Aprepitant-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Aprepitant-Vista (APREPITANT-VISTA)

Composition:

Active substance: aprepitant;

1 capsule contains 80 mg or 125 mg of aprepitant;

Excipients: sucrose, microcrystalline cellulose (sphere 500) (E 460), hydroxypropylcellulose (E 463), sodium lauryl sulfate;

Capsule shell – gelatin, titanium dioxide (E 171);

Capsule shell of the 125 mg capsule also contains iron oxide red (E 172).

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics:

80 mg capsules: hard, opaque gelatin capsules, size 2, with white body and cap, containing granules from white to almost white in color;

125 mg capsules: hard, opaque gelatin capsules, size 1, with white body and pink cap, containing granules from white to almost white in color.

Pharmacotherapeutic group. Agents acting on the digestive system and metabolism. Antiemetics and drugs used to relieve nausea. Other antiemetics. ATC code A04AD12.

Pharmacological Properties

Pharmacodynamics

Aprepitant is a selective high-affinity antagonist of human neurokinin 1 (NK1) receptors for substance P (P-neuropeptide of the tachykinin family). Additional screening studies demonstrated that aprepitant was at least 3000 times more selective for NK1 receptors than for other enzymes, ion channel transporters, and receptor sites, including dopamine and serotonin receptors, which are targets for therapy of chemotherapy-induced nausea and vomiting. NK1 receptor antagonists act on the central nervous system to inhibit the vomiting reflex triggered by cytotoxic chemotherapeutic agents such as cisplatin. Preclinical studies and human positron emission tomography (PET) studies using aprepitant have shown that it penetrates the brain and binds to brain NK1 receptors. The central nervous system effect of aprepitant is prolonged, suppressing both the acute and delayed phases of the vomiting reflex induced by cisplatin, and enhancing the antiemetic activity of the 5HT3 receptor antagonist ondansetron and the corticosteroid dexamethasone against cisplatin-induced vomiting.

Pharmacokinetics

Absorption. The mean absolute oral bioavailability of aprepitant is 67% for the 80 mg capsule and 59% for the 125 mg capsule. The mean maximum plasma concentration (Cmax) of aprepitant is reached approximately 4 hours (tmax) after administration. Administration of the capsule with a standard breakfast containing approximately 800 kcal results in a 40% increase in the AUC of aprepitant. This increase is considered not to be clinically significant.

The pharmacokinetics of aprepitant within the clinical dose range is nonlinear. In healthy young adults, the increase in AUC0–∞ was 26% greater than dose-proportional following single oral doses of 80 mg and 125 mg given after food intake. Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0–24h (mean ± SD) was 19.6 ± 2.5 μg × h/mL and 21.2 ± 6.3 μg × h/mL on Days 1 and 3, respectively. Cmax was 1.6 ± 0.36 μg/mL and 1.4 ± 0.22 μg/mL on Days 1 and 3, respectively.

Distribution. Aprepitant is highly bound to plasma proteins, averaging 97%. The mean geometric value of the steady-state volume of distribution (Vdss) in humans is approximately 66 L.

Metabolism. Aprepitant undergoes extensive metabolism. In healthy young volunteers, aprepitant accounted for about 19% of total radioactivity in plasma within 72 hours after a single intravenous dose of 100 mg [14C]-fosaprepitant (a prodrug of aprepitant), indicating the presence of metabolites in plasma. Twelve metabolites of aprepitant have been identified in human plasma. Metabolism of aprepitant occurs primarily through oxidation of the morpholine ring and its side chains, and the resulting metabolites exhibited only weak activity. In vitro studies using human liver microsomes showed that CYP3A4 is primarily responsible for the metabolism of aprepitant, with minor potential contributions from CYP1A2 and CYP2C19.

Elimination. Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via bile into feces. After a single intravenous dose of 100 mg [14C]-fosaprepitant (a prodrug of aprepitant) administered to healthy volunteers, 57% of radioactivity was recovered in urine and 45% in feces.

