Aprepitant

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

Aprepitant blocks the actions of chemicals in the body that trigger nausea and vomiting.

Aprepitant is used in adults and children to prevent nausea and vomiting caused by cancer chemotherapy. Aprepitant is also used (only in adults) to prevent nausea and vomiting that may be caused by surgery.

Aprepitant is given ahead of time and will not treat nausea or vomiting that you already have.

Aprepitant capsules are for use in adults and children who are at least 12 years old. Aprepitant oral suspension (liquid) can be given to adults and children as young as 6 months old.

Aprepitant may also be used for purposes not listed in this medication guide.

You should not take aprepitant if you also take pimozide. A serious drug interaction can occur when pimozide is used together with aprepitant.

You should not use aprepitant if you are allergic to it, or if you take another medicine called pimozide (Orap). Aprepitant can cause unwanted or dangerous effects when used with pimozide.

To make sure aprepitant is safe for you, tell your doctor if you have:

• liver disease.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Aprepitant can make birth control pills less effective. Ask your doctor about using a non-hormonal birth control to prevent pregnancy while you are taking aprepitant, and for 1 month after your last dose. Non-hormonal birth control includes barrier forms such as a condom or diaphragm with spermicide.

It is not known whether aprepitant passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

In people taking aprepitant to prevent nausea and vomiting caused by chemotherapy, the most common side effects include:

• tiredness
• nausea
• hiccups
• constipation
• diarrhea
• loss of appetite
• headache
• hair loss

In people taking aprepitant to prevent nausea and vomiting after surgery, the most common side effects are:

• constipation
• nausea
• itching
• fever
• low blood pressure
• headache

This is not a complete list of this medication’s side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Aprepitant Capsules, USP:

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 overall safety of Aprepitant was evaluated in approximately 6500 individuals.

Adverse Reactions in Adults in the Prevention of Nausea and Vomiting Associated with HEC and MEC

In 2 active-controlled, double-blind clinical trials in patients receiving highly emetogenic chemotherapy (HEC) (Studies 1 and 2), Aprepitant in combination with ondansetron and dexamethasone (Aprepitant regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see CLINICAL STUDIES (14.1)].

In 2 active-controlled clinical trials in patients receiving moderately emetogenic chemotherapy (MEC) (Studies 3 and 4), Aprepitant in combination with ondansetron and dexamethasone (Aprepitant regimen) was compared to ondansetron and dexamethasone alone (standard therapy) [see CLINICAL STUDIES (14.2)].The most common adverse reaction reported in patients who received MEC in pooled Studies 3 and 4 was dyspepsia (6% versus 4%).

Across these 4 studies there were 1412 patients treated with the Aprepitant regimen during Cycle 1 of chemotherapy and 1099 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. The most common adverse reactions reported in patients who received HEC and MEC in pooled Studies 1, 2, 3 and 4 are listed in Table 3.

In a pooled analysis of the HEC and MEC studies, less common adverse reactions reported in patients treated with the Aprepitant regimen are listed in Table 4.

In an additional active-controlled clinical study in 1169 patients receiving Aprepitant and HEC, the adverse reactions were generally similar to that seen in the other HEC studies with Aprepitant.

In another CINV study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving the Aprepitant regimen with cancer chemotherapy.

Adverse reactions in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.

Adverse Reactions in Adult Patients in the Prevention of PONV

In 2 active-controlled, double-blind clinical studies in patients receiving general anesthesia (Studies 7 and 8), 40-mg oral Aprepitant was compared to 4-mg intravenous ondansetron [see CLINICAL STUDIES (14.4)].

There were 564 patients treated with Aprepitant and 538 patients treated with ondansetron.

The most common adverse reactions reported in patients treated with Aprepitant for PONV in pooled Studies 7 and 8 are listed in Table 6.

*Reported in ≥3% of patients treated with the Aprepitant 40 mg and at a greater incidence than ondansetron.

In a pooled analysis of PONV studies, less common adverse reactions reported in patients treated with Aprepitant are listed in Table 7.

*Reported in >0.5% of patients treated with Aprepitant and at a greater incidence than ondansetron

In addition, two serious adverse reactions were reported in PONV clinical studies in patients taking a higher than recommended dose of Aprepitant: one case of constipation, and one case of sub-ileus.

