Apro

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT APRO (APRO)

Composition:

Active substance: aprepitant;

1 hard 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 for 80 mg: gelatin, titanium dioxide (E 171);

Capsule shell for 125 mg: gelatin, titanium dioxide (E 171); iron oxide red (E 172).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

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

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

Pharmacotherapeutic group. Drugs affecting the digestive system and metabolism. Antiemetic agents and drugs for relief of nausea. Other antiemetics.

ATC code A04AD12.

Pharmacological Properties

Pharmacodynamics

Aprepitant is a selective antagonist of neurokinin 1 (NK1) receptors with high affinity for substance P (P-neuropeptide from the tachykinin family) in humans. 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 inhibit the vomiting reflex mediated via the central nervous system in response to 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 action of aprepitant on the central nervous system is sufficiently 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 after administration (tmax). Oral administration of the capsule with a standard breakfast containing approximately 800 kcal results in a 40% increase in aprepitant AUC. This increase is considered not to be clinically significant.

The pharmacokinetics of aprepitant within the clinical dose range are nonlinear. In healthy young adults, the increase in AUC0–∞ was 26% greater than dose-proportional following single doses of 80 mg and 125 mg administered 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, on average 97%, to plasma proteins. 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 approximately 19% of radioactivity in plasma within 72 hours after a single 100 mg intravenous dose of [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 via oxidation in the morpholine ring and its side chains, and the resulting metabolites exhibited only weak activity. In vitro studies using human liver microsomes showed that aprepitant is predominantly metabolized by CYP3A4, 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.

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 Special Populations

Elderly. Following oral administration of aprepitant as 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.

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

Hepatic Impairment. Mild hepatic impairment (Child–Pugh Class A) does not have a clinically significant effect on the pharmacokinetics of aprepitant; no dose adjustment is required for these patients. Available data are insufficient to draw conclusions 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 aprepitant plasma protein binding 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 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 approximately 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 drug.

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 aprepitant treatment, mild transient induction of CYP2C9, CYP3A4, and glucuronidation occurs. Aprepitant is unlikely to interact with the P-glycoprotein transporter, as evidenced 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 by 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 orally administered active substances that are primarily metabolized by CYP3A4 and have a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, dihydroergotamine, ergotamine, fentanyl, and quinidine) should be done with caution.

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 the 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 on days 2 to 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 within 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 agents

In 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, interactions with orally administered chemotherapeutic agents that are primarily or partially metabolized by CYP3A4 (e.g., etoposide, vinorelbine) cannot be excluded. Caution and additional monitoring are recommended in patients receiving drugs primarily or partially metabolized by CYP3A4. Post-marketing reports have described cases of neurotoxicity (a potential adverse reaction of ifosfamide) with concomitant use of aprepitant and ifosfamide.

Immunosuppressants

During a three-day CINV treatment course, 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 duration 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 (e.g., 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 treatment course with aprepitant at a dose of 125 mg on day 1 and 80 mg/day on days 2 to 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 aprepitant treatment course and on days 4, 8, and 15. Aprepitant increased the AUC of midazolam by 25% on day 4 and decreased it 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 (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 a single oral 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 decrease 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 the end of the three-day aprepitant course. This effect persists for several days, then gradually diminishes and is not clinically significant two weeks after aprepitant treatment ends. Weak induction of glucuronidation is also observed with oral administration of 80 mg aprepitant for 7 days. There is no information on the effect on CYP2C8 and CYP2C19. Caution is recommended when using warfarin, acenocoumarol, tolbutamide, phenytoin, or other active substances metabolized by CYP2C9 during this period.

Warfarin. In patients receiving long-term warfarin therapy, close monitoring of prothrombin time (INR) is recommended during aprepitant treatment and for 2 weeks after each three-day course of aprepitant used for the 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% decrease in the minimum concentration of S(-) warfarin (a CYP2C9 substrate) was observed, accompanied by a 14% decrease in INR 5 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 decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on day 4, by 28% on day 8, and by 15% on day 15 when a single oral dose of tolbutamide 500 mg was administered before the three-day aprepitant course and on days 4, 8, and 15.

Hormonal contraceptives

The efficacy of hormonal contraceptives may be reduced during and for 28 days after aprepitant administration. Alternative or additional contraceptive methods should be used during treatment with Apro 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 125 mg on day 8 and 80 mg/day on days 9 and 10, 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 (active metabolite of dolasetron).

Effect of other drugs 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 decreased plasma concentrations of aprepitant, potentially reducing its efficacy. Concomitant use of aprepitant with herbal 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 together 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 85 mg or 170 mg with paroxetine 20 mg once daily decreased the AUC of both aprepitant and paroxetine by approximately 25% and Cmax by approximately 20%.

Special precautions for use

Patients with moderate to severe hepatic impairment. There are limited data in patients with moderate hepatic impairment; no data are available in patients with severe hepatic impairment. Aprepitant should be used with caution in such patients.

Interactions mediated by CYP3A4

Aprepitant should be used with caution in patients who are concurrently receiving medicinal products 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"). In addition, particular caution is advised 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 increase 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 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 (see section "Interaction with other medicinal products and other forms of interaction"). Concomitant use of aprepitant with herbal preparations containing St. John's wort (Hypericum perforatum) is not recommended.

Aprepitant should be used with caution when administered concomitantly with medicinal 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 (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use with warfarin (CYP2C9 substrate). Combined use of aprepitant with warfarin results in a reduction of prothrombin time, expressed as international normalized ratio (INR). In patients receiving chronic warfarin therapy, close monitoring of INR is recommended during aprepitant treatment and for 2 weeks following 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 efficacy 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 of aprepitant (see section "Interaction with other medicinal products and other forms of interaction").

