Aprepitant

Aprepitant is a substance P/Neurokinin 1 Receptor Antagonist belonging to Antiemetic agent.

Aprepitant is a substance P/neurokinin 1 receptor antagonist used to treat nausea and vomiting caused by chemotherapy and surgery.

Aprepitant is absorbed in the GI tract and its bioavailability is approximately 60%. Time taken to peak plasma concentration is approximately 4 hours. Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) is approximately 70 L in humans. Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, Aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-Aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of Aprepitant, which are only weakly active, have been identified in human plasma. Excreted mainly via urine and faeces.

Aprepitant shows side effects like Weakness, tiredness, dizziness, diarrhea, constipation, gas, stomach pain, heartburn, nausea, hiccups, loss of appetite, headache, fever, hair loss.

Aprepitant is available in the form of Oral capsule, Oral reconstitution powder, Injectable emulsion.

Aprepitant is available in India, US, Canada, Malaysia, Russia, China, Spain, France, Japan, Germany, Italy, and Australia.

Aprepitant belongs to the Antiemetic agent acts as a substance P/Neurokinin 1 Receptor Antagonist.

Aprepitant inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with Aprepitant have shown that it crosses the blood brain barrier and occupies brain NK1 receptors. Animal and human studies show that Aprepitant augments the antiemetic activity of the 5-HT₃-receptor antagonist ondansetron and the corticosteroid ethasone and inhibits both the acute and delayed phases of cisplatin induced emesis.

The Data of Onset and duration of action of Aprepitant is not clinically established.

The Tmax of Aprepitant is within 4 hours.

Aprepitant is available in the form of Oral capsule, Oral reconstitution powder, Injectable emulsion.

Aprepitant Capsule and Reconstitution powder is taken orally, while Injectable emulsion is given via intravenous route.

Aprepitant is an antiemetic medicine which is used along with other medications to prevent acute and delayed nausea and vomiting associated with cancer chemotherapy in adults and children above six months of age. It works by blocking the action of a natural substance that causes nausea and vomiting.

Aprepitant is a substance P/Neurokinin 1 Receptor Antagonist belonging to Antiemetic agent.

Aprepitant prevents emesis by inhibiting substance P/neurokinin 1 (NK₁) receptors. It enhances the antiemetic activity of 5HT₃ receptor antagonists and corticosteroids.

Aprepitant is approved for use in the following clinical indications

• Prevention of chemotherapy-induced nausea and vomiting
• Prevention of postoperative nausea and vomiting

• Prevention of chemotherapy-induced nausea and vomiting

Adult Dose:

• Prevention of acute and delayed nausea/vomiting associated with highly-emetogenic chemotherapy:

IV (single-dose aprepitant regimen): 130 mg ~30 minutes prior to chemotherapy on day 1 (in combination with a 5-HT₃ antagonist antiemetic on day 1 and oral dexamethasone on days 1 to 4).

Oral:

Capsules: 125 mg 1 hour prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (in combination with a 5-HT₃ antagonist antiemetic on day 1 and dexamethasone on days 1 to 4).

Suspension: Adults unable to swallow capsules: 3 mg/kg (maximum: 125 mg/dose) 1 hour prior to chemotherapy on day 1, followed by 2 mg/kg (maximum: 80 mg/dose) once daily on days 2 and 3 (in combination with a 5-HT₃ antagonist antiemetic on day 1 and dexamethasone on days 1 to 4).

• Prevention of nausea/vomiting associated with moderately emetogenic chemotherapy:

IV (3-day aprepitant regimen): 100 mg ~30 minutes prior to chemotherapy on day 1 (in combination with oral aprepitant 80 mg on days 2 and 3, a 5-HT₃ antagonist antiemetic on day 1 and dexamethasone on day 1).

Oral:

Capsules: 125 mg 1 hour prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3 (in combination with a 5-HT₃ antagonist antiemetic and dexamethasone on day 1).

