Akynzeo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AКІNЗEO® (AKYNZEO®)

Composition:

Active substances: netupitant, palonosetron hydrochloride calculated as palonosetron;

1 hard capsule contains 300 mg of netupitant and 0.56 mg of palonosetron hydrochloride, equivalent to 0.5 mg of palonosetron;

Excipients: netupitant tablets: microcrystalline cellulose (pH 101), sucrose ester of lauric acid, povidone K-30, sodium croscarmellose, purified water, silicon dioxide/hydrated colloidal silicon dioxide, sodium stearyl fumarate, magnesium stearate; soft capsule content of palonosetron: glycerol monocaprylocaprate (type I), glycerin (anhydrous), polyglyceryl dioleate, purified water, butylhydroxyanisole; soft capsule shell: gelatin, sorbitol (special mixture: 50% glycerin and 50% sorbitol solution), titanium dioxide, purified water; hard capsule shell: gelatin, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172), printing ink (shellac glaze ~45% (20% esterified) in ethanol, black iron oxide (E172), propylene glycol (E1520), ammonium hydroxide 28% (E527).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsule of size 0, caramel-white in color with black print "HE1" on the white part, containing three tablets – round, flat, almost white, with smooth beveled edges – and one soft gelatin capsule – smooth, from round to oval shape, opaque light beige in color.

Pharmacotherapeutic group.

Antiemetics and drugs used to relieve nausea. Serotonin (5-HT3) antagonists.

ATC code A04A A55.

Pharmacological properties.

Pharmacodynamics

Mechanism of action

Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1) receptors.

Palonosetron is a serotonin 5-HT3 receptor antagonist with high affinity for this receptor and little or no affinity for other receptors. Chemotherapeutic agents induce nausea and vomiting by stimulating the release of serotonin from enterochromaffin cells in the small intestine. Serotonin then activates 5-HT3 receptors located on afferent vagal nerve fibers, initiating the vomiting reflex.

Delayed vomiting has been associated with activation of neurokinin 1 (NK1) receptors of the tachykinin family (widely distributed in the central and peripheral nervous systems) by substance P. In vitro and in vivo studies have shown that netupitant inhibits substance P-mediated responses.

Netupitant has been shown to cross the blood-brain barrier, where NK1 receptor occupancy was 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in the striatum at 6, 24, 48, 72, and 96 hours after administration of a 300 mg dose of netupitant.

Clinical efficacy and safety

Based on two separate pivotal studies, oral administration of AKNINZEO® in combination with dexamethasone has been shown to prevent acute and delayed nausea and vomiting associated with highly emetogenic and moderately emetogenic cancer chemotherapy.

Study of highly emetogenic chemotherapy (HEC)

In a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial involving 694 cancer patients receiving chemotherapy regimens containing cisplatin (mean dose 75 mg/m²), the efficacy and safety of a single oral dose of netupitant in combination with palonosetron were compared to a single oral dose of palonosetron alone. The efficacy of AKNINZEO® was evaluated in 135 patients who received a single oral dose (netupitant 300 mg and palonosetron 0.5 mg) and in 136 patients who received monotherapy with palonosetron 0.5 mg.

The treatment regimens for AKNINZEO® and palonosetron 0.5 mg are presented in Table 1.

Table 1

Oral treatment regimen for vomiting, HEC study

The primary efficacy endpoint was the percentage of patients achieving complete objective response (defined as no vomiting, no use of rescue medication) during the 120-hour period (overall phase) following initiation of highly emetogenic chemotherapy.

The summary of the main results of this study is presented in Table 2.

Table 2

Proportion of patients receiving cisplatin-based chemotherapy who responded to treatment

‡ Acute phase: from 0 to 24 hours after cisplatin treatment.

† Delayed phase: from 25 to 120 hours after cisplatin treatment.

§ Overall: from 0 to 120 hours after cisplatin treatment.

