1. NAME OF THE MEDICINAL PRODUCT

Aprepitant 80mg hard capsules Taj Pharma
Aprepitant 125mg hard capsules Taj Pharma

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

a) Each hard gelatin capsule contains:
Aprepitant????????????????????????????????? 80mg
Excipients??????????????????????????????????? q.s
Empty gelatin capsule contains approved colours.

b) Each hard gelatin capsule contains:
Aprepitant????????????????????????????????? 125mg
Excipients??????????????????????????????????? q.s
Empty gelatin capsule contains approved colours.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule (capsule)

The 80 mg hard capsules are presented as opaque hard gelatin capsules of size No 2, with a white cap and white body, imprinted in black ink with ?80mg? on the body.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Prevention of nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults and adolescents from the age of 12.

Aprepitant 125 mg/80 mg capsules are given as part of combination therapy (see section 4.2).

4.2 Posology and method of administration

Posology

Adults

Aprepitant capsules are given for 3 days as part of a regimen that includes a corticosteroid and a 5-HT₃?antagonist.

The recommended dose is 125 mg orally once daily one hour before start of chemotherapy on Day 1 and 80 mg orally once daily on Days 2 and 3 in the morning.

The following regimens are recommended in adults for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy:

Highly Emetogenic Chemotherapy Regimen

	Day 1	Day 2	Day 3	Day 4
Aprepitant capsules	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?antagonists	Standard dose of 5-HT3?antagonists. See the product information for the selected 5-HT3?antagonist for appropriate dosing information	none	none	none

Dexamethasone?should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 to 4. The dose of dexamethasone accounts for active substance interactions.

Moderately Emetogenic Chemotherapy Regimen

	Day 1	Day 2	Day 3
Aprepitant capsules	125 mg orally	80 mg orally	80 mg orally
Dexamethasone	12 mg orally	none	none
5-HT3?antagonists	Standard dose of 5-HT3?antagonists. See the product information for the selected 5-HT3?antagonist for appropriate dosing information	none	none

Dexamethasone?should be administered 30 minutes prior to chemotherapy treatment on Day 1. The dose of dexamethasone accounts for active substance interactions.

Paediatric population

Adolescents (aged 12 through 17 years)

Aprepitant capsules are given for 3 days as part of a regimen that includes a 5-HT₃?antagonist. The recommended dose of capsules of Aprepitant capsules is 125 mg orally on Day 1 and 80 mg orally on Days 2 and 3. Aprepitant capsules are administered orally 1 hour prior to chemotherapy on Days 1, 2 and 3. If no chemotherapy is given on Days 2 and 3, Aprepitant capsules should be administered in the morning. See the Summary of Product Characteristics (SmPC) for the selected 5-HT₃?antagonist for appropriate dosing information. If a corticosteroid, such as dexamethasone, is co-administered with Aprepitant capsules the dose of the corticosteroid should be administered at 50 % of the usual dose (see sections 4.5 and 5.1).

The safety and efficacy of the 80 mg and 125 mg capsules have not been demonstrated in children less than 12 years of age. No data are available.

General

Efficacy data in combination with other corticosteroids and 5-HT₃?antagonists are limited. For

additional information on the co-administration with corticosteroids, see section 4.5. Please refer to the SmPC of co-administered 5-HT₃?antagonist medicinal products.

Special populations

Elderly (? 65 years)

No dose adjustment is necessary for the elderly (see section 5.2).

Gender

No dose adjustment is necessary based on gender (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with renal impairment or for patients with end stage renal disease undergoing haemodialysis (see section 5.2).

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment. There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment.

Aprepitant should be used with caution in these patients (see sections 4.4 and 5.2).

Method of administration

For oral use.

The hard capsule should be swallowed whole.

Aprepitant capsules may be taken with or without food.

4.3 Contraindications

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

Co-administration with pimozide, terfenadine, astemizole or cisapride (see section 4.5).

4.4 Special warnings and precautions for use

Patients with moderate to severe hepatic impairment

There are limited data in patients with moderate hepatic impairment and no data in patients with severe hepatic impairment. Aprepitant capsules should be used with caution in these patients (see section 5.2).

CYP3A4 interactions

Aprepitant capsules should be used with caution in patients receiving concomitant orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloid derivatives, fentanyl, and quinidine (see section 4.5). Additionally, concomitant administration with irinotecan should be approached with particular caution as the combination might result in increased toxicity.

Co-administration with warfarin (a CYP2C9 substrate)

In patients on chronic warfarin therapy, the International Normalised Ratio (INR) should be monitored closely during treatment with Aprepitant capsules and for 14 days following each 3-day course of Aprepitant capsules (see section 4.5).

Co-administration with hormonal contraceptives

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of Aprepitant capsules . Alternative non-hormonal back-up methods of contraception should be used during treatment with Aprepitant capsules and for 2 months following the last dose of Aprepitant capsules (see section 4.5).

Excipients

Aprepitant capsules capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.

Aprepitant capsules capsules contain sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Aprepitant (125 mg/80 mg) is a substrate, a moderate inhibitor and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. During treatment with Aprepitant capsules , CYP3A4 is inhibited. After the end of treatment, Aprepitant capsules cause a transient mild induction of CYP2C9, CYP3A4 and glucuronidation. Aprepitant does not seem to interact with the P-glycoprotein transporter, as suggested by the lack of interaction of aprepitant with digoxin.

Effect of aprepitant on the pharmacokinetics of other active substances

CYP3A4 inhibition

As a moderate inhibitor of CYP3A4, aprepitant (125 mg/80 mg) can increase plasma concentrations of co-administered active substances that are metabolised through CYP3A4. The total exposure of orally administered CYP3A4 substrates may increase up to approximately 3-fold during the 3-day treatment with Aprepitant capsules ; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. Aprepitant capsules must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride (see section 4.3). Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions. Caution is advised during concomitant administration of Aprepitant capsules and orally administered active substances that are metabolised primarily through CYP3A4 and with a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, diergotamine, ergotamine, fentanyl, and quinidine (see section 4.4).

