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Aprepitant

Drug Approvals

(US Adopted Name, rINN)

INNs in other languages (French, Latin, and Spanish): Aprepitant, Aprepitantum, L-754030, MK-869, MK-0869.

Adverse Effects and Precautions

AprepitantThe most common adverse effects associated with aprepitant are headache, constipation, diarrhoea, dyspepsia, anorexia, fatigue, hiccups, eructation, and dizziness. Increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) concentrations are common. Other reported effects have included abdominal pain, oedema, tinnitus, and flushing. Epigastric discomfort, dysgeusia, dry mouth, and stomatitis have also occurred. Thirst, polyuria, dysuria, haematuria, urinary frequency, arthralgia, myalgia, bradycardia, hyperglycaemia, disorientation, euphoria, anxiety, photosensitivity, and skin disorders have been reported. Anaemia and febrile neutropenia may occur. Other adverse effects reported include hypertension or hypotension, hyponatraemia, hypokalaemia, insomnia, miosis, reduced visual acuity, weight changes, sensory disturbances, throat irritation, sneezing, abnormal bowel sounds, acid reflux, perforating duodenal ulcer, dyspnoea, cough, wheezing, and hyperhidrosis. Conjunctivitis, pharyngitis, respiratory-tract infections, urinary-tract infections, candidiasis, and herpes simplex can occur. Stevens-Johnson syndrome and angioede-ma with urticaria have been reported.

Licensed product information recommends caution in patients with severe hepatic impairment as clinical data are lacking in this patient group.

Interactions

During its use for 3 or 4 days in the prevention of nausea and vomiting associated with cancer chemotherapy, aprepitant produces moderate inhibition of the cytochrome P450 isoenzyme CYP3A4. Exposure to oral CYP3A4 substrates may increase substantially the effect of aprepitant on intravenous CYP3 A4 substrates is expected to be less. However, on cessation of aprepitant a transient mild induction of CYP3A4 may become apparent with a maximum effect reached 3 to 5 days later this effect is maintained for a few days then slowly declines and is clinically insignificant about 2 weeks after stopping aprepitant. Caution is therefore required when using it with drugs that are primarily metabolised by this isoenzyme. Aprepitant should not be given with astemizole, cisapride, pimozide, or terfenadine as increased plasma concentrations of these drugs could cause serious life-threatening reactions. As aprepitant is also a substrate for CYP3A4, other drugs that inhibit or induce this isoenzyme may in turn increase or decrease plasma concentrations of aprepitant.

When aprepitant is used to prevent postoperative nausea and vomiting, in a single lower dose than that used with cancer chemotherapy, the effect of aprepitant on CYP3A4 is not expected to be clinically significant.

Aprepitant also causes a delayed induction of CYP2C9 and may lower plasma concentrations of drugs metabolised by this isoenzyme, such as warfarin, phenytoin, or tolbutamide.

Aprepitant may increase systemic exposure to corti-costeroids when given together it is recommended that the usual dose of oral dexamethasone be reduced by 50%, and the dose of methylprednisolone by about 25% when given intravenously, and by 50% when given orally. It should be noted that the dose of dexamethasone in the regimens recommended for nausea and vomiting associated with cancer chemotherapy already accounts for this interaction (see Administration, below).

The efficacy of oral contraceptives might be reduced by aprepitant. Licensed product information suggests that alternative methods of contraception should be used during and for 1 to 2 months after stopping any dose of aprepitant.

Pharmacokinetics

Aprepitant is absorbed from the gastrointestinal tract with peak plasma concentrations achieved after about 4 hours. Bioavailability is about 60% at usual doses. It crosses the blood-brain barrier plasma protein binding is reported to be more than 95%. Aprepitant undergoes extensive hepatic metabolism, mainly via oxidation by the cytochrome P450 isoenzyme CYP3A4 the isoen-zymes CYP1A2 and CYP2C19 mediate minor metabolic pathways. The resultant metabolites have weak activity and are excreted in the urine and in the faeces. Aprepitant is not excreted unchanged in the urine. The terminal half-life is about 9 to 13 hours.

Uses and Administration

Aprepitant is a neurokinin-1 (NK1) receptor antagonist used in the management of nausea and vomiting. It is given orally in doses up to 125 mg, with a corticosteroid and a 5-HT3 antagonist, in the prevention of acute and delayed nausea and vomiting associated with highly emetogenic or moderately emetogenic cancer chemotherapy (for details, see Administration, below).

For the prevention of postoperative nausea and vomiting a single oral dose of aprepitant 40 mg may be given within the 3 hours before induction of anaesthesia.

Administration. Licensed product information for aprepitant suggests the following 4-day regimen for the prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer chemotherapy:

• day 1: aprepitant 125 mg (given 1 hour before chemotherapy) with oral dexamethasone 12 mg and intravenous ondansetron 32 mg (both 30 minutes before chemotherapy)

• days 2 and 3: aprepitant 80 mg with oral dexamethasone 8 mg in the morning

• day 4: oral dexamethasone 8 mg in the morning.

In patients receiving moderately emetogenic chemotherapy, a 3-day regimen has been suggested as follows:

• day 1: aprepitant 125 mg (given 1 hour before chemotherapy) with oral dexamethasone 12mg (30 minutes before chemotherapy) ondansetron is given in 2 doses of 8 mg by mouth, one taken 30 to 60 minutes before chemotherapy, and one taken 8 hours after the first dose

• days 2 and 3: aprepitant 80 mg in the morning.

Administration in renal impairment. A study in 8 patients with severe renal impairment (24-hour creatinine clearance less than 30 mL/minute per 1.73 m) and 8 patients with end-stage renal disease requiring haemodialysis found that pharmacokinet-ic parameters of aprepitant were not sufficiently different from those in 16 matched controls to warrant dosage adjustment in renal impairment. Licensed product information concurs with this.

Preparations

Proprietary Preparations

Argentina: Emend Australia: Emend Belgium: Emend Brazil: Emend Czech Republic: Emend Denmark: Emend Finland: Emend France: Emend Germany: Emend Greece: Emend Hong Kong Emend Hungary: Emend Ireland: Emend Italy: Emend Malaysia: Emend Norway: Emend New Zealand: Emend Portugal: Emend Russia: Emend (3ivieHA) South Africa: Emend Singapore: Emend Spain: Emend Sweden: Emend Switzerland: Emend Thai.: Emend UK: Emend USA: Emend Venezuela: Emend.

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