Study of moderate emetogenic chemotherapy (MEC)

In a multicenter, randomized, double-blind, parallel-group study with active control to demonstrate superior efficacy and safety, a single oral dose of Akynzeo® was compared with a single oral dose of palonosetron 0.5 mg in cancer patients receiving their first cycle of anthracycline and cyclophosphamide chemotherapy for solid malignancies. At the time of the study, anthracycline and cyclophosphamide regimens were considered moderate emetogenic chemotherapy. According to recent guidelines, these regimens have since been reclassified as highly emetogenic.

All patients received a single oral dose of dexamethasone.

Table 3

Oral antiemetic regimen, MEC study

After completion of cycle 1, patients had the opportunity to participate in extended multi-cycle treatment, receiving the same treatment as in cycle 1. There was no predefined limit on the number of repeated consecutive cycles for any patient. Overall, 1450 patients (Akynzeo® product, n = 725; palonosetron, n = 725) received the investigational product. Of these, 1438 patients (98.8%) completed cycle 1, and 1286 patients (88.4%) continued extended multi-cycle treatment. Overall, 907 patients (62.3%) completed extended multi-cycle treatment by up to the eighth cycle.

Overall, 724 patients (99.9%) received cyclophosphamide. All patients were additionally treated with doxorubicin (68.0%) or epirubicin (32.0%).

The primary efficacy endpoint was the percentage of patients with complete objective response in the delayed phase from 25 to 120 hours after initiation of chemotherapy.

A summary of the main results of this study is presented in Table 4.

Table 4

Proportion of patients receiving anthracycline- and cyclophosphamide-based chemotherapy who responded to treatment, by group and phase – cycle 1.

* p-value from the Cochran-Mantel-Haenszel test, stratified by age, class, and region.

‡ Acute phase: from 0 to 24 hours after administration of the anthracycline and cyclophosphamide treatment regimen,

† Delayed phase: from 25 to 120 hours after administration of the anthracycline and cyclophosphamide treatment regimen,

§ Overall: from 0 to 120 hours after administration of the anthracycline and cyclophosphamide treatment regimen.

Patients continued participation in the extended multi-cycle treatment phase for up to 7 cycles of chemotherapy. The antiemetic effect of Akinzéo® was maintained in patients who continued treatment with the drug in each chemotherapy cycle.

The impact of nausea and vomiting on patients' daily lives was assessed using the Functional Living Index-Emesis (FLIE). The proportion of patients with no overall impact on daily life in the Akinzéo® study group (78.5%) was 6.3% higher (p-value = 0.005) than in the palonosetron study group (72.1%).

Safety study of the multi-cycle treatment phase in patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy

In a separate study, a total of 413 patients undergoing initial and repeated chemotherapy cycles (including regimens based on carboplatin, cisplatin, oxaliplatin, and doxorubicin) were randomized to receive Akinzéo® (n = 309) or aprepitant and palonosetron (n = 104). Safety and efficacy were maintained across all cycles.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Akinzéo® in all pediatric subpopulations for the prevention of acute or delayed nausea and vomiting associated with highly emetogenic and moderately emetogenic chemotherapy based on cisplatin in cancer (see section "Posology and method of administration").

Pharmacokinetics

Absorption

Netupitant

Exact data on the bioavailability of netupitant in humans are lacking; however, based on data from two intravenous administration studies, human bioavailability is estimated to be greater than 60%.

In single oral dose studies, netupitant was detectable in plasma within 15 minutes and 3 hours after dosing. Plasma concentrations followed first-order absorption kinetics and reached Cmax approximately 5 hours after administration. A supraproportional increase in Cmax and AUC parameters was observed for doses ranging from 10 mg to 300 mg.

In 82 healthy volunteers who received a single oral dose of 300 mg netupitant, the maximum plasma concentration (Cmax) was 486 ± 268 ng/mL (mean ± SD), the median time to reach maximum concentration (Tmax) was 5.25 hours, and the AUC value was 15,032 ± 6,858 h·ng/mL. In a pooled analysis, netupitant showed higher exposure in females compared to males; Cmax increased by 1.31-fold, AUC by 1.02-fold, and elimination half-life by 1.36-fold.

