Fosaprepitant Cipla 150 mg Solution

FOSAPREPITANT CIPLA in combination with other anti-emetic medicines, is indicated for the prevention of acute (0 to 24 hours) and delayed (> 24 to 120 hours) 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

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

Highly Emetogenic Chemotherapy Regimen

**Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the morning on Days 2 to 4. Dexamethasone should also be administered in the evenings on Days 3 and 4. The dose of dexamethasone accounts for active substance interactions.

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

Moderately Emetogenic Chemotherapy Regimen

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

Method of administration

FOSAPREPITANT CIPLA is administered intravenously on Day 1, as an infusion over 20 to 30 minutes initiated approximately 30 minutes prior to chemotherapy. FOSAPREPITANT CIPLA should be administered in conjunction with a corticosteroid and a 5-HT3 antagonist as specified in the tables above. The professional information for the co-administered 5-HT3 antagonist must be consulted prior to initiation of treatment with FOSAPREPITANT CIPLA. Information on instructions for reconstitution and dilution of the medicine before administration, see section 6.6.

FOSAPREPITANT CIPLA is contraindicated:

• In patients who are hypersensitive to aprepitant, polysorbate 80 or any other ingredients of FOSAPREPITANT CIPLA.
• Pregnancy and breastfeeding, see section 4.6.
• In co-administration with pimozide, terfenadine, astemizole or cisapride. Inhibition of cytochrome P450 isoenzyme 3A4 (CYP3A4) by aprepitant could result in elevated plasma concentrations of these medicines, potentially causing serious life-threatening reactions, see section 4.5.

Severe hepatic insufficiency (Child-Pugh score > 9)

There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency. Caution should be exercised when FOSAPREPITANT CIPLA is administered in these patients.

CYP3A4 interactions

FOSAPREPITANT CIPLA should be used with caution in patients receiving concomitant active substances that are metabolized 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 particular caution as the combination might result in increased toxicity.

Hypersensitivity reactions

Immediate hypersensitivity reactions including flushing, erythema, dyspnoea, and anaphylaxis/ anaphylactic shock have occurred during or soon after infusion of FOSAPREPITANT CIPLA. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who experience hypersensitivity reactions.

Administration and infusion site reactions

Infusion site reactions (ISRs) have been reported with the use of FOSAPREPITANT CIPLA, see section 4.8. The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant (e.g., anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Mild injection site thrombosis has been observed at higher doses without concomitant vesicant chemotherapy. FOSAPREPITANT CIPLA should not be given as a bolus injection but should always be diluted and given as a slow intravenous infusion, see section 4.2. FOSAPREPITANT CIPLA should not be administered intramuscularly or subcutaneously. If signs or symptoms of local irritation occur, the injection or infusion should be terminated and restarted in another vein.

Co-administration with warfarin (a CYP2C9 substrate)

Co-administration of FOSAPREPITANT CIPLA with warfarin may result in clinically significant decrease in the International Normalised Ratio (INR) or prothrombin time, In patients on chronic warfarin therapy, the INR should be monitored closely for the 2 week period, particularly at 7 to 10 days following initiation of FOSAPREPITANT CIPLA, see section 4.5.

Co-administration with hormonal contraceptives

The efficacy of hormonal contraceptives during and for 28 days after administration of FOSAPREPITANT CIPLA may be reduced. Alternative or non-hormonal back-up methods of contraception should be used during treatment with FOSAPREPITANT CIPLA and for 1 month following the last dose of FOSAPREPITANT CIPLA, see section 4.5.

Use in elderly

No dosage adjustment is necessary in elderly patients.

Lactose intolerance

FOSAPREPITANT CIPLA contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take FOSAPREPITANT CIPLA.

Paediatric Population

Safety and efficacy of FOSAPREPITANT CIPLA in paediatric patients have not been established, see section 4.2.