Corticosteroids

Dexamethasone: The usual oral dexamethasone dose should be reduced by approximately 50 % when co-administered with Aprepitant capsules 125 mg/80 mg regimen. The dose of dexamethasone in chemotherapy-induced nausea and vomiting clinical trials was chosen to account for active substance interactions (see section 4.2). Aprepitant, when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and aprepitant, when given as 80 mg/day with dexamethasone co-administered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, 2.2-fold on Days 1 and 5.

Methylprednisolone: The usual intravenously administered methylprednisolone dose should be reduced approximately 25 %, and the usual oral methylprednisolone dose should be reduced approximately 50 % when co-administered with Aprepitant capsules 125 mg/80 mg regimen. Aprepitant, when given as a regimen 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 co-administered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.

During continuous treatment with methylprednisolone, the AUC of methylprednisolone may decrease at later time points within 2 weeks following initiation of the aprepitant dose, due to the inducing effect of aprepitant on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone.

Chemotherapeutic medicinal products

In pharmacokinetic studies, aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, did not influence the pharmacokinetics of docetaxel administered intravenously on Day 1 or vinorelbine administered intravenously on Day 1 or Day 8. Because the effect of aprepitant on the pharmacokinetics of orally administered CYP3A4 substrates is greater than the effect of aprepitant on the pharmacokinetics of intravenously administered CYP3A4 substrates, an interaction with orally administered chemotherapeutic medicinal products metabolised primarily or partly by CYP3A4 (e.g. etoposide, vinorelbine) cannot be excluded. Caution is advised and additional monitoring may be appropriate in patients receiving medicinal products metabolized primarily or partly by CYP3A4 (see section 4.4). Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide co-administration.

Immunosuppressants

During the 3-day CINV regimen, a transient moderate increase followed by a mild decrease in exposure of immunosuppressants metabolised by CYP3A4 (e.g. cyclosporine, tacrolimus, everolimus and sirolimus) is expected. Given the short duration of the 3-day regimen and the time-dependent limited changes in exposure, dose reduction of the immunosuppressant is not recommended during the 3 days of co-administration with Aprepitant capsules.

Midazolam

The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolised via CYP3A4 (alprazolam, triazolam) should be considered when co-administering these medicinal products with Aprepitant capsules (125 mg/80 mg).

Aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of 2 mg midazolam was co-administered on Days 1 and 5 of a regimen of aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 to 5.

In another study with intravenous administration of midazolam, aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and 2 mg midazolam was given intravenously prior to the administration of the 3-day regimen of aprepitant and on Days 4, 8, and 15. Aprepitant increased the AUC of midazolam 25 % on Day 4 and decreased the AUC of midazolam 19 % on Day 8 and 4 % on Day 15. These effects were not considered clinically important.

In a third study with intravenous and oral administration of midazolam, aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, together with ondansetron 32 mg Day 1, dexamethasone 12 mg Day 1 and 8 mg Days 2-4. This combination (i.e. aprepitant, ondansetron and dexamethasone) decreased the AUC of oral midazolam 16 % on Day 6, 9 % on Day 8, 7 % on Day 15 and 17 % on Day 22. These effects were not considered clinically important.

An additional study was completed with intravenous administration of midazolam and aprepitant. Intravenous 2 mg midazolam was given 1 hour after oral administration of a single dose of aprepitant 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. This effect was not considered clinically important.

Induction

As a mild inducer of CYP2C9, CYP3A4 and glucuronidation, aprepitant can decrease plasma concentrations of substrates eliminated by these routes within two weeks following initiation of treatment. This effect may become apparent only after the end of a 3-day treatment with Aprepitant capsules . For CYP2C9 and CYP3A4 substrates the induction is transient with a maximum effect reached after 3-5 days after the end of the Aprepitant capsules 3-day treatment. The effect is maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after the end of Aprepitant capsules treatment. Mild induction of glucuronidation is also seen with 80 mg oral aprepitant given for 7 days. Data are lacking regarding effects on CYP2C8 and CYP2C19. Caution is advised when warfarin, acenocoumarol, tolbutamide, phenytoin or other active substances that are known to be metabolised by CYP2C9 are administered during this time period.

Warfarin

In patients on chronic warfarin therapy, the prothrombin time (INR) should be monitored closely during treatment with Aprepitant capsules and for 2 weeks following each 3-day course of Aprepitant capsules for chemotherapy-induced nausea and vomiting (see section 4.4). When a single 125 mg dose of aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilised on chronic warfarin therapy, there was no effect of aprepitant on the plasma AUC of R(+) or S(-) warfarin determined on Day 3; however, there was a 34 % decrease in S(-) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14 % decrease in INR 5 days after completion of treatment with aprepitant.

Tolbutamide

Aprepitant, when given as 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, 28 % on Day 8, and 15 % on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of aprepitant and on Days 4, 8, and 15.

Hormonal contraceptives

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of Aprepitant capsules. Alternative non-hormonal back-up methods of contraception should be used during treatment with Aprepitant capsules and for 2 months following the last dose of Aprepitant capsules.

In a clinical study, single doses of an oral contraceptive containing ethinyl estradiol and norethindrone were administered on Days 1 through 21 with aprepitant, given as a regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg intravenously on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. During days 9 through 21 in this study, there was as much as a 64 % decrease in ethinyl estradiol trough concentrations and as much as a 60 % decrease in norethindrone trough concentrations.

