of Akynzeo was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

Patient reported outcomes.

The impact of nausea and vomiting on patients' daily lives was assessed using the Functional Living Index-Emesis (FLIE), a validated specific patient reported outcome measure of the impact of nausea and vomiting on daily life. The proportion of patients with overall no impact in daily life was 6.3% higher (p-value = 0.005) in the Akynzeo group (78.5%) than in the palonosetron group (72.1%).
The proportion of patients with no impact in daily life of the vomiting domain was 5.6% higher (p-value = 0.001) in the Akynzeo group (90.1%) than in the palonosetron group (84.4%). The proportion of patients with no impact in daily life of the nausea domain was 5.8% higher (p-value = 0.015) in the Akynzeo group (71.5%) than in the palonosetron group (65.8%).

Safety study in patients receiving either highly emetogenic chemotherapy or moderately emetogenic chemotherapy.

In one multicentre, multinational, randomised, active controlled, double blind, double dummy, unbalanced (3:1), parallel group, clinical study the safety and the efficacy of a single oral dose of Akynzeo was compared to an antiemetic regimen with aprepitant and palonosetron in cancer patients scheduled to receive either a highly emetogenic chemotherapy or a moderately emetogenic chemotherapy regimen. Patients were metabolised (3:1) on day 1 of their first chemotherapy cycle, before administration of chemotherapy, to the two treatment groups, as displayed in Table 7, according to the emetogenicity regimen.

A total of 413 patients were randomised in the study, to receive either Akynzeo (n = 309) or aprepitant and palonosetron (n = 104).
Lung and respiratory tract, ovarian, colorectal and head and neck cancer were the most frequent cancer types, with 50% of patients having metastatic disease.
A total of 412 patients received study medication (Akynzeo n = 309; aprepitant and palonosetron n = 103), and 23 patients discontinued after randomisation and during any planned chemotherapy cycle. Of the 412 patients who were treated with study medication, 405 patients (98.1%) completed cycle 1 and 376 patients were scheduled for treatment in the following cycles up to a maximum of 14 cycles. A total of 165 patients (40.4%) completed at least 6 cycles of treatment.
Of the 309 patients who were randomised to the Akynzeo arm and received study medication, 155 (50.2%) were women; 84% were White, 15% Asian, 6% Hispanic, and 1% were Black. The age ranged from 27 to 76 years, with a median age of 57 years.
During the first cycle, a total of 75 patients (24.3%) who were randomised to the Akynzeo arm and received study medication were treated with a HEC regimen (cisplatin, 96% or dacarbazine, 4%). A total of 234 patients (75.7%) received a MEC regimen, the most common chemotherapeutic agents being carboplatin (60.3%), oxaliplatin (20.1%) and doxorubicin (11.1%).
The primary objective of the study was to assess the safety and tolerability of Akynzeo in initial and repeated cycles of chemotherapy. The secondary objective of the study was to describe its efficacy.
Akynzeo safety profile was comparable to aprepitant and palonosetron in patients undergoing initial and repeat cycles of MEC or HEC. Safety data in the Akynzeo arm have been integrated and described elsewhere (see Section 4.8 Adverse Effects (Undesirable Effects)).
In cycle 1, the proportion of patients with a CR was numerically higher in the Akynzeo arm compared to aprepitant and palonosetron for the delayed (83.2% vs. 77.7%) and overall (80.6% vs. 75.7%) phases. Efficacy was maintained throughout the study.
No clinically meaningful effect of Akynzeo on blood pressure, heart rate, and ECG parameters, including QTc, was observed and was comparable to aprepitant and palonosetron in CINV clinical studies.