The AUC0-∞ and Cmax of netupitant increased by 1.1- and 1.2-fold, respectively, after consumption of a high-fat meal.

Palonosetron

After oral administration, palonosetron is well absorbed, with an absolute bioavailability of 97%. After single oral doses using a buffered solution, mean maximum plasma concentrations (Cmax) and area under the concentration-time curve (AUC0-∞) were dose-proportional over the range of 3.0 to 80 µg/kg in healthy volunteers.

In 36 healthy men and women who received a single oral dose of 0.5 mg palonosetron, the mean maximum plasma concentration (Cmax) was 0.81 ± 1.66 ng/mL (mean ± SD), and the time to reach maximum concentration (Tmax) was 5.1 ± 1.7 hours. In women (n = 18), mean AUC was 35% higher and mean Cmax was 26% higher than in men (n = 18). In 12 cancer patients who received a single oral dose of 0.5 mg palonosetron one hour before chemotherapy, Cmax was 0.93 ± 0.34 ng/mL and the time to reach maximum concentration was 5.1 ± 5.9 hours. AUC values in cancer patients were 30% higher than in healthy volunteers. A high-fat meal did not affect Cmax or AUC after oral administration of palonosetron.

Distribution

Netupitant

After a single oral dose of 300 mg in cancer patients, netupitant distribution was characterized by a two-compartment model with an estimated mean systemic clearance of 20.5 L/h and a large volume of distribution in the central compartment (486 L). Plasma protein binding of netupitant and its two main metabolites M1 and M3 exceeds 99% at concentrations ranging from 10 to 1500 ng/mL. The third main metabolite, M2, is bound to plasma proteins by > 97%.

Palonosetron

The volume of distribution of palonosetron is approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is protein-bound in plasma.

Biotransformation

Netupitant

Three metabolites have been identified in human plasma after oral administration of netupitant at doses of 30 mg and higher (desmethyl derivative – M1, N-oxide derivative – M2, OH-methyl derivative – M3). In vitro metabolism studies showed that cytochrome CYP3A4, and to a lesser extent CYP2D6 and CYP2C9, are involved in netupitant metabolism. After a single oral dose of 300 mg netupitant, the ratio of mean netupitant plasma concentration to total radioactivity in plasma ranged from 0.13 to 0.49 over 96 hours post-dose. These ratios were time-dependent and gradually decreased within 24 hours after dosing, indicating rapid metabolism of netupitant. Mean Cmax values were approximately 11%, 47%, and 16% of the parent compound for M1, M2, and M3, respectively; M2 had the lowest AUC value compared to the parent compound (14%), while mean AUC values for M1 and M3 were approximately 29% and 33% of the parent compound, respectively. All metabolites M1, M2, and M3 have been shown to be pharmacologically active in animal pharmacodynamic models, with M3 being the most active and M2 the least active.

Palonosetron

Palonosetron is eliminated via multiple pathways, with approximately 50% undergoing metabolism to form two main metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. Each of these metabolites has less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies showed that cytochrome CYP2D6, and to a lesser extent CYP3A4 and CYP1A2, are involved in palonosetron metabolism. However, clinical pharmacokinetic parameters do not differ significantly between poor and extensive metabolizers of CYP2D6 substrates.

Elimination

Netupitant

After administration of a single dose of Akinzéo®, netupitant is eliminated from the body in a multi-exponential manner, with a mean elimination half-life of 88 hours in cancer patients.

Renal clearance is not the primary route of elimination of netupitant metabolites. On average, less than 1% of the oral dose of netupitant is excreted unchanged in urine; overall, 3.95% and 70.7% of the radioactive dose were excreted in urine and feces, respectively.

Approximately half of the radioactivity administered orally as [14C]-netupitant was excreted in urine and feces within 120 hours after dosing. It is estimated that complete elimination via both routes took 29–30 days after administration.

