Vomend Combi Pack Capsule

VOMEND in combination with other anti-emetic medicines, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of:

• Highly emetogenic cancer chemotherapy (see section 4.2).
• Moderately emetogenic cancer chemotherapy (see section 4.2).

Posology

VOMEND is given for 3 days as part of a regimen that includes a corticosteroid for 4 days and a 5-HT 3 antagonist on day one. The professional information for the co-administered 5- HT 3 antagonist must be referred to prior to the initiation of treatment with [PRODUCT NAME]. The recommended dose of VOMEND is 125 mg orally 1 hour prior to chemotherapy (Day 1) and 80 mg once daily in the morning, on Days 2 and 3.

Recommended dosing for the prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy:

** Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 u2013 4. The dose of dexamethasone accounts for interactions.

*** See the professional information for the selected 5-HT 3 antagonist for appropriate dosing information.

Recommended dosing for the prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy:

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

*** See the professional information for the selected 5-HT 3 antagonist for appropriate dosing information.

See section 4.5 for additional information on the administration of VOMEND with corticosteroids. Refer to the professional information for co-administered anti-emetic medicines.

Special populations

No dosage adjustment is necessary based on age, gender, race or body mass index (BMI).

Renal impairment

No dosage adjustment is necessary for patients with severe renal insufficiency (creatinine clearance < 30 mL/min) or for patients with end stage renal disease undergoing haemodialysis.

Hepatic impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic insufficiency (Child-Pugh score 5 to 9). There are no clinical data in patients with severe hepatic insufficiency (Child-Pugh score > 9).

Method of administration

For oral use VOMEND can be taken with or without food.

Hypersensitivity to aprepitant or to any of the inactive ingredients of VOMEND (see section 6.1). VOMEND should not be used concurrently with pimozide, terfenadine, astemizole or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by VOMEND could result in elevated plasma concentrations of these medicines, potentially causing serious or life-threatening reactions (see section 4.5).

Paediatric use: The safety and efficacy of VOMEND in paediatric patients have not been established.

Patients with severe hepatic impairment

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

CYP3A4 interactions

VOMEND 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 ciclosporin, tacrolimus, sirolimus, everolimus, alfentanil, ergot alkaloid derivatives, fentanyl, and quinidine (see section 4.5). Additionally, concomitant administration with irinotecan should be approached with caution as the combination might result in increased toxicity.

Co-administration with warfarin (a CYP2C9 substrate)

Co-administration of VOMEND with warfarin may result in a clinically significant decrease in international normalised ratio (INR) or prothrombin time. In patients on chronic warfarin therapy, the INR should be monitored closely during treatment with VOMEND and for 14 days following each 3-day course of VOMEND (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 [PRODUCT NAME]. Alternative non-hormonal back-up methods of contraception should be used during treatment with VOMEND and for 1 month following the last dose of VOMEND (see section 4.5).

Use in the elderly

The efficacy and safety of VOMEND in the elderly (65 years and older) were comparable to those seen in younger patients (< 65 years). No dosage adjustment is necessary in elderly patients.

Sucrose

VOMEND capsules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take [PRODUCT NAME].

Effect of aprepitant on the pharmacokinetics of other medicines

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. During treatment with [PRODUCT NAME], CYP3A4 is inhibited. After the end of treatment, VOMEND causes 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.

CYP3A4 inhibition

As a moderate inhibitor of CYP3A4, aprepitant can increase plasma concentrations of co-administered medicines 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 [PRODUCT NAME]; the effect of aprepitant on the plasma concentrations of intravenously administered CYP3A4 substrates is expected to be smaller. VOMEND 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 VOMEND 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: VOMEND when given as a regimen of 125 mg with dexamethasone co-administered orally as 20 mg on Day 1, and VOMEND 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. The usual oral dexamethasone dose should be reduced by approximately 50 % when co-administered with VOMEND to achieve exposures of dexamethasone similar to those obtained when it is given without [PRODUCT NAME]. The daily dose of dexamethasone administered in clinical studies with VOMEND reflects an approximate 50 % reduction of the dose of dexamethasone (see section 4.2).

Methylprednisolone: VOMEND 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. The usual intravenously administered methylprednisolone dose should be reduced by approximately 25 %, and the usual oral methylprednisolone dose should be reduced approximately 50 % when co-administered with [PRODUCT NAME], to achieve exposures of methylprednisolone similar to those obtained when it is given without [PRODUCT NAME]. During continuous treatment with methylprednisolone, the AUC of methylprednisolone may decrease at later time points within 2 weeks following initiation of the VOMEND dose, due to the inducing effect of VOMEND on CYP3A4. This effect may be expected to be more pronounced for orally administered methylprednisolone.

Chemotherapeutic medicines

In clinical studies, aprepitant was administered with the following chemotherapeutic medicines metabolised primarily or in part by CYP3A4 (e.g. etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan and paclitaxel). The doses of these medicines were not adjusted to account for potential medicine interactions. Caution is advised and additional monitoring may be appropriate in patients receiving medicines metabolised 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 [PRODUCT NAME].

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 medicines with [PRODUCT NAME]. VOMEND 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 VOMEND 125 mg on Day 1 and 80 mg/day on Days 2 to 5.