Other Studies

Angioedema and urticaria were reported as serious adverse reactions in a patient receiving Aprepitant in a non-CINV/non-PONV study (Aprepitant is only approved in the CINV and PONV populations).

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 anaphylactic reactions [see CONTRAINDICATIONS (4)].

Nervous system disorders

Ifosfamide-induced neurotoxicity reported after Aprepitant and ifosfamide coadministration.

Pregnancy

Risk Summary

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.

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 25 mg/kg/day (rabbits). No embryofetal lethality or malformations were observed at any dose levels 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 1.5 times the adult exposure at the 125-mg/80‑mg/80-mg Aprepitant regimen. Aprepitant crosses the placenta in rats and rabbits.

Lactation

Lactation studies have not been conducted to assess the presence of Aprepitant in human milk, the effects on the breastfed infant, or the effects on milk production. Aprepitant is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Aprepitant and any potential adverse effects on the breastfed infant from Aprepitant or from the underlying maternal condition.

Pediatric Use

Prevention of Nausea and Vomiting Associated with HEC or MEC

The safety and effectiveness of Aprepitant for the prevention of nausea and vomiting associated with HEC or MEC have not been established in patients less than 6 months.

Prevention of Postoperative Nausea and Vomiting (PONV)

The safety and effectiveness of Aprepitant have not been established for the prevention of postoperative nausea and vomiting 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.

Pediatric use information is approved for Merck Sharp & Dohme Corp.’s EMEND® (Aprepitant) capsules. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that information.

Geriatric Use

Of the 544 adult cancer patients treated with Aprepitant in CINV clinical studies, 31% were aged 65 and over, while 5% were aged 75 and over. Of the 1120 adult cancer patients treated with Aprepitant in PONV clinical studies, 7% were aged 65 and over, while 2% were aged 75 and over. Other reported clinical experience with Aprepitant has not identified differences in responses between elderly and younger patients. In general, use caution when dosing elderly patients as they have a greater frequency of decreased hepatic, renal or cardiac function and concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY (12.3)].

Patients With Renal Impairment

The pharmacokinetics of Aprepitant in patients with severe renal impairment and those with end stage renal disease (ESRD) requiring hemodialysis were similar to those of healthy subjects with normal renal function. No dosage adjustment is necessary for patients with any degree of renal impairment or for patients with ESRD undergoing hemodialysis.

Patients With Hepatic Impairment

The pharmacokinetics of Aprepitant in patients with mild and moderate hepatic impairment were similar to those of healthy subjects with normal hepatic function. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh score 5 to 9). There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score greater than 9). Therefore, additional monitoring for adverse reactions in these patients may be warranted when Aprepitant is administered [see CLINICAL PHARMACOLOGY (12.3)].

Aprepitant capsules, USP contain the active ingredient, Aprepitant. Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, an antiemetic agent, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.

Its molecular formula is C23H21F7N4O3, and its structural formula is:

Aprepitant is a white to off-white crystalline solid, with a molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.

Each Aprepitant capsule for oral administration contains either 40 mg, 80 mg or 125 mg of Aprepitant and the following inactive ingredients: hydroxypropyl cellulose, microcrystalline cellulose, sodium lauryl sulfate and sucrose.

The Aprepitant capsule shell for 40 mg and 80 mg consists of gelatin and titanium dioxide.

The Aprepitant capsule shell for 125 mg consists of FD&C Blue # 1, gelatin and titanium dioxide.

The capsule is printed with edible black pharmaceutical ink. The printing ink contains black iron oxide, propylene glycol and shellac.

Dissolution Test 2 is used.

NDC 0781-2321-51

Aprepitant Capsules, USP

40 mg

Rx only

5 Capsules

WARNING: Do not use if blisters are torn, broken or missing.

This unit-dose package is not child-resistant.

(For institutional use only)

SANDOZ

• Antiemetic
• Substance P/Neurokinin 1 Receptor Antagonist

Following a single oral aprepitant dose ranging from 40 to 375 mg, the AUC of aprepitant was ~27% higher and the Cmax was ~19% higher in Hispanic patients compared with Caucasian patients (there was no difference in AUC and Cmax between Black patients and Caucasian patients). The AUC of aprepitant was ~74% higher and the Cmax was ~47% higher in Asian patients compared with Caucasian patients. These differences are not

No dosage adjustment necessary.