Palonosetron

After administration of a single oral dose of 0.75 mg [14C]-palonosetron in six healthy volunteers, 85–93% of total radioactivity was excreted in urine and 5–8% in feces. The amount of unchanged palonosetron excreted in urine is approximately 40% of the administered dose. In healthy volunteers who received 0.5 mg palonosetron capsules, the elimination half-life (t½) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer patients it was 48 ± 19 hours. After intravenous administration of a single dose of palonosetron (approximately 0.75 mg), total clearance of palonosetron in healthy volunteers was 160 ± 35 mL/h/kg (mean ± SD), and renal clearance was 66.5 ± 18.2 mL/h/kg.

Special populations

Hepatic impairment

Netupitant

Maximum concentrations and overall exposure to netupitant were increased in patients with mild (n = 8), moderate (n = 8), and severe (n = 2) hepatic impairment compared to healthy volunteers, although both study groups (healthy and those with hepatic impairment) showed considerable individual variability. Compared to healthy volunteers, Cmax, AUC0-t, and AUC0-∞ of netupitant were 11%, 28%, and 19% higher in patients with mild hepatic impairment and 70%, 88%, and 143% higher in patients with moderate hepatic impairment, respectively. Therefore, dose adjustment is not required in patients with mild or moderate hepatic impairment. There is insufficient data on the use of the drug in patients with severe hepatic impairment (≥ 9 on the Child-Pugh scale).

Palonosetron

Hepatic impairment does not significantly affect the total clearance of palonosetron compared to healthy volunteers. Although the terminal half-life and mean systemic exposure of palonosetron are increased in patients with severe hepatic impairment, dose reduction is not required.

Renal impairment

Netupitant

Specific studies evaluating the effect of netupitant in patients with renal impairment have not been conducted. In absorption, distribution, metabolism, and excretion studies, less than 5% of netupitant-related substances were excreted in urine, and less than 1% of the netupitant dose was excreted unchanged. Therefore, any accumulation of netupitant or its metabolites after a single dose would be negligible. Furthermore, population pharmacokinetic studies showed no correlation between netupitant PK parameters and markers of renal impairment.

Palonosetron

Moderate and severe renal impairment do not affect the PK parameters of palonosetron. Total systemic exposure to intravenously administered palonosetron is increased by approximately 28% in patients with severe renal impairment compared to healthy volunteers. In population pharmacokinetic studies, patients with reduced creatinine clearance (CLCR) also had reduced palonosetron clearance, but this did not lead to significant changes in palonosetron exposure.

Therefore, Akinzéo® can be administered without dose adjustment in patients with renal impairment.

Neither netupitant nor palonosetron has been evaluated in patients with end-stage renal disease.

Non-clinical safety data

Palonosetron

Effects observed in non-clinical studies occurred only at exposures substantially exceeding the maximum human exposures, indicating limited relevance for clinical use.

Non-clinical studies indicate that palonosetron may block ion channels involved in ventricular depolarization and repolarization and prolong action potential duration only at very high concentrations. After a one-month repeated oral toxicity study in rats, degeneration of the epithelium of the vas deferens was associated with palonosetron. Animal studies did not show direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Data on placental transfer of palonosetron from animal studies are limited (see section "Use during pregnancy or breastfeeding"). Palonosetron is not mutagenic. Daily administration of high doses of palonosetron (each dose at least 15 times higher than the therapeutic dose in humans) for two years resulted in increased incidence of liver tumors, endocrine tumors (in the thyroid gland, pituitary, pancreas, adrenal medulla), and skin tumors in rats, but not in mice. The underlying mechanisms are not fully understood; however, given the high doses used and the fact that the drug is intended for single use, these findings are not considered clinically relevant.

Netupitant and combination with palonosetron

In non-clinical studies based on pharmacological safety assessment and single and repeated dose toxicity, effects were observed only at doses exceeding the maximum human doses, indicating limited relevance for clinical use. Phospholipidosis (foamy macrophages) was observed in rats and dogs during repeated administration of netupitant. These findings were reversible or partially reversible after a recovery period. The significance of these findings for humans is unknown.

