Aponvie Drug Information

is indicated for the prevention of postoperative nausea and vomiting (PONV) in adults. APONVIE is a substance P/neurokinin-1 (NK 1 ) receptor antagonist, indicated for the prevention of postoperative nausea and vomiting (PONV) in adults. Limitations of Use : APONVIE has not been studied for treatment of established nausea and vomiting.

Limitations of Use APONVIE has not been studied for the treatment of established nausea and vomiting.

Recommended Dosage

The recommended dose in adults of APONVIE is 32 mg administered as a 30 second intravenous injection prior to induction of anesthesia.

Preparation and

Administration Inspect the vial for particulate matter and discoloration prior to administration; discard if present. APONVIE is opaque and off-white to amber in color. Aseptically withdraw 4.4 mL from the vial.

Flush the infusion line with normal saline before and after administration of APONVIE.

Compatibilities

APONVIE is compatible with 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, and solutions containing divalent cations (e.g., calcium, magnesium), including Lactated Ringer's Solution.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of APONVIE for prevention of PONV was evaluated as a single dose in healthy subjects and established from adequate and well-controlled studies of oral aprepitant . Adverse reactions observed in these studies are described below. Safety of APONVIE A total of 51 healthy subjects received a single 32 mg dose of APONVIE as a 30 second intravenous injection.

Adverse reactions reported in at least 3% of subjects were constipation (8%), fatigue (6%), and headache (4%). Safety of Oral Aprepitant In 2 active-controlled, double-blind clinical studies in patients receiving general anesthesia (Studies 1 and 2), 40 mg oral aprepitant was compared to 4 mg intravenous ondansetron . There were 564 patients treated with oral aprepitant and 538 patients treated with ondansetron. The most common adverse reactions reported in patients treated with oral aprepitant for PONV in pooled Studies 1 and 2 are listed in Table 1. Table 1: Most Common Adverse Reactions in Oral Aprepitant-Treated Patients in a Pooled Analysis of PONV Studies Reported in ≥3% of patients treated with oral aprepitant 40 mg and at a greater incidence than with ondansetron. Oral Aprepitant 40 mg (N = 564) Ondansetron (N = 538) Constipation 9% 8% hypotension 6% 5% In a pooled analysis of PONV studies, less common adverse reactions reported in more than 0.5% of patients treated with oral aprepitant and at a greater incidence than ondansetron were dizziness and urticaria.

In addition, two serious adverse reactions were reported in PONV clinical studies of oral aprepitant in patients taking a higher than recommended dose: one case of constipation, and one case of sub-ileus. Other Studies Angioedema, urticaria, and Stevens-Johnson syndrome were reported as serious adverse reactions in patients receiving oral aprepitant in non-PONV studies.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders : pruritus, rash, urticaria, Stevens-Johnson syndrome/toxic epidermal necrolysis . Immune system disorders : hypersensitivity reactions including anaphylaxis and anaphylactic shock . Nervous system disorders : ifosfamide-induced neurotoxicity reported after aprepitant and ifosfamide coadministration.

Effect of Aprepitant on the Pharmacokinetics of Other Drugs Aprepitant is a

substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9 . Table 2 includes drug interactions affecting drugs co-administered with APONVIE and instructions for preventing or managing them. Table 2: Drug Interactions Affecting Drugs When Co-Administered with APONVIE Pimozide Clinical Impact Increased pimozide exposure. Intervention APONVIE is contraindicated . Hormonal Contraceptives Clinical Impact Decreased hormonal exposure for 28 days after administration of APONVIE . Intervention Effective alternative or back-up methods of contraception (such as condoms and spermicides) should be used for 1 month following administration of APONVIE. Examples birth control pills, transdermal systems, implants, and certain intrauterine systems CYP2C9 Substrates Warfarin Clinical Impact Decreased warfarin exposure and decreased prothrombin time (INR) . Intervention In patients on chronic warfarin therapy, monitor prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following administration of APONVIE. Other Antiemetic Agents 5-HT 3 Antagonists Clinical Impact No change in the exposure of the 5-HT 3 antagonist.

Intervention No dosage adjustment needed. Examples ondansetron, granisetron, dolasetron Corticosteroids Clinical Impact No clinically significant change in the exposure of dexamethasone or methylprednisolone. Intervention No dosage adjustment needed.

Effect of Other Drugs on the Pharmacokinetics of Aprepitant Aprepitant is a

CYP3A4 substrate . Table 3 includes drug interactions affecting APONVIE when co-administered with other drugs and instructions for preventing them. Table 3: Drug Interactions Affecting APONVIE When Co-Administered with Other Drugs Strong CYP3A4 Inhibitors Clinical Impact Significantly increased exposure of aprepitant may increase the risk of adverse reactions associated with APONVIE. Intervention Avoid concomitant use of APONVIE. Examples ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4 Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of APONVIE. Intervention Avoid concomitant use of APONVIE. Examples rifampin, carbamazepine, phenytoin

Pregnancy Risk Summary There are insufficient data on aprepitant use in pregnant women to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Avoid use of APONVIE in pregnant women due to the alcohol content (see Clinical Considerations ). In animal reproduction studies, no adverse developmental effects were observed in rats or rabbits exposed during the period of organogenesis to systemic drug concentrations (area under the plasma-concentration time curve ) of oral aprepitant approximately 4.8 times the exposure at the recommended human dose of APONVIE (see Data ). The background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions APONVIE contains alcohol. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.

There is no safe level of alcohol exposure in pregnancy; therefore, avoid use of APONVIE in pregnant women. Data Animal Data In embryofetal development studies in rats and rabbits, aprepitant was administered during the period of organogenesis at oral doses up to 1000 mg/kg twice daily (rats) and up to the maximum tolerated dose of 125 mg/kg/day (rabbits). No embryofetal lethality or malformations were observed at any dose level in either species. The exposures (AUC) in pregnant rats at 1000 mg/kg twice daily and in pregnant rabbits at 125 mg/kg/day were approximately 4.8 times the exposure at the recommended human dose of APONVIE. Aprepitant crosses the placenta in rats and rabbits.

Pediatric Use The safety and effectiveness of APONVIE have not been established in pediatric patients. Juvenile Animal Study A study was conducted in young rats to evaluate the effects of aprepitant on growth and on neurobehavioral and sexual development. Rats were treated at oral doses up to the maximum feasible dose of 1000 mg/kg twice daily from the early postnatal period (Postnatal Day 10) through Postnatal Day 58. Slight changes in the onset of sexual maturation were observed in female and male rats; however, there were no effects on mating, fertility, embryonic-fetal survival, or histomorphology of the reproductive organs.

There were no effects in neurobehavioral tests of sensory function, motor function, and learning and memory.

is contraindicated in patients: with a history of hypersensitivity to aprepitant or any component of the product . Hypersensitivity reactions have included anaphylaxis . taking pimozide. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of pimozide, which is a CYP3A4 substrate, potentially causing serious or life-threatening reactions, such as QT prolongation, a known adverse reaction of pimozide . Known hypersensitivity to any component of this product. Concurrent use with pimozide.

Headache, fatigue, and dizziness were reported in healthy subjects receiving a single dose of 100 or 130 mg aprepitant injectable emulsion (3.1 to 4 times the recommended dose). Drowsiness and headache were reported in one patient who ingested 1440 mg of oral aprepitant. In the event of overdose, general supportive treatment and monitoring should be provided. Aprepitant is not removed by hemodialysis.