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 and treatment. This effect may become apparent only after the end of a 3-day treatment with [PRODUCT NAME]. For CYP2C9 and CYP3A4 substrates, the induction is transient with a maximum effect reached 3 u2013 5 days after end of the VOMEND 3-day treatment. The effect is maintained for a few days, thereafter slowly declines and is clinically insignificant by two weeks after end of VOMEND 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 period.

Warfarin

In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days following initiation of the 3-day regimen of VOMEND with each chemotherapy cycle. A single 125 mg dose of VOMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy individuals who were stabilised on chronic warfarin therapy. Although there was no effect of VOMEND on the plasma AUC of R (+) or S (-) warfarin determined on Day 3, 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 [PRODUCT NAME].

Tolbutamide

VOMEND 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 VOMEND 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 [PRODUCT NAME]. Alternative non-hormonal back-up methods of contraception should be used during treatment with VOMEND and for 2 months following the last dose of [PRODUCT NAME].

5-HT 3 antagonists

VOMEND did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Effect of other medicines on the pharmacokinetics of aprepitant

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

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

Concomitant administration of VOMEND with herbal preparations containing St John's Wort (Hypericum perforatum) is not recommended.

Ketoconazole

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

Rifampicin

When a single 375 mg dose of VOMEND 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 %.

Additional interactions

Diltiazem

In patients with mild to moderate hypertension, administration of VOMEND once daily with 120 mg diltiazem 3 times daily for 5 days, resulted in a 2-fold increase of VOMEND AUC and a simultaneous 1,7-fold increase of diltiazem AUC. These effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone.

Paroxetine

Co-administration of once daily doses of VOMEND with 20 mg paroxetine once daily resulted in a decrease in AUC by approximately 25 % and C max by approximately 20 % of both VOMEND and paroxetine.

Paediatric population

Interaction study in paediatric population is not known.

Contraception in males and females

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of [PRODUCT NAME]. Alternative non-hormonal back-up methods of contraception should be used during treatment with VOMEND and for 2 months following the last dose of VOMEND (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. Therefore, the safety and efficacy of PN in pregnancy has not been established as there are no adequate and well-controlled studies.

Lactation

Aprepitant is excreted in the milk of lactating rats. It is not known whether aprepitant is excreted in human milk; therefore, breastfeeding is not recommended during treatment with [PRODUCT NAME].

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.

VOMEND may have an influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of VOMEND (see section 4.8).

Summary of the safety profile

Infections and infestations: Less frequent: Candidiasis, staphylococcal infection.

Blood and lymphatic system disorders: Less frequent: Febrile neutropenia, anaemia.

Immune system disorders: Frequency unknown: Hypersensitivity reactions (including anaphylactic reactions).

Metabolism and nutrition disorders: Frequent: Decreased appetite. Less frequent: Polydipsia.

Psychiatric disorders: Less frequent: Anxiety, disorientation, euphoric mood.

Nervous system disorders: Frequent: Headache. Less frequent: Dizziness, somnolence, cognitive disorder, lethargy, dysgeusia.

Eye disorders: Less frequent: Conjunctivitis.

Ear and labyrinth disorders: Less frequent: Tinnitus.

Cardiac disorders: Less frequent: Palpitations, bradycardia, cardiovascular disorder.

Vascular disorders: Less frequent: Hot flush/flushing.

Respiratory, thoracic and mediastinal disorders: Frequent: Hiccups. Less frequent: Oropharyngeal pain, sneezing, cough, post-nasal drip, throat irritation.

Gastrointestinal disorders: Frequent: Constipation, dyspepsia. Less frequent: Eructation, nausea, gastro-oesophageal reflux disease, vomiting, abdominal pain, dry mouth, flatulence, hard faeces, duodenal ulcer perforation, stomatitis, abdominal distension, neutropenic colitis.

Skin and subcutaneous tissue disorders: Less frequent: Rash, acne, photosensitivity reaction, hyperhidrosis, seborrhoea, skin lesion, pruritic rash, Stevens-Johnson syndrome/toxic epidermal necrolysis. Frequency unknown: Pruritus, urticaria.

Musculoskeletal, connective tissue and bone disorders: Less frequent: Muscle spasms, muscle weakness.

Renal and urinary disorders: Less frequent: Dysuria, pollakiuria.

General disorders and administrative site conditions: Frequent: Fatigue. Less frequent: Asthenia, malaise, oedema, chest discomfort, gait disturbance.

Investigations: Frequent: Increased ALT. Less frequent: Increased AST, increased blood alkaline phosphatase, increased urine output, positive red blood cells in urine, decreased blood sodium, decreased weight, glucose present in urine, decreased neutrophil count.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of VOMEND is important. It allows continued monitoring of the benefit/risk balance of [PRODUCT NAME]. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Symptoms

Drowsiness and headache were reported in one patient who ingested 1 440 mg of [PRODUCT NAME].

Treatment

No specific information is available on the treatment of overdosage with [PRODUCT NAME]. In the event of overdose, VOMEND should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of [PRODUCT NAME], emesis induced by another medicine may not be effective. VOMEND cannot be removed by haemodialysis.