Non-clinical studies indicate that netupitant and its metabolites, as well as the combination with palonosetron, may block ion channels involved in ventricular depolarization and repolarization and prolong action potential duration only at very high concentrations. Reproductive toxicity studies in animals with netupitant did not show direct or indirect harmful effects on reproductive function, parturition, or postnatal development. Increased incidence of fetal limb positional abnormalities, fused sternum segments, and absence of an accessory lung lobe were observed in rabbits after daily administration of netupitant at doses of 10 mg/kg/day and higher during the organogenesis period. In a dose-range finding study in rabbits, cleft palate, microphthalmia, and aphakia were observed in four fetuses from one litter in the group receiving 30 mg/kg/day. The significance of these findings for humans is unknown. Data on placental transfer and excretion into milk from animal studies are lacking. Netupitant is not mutagenic.

Clinical characteristics.

Indications.

• Prevention of acute or delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy based on cisplatin in adults.
• Prevention of acute or delayed nausea and vomiting associated with moderately emetogenic cancer chemotherapy in adults.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients.

Pregnancy.

Interaction with other medicinal products and other forms of interaction.

When netupitant/palonosetron, capsules, are used concomitantly with another inhibitor of cytochrome CYP3A4, plasma concentrations of netupitant may be increased. Concomitant use of Akynzeo® with medicinal products that induce CYP3A4 enzyme activity may reduce netupitant plasma concentrations, potentially leading to reduced efficacy of the drug. This medication may increase plasma concentrations of concomitantly administered drugs metabolized by cytochrome CYP3A4.

In humans, netupitant is primarily eliminated via hepatic metabolism mediated by cytochrome CYP3A4, with minimal renal excretion. Netupitant at a dose of 300 mg in humans is a substrate and a moderate inhibitor of cytochrome CYP3A4. Palonosetron is eliminated from the body via renal and metabolic pathways, with the latter mediated by several cytochrome CYP enzymes. Palonosetron is predominantly metabolized by cytochrome CYP2D6, with minor contributions from CYP3A4 and CYP1A2 isoenzymes. In vitro studies indicate that palonosetron does not inhibit or induce cytochrome P450 isoenzymes at clinically relevant concentrations.

Interaction between netupitant and palonosetron upon oral administration

Clinically significant pharmacokinetic interactions between netupitant and palonosetron upon oral administration are absent.

Interaction with cytochrome CYP3A4 substrates

Dexamethasone

Concomitant administration of a single 300 mg dose of netupitant with dexamethasone (20 mg on Day 1, followed by 8 mg twice daily on Days 2–4) significantly increased the time- and dose-dependent exposure to dexamethasone. AUC0–24 (Day 1), AUC24–36 (Day 2), AUC84–108, and AUC84–∞ (Day 4) of dexamethasone increased by 2.4-fold when co-administered with 300 mg of netupitant. The pharmacokinetic profile of netupitant was not altered when administered concomitantly with dexamethasone.

Therefore, the oral dose of dexamethasone should be reduced by approximately 50% when administered concomitantly with netupitant/palonosetron, capsules (see section "Posology and method of administration").

Chemotherapeutic agents (docetaxel, etoposide, cyclophosphamide)

Concomitant administration of netupitant/palonosetron, capsules, increased exposure to docetaxel and etoposide by 37% and 21%, respectively. No consistent effect was observed when cyclophosphamide was administered concomitantly with netupitant.

Oral contraceptives

Netupitant/palonosetron, capsules, administered orally, did not affect the AUC of ethinylestradiol and increased the AUC of levonorgestrel by 1.4-fold following a single dose of 60 mcg ethinylestradiol and 300 mcg levonorgestrel. The clinical impact on hormonal contraceptive efficacy is unlikely. No relevant changes in the pharmacokinetics of netupitant or palonosetron were observed.

Erythromycin and midazolam

Exposure to erythromycin and midazolam increased by approximately 1.3-fold and 2.4-fold, respectively, when administered concomitantly with netupitant. These effects are not considered clinically significant. Concomitant administration of netupitant with midazolam or erythromycin did not affect its pharmacokinetic profile. When these active substances are used concomitantly with netupitant/palonosetron, capsules, potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized by cytochrome CYP3A4 (e.g., alprazolam, triazolam) should be considered.