The plasma clearance of aprepitant is dose-dependent, decreasing with increasing dose, and ranges from approximately 60 to 72 mL/min within the therapeutic dose range. The terminal elimination half-life ranges from approximately 9 to 13 hours. Pharmacokinetics in Specific Populations

Elderly. Following oral administration of aprepitant at a single 125 mg dose on Day 1 and 80 mg once daily from Day 2 to Day 5, the AUC0–24h of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly patients (≥65 years) compared to younger adults. Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly patients compared to younger adults. These differences are not considered clinically significant. No dose adjustment of aprepitant is required for elderly patients.

Sex. Following oral administration of a single 125 mg dose of aprepitant, Cmax was 16% higher in women than in men. The elimination half-life of aprepitant was 25% shorter in women than in men, while Tmax was reached in approximately the same time. These differences are not considered clinically significant. No dose adjustment of aprepitant is required based on patient sex.

Hepatic Impairment. Mild hepatic impairment (Child–Pugh Class A) does not have a clinically significant effect on the pharmacokinetics of aprepitant; dose adjustment is not required for these patients. Based on available data, no conclusions can be drawn regarding the effect of moderate hepatic impairment (Child–Pugh Class B) on the pharmacokinetics of aprepitant. There are no clinical or pharmacokinetic data available for patients with severe hepatic impairment (Child–Pugh Class C).

Renal Impairment. Aprepitant at a single 240 mg dose was administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) and to patients with end-stage renal disease requiring hemodialysis.

In patients with severe renal impairment, the AUC0–∞ of total aprepitant (unbound and protein-bound) decreased by 21% and Cmax decreased by 32% compared to healthy volunteers. In patients with end-stage renal disease undergoing hemodialysis, AUC0–∞ of total aprepitant decreased by 42% and Cmax by 32%. Due to the slight reduction in plasma protein binding of aprepitant associated with renal disease, the AUC of pharmacologically active unbound aprepitant did not change significantly in patients with renal impairment compared to healthy volunteers. Hemodialysis performed 4 or 48 hours after drug administration had no substantial effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.

No dose adjustment of aprepitant is required for patients with renal impairment or for patients with end-stage renal disease undergoing hemodialysis.

Concentration–Effect Relationship

PET studies using a highly specific NK1 receptor radioligand in healthy young men demonstrated that aprepitant penetrates the brain and occupies NK1 receptors in a dose-dependent and plasma concentration-dependent manner. Plasma concentrations of aprepitant achieved with the three-day dosing regimen provide 95% occupancy of brain NK1 receptors.

Clinical characteristics.

Indications.

In combination therapy:

• prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based anticancer chemotherapy in adults;
• prevention of nausea and vomiting associated with moderately emetogenic anticancer chemotherapy in adults.

Contraindications.

The medicinal product is contraindicated in patients with hypersensitivity to any component of the preparation.

The medicinal product should not be used concomitantly with pimozide, terfenadine, astemizole, or cisapride.

Interaction with other medicinal products and other forms of interaction.

Aprepitant (125 mg/80 mg) is a substrate, moderate inhibitor, and inducer of CYP3A4. In addition, aprepitant is an inducer of CYP2C9. During treatment with aprepitant, CYP3A4 activity is inhibited. After completion of treatment, aprepitant causes mild transient induction of CYP2C9, CYP3A4, and glucuronidation. Aprepitant is unlikely to interact with the P-glycoprotein transporter, as confirmed by the absence of interaction between aprepitant and digoxin.

Effect of aprepitant on the pharmacokinetics of other active substances.

Inhibition of CYP3A4 activity.

As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) may increase plasma concentrations of active substances metabolized via CYP3A4 when used concomitantly. The overall exposure to orally administered CYP3A4 substrates may increase approximately threefold during the three-day treatment with aprepitant; the effect of aprepitant on plasma concentrations of intravenously administered CYP3A4 substrates is expected to be less pronounced. Aprepitant should not be used concomitantly with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 activity by aprepitant may lead to increased plasma concentrations of these active substances, potentially causing serious or life-threatening reactions. Concomitant use of aprepitant with active substances administered orally and predominantly metabolized via CYP3A4 and having a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, dihydroergotamine, ergotamine, fentanyl, and quinidine, is recommended with caution (see section "Special precautions for use").

