Aprepitant – Uses, Dosage, Side Effects, Interactions

Aprepitant, an antiemetic, is a substance P/neurokinin 1 (NK1) receptor antagonist which, in combination with other antiemetic agents, is indicated for the prevention of acute? and delayed nausea? and vomiting? associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT₃), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea? and vomiting? (CI NV).

Use in Cancer

Aprepitant is approved to be used with other drugs to prevent:

• Nausea? and vomiting? caused by chemotherapy and nausea? and vomiting? after surgery.

Contraindications

Few contraindications exist to the use of aprepitant or fosaprepitant.[rx][rx]

• Prior hypersensitivity reactions and the co-administration of pimozide or cisapride are the commonly cited drug reactions of pimozide. Pimozide is a CYP3A4 substrate, and inhibition of CYP3A4 by aprepitant can increase plasma levels of pimozide, increasing the risk of QT prolongation.[rx]
• Relative contraindications include medications that get metabolized via CYP3A4 metabolism and have narrow therapeutic indexes, as the decreased metabolism of these medications may cause toxicity.
• are allergic to aprepitant or to any of the ingredients of the medication
• are also taking any of the following medications: pimozide, terfenadine, astemizole, or cisapride

Dosage?

Strengths: 80 mg; 125 mg; 40 mg; 125 mg-80 mg; 130 mg/18 mL

Adult Patients

Nausea?/Vomiting?

MODERATELY TO HIGHLY EMETOGENIC CANCER CHEMOTHERAPY (HEC/MEC):
Oral Capsules:

• Day 1: 125 mg orally once 1 hour before chemotherapy
• Days 2 and 3: 80 mg orally once a day, 1 hour before chemotherapy OR in the morning (if chemotherapy is not given on Days 2 and 3)
• Duration of therapy: 3 days/cycle

Oral Suspension:

• Day 1: 3 mg/kg orally once 1 hour before chemotherapy
• Maximum dose: 125 mg/dose
• Days 2 to 3: 2 mg/kg orally once a day, 1 hour before chemotherapy OR in the morning (if chemotherapy is not given on Days 2 and 3)
• Maximum dose: 80 mg/dose
• Duration of therapy: 3 days/cycle

Parenteral:

• Single-Dose Regimen (HEC/MEC): 130 mg IV via 2-minute injection OR infused over 30 minutes ONCE, completing administration 30 minutes before chemotherapy

3-Day Regimen with Oral Formulations (MEC):

• Day 1: 100 mg IV via 2-minute injection OR infused over 30 minutes ONCE, completing administration 30 minutes before chemotherapy
• Days 2 to 3: 80 mg orally once a day

Chemotherapy-Induced Nausea? and Vomiting? (CINV)

Chemotherapy agents are broadly divided into five emetogenic levels. Each level states the expected frequency of emesis if the patient receives no prophylactic antiemetic.[rx]

• High – over 90 percent risk of emesis
• Moderate – over 30 and up to 90 percent risk of emesis
• Low – 10 to 30 percent risk of emesis
• Minimal – under10 percent risk of emesis

The Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN) make antiemetic therapy-based guidelines based on the risk of emesis.[rx] An (NK-1) receptor antagonist is recommended in combination with a 5-HT3 receptor antagonist (e.g., ondansetron) and a glucocorticoid (often dexamethasone) for highly emetogenic chemotherapy (HECT) and moderately emetogenic chemotherapy (MECT).[rx][rx]

Aprepitant is available as a capsule for PO administration in 40 mg, 80 mg, and 125 mg strengths. It is also available in a prodrug preparation known as a fosaprepitant for intravenous administration. Fosaprepitant comes in powder form for reconstitution in 150 mg/ vial strength. A standard recommendation for highly emetogenic chemotherapy-induced nausea and vomiting? prevention (CINV) would include a 125 mg capsule given PO one hour before administering chemotherapy on day one, often combined with a 5-HT3 antagonist and dexamethasone.[rx]

The 80 mg capsule is given 1 hour before chemotherapy on days two and three, often combined with a 5HT-3 antagonist and dexamethasone. The intravenous preparation, fosaprepitant, is administered as a one-time 150 mg dose given 30 minutes before chemotherapy. No repeat dosing is necessary when using fosaprepitant.[rx] It bears mentioning that multiple dosing regimens exist based on the prescribed chemotherapy regimen and institutional practices. Consultation with the treating oncologist and pharmacist, as well as up-to-date reference literature, is recommended.