When administered intravenously, Fosaprepitant is rapidly converted to aprepitant. Therefore, interactions following administration of FOSAPREPITANT CIPLA are likely to occur with medicines that interacts with oral aprepitant. Aprepitant is a substrate, a weak to moderate inhibitor and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. FOSAPREPITANT CIPLA given as a single dose, is a weak inhibitor of CYP3A4, and thereby, may increase the plasma concentrations of co-administered medicines that are metabolised through CYP3A4. It does not induce CYP3A4. It is anticipated that FOSAPREPITANT CIPLA would cause less or no greater induction of CYP2C9 than that caused by the administration of oral aprepitant (see Warfarin and Tolbutamide below). FOSAPREPITANT CIPLA must not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by Fosaprepitant could result in elevated plasma concentrations of these active substances, potentially causing serious or life-threatening reactions, see section 4.3. Aprepitant has been shown to induce the metabolism of S(-) warfarin and tolbutamide, which are metabolised through CYP2C9. Co-administration of FOSAPREPITANT CIPLA with these medicines or other medicines that are known to be metabolised by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these medicines. FOSAPREPITANT CIPLA is unlikely to interact with medicines that are substrates for the P-glycoprotein transporter, due to the lack interaction of oral aprepitant with digoxin.

5-HT3 antagonists

Interaction studies with Fosaprepitant 150 mg and 5-HT3 antagonists have not been conducted; however, in clinical interaction studies, the oral aprepitant regimen did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Therefore, there is no evidence of interaction with the use of FOSAPREPITANT CIPLA and 5-HT3 antagonists.

Corticosteroids

Dexamethasone: FOSAPREPITANT CIPLA administered as a single intravenous dose on Day 1 increased the AUC 0-24hr of dexamethasone, a CYP3A4 substrate, by 2.0 fold on Days 1 and 2 when dexamethasone was co-administered as a single 8 mg oral dose on Days 1, 2, and 3. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when co-administered with FOSAPREPITANT CIPLA on Day 1 to achieve exposure of dexamethasone similar to those obtained when given without FOSAPREPITANT CIPLA, see section 4.2.

Methylprednisolone: Oral aprepitant, when given as 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 at 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.

Chemotherapeutic medicines

Caution and careful monitoring are advised in patients receiving etoposide, vinorelbine, docetaxel, ifosfamide, cyclophosphamide, irinotecan and paclitaxel or other chemotherapy medicines metabolised primarily by CYP3A4. Post-marketing events of neurotoxicity, a potential adverse reaction of ifosfamide, have been reported after aprepitant and ifosfamide co-administration, see section 4.4.

Warfarin

In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the first two-week period particularly at 7 to 10 days, following initiation of the use of FOSAPREPITANT CIPLA with each chemotherapy cycle. Prothrombin time (INR) should be done more frequently while using FOSAPREPITANT CIPLA.

Tolbutamide

Diabetic patients using tolbutamide should be monitored for glucose changes.

Hormonal contraceptives

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of FOSAPREPITANT CIPLA. Alternative non-hormonal back-up methods of contraception should be used during treatment with FOSAPREPITANT CIPLA and for 1 month following the last dose of FOSAPREPITANT CIPLA.

Midazolam

FOSAPREPITANT CIPLA administered as a single intravenous dose on Day 1 increased the AUC 0-u221e of midazolam by approximately 1.8-fold on Day 1 and had no effect (1.0-fold) on Day 4 when midazolam was co-administered as a single oral dose of 2 mg on Day 1 and 4. FOSAPREPITANT CIPLA IV is a weak CYP3A4 inhibitor as a single dose on Day 1 with no evidence of inhibition or induction of CYP3A4 observed on Day 4. In addition, when FOSAPREPITANT CIPLA was administered as a dose of 100mg over 15 minutes along with a single dose of midazolam 2 mg, the plasma AUC of midazolam was increased by 1.6-fold. This effect was not considered clinically important. Oral aprepitant increased the AUC of midazolam, by 2.3-fold on Day1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was co-administered on Day 1 and Day 5 of a regimen of oral aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 through 5. 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 FOSAPREPITANT CIPLA.