Corticosteroids.

Dexamethasone.

When used concomitantly with aprepitant at doses of 125 mg/80 mg, the usual oral dose of dexamethasone should be reduced by approximately 50%. The dexamethasone dose used in clinical studies for prevention of chemotherapy-induced nausea and vomiting (CINV) was selected considering the interaction between active substances. Aprepitant administered at a dose of 125 mg in combination with oral dexamethasone 20 mg on day 1, and aprepitant at a dose of 80 mg in combination with oral dexamethasone 8 mg from day 2 to day 5, increased the area under the concentration–time curve (AUC) of dexamethasone (a CYP3A4 substrate) by 2.2-fold on days 1 and 5.

Methylprednisolone.

When used concomitantly with aprepitant at doses of 125 mg/80 mg, the usual intravenous dose of methylprednisolone should be reduced by approximately 25%, and the usual oral dose of methylprednisolone should be reduced by approximately 50%. Aprepitant administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3 increased the AUC of methylprednisolone (a CYP3A4 substrate) by 1.3-fold on day 1 and by 2.5-fold on day 3 when methylprednisolone was administered intravenously at a dose of 125 mg on day 1 and orally at a dose of 40 mg on days 2 and 3.

During prolonged treatment with methylprednisolone, the AUC of methylprednisolone may decrease as early as 2 weeks after initiation of aprepitant due to the inducing effect of aprepitant on CYP3A4. This effect is expected to be more pronounced with oral administration of methylprednisolone.

Chemotherapeutic medicinal products.

During pharmacokinetic studies, aprepitant administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3 did not affect the pharmacokinetics of intravenously administered docetaxel on day 1 or intravenously administered vinorelbine on day 1 or day 8. Since the effect of aprepitant on the pharmacokinetics of oral CYP3A4 substrates is more pronounced than on intravenous CYP3A4 substrates, interaction with orally administered chemotherapeutic agents metabolized primarily or partially by CYP3A4 (e.g., etoposide, vinorelbine) cannot be excluded. Caution is recommended, and additional monitoring should be performed in patients receiving medicinal products metabolized primarily or partially by CYP3A4. In the post-marketing period, cases of neurotoxicity (a potential adverse reaction of ifosfamide) have been reported with concomitant use of aprepitant and ifosfamide.

Immunosuppressants.

During a three-day course of therapy for CINV, a transient moderate increase followed by a slight decrease in exposure to immunosuppressants metabolized by CYP3A4 (e.g., cyclosporine, tacrolimus, everolimus, and sirolimus) is expected. Given the short three-day treatment course and limited time-dependent changes in exposure, dose reduction of immunosuppressants during concomitant use with aprepitant is not recommended.

Midazolam.

Potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized by CYP3A4 (alprazolam, triazolam) should be considered when these agents are used concomitantly with aprepitant (125 mg/80 mg).

Aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on day 1 and by 3.3-fold on day 5 when a single oral dose of midazolam 2 mg was administered on days 1 and 5 during a course of aprepitant treatment at a dose of 125 mg on day 1 and 80 mg/day from day 2 to day 5.

In another study with intravenous midazolam, aprepitant was administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3, and midazolam was administered intravenously at a dose of 2 mg before the three-day course of aprepitant treatment and on days 4, 8, and 15. Aprepitant increased the AUC of midazolam by 25% on day 4 and decreased the AUC of midazolam by 19% on day 8 and by 4% on day 15. These effects were considered not clinically significant.

In a third study with intravenous and oral midazolam, aprepitant was administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3 together with ondansetron 32 mg on day 1, dexamethasone 12 mg on day 1, and 8 mg/day on days 2–4. This combination (i.e., aprepitant, ondansetron, and dexamethasone) decreased the AUC of midazolam by 16% on day 6, by 9% on day 8, by 7% on day 15, and by 17% on day 22. These effects were considered not clinically significant. An additional study with intravenous midazolam and aprepitant was conducted. Midazolam was administered intravenously at a dose of 2 mg one hour after oral administration of a single dose of aprepitant 125 mg. The plasma AUC of midazolam increased by 1.5-fold. This effect was considered not clinically significant.