Postoperative Nausea and Vomiting (PONV) and Post-discharge Nausea and Vomiting (PDNV)

Aprepitant 40 mg capsule is administered PO within three hours of induction to prevent anesthesia-induced postoperative nausea and vomiting. Due to its increased cost compared with other antiemetics used in anesthesia practice, its use should only be for patients at high risk of nausea and vomiting or in whom the act of vomiting would jeopardize surgical repair.[rx]

The Apfel score is a validated and frequently used scoring system to predict postoperative nausea and vomiting risk.[rx] Antiemetic regimens that include aprepitant can be prescribed based on the calculated risk. Fosaprepitant has not yet received an indication for postoperative nausea and vomiting though future use in NPO patients is under exploration. It is expected to have similar efficacy to an equipotent dose of aprepitant.[rx]

Pediatric Patients

Nausea/Vomiting

MEC/HEC:

• 6 months to less than 12 years

GREATER THAN 6 kg:
Oral Suspension:

• Day 1: 3 mg/kg orally once 1 hour before chemotherapy
• Maximum dose: 125 mg/day
• Days 2 to 3: 2 mg/kg orally once a day, 1 hour before chemotherapy OR in the morning (if chemotherapy is not given on Days 2 and 3)
• Maximum dose: 80 mg/day
• Duration of therapy: 3 days/cycle

12 years and older:
Oral Capsules:

• Day 1: 125 mg orally once 1 hour before chemotherapy
• Days 2 and 3: 80 mg orally once a day, 1 hour before chemotherapy OR in the morning (if chemotherapy is not given on Days 2 and 3)
• Duration of therapy: 3 days/cycle

Oral Suspension:

• Day 1: 3 mg/kg orally once 1 hour before chemotherapy
• Maximum dose: 125 mg/dose
• Days 2 to 3: 2 mg/kg orally once a day, 1 hour before chemotherapy OR in the morning (if chemotherapy is not given on Days 2 and 3)
• Maximum dose: 80 mg/dose
• Duration of therapy: 3 days/cycle

Chemotherapy-Induced Nausea and Vomiting (CINV)

Oral capsules may be used in the same manner as adult patients if the pediatric patient is greater than 12 years of age or under the age of 12 and greater than 30 kg.[rx] Aprepitant is available for oral suspension prepared by mixing the contents of one pouch of powder with 4.6 ml of water. The resulting suspension yields a 25 mg/ml strength for oral administration to pediatric patients or adults who cannot swallow capsules.

Oral suspension is the dose form of choice for pediatric patients over six months of age up to 12 years old or 30 kg. A standard regimen for highly emetogenic chemotherapy is a dose of 3 mg/kg PO 1 hour (before chemotherapy) on day one and 2 mg/kg PO 1 hour (before chemotherapy) on day 2.[rx] Similar to adults, aprepitant often gets combined with a weight-based dose of ondansetron and dexamethasone on both days.

Fosaprepitant may be substituted for oral suspension if the patient cannot tolerate PO administration and has intravenous (IV) access. The dosing of fosaprepitant is age-stratified and adjusted within the age group depending on whether it is used as a monotherapy or combined with dexamethasone and a 5HT-3 antagonist. It is worth noting that multiple dosing regimens exist based on the prescribed chemotherapy regimen and institutional practices, just as in adults. Therefore, consultation with the treating oncologist and pharmacist and reviewing up-to-date reference literature is recommended.