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

Serotonin syndrome has been reported 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 "Special warnings and precautions for use").

Effect of other medicinal products on the pharmacokinetics of Akynzeo®

Netupitant is primarily metabolized by cytochrome CYP3A4; therefore, concomitant use of medicinal products that inhibit or induce CYP3A4 activity may affect netupitant plasma concentrations. Thus, caution is advised when Akynzeo® is used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole), and concomitant use with strong CYP3A4 inducers (e.g., rifampicin) should be avoided. Additionally, this medicinal product should be used with caution in patients receiving orally administered drugs with a narrow therapeutic index that are primarily metabolized by CYP3A4, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, dihydroergotamine, ergotamine, fentanyl, and quinidine.

Effect of ketoconazole and rifampicin

Administration of the CYP3A4 inhibitor ketoconazole with netupitant/palonosetron, capsules, increased netupitant AUC in urine by 1.8-fold and Cmax by 1.3-fold compared to monotherapy with netupitant/palonosetron, capsules. Concomitant administration with ketoconazole did not affect the pharmacokinetics of palonosetron.

Administration of the CYP3A4 inducer rifampicin together with Akynzeo® reduced netupitant AUC in urine by 5.2-fold and Cmax by 2.6-fold. Concomitant administration of rifampicin did not affect the pharmacokinetics of palonosetron. Therefore, caution is advised when Akynzeo® is used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole), and concomitant use with strong CYP3A4 inducers (e.g., rifampicin) should be avoided.

Additional interactions

It is unlikely that netupitant/palonosetron, capsules, interact with medicinal products that are substrates of P-glycoprotein. Netupitant is not a substrate of P-glycoprotein. No changes in digoxin pharmacokinetics were observed when netupitant was administered concomitantly with digoxin on Day 8 of a 12-day treatment regimen.

Inhibition of the breast cancer resistance protein (BCRP) transporter and UGT2B7 isoenzyme by netupitant and its metabolites is unlikely, and if it occurs, is of minimal clinical significance.

In vitro data show that netupitant inhibits UGT2B7; the clinical relevance of this effect has not been established. Caution is recommended when netupitant is used concomitantly with oral substrates of this enzyme (e.g., zidovudine, valproic acid, morphine).

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

In vitro data suggest that netupitant is an inhibitor of P-glycoprotein. In a study conducted in healthy volunteers, netupitant did not affect digoxin exposure, a P-glycoprotein substrate, but increased its Cmax by 1.09-fold [90% CI – 0.9–1.31]. Such an effect may be more pronounced and potentially clinically significant in cancer patients, particularly in those with impaired renal function. Therefore, caution is recommended when netupitant is used concomitantly with digoxin or other P-glycoprotein substrates such as dabigatran or colchicine.

Special precautions for use.

Constipation

Since palonosetron may increase colonic transit time, patients with a history of constipation or signs of subacute bowel obstruction should be monitored after administration of the medicinal product (see section "Adverse reactions").

Serotonin syndrome

Cases of serotonin syndrome have been reported with the use of 5-HT3 antagonists, either as monotherapy or in combination with other serotonergic medicinal products, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Appropriate monitoring is recommended for patients presenting symptoms suggestive of serotonin syndrome (see section "Adverse reactions").

QT interval prolongation

An ECG monitoring study was conducted in healthy male and female volunteers who received netupitant orally at a dose of 200 mg or 600 mg in combination with oral palonosetron at a dose of 0.5 mg or 1.5 mg, respectively. The study did not show any clinically relevant effects on ECG parameters: the largest placebo-corrected and baseline-adjusted QT interval was 7.0 ms (one-sided upper bound of the 95% confidence interval 8.8 ms), observed 16 hours after administration of doses exceeding the therapeutic dose (600 mg netupitant and 1.5 mg palonosetron). The upper bound of the 95% confidence interval for the placebo-corrected and baseline-adjusted QT interval remained within 10 ms at all time points over 2 days following administration of the investigational drug.