Induction.

As a weak inducer of CYP2C9, CYP3A4, and glucuronidation, aprepitant may reduce plasma concentrations of substrates eliminated via these pathways within 2 weeks after initiation of treatment. This effect may manifest only after completion of aprepitant treatment. For CYP2C9 and CYP3A4 substrates, induction is transient, reaching maximum effect 3–5 days after completion of the three-day aprepitant course. This effect persists for several days, then gradually diminishes and is not clinically significant two weeks after completion of aprepitant treatment. Weak induction of glucuronidation is also observed after oral administration of 80 mg aprepitant for 7 days. Information regarding the effect on CYP2C8 and CYP2C19 is lacking. Caution is recommended during this period when using warfarin, acenocoumarol, tolbutamide, phenytoin, or other active substances metabolized by CYP2C9.

Warfarin.

In patients receiving long-term warfarin therapy, close monitoring of prothrombin time (INR) is required during aprepitant treatment and for 2 weeks after each three-day course of aprepitant used for prevention of chemotherapy-induced nausea and vomiting. In healthy volunteers stabilized on chronic warfarin therapy, administration of a single dose of aprepitant 125 mg on day 1 and 80 mg/day on days 2 and 3 did not affect plasma AUC of R(+) or S(-) warfarin measured on day 3; however, a 34% reduction in the minimum concentration of S(-) warfarin (a CYP2C9 substrate) was observed, accompanied by a 14% reduction in INR five days after completion of aprepitant administration.

Tolbutamide. Aprepitant administered at a dose of 125 mg on day 1 and 80 mg/day on days 2 and 3 reduced the AUC of tolbutamide (a CYP2C9 substrate) by 23% on day 4, by 28% on day 8, and by 15% on day 15 after oral administration of a single 500 mg dose of tolbutamide before initiation of the three-day aprepitant course and on days 4, 8, and 15.

Hormonal contraceptives.

During and for 28 days after aprepitant administration, the effectiveness of hormonal contraceptives may be reduced. Alternative or additional contraceptive methods should be used during aprepitant treatment and for 2 months after the last dose of aprepitant. In a clinical study, single doses of oral contraceptives containing ethinylestradiol and norethindrone were administered from day 1 to day 21 together with aprepitant administered at a dose of 125 mg on day 8 and 80 mg/day on days 9 and 10, with intravenous ondansetron 32 mg on day 8, and oral dexamethasone 12 mg on day 8 and 8 mg/day on days 9, 10, and 11. From day 9 to day 21 of this study, minimum concentrations of ethinylestradiol decreased by up to 64% and minimum concentrations of norethindrone decreased by up to 60%.

5-HT3 antagonists.

In clinical interaction studies, aprepitant did not show clinically significant effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Effect of other medicinal products on the pharmacokinetics of aprepitant.

Aprepitant should be used with caution concomitantly with active substances that inhibit CYP3A4 activity (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and protease inhibitors), as such combinations are expected to increase plasma concentrations of aprepitant.

Concomitant use of aprepitant with active substances that strongly induce CYP3A4 activity (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided, as such combinations lead to reduced plasma concentrations of aprepitant, potentially resulting in decreased efficacy of aprepitant. Concomitant use of aprepitant with herbal medicinal products containing St. John's wort (Hypericum perforatum) is not recommended.

Ketoconazole.

When a single dose of aprepitant 125 mg was administered on day 5 of a 10-day course of ketoconazole (a potent CYP3A4 inhibitor) at a dose of 400 mg/day, the AUC of aprepitant increased approximately fivefold, and the mean terminal half-life of aprepitant increased approximately threefold.

Rifampicin.

When a single dose of aprepitant 375 mg was administered on day 9 of a 14-day course of rifampicin (a potent CYP3A4 inducer) at a dose of 600 mg/day, the AUC of aprepitant decreased by 91%, and the mean terminal half-life decreased by 68%.