5-HT₃?antagonists

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

Effect of other medicinal products on the pharmacokinetics of aprepitant

Concomitant administration of Aprepitant capsules with active substances that inhibit CYP3A4 activity (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and protease inhibitors) should be approached cautiously, as the combination is expected to result in several-fold increased plasma concentrations of aprepitant (see section 4.4).

Concomitant administration of Aprepitant capsules with active substances that strongly induce CYP3A4 activity (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital) should be avoided as the combination results in reductions of the plasma concentrations of aprepitant that may result in decreased efficacy of Aprepitant capsules.

Concomitant administration of Aprepitant capsules with herbal preparations containing St. John’s Wort?(Hypericum perforatum)?is not recommended.

Ketoconazole

When a single 125 mg dose of aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold.

Rifampicin

When a single 375 mg dose of aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampicin, a strong CYP3A4 inducer, the AUC of aprepitant decreased 91 % and the mean terminal half-life decreased 68%.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Contraception in males and females

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of Aprepitant capsules. Alternative non-hormonal back-up methods of contraception should be used during treatment with Aprepitant capsules and for 2 months following the last dose of Aprepitant capsules (see sections 4.4 and 4.5).

Pregnancy

For aprepitant no clinical data on exposed pregnancies are available. The potential for reproductive toxicity of aprepitant has not been fully characterised, since exposure levels above the therapeutic exposure in humans at the 125 mg/80 mg dose could not be attained in animal studies. These studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). The potential effects on reproduction of alterations in neurokinin regulation are unknown. Aprepitant capsules should not be used during pregnancy unless clearly necessary.

Breast-feeding

Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breast-feeding is not recommended during treatment with Aprepitant capsules.

Fertility

The potential for effects of aprepitant on fertility has not been fully characterised because exposure levels above the therapeutic exposure in humans could not be attained in animal studies. These fertility studies did not indicate direct or indirect harmful effects with respect to mating performance, fertility, embryonic/foetal development, or sperm count and motility (see section 5.3).

4.7 Effects on ability to drive and use machines

Aprepitant capsules may have minor influence on the ability to drive, cycle and use machines. Dizziness and fatigue may occur following administration of Aprepitant capsules (see section 4.8).

4.8 Undesirable effects

Summary of the safety profile

The safety profile of aprepitant was evaluated in approximately 6,500 adults in more than 50 studies and 184 children and adolescents in 2 pivotal paediatric clinical trials.

The most common adverse reactions reported at a greater incidence in adults treated with the aprepitant regimen than with standard therapy in patients receiving Highly Emetogenic Chemotherapy (HEC) were: hiccups (4.6 % versus 2.9 %), alanine aminotransferase (ALT) increased (2.8 % versus 1.1 %), dyspepsia (2.6 % versus 2.0 %), constipation (2.4 % versus 2.0 %), headache (2.0 % versus 1.8 %), and decreased appetite (2.0 % versus 0.5 %). The most common adverse reaction reported at a greater incidence in patients treated with the aprepitant regimen than with standard therapy in patients receiving Moderately Emetogenic Chemotherapy (MEC) was fatigue (1.4 % versus 0.9 %).

The most common adverse reactions reported at a greater incidence in paediatric patients treated with the aprepitant regimen than with the control regimen while receiving emetogenic cancer chemotherapy were hiccups (3.3 % versus 0.0 %) and flushing (1.1 % versus 0.0 %).

Tabulated list of adverse reactions

The following adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with aprepitant than with standard therapy in adults or paediatric patients or in post-marketing use. The frequency categories given in the table are based on the studies in adults; the observed frequencies in the paediatric studies were similar or lower, unless shown in the table. Some less common ADRs in the adult population were not observed in the paediatric studies.

Frequencies are 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) and very rare (< 1/10,000), not known (cannot be estimated from the available data).

System organ class	Adverse reaction	Frequency
Infection and infestations	candidiasis, staphylococcal infection	rare
Blood and lymphatic system disorders	febrile neutropenia, anaemia	uncommon
Immune system disorders	hypersensitivity reactions including anaphylactic reactions	not known
Metabolism and nutrition disorders	decreased appetite	common
	polydipsia	rare
Psychiatric disorders	anxiety	uncommon
	disorientation, euphoric mood	rare
Nervous system disorders	headache	common
	dizziness, somnolence	uncommon
	cognitive disorder, lethargy, dysgeusia	rare
Eye disorders	conjunctivitis	rare
Ear and labyrinth disorders	tinnitus	rare
Cardiac disorders	palpitations	uncommon
	bradycardia, cardiovascular disorder	rare
Vascular disorders	hot flush/flushing	uncommon
Respiratory, thoracic and mediastinal disorders	hiccups	common
	oropharyngeal pain, sneezing, cough, postnasal drip, throat irritation	rare
Gastrointestinal disorders	constipation, dyspepsia	common
	eructation, nausea?, vomiting?, gastroesophageal reflux disease, abdominal pain, dry mouth, flatulence	uncommon
	duodenal ulcer perforation, stomatitis, abdominal distension, faeces hard, neutropenic colitis	rare
Skin and subcutaneous tissue disorders	rash, acne	uncommon
	photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, rash pruritic, Stevens-Johnson syndrome/toxic epidermal necrolysis	rare
	pruritus, urticaria	not known
Musculoskeletal and connective tissue disorders	muscular weakness, muscle spasms	rare
Renal and urinary disorders	dysuria	uncommon
	pollakiuria	rare
General disorders and administration site conditions	fatigue	common
	asthenia, malaise	uncommon
	oedema, chest discomfort, gait disturbance	rare
Investigations	ALT increased	common
	AST increased, blood alkaline phosphatase increased	uncommon
	red blood cells urine positive, blood sodium decreased, weight decreased, neutrophil count decreased, glucose urine present, urine output increased	rare

^??Nausea and vomiting were efficacy parameters in the first 5 days of post-chemotherapy treatment and were reported as adverse reactions only thereafter.

