4.1. Therapeutic indications

Akynzeo is indicated in adults for the:

- Prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin‑based cancer chemotherapy.

- Prevention of acute and delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy.

4.2. Posology and method of administration

Posology

One 300 mg/0.5 mg capsule should be administered approximately one hour prior to the start of each chemotherapy cycle.

The recommended oral dexamethasone dose should be reduced by approximately 50 % when co-administered with netupitant/palonosetron capsules (see section 4.5 and clinical studies administration schedule in section 5.1).

Special populations

Elderly people

No dosage adjustment is necessary for elderly patients. Caution should be exercised when using this medicinal product in patients over 75 years, due to the long half-life of the active substances and the limited experience in this population.

Renal impairment

Dosage adjustment is not considered necessary in patients with mild to severe renal impairment. Renal excretion for netupitant is negligible. Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure to intravenous palonosetron increased by approximately 28% in severe renal impairment relative to healthy subjects. The pharmacokinetics of palonosetron or netupitant has not been studied in subjects with end-stage renal disease requiring hemodialysis and no data on the effectiveness or safety of netupitant/palonosetron capsules in these patients are available. Therefore, use in these patients should be avoided.

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 of netupitant, this medicinal product should be used with caution in these patients (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of Akynzeo capsules in the paediatric population have not been established. No data are available.

Method of administration

For oral use.

The hard capsule should be swallowed whole.

It can be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

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 (see section 4.8).

Serotonin syndrome

There have been reports of serotonin syndrome with the use of 5-HT3 antagonists either alone or in combination with other serotonergic medicinal products (including selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors (SNRIs). Appropriate observation of patients for serotonin syndrome-like symptoms is advised (see section 4.8).

QT Prolongation

An ECG study was conducted in adult male and female healthy volunteers with oral netupitant either 200 or 600 mg administered in combination with oral palonosetron 0.5 or 1.5 mg, respectively. The study demonstrated no clinically important effects on ECG parameters: the largest point estimate of the placebo and baseline corrected QTc interval was 7.0 ms (one-sided upper 95% confidence limit 8.8 ms), observed 16 hours after the administration of supratherapeutic doses (600 mg netupitant and 1.5 mg palonosetron). Upper 95% confidence limit of the point estimates of placebo and baseline corrected QTcI was constantly within 10 ms at all time points over 2 days after study substance administration.

However, since netupitant/palonosetron capsules contains a 5-HT3 receptor antagonist, caution should be exercised in concomitant use 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, bradyarrhythmia, conduction disturbances and in patients taking anti-arrhythmic medicinal products or other medicinal products that lead to QT prolongation or electrolyte abnormalities. Hypokalaemia and hypomagnesaemia should be corrected prior to administration.

Caution should be exercised in patients with severe hepatic impairment since limited data are available in these patients.

This medicinal product should be used with caution in patients receiving concomitant orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range (see section 4.5).

Chemotherapeutic agents that are substrates for CYP3A4

Netupitant is a moderate inhibitor of CYP3A4 and can increase the exposure of chemotherapeutic agents that are substrates for CYP3A4 e.g. docetaxel (see section 4.5). Therefore, patients should be monitored for increased toxicity of chemotherapeutic agents that are substrates for CYP3A4, including irinotecan. Furthermore, netupitant may also affect the efficacy of chemotherapeutic agents that need activation by CYP3A4 metabolism.

Excipients

This medicinal product contains 7 mg of sorbitol in each hard capsule.

This medicinal product also contains 20 mg of sucrose in each capsule. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium per (23 mg) per hard capsule, that is to say essentially 'sodium-free'.

It 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 (see section 4.8).

4.5. Interaction with other medicinal products and other forms of interaction

When netupitant/palonosetron capsules are used concomitantly with another CYP3A4 inhibitor, netupitant plasma concentrations could be elevated. When this medicinal product is used concomitantly with medicinal products that induce CYP3A4 activity, netupitant plasma concentrations could be reduced and this may result in decreased efficacy. This medicinal product can increase plasma concentrations of concomitantly administered medicinal products that are metabolised via CYP3A4.

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. Palonosetron is mainly metabolised by CYP2D6, with minor contribution by CYP3A4 and CYP1A2 isoenzymes. Based on in vitro studies, palonosetron does not inhibit or induce cytochrome P450 isoenzyme at clinically relevant concentrations.