Diltiazem.

In patients with moderate hypertension, administration of aprepitant 230 mg once daily concomitantly with diltiazem 120 mg three times daily for 5 days increased the AUC of aprepitant twofold and simultaneously increased the AUC of diltiazem by 1.7-fold. This pharmacokinetic effect did not affect ECG, heart rate, or blood pressure, except for changes caused by diltiazem alone.

Paroxetine.

Concomitant administration of aprepitant at a dose of 85 mg or 170 mg with paroxetine 20 mg once daily reduced the AUC of both aprepitant and paroxetine by approximately 25% and Cmax by approximately 20%.

Pediatric patients.

Interaction studies have been conducted only in adult patients.

Special precautions for use.

Patients with moderate to severe hepatic impairment.
Limited data are available in patients with moderate hepatic impairment; no data are available in patients with severe hepatic impairment. The medicinal product should be used with caution in such patients.

Interactions mediated by CYP3A4.

The medicinal product should be used with caution in patients who are concurrently receiving drugs that are predominantly metabolized by the CYP3A4 system and have a narrow therapeutic index, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, dihydroergotamine, ergotamine, fentanyl, and quinidine (see section "Interaction with other medicinal products and other forms of interaction"). Additionally, particular caution should be exercised when co-administering with irinotecan, as this combination may lead to increased toxicity.

Concomitant administration of aprepitant with ergot alkaloid derivatives that are CYP3A4 substrates may lead to increased plasma concentrations of these active substances. Therefore, caution is recommended due to the potential risk of ergot-related toxic effects.

Concomitant use of aprepitant with medicinal products that strongly induce CYP3A4 activity (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided, as such combinations lead to reduced plasma concentrations of aprepitant (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of aprepitant with herbal products containing St. John's wort (Hypericum perforatum) is not recommended.

Aprepitant should be used with caution concomitantly with medicinal products that strongly inhibit CYP3A4 activity (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, and protease inhibitors), as such combinations are expected to increase plasma concentrations of aprepitant (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with warfarin (CYP2C9 substrate).
Co-administration of aprepitant with warfarin leads to a reduction in prothrombin time, expressed as the international normalized ratio (INR). In patients receiving stable warfarin therapy, close INR monitoring should be performed during aprepitant treatment and for 2 weeks after each 3-day course of aprepitant used for the prevention of chemotherapy-induced nausea and vomiting (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with hormonal contraceptives.
The effectiveness of hormonal contraceptives may be reduced during and for 28 days after aprepitant administration. Alternative additional non-hormonal contraceptive methods should be used during treatment and for 2 months after the last dose of aprepitant (see section "Interaction with other medicinal products and other forms of interaction").

Important information about excipients.

Aprepitant-Vista contains sucrose. Therefore, patients with rare hereditary disorders such as fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product.

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

Use during pregnancy or breastfeeding.

Contraception in men and women.

The effectiveness of hormonal contraceptives may be reduced during and for 28 days after aprepitant administration. Alternative additional non-hormonal contraceptive methods should be used during treatment with aprepitant and for 2 months after the last dose (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Pregnancy.

There are no clinical data on the use of aprepitant during pregnancy. The potential for reproductive toxicity of aprepitant has not been fully established, as exposure levels exceeding therapeutic exposure in humans at the 125 mg/80 mg dose cannot be achieved in animal studies. These studies did not show any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. The potential impact of neurokinin regulation on reproductive function is unknown. The medicinal product should not be used during pregnancy except in cases of clear necessity.

Breastfeeding.

Aprepitant penetrates into the milk of lactating rats. It is unknown whether the drug passes into human breast milk; therefore, breastfeeding is not recommended during treatment with aprepitant.

Fertility.

The potential effect of aprepitant on fertility has not been fully evaluated, as exposure levels exceeding therapeutic exposure in humans cannot be achieved in animal studies. Fertility studies did not demonstrate any direct or indirect adverse effects on mating, fertility, embryonic/fetal development, sperm count, or sperm motility.