Description of selected adverse reactions

The adverse reactions profiles in adults in the Multiple-Cycle extension of HEC and MEC studies for up to 6 additional cycles of chemotherapy were generally similar to those observed in Cycle 1.

In an additional active-controlled clinical study in 1,169 adult patients receiving aprepitant and HEC, the adverse reactions profile was generally similar to that seen in the other HEC studies with aprepitant.

Additional adverse reactions were observed in adult patients treated with aprepitant for postoperative nausea and vomiting (PONV) and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, constipation*, dysarthria, dyspnoea, hypoaesthesia, insomnia, miosis, nausea, sensory disturbance, stomach discomfort, sub-ileus*, visual acuity reduced, wheezing.

*Reported in patients taking a higher dose of aprepitant.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

4.9 Overdose

In the event of overdose, Aprepitant capsules should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, emesis induced by a medicinal product may not be effective.

Aprepitant cannot be removed by haemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, Other antiemetics

Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK₁) receptors.

3-day regimen of aprepitant in adults

In 2 randomised, double-blind studies encompassing a total of 1,094 adult patients receiving chemotherapy that included cisplatin ? 70 mg/m², aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with a standard regimen (placebo plus ondansetron 32 mg intravenously administered on Day 1 plus dexamethasone 20 mg orally on Day 1 and 8 mg orally twice daily on Days 2 to 4). Although a 32 mg intravenous dose of ondansetron was used in clinical trials, this is no longer the recommended dose. See the product information for the selected 5-HT₃?antagonist for appropriate dosing information.

Efficacy was based on evaluation of the following composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. The results were evaluated for each individual study and for the 2 studies combined.

A summary of the key study results from the combined analysis is shown in Table 1.

Table 1

Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase ? Cycle 1

	Aprepitant regimen (N= 521)??	Standard therapy (N= 524)??	Differences*
	%	%	%	(95 % CI)
COMPOSITE MEASURES
Complete response (no emesis and no rescue therapy)
Overall (0-120 hours)	67.7	47.8	19.9	(14.0, 25.8)
0-24 hours	86.0	73.2	12.7	(7.9, 17.6)
25-120 hours	71.5	51.2	20.3	(14.5, 26.1)
INDIVIDUAL MEASURES
No emesis (no emetic episodes regardless of use of rescue therapy)
Overall (0-120 hours)	71.9	49.7	22.2	(16.4, 28.0)
0-24 hours	86.8	74.0	12.7	(8.0, 17.5)
25-120 hours	76.2	53.5	22.6	(17.0, 28.2)
No significant nausea (maximum VAS < 25 mm on a scale of 0-100 mm)
Overall (0-120 hours)	72.1	64.9	7.2	(1.6, 12.8)
25-120 hours	74.0	66.9	7.1	(1.5, 12.6)

^*?The confidence intervals were calculated with no adjustment for gender and concomitant chemotherapy, which were included in the primary analysis of odds ratios and logistic models.

^?One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses; one patient in the Standard regimen only had data in the delayed phase and was excluded from the overall and acute phase analyses.

The estimated time to first emesis in the combined analysis is depicted by the Kaplan-Meier plot in Figure 1.

Figure 1

Percent of adult patients receiving Highly Emetogenic Chemotherapy who remain emesis free over time ? Cycle 1

Statistically significant differences in efficacy were also observed in each of the 2 individual studies.

In the same 2 clinical studies, 851 adult patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles.

In a randomised, double-blind study in a total of 866 adult patients (864 females, 2 males) receiving chemotherapy that included cyclophosphamide 750-1,500 mg/m²; or cyclophosphamide 500-1,500 mg/m^2?and doxorubicin (< 60 mg/m²) or epirubicin (< 100 mg/m²), aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo plus ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1).

Efficacy was based on evaluation of the composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1.

A summary of the key study results is shown in Table 2.

Table 2

Percent of adult patients responding by treatment group and phase ? Cycle 1

Moderately Emetogenic Chemotherapy

	Aprepitant regimen (N= 433)??	Standard therapy (N=424)	Differences*
	%	%	%	(95 % CI)
COMPOSITE MEASURES
Complete response (no emesis and no rescue therapy)
Overall (0-120 hours)	50.8	42.5	8.3	(1.6, 15.0)
0-24 hours	75.7	69.0	6.7	(0.7, 12.7)
25-120 hours	55.4	49.1	6.3	(-0.4, 13.0)
INDIVIDUAL MEASURES
No emesis (no emetic episodes regardless of use of rescue therapy)
Overall (0-120 hours)	75.7	58.7	17.0	(10.8, 23.2)
0-24 hours	87.5	77.3	10.2	(5.1, 15.3)
25-120 hours	80.8	69.1	11.7	(5.9, 17.5)
No significant nausea (maximum VAS < 25 mm on a scale of 0-100 mm)
Overall (0-120 hours)	60.9	55.7	5.3	(-1.3, 11.9)
0-24 hours	79.5	78.3	1.3	(-4.2, 6.8)
25-120 hours	65.3	61.5	3.9	(-2.6, 10.3)

^*?The confidence intervals were calculated with no adjustment for age category (< 55 years, ? 55 years) and investigator group, which were included in the primary analysis of odds ratios and logistic models.

^??One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses.

In the same clinical study, 744 adult patients continued into the Multiple-Cycle extension for up to 3 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles.

In a second multicentre, randomised, double-blind, parallel-group, clinical study, the aprepitant regimen was compared with standard therapy in 848 adult patients (652 females, 196 males) receiving a chemotherapy regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenously (< 1,500 mg/m²); or cytarabine intravenously (> 1 g/m²). Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumour types including 52 % with breast cancer, 21 % with gastrointestinal cancers including colorectal cancer, 13 % with lung cancer and 6 % with gynaecological cancers. The aprepitant regimen in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo in combination with ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1).