Interaction between oral netupitant and oral palonosetron:

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

Interaction with CYP3A4 substrates:

Dexamethasone

Co-administration of a single dose of 300 mg netupitant with a dexamethasone regimen (20 mg on Day 1, followed by 8 mg twice daily from Day 2 to Day 4) significantly increased the exposure to dexamethasone in a time and dose dependent manner. The AUC0-24 (Day 1), the AUC24-36 (Day 2) and the AUC84-108 and AUC84-∞ (Day 4) of dexamethasone increased 2.4-fold, with co-administration of 300 mg netupitant. The pharmacokinetic profile of netupitant was unchanged when administered in combination with dexamethasone.

As such, the oral dexamethasone dose should be reduced by approximately 50% when co-administered with netupitant/palonosetron capsules (see section 4.2).

Chemotherapeutic medicinal products (docetaxel, etoposide, cyclophosphamide)

Exposure to docetaxel and etoposide was increased 37% and 21%, respectively, when co-administered with netupitant/palonosetron capsules. No consistent effect was seen with cyclophosphamide after netupitant co-administration.

Oral contraceptives

Netupitant/palonosetron capsules, when given with a single oral dose of 60 μg ethinylestradiol and 300 μg 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 of 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 co-administered with netupitant. These effects were not considered clinically important. 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 metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these active substances with netupitant/palonosetron capsules.

Serotonergic medicinal products (e.g. SSRIs and SNRIs)

There have been reports of serotonin syndrome following concomitant use of 5-HT3 antagonists and other serotonergic medicinal products (including SSRIs such as fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram or escitalopram and SNRIs such as venlafaxine or duloxetine) (see section 4.4).

Effect of other medicinal products on the pharmacokinetics of Akynzeo

Netupitant is mainly metabolized by CYP3A4; therefore, co-administration with medicinal products that inhibit or induce CYP3A4 activity may influence plasma concentrations of netupitant. Consequently, concomitant administration with strong CYP3A4 inhibitors (e.g., ketoconazole) should be approached with caution and concomitant administration with strong CYP3A4 inducers (e.g., rifampicin) should be avoided. Moreover, this medicinal product should be used with caution in patients receiving concomitant orally administered active substances with a narrow therapeutic range that are primarily metabolized by CYP3A4, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine.

Effect of ketoconazole and rifampicin

Administration of the CYP3A4 inhibitor ketoconazole with netupitant/palonosetron capsules increased the AUC of netupitant 1.8 fold and Cmax 1.3 fold when compared to the administration of netupitant/palonosetron capsules alone. Co-administration with ketoconazole did not affect the pharmacokinetics of palonosetron.

Administration of the CYP3A4 inducer rifampicin with Akynzeo alone decreased the AUC of netupitant 5.2 fold and Cmax 2.6 fold. Co-administration of rifampicin did not affect the pharmacokinetics of palonosetron. Consequently, concomitant administration with strong CYP3A4 inhibitors (e.g., ketoconazole) should be approached with caution and concomitant administration with strong CYP3A4 inducers (e.g. rifampicin) should be avoided.

Additional interactions

Netupitant/palonosetron capsules are unlikely to interact with medicinal products which are P-gp substrates. Netupitant is not a substrate for P-gp. When netupitant was administered on Day 8 of a 12‑day regimen of digoxin, no changes in digoxin pharmacokinetics were observed.

Inhibition of the efflux transported BCRP and glucuronidation isozyme UGT2B7 by netupitant and its metabolites is unlikely and, if it occurs, of scarce clinical relevance.

In vitro data shows that netupitant inhibits UGT2B7, the magnitude of such an effect in the clinical setting is not established. Caution is recommended when netupitant is combined with an oral substrate of this enzyme (e.g.zidovudine, valproic acid, morphine).

In vitro data suggests that netupitant inhibits the efflux of transporter BCRP. The clinical relevance of this effect is not established.

In vitro data show that netupitant is a P-gp inhibitor. In a study performed in healthy volunteers, netupitant does not affect the exposure of digoxin, a P-gp substrate, whereas it increases its Cmax by 1.09 fold [90%CI 0.9-1.31]. It is not 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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/ contraception in females

Women of childbearing potential should not be pregnant or become pregnant while on treatment with netupitant/palonosetron capsules. 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.

Pregnancy

Netupitant

There are no data about the use of netupitant in pregnant women. Studies in animals have shown reproductive toxicity including teratogenic effects in rabbit without safety margin (see section 5.3).

Palonosetron

There are no data about the use of palonosetron in pregnant women. Animal data do not indicate direct or indirect harmful effects of palonosetron with the respect to reproductive toxicity (see section 5.3).

Netupitant/palonosetron capsules are contraindicated during pregnancy (see section 4.3).

Breast‑feeding

It is unknown whether palonosetron or netupitant are excreted in human milk. A risk to the suckling child cannot be excluded. Netupitant/palonosetron capsules should not be used during breast-feeding. Breast-feeding should be discontinued during treatment with this medicinal product and for 1 month after the last dose.