Effects on ability to drive and use machines.

Aprepitant may have a minor influence on the ability to drive and use machines. Dizziness and increased fatigue may occur after administration of the medicinal product.

Dosage and Administration

The capsule should be swallowed whole.

Aprepitant-Vista can be taken with or without food.

Aprepitant-Vista should be administered for 3 consecutive days as part of a regimen that includes a corticosteroid and a 5-HT3 antagonist. The recommended dose of aprepitant is 125 mg orally (p.o.) 1 hour before chemotherapy (on Day 1) and 80 mg once daily in the morning on Days 2 and 3. The treatment regimens outlined below are recommended for the prevention of nausea and vomiting associated with emetogenic anticancer chemotherapy.

Regimen for chemotherapy with high emetogenic risk.

	Day 1	Day 2	Day 3	Day 4
Aprepitant-Vista	125 mg p.o.	80 mg p.o.	80 mg p.o.	None
Dexamethasone	12 mg p.o.	8 mg p.o.	8 mg p.o.	8 mg p.o.
5-HT3 antagonist	standard dose of 5-HT3 antagonist (refer to the instructions for the selected 5-HT3 antagonist for the appropriate dose)	None	None	None

Dexamethasone should be administered 30 minutes prior to chemotherapy on day 1 and in the morning from days 2 to 4. The dose of dexamethasone was selected considering drug interactions.

Regimen for chemotherapy with moderate emetogenic risk.

	Day 1	Day 2	Day 3
Aprepitant-Vista	125 mg p.o.	80 mg p.o.	80 mg p.o.
Dexamethasone	12 mg p.o.	None	None
5-HT3 antagonist	standard dose of 5-HT3 antagonist (refer to the instructions for the selected 5-HT3 antagonist for the appropriate dose)	None	None

Dexamethasone should be administered 30 minutes prior to chemotherapy on Day 1. The dose of dexamethasone was selected considering drug interactions. Limited data are available on the efficacy of combining with other corticosteroids and 5-HT3 antagonists. For additional information on concomitant use with corticosteroids, see section “Interaction with other medicinal products and other forms of interactions”. The prescribing information of the concurrently administered 5-HT3 antagonist should be consulted.

Special patient groups.

Elderly patients (≥ 65 years of age). Dose adjustment is not required for elderly patients.

Gender. Dose adjustment based on gender is not required.

Patients with renal impairment. Dose adjustment is not required for patients with renal impairment or for patients with end-stage renal disease undergoing hemodialysis.

Patients with hepatic impairment. Dose adjustment is not required for patients with mild hepatic impairment. Data on use in patients with moderate hepatic impairment are limited, and information on use in patients with severe hepatic impairment is lacking. Aprepitant should be used with caution in these patients.

Children.

The safety and efficacy of aprepitant in children and adolescents (under 18 years of age) have not been established. Due to lack of data, the medicinal product is not recommended for use in these patients.

Overdose.

In case of overdose, aprepitant should be discontinued and general supportive treatment initiated, along with appropriate monitoring. Because of the antiemetic activity of aprepitant, emetic agents will be ineffective. Aprepitant is not removed by hemodialysis.

Adverse reactions.

Summary of safety profile.

The safety profile of aprepitant was evaluated in approximately 6,500 adults across more than 50 studies and in 184 pediatric patients in two pivotal pediatric clinical trials.

In patients treated with aprepitant during chemotherapy with high emetogenic risk, the most commonly reported drug-related adverse reactions were hiccup (4.6%), increased ALT levels (2.8%), dyspepsia (2.6%), constipation (2.4%), headache (2.0%), and decreased appetite (2.0%). The most commonly reported adverse reaction associated with aprepitant during therapy with aprepitant in patients receiving chemotherapy with moderate emetogenic risk was fatigue (1.4%).

The most commonly reported adverse reactions in pediatric patients receiving aprepitant during emetogenic cancer chemotherapy were hiccup (3.3%) and hot flashes (1.1%).