Efficacy was based on the evaluation of the following primary and key secondary endpoints: No vomiting in the overall period (0 to 120 hours post-chemotherapy), evaluation of safety and tolerability of the aprepitant regimen for chemotherapy induced nausea and vomiting (CINV), and complete response (defined as no vomiting and no use of rescue therapy) in the overall period (0 to120 hours post-chemotherapy). Additionally, no significant nausea in the overall period (0 to120 hours post-chemotherapy) was evaluated as an exploratory endpoint, and in the acute and delayed phases as a post-hoc analysis.

A summary of the key study results is shown in Table 3.

Table 3

Percent of adult patients responding by treatment group and phase for Study 2 ? Cycle 1

Moderately Emetogenic Chemotherapy

	Aprepitant regimen (N= 425)	Standard therapy (N=406)	Differences*
	%	%	%	(95 % CI)
Complete response (no emesis and no rescue therapy)
Overall (0-120 hours)	68.7	56.3	12.4	(5.9, 18.9)
0-24 hours	89.2	80.3	8.9	(4.0, 13.8)
25-120 hours	70.8	60.9	9.9	(3.5, 16.3)
No emesis (no emetic episodes regardless of use of rescue therapy)
Overall (0-120 hours)	76.2	62.1	14.1	(7.9, 20.3)
0-24 hours	92.0	83.7	8.3	(3.9, 12.7)
25-120 hours	77.9	66.8	11.1	(5.1, 17.1)
No significant nausea (maximum VAS < 25 mm on a scale of 0-100 mm)
Overall (0-120 hours)	73.6	66.4	7.2	(1.0, 13.4)
0-24 hours	90.9	86.3	4.6	(0.2, 9.0)
25-120 hours	74.9	69.5	5.4	(-0.7, 11.5)

^*The confidence intervals were calculated with no adjustment for gender and region, which were included in the primary analysis using logistic models.

The benefit of aprepitant combination therapy in the full study population was mainly driven by the results observed in patients with poor control with the standard regimen such as in women, even though the results were numerically better regardless of age, tumour type or gender. Complete response to the aprepitant regimen and standard therapy, respectively, was reached in 209/324 (65 %) and 161/320 (50 %) in women and 83/101 (82 %) and 68/87 (78 %) of men.

Paediatric population

In a randomised, double-blind, active comparator-controlled clinical study that included 302 children and adolescents (aged 6 months to 17 years) receiving moderately or highly emetogenic chemotherapy, the aprepitant regimen was compared to a control regimen for the prevention of CINV.

The efficacy of the aprepitant regimen was evaluated in a single cycle (Cycle 1). Patients had the opportunity to receive open-label aprepitant in subsequent cycles (Optional Cycles 2-6); however efficacy was not assessed in these optional cycles. The aprepitant regimen for adolescents aged 12 through 17 years (n=47) consisted of aprepitant capsules 125 mg orally on Day 1 and 80 mg/day on Days 2 and 3 in combination with ondansetron on Day 1. The aprepitant regimen for children aged 6 months to less than 12 years (n=105) consisted of aprepitant powder for oral suspension 3.0 mg/kg (up to 125 mg) orally on Day 1 and 2.0 mg/kg (up to 80 mg) orally on Days 2 and 3 in combination with ondansetron on Day 1. The control regimen in adolescents aged 12 through 17 years (n=48) and children aged 6 months to less than 12 years (n=102) consisted of placebo for aprepitant on Days 1, 2 and 3 in combination with ondansetron on Day 1. Aprepitant or placebo and ondansetron were administered 1 hour and 30 minutes prior to initiation of chemotherapy, respectively. Intravenous dexamethasone was permitted as part of the antiemetic regimen for paediatric patients in both age groups, at the discretion of the physician. A dose reduction (50 %) of dexamethasone was required for paediatric patients receiving aprepitant. No dose reduction was required for paediatric patients receiving the control regimen. Of the paediatric patients, 29 % in the aprepitant regimen and 28 % in the control regimen used dexamethasone as part of the regimen in Cycle 1.

The antiemetic activity of aprepitant was evaluated over a 5-day (120 hour) period following the initiation of chemotherapy on Day 1. The primary endpoint was complete response in the delayed phase (25 to 120 hours following initiation of chemotherapy) in Cycle 1. A summary of the key study results are shown in Table 4.

Table 4

Number (%) of paediatric patients with complete response and no vomiting by treatment group and phase ? Cycle 1 (Intent to treat population)

	Aprepitant regimen n/m (%)	Control regimen n/m (%)
PRIMARY ENDPOINT
Complete response*?? Delayed phase	77/152 (50.7)?	39/150 (26.0)
OTHER PRESPECIFIED ENDPOINTS
Complete response*?? Acute phase	101/152 (66.4)?	78/150 (52.0)
Complete response*?? Overall phase	61/152 (40.1)?	30/150 (20.0)
No vomiting??? Overall phase	71/152 (46.7)?	32/150 (21.3)
*Complete response = No vomiting or retching or dry heaves and no use of rescue medication. ??p < 0.01 when compared to control regimen ??p < 0.05 when compared to control regimen ??No vomiting = No vomiting or retching or dry heaves n/m = Number of patients with desired response/number of patients included in time point. Acute phase: 0 to 24 hours following initiation of chemotherapy. Delayed phase: 25 to 120 hours following initiation of chemotherapy. Overall phase: 0 to 120 hours following initiation of chemotherapy.