Excipients. The medicinal product contains sucrose. Therefore, patients with rare hereditary problems of 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 efficacy 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 of aprepitant.

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. Aprepitant 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 Apro.

Fertility. The potential effect of aprepitant on fertility has not been fully studied, as exposure levels exceeding human therapeutic exposure 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.

Ability to affect reaction speed when driving or operating machinery.

Apro may have a minor influence on the ability to drive or operate machinery. Dizziness and increased fatigue may occur after administration of the drug.

Dosage and Administration

The capsule should be swallowed whole.

Aprepitant may be taken with or without food.

Aprepitant 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.) administered 1 hour before chemotherapy on day 1, followed by 80 mg once daily in the morning on days 2 and 3.

The treatment regimens described 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	125 mg orally	80 mg orally	80 mg orally	None
Dexamethasone	12 mg orally	8 mg orally	8 mg orally	8 mg orally
5-HT3 antagonist	standard dose of 5-HT3 antagonist (refer to the instructions for the selected 5-HT3 antagonist for the appropriate dose) 5-HT3 antagonist)	None	None	None

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

Regimen for chemotherapy with moderate emetogenic risk

	Day 1	Day 2	Day 3
Aprepitant	125 mg orally	80 mg orally	80 mg orally
Dexamethasone	12 mg orally	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 combination 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). No dose adjustment is necessary for elderly patients.

Gender. No dose adjustment is required based on gender.

Patients with renal impairment. No dose adjustment is necessary for patients with renal impairment or for patients with end-stage renal disease undergoing hemodialysis.

Patients with hepatic impairment. No dose adjustment is required for patients with mild hepatic impairment. Limited data are available on the use in patients with moderate hepatic impairment, and there is no information on use in patients with severe hepatic impairment. Aprepitant should be used with caution in such patients.

Children.

The safety and efficacy of aprepitant in children and adolescents (under 18 years of age) have not been established. There are no data available; therefore, the use of the drug is not recommended in these patients.

Overdose.

In case of overdose, aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Due to the antiemetic activity of aprepitant, emetic agents will be ineffective. Aprepitant is not removed by hemodialysis.

Adverse Reactions

In patients treated with aprepitant during chemotherapy with high emetogenic potential, the most common adverse reactions attributed to the drug were: hiccups (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 the drug during aprepitant therapy in patients receiving chemotherapy with moderate emetogenic potential was fatigue (1.4%).

The adverse reactions listed below were observed in a pooled analysis of studies involving chemotherapy with either high or moderate emetogenic potential, occurring more frequently in patients receiving aprepitant than in those receiving standard therapy, as well as during post-marketing use.

Frequency is defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data).

Infections and infestations: rare – candidiasis, staphylococcal infection.

Blood and lymphatic system disorders: uncommon – febrile neutropenia, anemia.

Immune system disorders: not known – hypersensitivity reactions, including anaphylactic reactions.

Metabolism and nutrition disorders: common – decreased appetite; rare – polydipsia.

Psychiatric disorders: uncommon – anxiety; rare – disorientation, euphoric mood.

Nervous system disorders: common – headache; uncommon – dizziness, somnolence; rare – cognitive disorders, lethargy, dysgeusia.

Eye disorders: rare – conjunctivitis.

Ear and labyrinth disorders: rare – tinnitus.

Cardiac disorders: uncommon – palpitations; rare – bradycardia, cardiovascular disorders.

Vascular disorders: uncommon – hot flushes.

Respiratory, thoracic and mediastinal disorders: common – hiccups; rare – oropharyngeal pain, sneezing, cough, postnasal drip, laryngeal irritation.

Gastrointestinal disorders: common – constipation, dyspepsia; uncommon – belching, nausea*, vomiting*, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence; rare – duodenal ulcer perforation, stomatitis, abdominal distension, hard stools, neutropenic colitis.

Skin and subcutaneous tissue disorders: uncommon – rash, acne; rare – photosensitivity reaction, hyperhidrosis, seborrhea, skin lesions, pruritic rash, Stevens-Johnson syndrome/toxic epidermal necrolysis; not known – pruritus, urticaria.

Musculoskeletal and connective tissue disorders: rare – muscle weakness, muscle spasms.

Renal and urinary disorders: uncommon – dysuria; rare – polyuria.

General disorders and administration site conditions: common – fatigue; uncommon – asthenia, malaise; rare – swelling, chest discomfort, gait disturbance.

Investigations: common – increased ALT; uncommon – increased AST, increased alkaline phosphatase; rare – positive urine blood test, decreased blood sodium, weight loss, decreased neutrophil count, glucosuria, increased diuresis.

*Nausea and vomiting were efficacy parameters during the first 5 days following chemotherapy and were considered adverse reactions only after this period.

The nature of adverse reactions observed during multiple cycles (up to 6 cycles) of chemotherapy was similar to that observed during the first cycle.

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

Non-CTC Studies

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

* Reported in patients who received high-dose aprepitant.

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, pharmacists, patients, or their legal representatives should report all 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.

The medicinal product does not require special storage conditions.

Keep out of reach of children.

Packaging.

3 hard capsules. The combination pack contains 1 capsule of 125 mg and 2 capsules of 80 mg in blisters; 2 blisters per carton.

Prescription category.

Prescription only.

Manufacturer.

RONtIS HELLAS MEDICAL AND PHARMACEUTICAL PRODUCTS S.A. /
Rontis Hellas Medical And Pharmaceutical Products S.A.

Manufacturer's address and place of business.

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