The adverse reactions listed below were observed in the pooled analysis of chemotherapy trials with high or moderate emetogenic potential at a higher frequency in patients receiving aprepitant compared to those receiving standard treatment, as well as during post-marketing use. The frequency categories listed in the table are based on studies in adults; observed frequencies in pediatric studies were similar or lower unless otherwise indicated in the table. Some less common adverse reactions observed in adults were not observed in pediatric studies. Frequency is defined as: 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 (frequency cannot be estimated from the available data).

System organ class	Adverse reaction	Frequency
Infections and infestations	candidiasis, staphylococcal infection	rare
Blood and lymphatic system disorders	febrile neutropenia, anemia	uncommon
Immune system disorders	hypersensitivity reactions, including anaphylactic reactions	unknown
Metabolism and nutrition disorders	decreased appetite polydipsia	common rare
Psychiatric disorders	anxiety confusion, euphoric mood	uncommon rare
Nervous system disorders	headache dizziness, somnolence cognitive disorders, lethargy, dysgeusia	common uncommon rare
Eye disorders	conjunctivitis	rare
Ear and labyrinth disorders	tinnitus	rare
Cardiac disorders	palpitations, hot flushes bradycardia; cardiovascular disorders	uncommon rare
Respiratory, thoracic and mediastinal disorders	hiccups oropharyngeal pain, sneezing, cough, postnasal drip syndrome, laryngeal irritation	common rare
Gastrointestinal disorders	constipation, dyspepsia eructation, nausea*, vomiting*, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence duodenal ulcer perforation, stomatitis, abdominal distension, hard feces, neutropenic colitis	common uncommon rare
Skin and subcutaneous tissue disorders	rash, acne photosensitivity reaction, hyperhidrosis, seborrhea, skin lesions, red itchy rash, Stevens-Johnson syndrome/toxic epidermal necrolysis pruritus, urticaria	uncommon rare unknown
Musculoskeletal and connective tissue disorders	muscle weakness, muscle spasms	rare
Renal and urinary disorders	dysuria polyuria	uncommon rare
General disorders and administration site conditions	increased fatigue asthenia, malaise edema, chest discomfort, gait disturbance	common uncommon rare
Investigations	increased ALT increased AST, increased alkaline phosphatase levels positive urine erythrocyte test, decreased blood sodium levels, weight loss, decreased neutrophil count, presence of glucose in urine, increased diuresis	common uncommon rare

*Nausea and vomiting were efficacy parameters during the first 5 days following chemotherapy and were considered adverse reactions only after this period. The pattern of adverse reactions observed during multiple cycles (up to 6 cycles) of chemotherapy was similar to that observed in cycle 1.

In an additional active-controlled clinical trial involving 1169 patients receiving aprepitant and chemotherapy with high emetogenic potential, the adverse reaction profile was generally similar to that observed in other studies of high emetogenic potential chemotherapy with aprepitant.

Non-NSAID studies.

Additional adverse reactions were observed in patients receiving a single 40 mg dose of aprepitant for the treatment of postoperative nausea and vomiting, more frequently than with ondansetron: upper abdominal pain, abnormal bowel sounds, constipation*, dysarthria, dyspnea, hypoesthesia, insomnia, miosis, nausea, sensory disturbances, stomach discomfort, partial intestinal obstruction*, decreased visual acuity, hoarseness.

*Reported in patients who received high-dose aprepitant.

Reporting suspected adverse reactions.

Reporting adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Packaging.

2 capsules per blister; 1 blister per cardboard box (for 80 mg dosage);

1 capsule per blister; 6 blisters per cardboard box (for 80 mg dosage);

1 capsule per blister; 5 blisters per cardboard box (for 125 mg dosage);

1 capsule per blister; 6 blisters per cardboard box (for 125 mg dosage);

Combination pack: 3 capsules; 1 capsule of 125 mg in a blister + 2 capsules of 80 mg in a blister; 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

RONDIS HELLAS MEDICAL AND PHARMACEUTICAL PRODUCTS S.A.

Manufacturer's address and location of operations.

Larissa Industrial Area, P.O. Box 3012, Larissa, 41 500, Greece.