The estimated time to first vomiting after initiation of chemotherapy treatment was longer with the aprepitant regimen (estimated median time to first vomiting was 94.5 hours) compared with the control regimen group (estimated median time to first vomiting was 26.0 hours) as depicted in the Kaplan-Meier curves in Figure 2.

Figure 2

Time to first vomiting episode from start of chemotherapy administration – paediatric patients in the overall phase-Cycle 1 (Intent to treat population)

An analysis of efficacy in subpopulations in Cycle 1 demonstrated that, regardless of age category, gender, use of dexamethasone for antiemetic prophylaxis, and emetogenicity of chemotherapy, the aprepitant regimen provided better control than the control regimen with respect to the complete response endpoints.

5.2 Pharmacokinetic properties

Aprepitant displays non-linear pharmacokinetics. Both clearance and absolute bioavailability decrease with increasing dose.

Absorption

The mean absolute oral bioavailability of aprepitant is 67 % for the 80 mg capsule and 59 % for the 125 mg capsule. The mean peak plasma concentration (C_max) of aprepitant occurred at approximately 4 hours (t_max). Oral administration of the capsule with an approximately 800 Kcal standard breakfast resulted in an up to 40 % increase in AUC of aprepitant. This increase is not considered clinically relevant.

The pharmacokinetics of aprepitant is non-linear across the clinical dose range. In healthy young adults, the increase in AUC_0-??was 26 % greater than dose proportional between 80 mg and 125 mg single doses administered in the fed state.

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 AUC_0-24hr?(mean?SD) was 19.6 ? 2.5 ?g?h/mL and 21.2 ? 6.3 ?g?h/mL on Days 1 and 3, respectively. C_max?was 1.6 ? 0.36 ?g/mL and 1.4 ? 0.22 ?g/mL on Days 1 and 3, respectively.

Distribution

Aprepitant is highly protein bound, with a mean of 97 %. The geometric mean apparent volume of distribution at steady state (Vd_ss) is approximately 66 L in humans.

Biotransformation

Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 19 % of the radioactivity in plasma over 72 hours following a single intravenous administration 100 mg dose of [¹⁴C]-fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active.?In vitro?studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19.

Elimination

Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and?via?biliary excretion in faeces. Following a single intravenously administered 100 mg dose of [¹⁴C]-fosaprepitant, a prodrug for aprepitant, to healthy subjects, 57 % of the radioactivity was recovered in urine and 45 % in faeces.

The plasma clearance of aprepitant is dose-dependent, decreasing with increased dose and ranged from approximately 60 to 72 mL/min in the therapeutic dose range. The terminal half-life ranged from approximately 9 to 13 hours.

Pharmacokinetics in special populations

Elderly:?Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC_0-24hr?of aprepitant was 21 % higher on Day 1 and 36 % higher on Day 5 in elderly (? 65 years) relative to younger adults. The C_max?was 10 % higher on Day 1 and 24 % higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful.

No dose adjustment for Aprepitant capsules is necessary in elderly patients.

Gender:?Following oral administration of a single 125 mg dose of aprepitant, the C_max?for aprepitant is 16 % higher in females as compared with males. The half-life of aprepitant is 25 % lower in females as compared with males and its t_max?occurs at approximately the same time. These differences are not considered clinically meaningful.

No dose adjustment for Aprepitant capsules is necessary based on gender.

Hepatic impairment:?Mild hepatic impairment (Child-Pugh class A) does not affect the

pharmacokinetics of aprepitant to a clinically relevant extent. No dose adjustment is necessary for patients with mild hepatic impairment. Conclusions regarding the influence of moderate hepatic impairment (Child-Pugh class B) on aprepitant pharmacokinetics cannot be drawn from available data. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment:?A single 240 mg dose of aprepitant was administered to patients with severe renal impairment (CrCl < 30 mL/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis.

In patients with severe renal impairment, the AUC_0-??of total aprepitant (unbound and protein bound) decreased by 21 % and C_max?decreased by 32 %, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC_0-??of total aprepitant decreased by 42 % and C_max?decreased by 32 %. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound aprepitant was not significantly affected in patients with renal impairment compared with healthy subjects. Haemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2 % of the dose was recovered in the dialysate.

No dose adjustment for Aprepitant capsules is necessary for patients with renal impairment or for patients with ESRD undergoing haemodialysis.

Paediatric population:?As part of a 3-day regimen, dosing of aprepitant capsules (125/80/80 mg) in adolescent patients (aged 12 through 17 years) achieved an AUC_0-24hr?above 17 ?g?hr/mL on Day 1 with concentrations (C_min) at the end of Days 2 and 3 above 0.4 ?g/mL in a majority of patients. The median peak plasma concentration (C_max) was approximately 1.3 ?g/mL on Day 1, occurring at approximately 4 hours. As part of a 3-day regimen, dosing of aprepitant powder for oral suspension (3/2/2-mg/kg) in patients aged 6 months to less than12 years achieved an AUC_0-24hr?above 17 ?g?hr/mL on Day 1 with concentrations (C_min) at the end of Days 2 and 3 above 0.1 ?g/mL in a majority of patients. The median peak plasma concentration (C_max) was approximately 1.2 ?g/mL on Day 1, occurring between 5 and 7 hours.

A population pharmacokinetic analysis of aprepitant in paediatric patients (aged 6 months through 17 years) suggests that gender and race have no clinically meaningful effect on the pharmacokinetics of aprepitant.

Relationship between concentration and effect

Using a highly specific NK₁-receptor tracer, positron emission tomography (PET) studies in healthy young men have shown that aprepitant penetrates into the brain and occupies NK₁?receptors in a dose- and plasma-concentration-dependent manner. Aprepitant plasma concentrations achieved with the 3-day regimen of Aprepitant capsules are predicted to provide greater than 95 % occupancy of brain NK_1?receptors.