ESRD undergoing dialysis: No dosage adjustment necessary. Aprepitant is not removed by hemodialysis.

Adverse reactions may be reported in combination with other antiemetic agents. As reported for highly emetogenic cancer chemotherapy or moderately emetogenic cancer chemotherapy, unless otherwise noted as reported for postoperative nausea and vomiting (PONV).

>10%:

Central nervous system: Fatigue (adults: 13%; children & adolescents: 5%)

Hematologic & oncologic: Neutropenia (children & adolescents: 13%; adults: <3%)

0.5% to 10%:

Cardiovascular: Hypotension (PONV: 6%), bradycardia (PONV: <3%), flushing (<3%), palpitations (<3%), peripheral edema (<3%), syncope (PONV: <3%)

Central nervous system: Headache (children & adolescents: 9%), dizziness (<3% to 5%), anxiety (<3%), hypoesthesia (PONV: <3%), hypothermia (PONV: <3%), malaise (<3%), peripheral neuropathy (<3%), abnormal behavior (children & adolescents: 2%), agitation (children & adolescents: 2%)

Dermatologic: Alopecia (<3%), hyperhidrosis (<3%), skin rash (<3%), urticaria (<3%)

Endocrine & metabolic: Dehydration (≤3%), decreased serum albumin (PONV: <3%), decreased serum potassium (PONV: <3%), decreased serum sodium (<3%), hot flash (<3), hypokalemia (<3%), hypovolemia (PONV: <3%), increased serum glucose (PONV: <3%), weight loss (<3%)

Gastrointestinal: Constipation (PONV: 9%), diarrhea (6% to 9%), dyspepsia (≤7%), abdominal pain (≤6%), hiccups (4% to 5%), decreased appetite (<3% to 5%), dysgeusia (<3%), eructation (<3%), flatulence (<3%), gastritis (<3%), gastroesophageal reflux disease (<3%), nausea (<3%), vomiting (<3%), xerostomia (<3%)

Genitourinary: Proteinuria (<3%)

Hematologic & oncologic: Decreased hemoglobin (children & adolescents: 5%), decreased white blood cell count (≤4%), anemia (<3%), febrile neutropenia (<3%), hematoma (PONV: <3%), thrombocytopenia (<3%)

Hepatic: Increased serum ALT (3%), increased serum alkaline phosphatase (<3%), increased serum AST (<3%), increased serum bilirubin (PONV: <3%)

Infection: Candidiasis (<3%), postoperative infection (PONV: <3%)

Neuromuscular & skeletal: Weakness (≤7%), musculoskeletal pain (<3%)

Renal: Increased blood urea nitrogen (<3%)

Respiratory: Cough (<3% to 5%), dyspnea (<3%), hypoxia (PONV: <3%), oropharyngeal pain (<3%), pharyngitis (<3%), respiratory depression (PONV: <3%)

Miscellaneous: Wound dehiscence (PONV: <3%)

<0.5% (Limited to important or life-threatening): Anaphylaxis, angioedema, hypersensitivity reaction, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity reactions, including anaphylactic reactions have been reported.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with severe hepatic impairment (Child-Pugh class C); has not been studied.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Due to a risk of significantly increased pimozide plasma concentrations and potential for QT prolongation, concurrent use with pimozide is contraindicated. Other CYP3A4-mediated drug interactions may occur. In patients receiving concurrent warfarin, a clinically significant decrease in INR or prothrombin time (PT) may occur; monitor INR/PT for 2 weeks (particularly at 7 to 10 days) following aprepitant administration.

Special populations:

• Pediatrics: For prevention of chemotherapy-induced nausea and vomiting, use is not recommended in pediatric patients weighing <6 kg. Not approved for prevention of postoperative nausea and vomiting in children.

In patients receiving concurrent warfarin, monitor INR/PT for 2 weeks (particularly at 7 to 10 days) following aprepitant administration; signs/symptoms of hypersensitivity reaction.

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience loss of strength and energy, diarrhea, lack of appetite, abdominal pain, hiccups, constipation, headache, or heartburn. Have patient report immediately to prescriber signs of infection, severe dizziness, passing out, dry mouth, dry eyes, increased thirst, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

No dosage adjustment is necessary in patients with renal insufficiency.

Consult WARNINGS section for dosing related precautions.

There are no data on the excretion of aprepitant into human milk. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions due to aprepitant in nursing infants, and the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.