Since netupitant/palonosetron capsules contain a 5-HT3 receptor antagonist, caution is advised when co-administering with other medicinal products known to prolong the QT interval, and in patients who have or may develop prolonged QT interval, particularly those with personal or familial predisposition to prolonged QT interval, electrolyte imbalances, congestive heart failure, bradyarrhythmias, conduction disorders, or patients receiving antiarrhythmic drugs or other medicinal products causing QT prolongation or electrolyte disturbances. Hypokalaemia and hypomagnesaemia should be corrected prior to initiating treatment.

Caution should be exercised when administering to patients with severe hepatic impairment, as there is limited data on use of the medicinal product in such patients.

This medicinal product should be used with caution in patients who are concurrently receiving orally administered drugs metabolized by cytochrome CYP3A4 and having a narrow therapeutic index (see section "Interaction with other medicinal products and other forms of interaction").

Chemotherapeutic agents that are substrates of cytochrome CYP3A4

Netupitant is a moderate inhibitor of cytochrome CYP3A4 and may enhance the effects of chemotherapeutic agents that are substrates of cytochrome CYP3A4, such as docetaxel (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, patients should be monitored for increased toxicity associated with chemotherapeutic agents that are substrates of cytochrome CYP3A4, including irinotecan. Additionally, netupitant may also affect the efficacy of chemotherapeutic agents that require activation via the cytochrome CYP3A4 metabolic pathway.

Excipients

The medicinal product Akindi® contains sorbitol (special mixture: 50% glycerol and 50% sorbitol solution) 7 mg per hard capsule. The additive effect should be considered when co-administering medicinal products and food products containing sorbitol (or fructose). The sorbitol content in orally administered medicinal products, when taken concomitantly with other oral medicinal products, may affect their bioavailability.

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

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, i.e., essentially "sodium-free".

It may also contain traces of lecithin derived from soy. Therefore, patients with known hypersensitivity to peanuts or soy should be monitored for signs of allergic reactions (see section "Adverse reactions").

Use during pregnancy or breastfeeding

Use of netupitant/palonosetron capsules is contraindicated during pregnancy (see section "Contraindications").

Women of childbearing potential / contraception in women

Women of childbearing potential must not become pregnant or be pregnant during treatment with netupitant/palonosetron capsules. A pregnancy test should be performed in all premenopausal women prior to starting treatment. Women of childbearing potential must use effective contraception during therapy and for one month after completion of treatment with this medicinal product.

Pregnancy

Netupitant

There are no data on the use of netupitant in pregnant women. Animal studies have shown reproductive toxicity, including teratogenic effects in rabbits without a safety margin (see section "Preclinical safety data").

Palonosetron

There are no data on the use of palonosetron in pregnant women. Data from animal studies do not indicate a direct or indirect harmful effect of palonosetron on reproductive function (see section "Preclinical safety data").

Breastfeeding

It is unknown whether palonosetron or netupitant is excreted in human breast milk. The risk to the nursing infant cannot be excluded. Netupitant/palonosetron capsules should not be used during breastfeeding. Breastfeeding must be discontinued during treatment with Akindi® and for 1 month after receiving the last dose.

Fertility

Netupitant

In animal studies, no effect on fertility was observed.

Palonosetron

In rat studies, degeneration of the epithelium of the vas deferens was observed (see section "Preclinical safety data").

Effects on ability to drive and use machines.

Netupitant/palonosetron capsules have a moderate influence on the ability to drive and use machines. Since the medicinal product may cause dizziness, somnolence, or fatigue, patients should be cautioned against driving or operating machinery if such symptoms occur.

Administration and Dosage

For oral use.

The hard capsule should be swallowed whole, without opening, as it contains 4 separate pharmaceutical components that must be administered simultaneously.

It may be taken regardless of food intake.

Adults

One hard capsule of Akynzeo® should be administered approximately one hour before the start of each chemotherapy cycle.