5.3 Preclinical safety data

Pre-clinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. However, it should be noted that systemic exposure in rodents was similar or even lower than the therapeutic exposure in humans at the 125 mg/80 mg dose. In particular, although no adverse effects were noted in reproduction studies at human exposure levels, the animal exposures are not sufficient to make an adequate risk assessment in man.

In a juvenile toxicity study in rats treated from postnatal day 10 to day 63 aprepitant led to an earlier vaginal opening in females from 250 mg/kg b.i.d. and to a delayed preputial separation in males, from10 mg/kg b.i.d. There were no margins to clinically relevant exposure. There were no treatment-related effects on mating, fertility or embryonic/foetal survival, and no pathological changes in the reproductive organs. In a juvenile toxicity study in dogs treated from postnatal day 14 to day 42, a decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen in females from 4 mg/kg/day. There were no margins to clinically relevant exposure of aprepitant. For short term treatment according to recommended dose regimen these findings are considered unlikely to be clinically relevant.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content

Hypromellose, Poloxamer

Sucrose, Cellulose, microcrystalline

Capsule shell (80 mg)

Gelatin

Sodium laurilsulfate

Titanium dioxide

Black printing ink

Shellac

Iron oxide black

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

30 months

6.4 Special precautions for storage

Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

Tablets are packed in Bottle/Alu-Alu blisters

Pack Size of: 7, 14, 28, 30, 50, 90, 100 or 200 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7.Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA).

Aprepitant 80mg Capsules Taj Pharma

Patient information leaflet: Important for the user

(Aprepitant)

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. If you are the parent of a child taking

Aprepitant Hard Capsules, please read this information carefully.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you or the child only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you or the child gets any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

The full name of this medicine is Aprepitant Hard Capsules but within this leaflet, it will be referred to as Aprepitant Capsules.

What is in this leaflet

1 What Aprepitant Capsules are and what they are used for
2 What you need to know before you take or give Aprepitant Capsules
3 How to take Aprepitant Capsules
4 Possible side effects
5 How to store Aprepitant Capsules
6 Contents of the pack and other information

1. WHAT APREPITANT CAPSULES ARE AND WHAT THEY ARE USED FOR

Aprepitant Capsules contain the active substance aprepitant and belongs to a group of medicines called ?neurokinin 1 (NK1) receptor

antagonists? . The brain has a specific area

that controls nausea and vomiting. Aprepitant Capsules work by blocking signals to that area, thereby reducing nausea and vomiting.

Aprepitant? Capsules are used in adults and adolescents from the age of 12 years in combination with other medicines to prevent nausea and vomiting caused by medicines used in chemotherapy (cancer treatment) that are strong and moderate triggers of nausea and vomiting (such as cisplatin, cyclophosphamide, doxorubicin or epirubicin).

2 WHAT YOU NEED TO KNOW BEFORE YOU TAKES OR GIVE APREPITANT CAPSULES

Do not take Aprepitant Capsules:

• if you or your child is allergic to aprepitant or any of the other ingredients of this medicine (listed in section 6).
• with medicines containing:
• pimozide (used to treat psychiatric illnesses)
• terfenadine and astemizole (used for hay fever and other allergic conditions)
• cisapride (used for treating digestive problems).

Tell the doctor if you or your child is taking these medicines since the treatment must be modified before you or your child starts taking Aprepitant Capsules.

Warnings and precautions

Talk to the doctor, pharmacist or nurse before taking Aprepitant Capsules or giving this medicine to your child.

Before treatment with Aprepitant Capsules, tell the doctor if you or your child has liver disease because the liver is important in breaking down this medicine in the body. The doctor may therefore have to monitor the condition of your or your child?s liver.

Children and adolescents

Do not give Aprepitant Capsules 80mg and 125mg capsules to children under 12 years of age, because the 80mg and 125mg capsules have not been studied in this population.

Other medicines and Aprepitant Capsules

Aprepitant Capsules can affect other medicines both, during and after treatment with Aprepitant Capsules . There are some medicines that should not be taken with Aprepitant Capsules (such as pimozide, terfenadine, astemizole, and cisapride) or that require a dose adjustment (see also ?Do not take Aprepitant Capsules ?).

The effects of Aprepitant Capsules or other medicines might be influenced if you or your child takes Aprepitant Capsules together with other medicines including those listed below. Please talk to the doctor or pharmacist if you or your child are taking any of the following medicines:

• birth control medicines which can include birth control pills, skin patches, implants, and certain Intrauterine devices (IUDs) that release hormones may not work adequately when taken together with Aprepitant Capsules. Another or additional non-hormonal form of birth control should be used during treatment with Aprepitant Capsules and for up to 2 months after taking Aprepitant Capsules
• cyclosporine, tacrolimus, sirolimus, everolimus (immunosuppressants)
• alfentanil, fentanyl (used to treat pain)
• quinidine (used to treat an irregular heart beat)
• irinotecan, etoposide, vinorelbine, ifosfamide (medicines used to treat cancer)
• medicines containing ergot alkaloid derivatives such as ergotamine and diergotamine (used for treating migraines)
• warfarin, acenocoumarol (blood thinners; blood tests may be required)
• rifampicin, clarithromycin, telithromycin (antibiotics used to treat infections)
• phenytoin (a medicine used to treat seizures)
• carbamazepine (used to treat depression and epilepsy)
• midazolam, triazolam, phenobarbital (medicines used to produce calmness or help you sleep)
• John?s Wort (a herbal preparation used to treat depression)
• protease inhibitors (used to treat HIV infections)
• ketoconazole, except shampoo (used to treat Cushing?s syndrome – when the body produces an excess of cortisol)
• itraconazole, voriconazole, posaconazole (antifungals)
• nefazodone (used to treat depression)
• corticosteroids (such as dexamethasone and methylprednisolone)
• anti-anxiety medicines (such as alprazolam)
• tolbutamide (a medicine used to treat diabetes)

Tell the doctor or pharmacist if you or your child is taking, has recently taken or might take any other medicines.