Effect of other medicines on the pharmacokinetics of aprepitant

FOSAPREPITANT CIPLA should be used with caution in patients receiving concomitant medicines including chemotherapy medicines that are primarily metabolized through CYP3A4. Aprepitant is a substrate for CYP3A4, therefore, co-administration of FOSAPREPITANT CIPLA with medicines that inhibit CYP3A4 activity, may result in increased plasma concentration of aprepitant. Consequently, co-administration of FOSAPREPITANT CIPLA with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (e.g. diltiazem) results in 2-fold increase in plasma concentration of aprepitant, concomitant administration should also be approached with caution. Co-administration of FOSAPREPITANT CIPLA with medicines that strongly induce CYP3A4 activity (e.g. rifampicin, carbamazepine, phenytoin) may result in reduced plasma concentration of aprepitant that may result in decreased efficacy of FOSAPREPITANT CIPLA. Concomitant administration of Fosaprepitant with herbal preparations containing St. John's Wort (Hypericum perforatum) is not recommended.

Ketoconazole

Concomitant administration of Fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously.

Rifampicin

Concomitant administration of Fosaprepitant or aprepitant with medicines that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.

Diltiazem

In patients with mild to moderate hypertension, infusion of FOSAPREPITANT CIPLA over 15 minutes with diltiazem 120 mg 3 times daily, may result in an increased diltiazem AUC and a meaningful decrease in blood pressure, with no clinically meaningful change in heart rate, or PR interval.

Paediatric population

Safety and efficacy of FOSAPREPITANT CIPLA in paediatric patients have not been established.

Women of childbearing potential / Contraception in males and females

The efficacy of hormonal contraceptives may be reduced during and for 28 days after administration of FOSAPREPITANT CIPLA. Alternative or non-hormonal back-up methods of contraception should be used during treatment with FOSAPREPITANT CIPLA and for 1 month following the last dose of FOSAPREPITANT CIPLA, see section 4.4 and 4.5.

Pregnancy

FOSAPREPITANT CIPLA is contraindicated in pregnancy, see section 4.3.

Breastfeeding

Mothers on treatment with FOSAPREPITANT CIPLA should not breastfeed their infants, as Breastfeeding is contraindicated during therapy with FOSAPREPITANT CIPLA, see section 4.3.

FOSAPREPITANT CIPLA may cause side effects such as nausea dizziness which may affect the patient's ability to drive and use machines.

a) Summary of the safety profile

Since FOSAPREPITANT CIPLA is converted to aprepitant, those adverse reactions associated with aprepitant are expected to occur with FOSAPREPITANT CIPLA. The frequency of occurrence of adverse events are described as follows:

Frequent: u2018 more frequentu2019, u2018very commonu2019 and u2018commonu2019

Less Frequent: u2018 single reportsu2019 or u2018isolated reportsu2019, u2018uncommonu2019, u2018rareu2019, u2018very rareu2019

Oral aprepitant

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, alanine aminotransferase (ALT) increased, dyspepsia, constipation, headache, and decreased appetite. 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. 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 and flushing.

b) Tabulated list of adverse reactions - aprepitant

Below adverse reactions were observed in a pooled analysis of the HEC and MEC studies at a greater incidence with oral aprepitant than with standard therapy in adults or paediatric patients or in post-marketing use.

Tabulated list of adverse reactions u2013 Fosaprepitant

The following additional clinically important medicine-related adverse reactions occurred with Fosaprepitant 150 mg and have not been reported in earlier with oral aprepitant as described above.

c) Description of selected adverse reactions

Additional adverse reactions were observed in adult patients treated with aprepitant for post-operative nausea and vomiting (PONV) and a greater incidence than with ondansetron: abdominal pain upper, bowel sounds abnormal, constipation*, dysarthria, dyspnoea, hypoesthesia, 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care 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 or [email protected] or telephone 080 222 6662 (toll free).

In the event of overdose, FOSAPREPITANT CIPLA should be discontinued and general supportive treatment and monitoring should be provided. Aprepitant cannot be removed by haemodialysis.