Fertility

Netupitant

No effect on fertility has been observed in animal studies.

Palonosetron

Degeneration of seminiferous epithelium has been observed in rat study (see section 5.3).

4.7. Effects on ability to drive and use machines

Netupitant/palonosetron capsules have moderate influence on the ability to drive and use machines. Since it may induce dizziness, somnolence or fatigue, patients should be cautioned not to drive or use machines if such symptoms occur.

4.8. Undesirable effects

Summary of the safety profile

Common adverse reactions reported with netupitant/palonosetron capsules were headache (3.6%), constipation (3.0%) and fatigue (1.2%).

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA body system organ class and frequency.

The following convention has been used for classification of frequency:

Very common (≥1/10),

Common (≥1/100 to <1/10),

Uncommon (≥1/1,000 to <1/100),

Rare (≥1/10,000 to <1/1,000),

Very rare (<1/10,000),

Not known (cannot be estimated from the available data).

Table1: Adverse reactions

System organ class

Common

Uncommon

Rare

Infections and infestations

Cystitis

Blood and lymphatic system disorders

Neutropenia

Leukopenia

Leucocytosis

Lymphocytosis

Metabolism and nutrition disorders

Decreased appetite

Hypokalaemia

Psychiatric disorders

Insomnia

Acute psychosis

Mood altered

Sleep disorder

Nervous system disorders

Headache

Dizziness

Hypoaesthesia

Somnolence

Eye disorders

Conjunctivitis

Vision blurred

Ear and labyrinth disorders

Vertigo

Tinnitus

Cardiac disorders

Atrioventricular block first degree

Arrhythmia

Cardiomyopathy

Atrioventricular block second degree

Conduction disorder

Bundle branch block left

Tachycardia

Bundle branch block right

Mitral valve incompetence

Myocardial ischaemia

Ventricular extrasystoles

Vascular disorders

Hypertension

Flushing

Hypotension

Respiratory, thoracic and mediastinal disorders

Hiccups

Gastrointestinal disorders

Constipation

Abdominal distension

Dry mouth

Abdominal pain

Dysphagia

Diarrhoea

Eructation

Dyspepsia

Haemorrhoids

Flatulence

Tongue coated

Nausea

Vomiting

Skin and subcutaneous tissue disorders

Alopecia

Erythema

Urticaria

Pruritus

Rash

Musculoskeletal and connective tissue disorders

Back pain

Pain in extremities

General disorders and administration site conditions

Fatigue

Asthenia

Feeling hot

Non-cardiac chest pain

Product taste abnormal

Investigations

Liver transaminases increased

Blood bilirubin increased

Blood alkaline phosphatase increased

Blood creatine phosphokinase increased

Blood creatinine increased

Blood creatine phosphokinase MB increased

Electrocardiogram QT prolonged

Blood urea increased

Electrocardiogram ST segment depression

Electrocardiogram ST-T segment abnormal

Myoglobin blood increased

Neutrophil count increased

Troponin increased

Post-marketing data indicates that the adverse reactions profile is generally similar to that seen in clinical trials.

Description of selected adverse reactions

Netupitant:

No common adverse reactions are attributable to netupitant, the new component of the fixed combination.

Palonosetron:

Cases of constipation with faecal impaction requiring hospitalisation have been reported in association with palonosetron 0.75 mg.

In addition, eye swelling, dyspnoea and myalgia as adverse reactions have been reported with oral palonosetron but not observed during the development of this medicinal product. All these reactions were uncommon.

Very rare cases of anaphylaxis, anaphylactic/anaphylactoid reactions and shock have been reported from the post-marketing use of intravenous palonosetron. The signs may include hives, itch, angioedema, low blood pressure, throat tightness, chest tightness, dyspnoea, loss of consciousness.

There have also been reports of serotonin syndrome. The signs may include tremor, agitation, sweating, myoclonic movements, hypertonia and fever.

Netupitant and Palonosetron Combinate Capsule:

This medicinal product may 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. The signs may include hives, skin rash, itching, difficulty breathing or swallowing, swollen mouth, face, lips, tongue or throat and sometimes a drop-in blood pressure.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme (Website: www.mhra.gov.uk/yellowcard).

4.9. Overdose

Based on the experience with healthy subjects exposed to oral netupitant 600 mg in combination with palonosetron 1.50 mg the potential acute symptoms of overdose are headache, dizziness, constipation, anxiety, palpitations, euphoric mood and pain in the legs. In case of overdose, the medicinal product 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 overdose.