Pregnancy and breast-feeding

This medicine should not be used during pregnancy unless clearly necessary. If you or your child are pregnant or breast-feeding, think you/they may be pregnant or planning to have a baby, ask the doctor for advice before taking this medicine.

For information regarding birth control, see ?Other medicines and Aprepitant Capsules ?.

It is not known whether Aprepitant Capsules are excreted in human milk; therefore, breast- feeding is not recommended during treatment with this medicine. It is important that you tell the doctor if you or your child is breast-feeding or is planning to breast-feed before taking this medicine.

Driving???? and????? using????? machines It should be taken into account that some people feel dizzy and sleepy after taking

Aprepitant Capsules. If you or your child feels dizzy or sleepy, avoid driving, riding a bicycle or using machines or tools after taking this medicine (see ?Possible side effects?).

Aprepitant Capsules contain sucrose Aprepitant Capsules contain sucrose. If you or your child has been told by the doctor that you or your child has an intolerance to some sugars, contact the doctor before taking this medicine.

Aprepitant hard capsules contain sodium

This medicine contains less than 1 mmol sodium (23mg) per capsule, that is to say essentially ?sodium-free?.

3 HOW TO TAKE APREPITANT CAPSULES

Always take this medicine or give this medicine to your child exactly as the doctor, pharmacist or nurse has told you. Check with the doctor, pharmacist or nurse if you are not sure.

Always take Aprepitant Capsules together with other medicines to prevent nausea and vomiting. After treatment with Aprepitant Capsules, the doctor may ask you or your child to continue taking other medicines including a corticosteroid (such as dexamethasone) and a ?5HT3 antagonist? (such as ondansetron) for preventing nausea and vomiting. Check with the doctor, pharmacist or nurse if you are not sure.

The recommended dose of Aprepitant Capsules is:

Day 1: one 125mg capsule 1 hour before you start your chemotherapy session

And Days 2 and 3: one 80mg capsule each day

If no chemotherapy is given, take Aprepitant Capsules in the morning.

If chemotherapy is given, take Aprepitant Capsules 1 hour before you start your chemotherapy session.

This medicine is for oral use. Swallow the capsule whole with some liquid. Aprepitant Capsules can be taken with or without food.

If you take more Aprepitant Capsules than you should

Do not take more capsules than prescribed by your doctor. If you or your child has taken too many capsules, contact your doctor immediately.

If you forget to take Aprepitant Capsules

If you or your child has missed a dose, contact your doctor for advice.

If you have any further questions on the use of this medicine, ask the doctor or pharmacist.

4 POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop taking Aprepitant Capsules and see a doctor immediately if you or your child notices any of the following side effects, which may be serious, and for which you or your child may need urgent medical treatment:

• Hives, rash, itching, difficulty breathing or swallowing (frequency not known, cannot be estimated from the available data); these are signs of an allergic reaction.

Other side effects

Common: may affect up to 1 in 10 people

• constipation, indigestion
• headache
• tiredness
• loss of appetite
• hiccups
• increased amount of liver enzymes in your blood

Uncommon: may affect up to 1 in 100 people

• dizziness, sleepiness
• acne, rash
• anxiousness
• burping, nausea, vomiting, heartburn, stomach pain, dry mouth, passing wind
• increased painful or burning urination
• weakness, generally feeling unwell
• hot flush/reddening of the face or skin
• fast or irregular heartbeats
• fever with increased risk of infection, lowering of red blood cells

Rare: may affect up to 1 in 1,000 people

• difficulty thinking, lack of energy, taste disturbance
• sensitivity of the skin to sun, excessive sweating, oily skin, sores on skin, itching rash, Stevens-Johnson syndrome/toxic epidermal necrolysis (rare severe skin reaction)
• euphoria (feeling of extreme happiness), disorientation
• bacterial infection, fungal infection
• severe constipation, stomach ulcer, inflammation of the small intestine and colon, sores in mouth, bloating
• frequent urination, passing more urine than normal, presence of sugar or blood in urine
• chest discomfort, swelling, change in the manner of walking
• cough, mucus in back of throat, throat irritation, sneezing, sore throat
• eye discharge and itching
• ringing in the ear
• muscle spasms, muscle weakness
• excessive thirst
• slow heartbeat, heart and blood vessel disease
• lowering of white blood cells, low sodium levels in the blood, weight loss

Reporting of side effects

If you or your child gets any side effects, talk to your doctor, pharmacist or nurse.

5. HOW TO STORE APREPITANT CAPSULES

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the blister after ?EXP?. The expiry date refers to the last day of that month.

Store in the original package in order to protect from moisture.

Do not remove the capsule from its blister until you are ready to take it.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Contents of the pack and other information

What Aprepitant Capsules contain

a) Each hard gelatin capsule contains:
Aprepitant????????????????????????????????? 80mg
Excipients??????????????????????????????????? q.s
Empty gelatin capsule contains approved colours.

b) Each hard gelatin capsule contains:
Aprepitant????????????????????????????????? 125mg
Excipients??????????????????????????????????? q.s
Empty gelatin capsule contains approved colours.

What Aprepitant Capsules look like and contents of the pack

Tablets are packed in Bottle/Alu-Alu blisters

Pack Size of: 7, 14, 28, 30, 50, 90, 100 or 200 tablets.

Not all pack sizes may be marketed.

7. Manufactured in India By:
TAJ PHARMACEUTICALS LIMITED
at SURVEY NO.188/1 TO 189/1,190/1 TO 4,
ATHIYAWAD, DABHEL, DAMAN- 396210 (INDIA)