The recommended dose of orally administered dexamethasone should be reduced by approximately 50% when co-administered with netupitant/palonosetron capsules (see section "Interaction with Other Medicinal Products and Other Forms of Interaction" and the clinical trial regimen outlined in section "Pharmacodynamics").

Elderly Patients

Dose adjustment is not required for elderly patients. Caution should be exercised when administering this medication to patients aged 75 years and older due to the prolonged elimination half-life of the active substances and limited experience in this population.

Renal Impairment

Dose adjustment is not considered necessary for patients with mild or severe renal impairment. Netupitant is excreted in minimal amounts via the kidneys. Mild to moderate renal impairment does not affect the pharmacokinetic parameters of palonosetron. Total systemic exposure to intravenously administered palonosetron increases by approximately 28% in patients with severe renal impairment compared to those with normal renal function. The pharmacokinetics of palonosetron or netupitant have not been studied in patients with end-stage renal disease requiring hemodialysis, and there are no data on the efficacy and safety of netupitant/palonosetron capsules in such patients. Therefore, use in these patients should be avoided.

Hepatic Impairment

Dose adjustment is not required for patients with mild or moderate hepatic impairment (Child-Pugh class 5–8). There is insufficient data on the use of the drug in patients with severe hepatic impairment (Child-Pugh class ≥9). Akynzeo® should be used with caution in patients with severe hepatic impairment, as this may lead to increased exposure to netupitant (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Children

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

Overdose

Based on a study conducted in healthy volunteers who received oral netupitant 600 mg in combination with palonosetron 1.50 mg, potential acute symptoms of overdose may include headache, dizziness, constipation, anxiety, tachycardia, euphoric mood, and leg pain. In case of overdose, administration of the drug should be discontinued, and general supportive care and monitoring should be provided. Emetic treatments may be ineffective due to the antiemetic activity of netupitant and palonosetron. Dialysis has not been studied. However, due to the large volume of distribution of both palonosetron and netupitant, dialysis is unlikely to be an effective treatment for overdose.

Adverse reactions.

Summary of safety profile

The most commonly reported adverse reactions 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 system organ class and frequency of occurrence.

The following criteria were used to classify the frequency of adverse reactions:

Very common (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1000 to < 1/100)

Rare (≥ 1/10000 to < 1/1000)

Very rare (< 1/10000)

Not known (cannot be estimated from available data).

Table 5

Adverse reactions

Post-marketing data indicate that the overall safety profile is generally similar to that observed in clinical studies.

Description of selected adverse reactions

Netupitant

No common adverse reactions have been associated with the use of netupitant, the new component of the fixed combination.

Palonosetron

Cases of constipation with fecal impaction following administration of palonosetron at a dose of 0.75 mg, requiring hospitalization of patients, have been reported.

In addition, the following adverse reactions have been observed with oral administration of palonosetron: eye swelling, dyspnea, and myalgia; however, these were not observed during the development of Akezeto®. All of these reactions occurred infrequently.

Very rare cases of adverse reactions such as anaphylaxis, anaphylactic/anaphylactoid reactions, and shock have been reported. Symptoms may include urticaria, pruritus, angioedema, hypotension, throat or chest tightness, dyspnea, and loss of consciousness.

There have also been reports of serotonin syndrome, characterized by tremor, agitation, sweating, myoclonus, hypertension, and fever.

Netupitant and palonosetron, combination capsule

This medicinal product may contain traces of lecithin derived from soy. Therefore, allergic reactions such as urticaria, skin rash, pruritus, difficulty breathing or swallowing, mucosal swelling of the mouth, face, lips, tongue, or throat, and sometimes hypotension may occur in patients with known hypersensitivity to peanuts and soy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store at a temperature not exceeding 25 ºC. Keep out of reach and sight of children.

Packaging.

1 capsule in an aluminum blister. 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Helsinn Birex Pharmaceuticals Ltd.

Manufacturer's address.

Damastown, Mulhuddart, Dublin 15, Ireland.

Marketing Authorization Holder.

Helsinn Healthcare SA.

Address of Marketing Authorization Holder.

Via Pian Scairolo 9, 6912 Lugano, Switzerland.