Side Effects

The Most Common

• weakness
• tiredness
• dizziness
• diarrhea
• constipation
• gas
• stomach pain
• heartburn
• nausea
• hiccups
• loss of appetite
• headache
• fever
• hair loss
• hives
• rash
• itching
• skin peeling or blisters
• difficulty breathing or swallowing

More Common

• Common side effects (defined as > 10 percent incidence) are headache, fatigue, anorexia, constipation, diarrhea, nausea, and hiccups.
• Less common side effects (defined as 1 to 10 percent incidence) include dizziness, insomnia, bradycardia, hypotension, pharyngolaryngeal pain, mucosal inflammation, stomatitis, dyspepsia, anemia, neutropenia, hot flash, pruritus, dehydration, and fever.
• abdominal pain
• changed sense of taste
• constipation
• diarrhea
• dizziness
• dry mouth
• fatigue
• flushing
• hair loss
• headache
• hiccups
• loss of appetite
• muscle cramps
• upset stomach
• vomiting
• weakness

Rare

• Rare side effects (defined as less than one percent incidence) include candidiasis, staphylococcal infection, febrile neutropenia, weight gain, polydipsia, disorientation, euphoria, vivid dreams, cognitive disorder, lethargy, somnolence, conjunctivitis, cough, acid reflux, epigastric discomfort, malaise, and chills.
• anxiousness
• fever
• low blood pressure
• increased sweating
• painful, burning urination
• red, itchy eyes with discharge
• ringing in the ears
• signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
• severe rash, itching, or swelling of the hands and feet
• signs of a severe skin reaction such as blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort
• symptoms of a severe allergic reaction (e.g., difficulty breathing; hives; swelling of the face, eyes, lips, tongue, or throat)

Drug Interactions

There may be an interaction between the aprepitant and any of the following:

• alpha-blockers (e.g., alfuzosin, doxazosin, tamsulosin)
• amiodarone
• anti-cancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
• anti-psychotics (e.g., aripiprazole, olanzapine, pimozide, quetiapine, risperidone)
• apixaban
• “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
• barbiturates (e.g., butalbital, pentobarbital phenobarbital)
• benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
• birth control pills (estrogens, progestins)
• bosentan
• buprenorphine
• buspirone
• calcitriol
• calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
• cannabis
• celecoxib
• chloroquine
• cobicistat
• colchicine
• conivaptan
• oral corticosteroids (e.g., dexamethasone, hydrocortisone, prednisone)
• cyclosporine
• dantrolene
• dapsone
• deferasirox
• diclofenac
• disopyramide
• dofetilide
• domperidone
• dronedarone
• eletriptan
• enzalutamide
• eplerenone
• estrogens (e.g., conjugated estrogen, estradiol, ethinyl estradiol)
• everolimus
• fentanyl
• fludrocortisone
• “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
• grapefruit juice
• guanfacine
• HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delavirdine, efavirenz, etravirine, nevirapine)
• HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
• hydrocodone
• hydroxyzine
• ivabradine
• losartan
• macrolide antibiotics (e.g., clarithromycin, erythromycin)
• maraviroc
• mefloquine
• methadone
• mifepristone
• mirtazapine
• modafinil
• naloxegol
• nefazodone
• nitrates (e.g., isosorbide dinitrate, isosorbide mononitrate)
• oxycodone
• pimecrolimus
• praziquantel
• primaquine
• progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
• propafenone
• protein kinase inhibitors (e.g., bosutinib, crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib)
• quinidine
• quinine
• rifabutin
• rifampin
• rilpivirine
• St. John’s wort
• salmeterol
• seizure medications (e.g., carbamazepine, gabapentin, levetiracetam, phenytoin, topiramate)
• selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, paroxetine, sertraline)
• serotonin/norepinephrine reuptake inhibitors (SNRIs; desvenlafaxine, duloxetine, venlafaxine)
• sildenafil
• siltuximab
• simeprevir
• sirolimus
• “statin” anti-cholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
• “sulfa” antibiotics (e.g., sulfamethoxazole, sulfadiazine)
• sulfonamide diabetes medications (e.g, gliclazide, glyburide)
• tacrolimus
• tamoxifen
• ticagrelor
• ticlopidine
• tocilizumab
• tolterodine
• tolvaptan
• trazodone
• tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
• trimethoprim
• ulipristal
• warfarin
• zafirlukast
• zolpidem
• zopiclone

Pregnancy and Lactation

FDA Pregnancy category drug B

Pregnancy

This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Breast-feeding

It is not known if aprepitant passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. The safety and effectiveness of using this medication have not been established for children less than 18 years of age.

References