Suspension: Adults unable to swallow capsules: 3 mg/kg (maximum: 125 mg/dose) 1 hour prior to chemotherapy on day 1, followed by 2 mg/kg (maximum: 80 mg/dose) once daily on days 2 and 3 (in combination with a 5-HT₃ antagonist antiemetic and dexamethasone on day 1).

• Prevention of delayed nausea/vomiting associated with moderately emetogenic chemotherapy:

IV (single-dose aprepitant regimen): 130 mg ~30 minutes prior to chemotherapy on day 1 (in combination with a 5-HT₃ antagonist antiemetic on day 1 and dexamethasone on day 1).

Pediatric Dose:

• Chemotherapy-induced nausea and vomiting (CINV), prevention; highly and moderately emetogenic chemotherapy

Infants ≥6 months and Children <12 years weighing 6 to <30 kg: Oral: Oral suspension: 3 mg/kg 1 hour prior to chemotherapy on day 1, then 2 mg/kg/dose once daily on days 2 and 3.

Children <12 years weighing ≥30 kg, Children ≥12 years, and Adolescents: Oral: Capsules, Oral suspension: 125 mg 1 hour prior to chemotherapy on day 1, followed by 80 mg once daily on days 2 and 3.

• Prevention of postoperative nausea and vomiting

Oral:

Capsule: 40 mg within 3 hours prior to anesthesia induction.

Aprepitant is available in various strengths as 80 mg; 125 mg; 40 mg; 125 mg-80 mg; 130 mg/18 mL.

Aprepitant is available in the form of Oral capsule, Oral reconstitution powder, Injectable emulsion.

• Dosage Adjustment in Hepatic impairment Patient

Mild-to-moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Aprepitant is contraindicated in patients with

• patients who are hypersensitive to any component of the product.
• Aprepitant is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). Aprepitant should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by Aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions.

• CYP3A4 Interactions

Aprepitant, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by Aprepitant, 125 mg/80 mg regimen, could result in elevated plasma concentrations of these concomitant medications. Weak inhibition of CYP3A4 by a single 40 mg dose of Aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. When Aprepitant is used concomitantly with another CYP3A4 inhibitor, Aprepitant plasma concentrations could be elevated. When Aprepitant is used concomitantly with medications that induce CYP3A4 activity, Aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of APREPITANT. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine and vincristine. In clinical studies, aprepitant (125 mg/80 mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when aprepitant (125 mg/80 mg regimen) was co-administered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.

• Coadministration with Warfarin (a CYP2C9 substrate)

Coadministration of aprepitant with warfarin may result in a clinically significant decrease in International Normalized Ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle, or following administration of a single 40 mg dose of aprepitant for the prevention of postoperative nausea and vomiting.

• Coadministration with Hormonal Contraceptives

Upon coadministration with aprepitant, the efficacy of hormonal contraceptives during and for 28 days following the last dose of aprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with aprepitant and for 1 month following the last dose of aprepitant. Patients with Severe Hepatic Impairment There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when aprepitant is administered in these patients.

• Chronic Continuous Use

Chronic continuous use of aprepitant for prevention of nausea and vomiting is not recommended because it has not been studied; and because the drug interaction profile may change during chronic continuous use.

Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from Aprepitant and because of the potential for tumorigenicity shown for Aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, considering the importance of the drug to the mother.

Pregnancy Category B

Teratogenic effects

Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0-24hr of 31.3 mcg hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0-24hr of 26.9 mcg hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to Aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Common

• Hypotension, bradycardia, flushing, palpitations, peripheral edema, syncope Headache , dizziness, anxiety, hypoesthesia, hypothermia, malaise, peripheral neuropathy, abnormal behavior, agitation, Pruritus, alopecia, hyperhidrosis, skin rash, urticaria, Dehydration , decreased serum albumin, decreased serum potassium, decreased serum sodium, hot flash , hypokalemia, hypovolemia, increased serum glucose, weight loss, Constipation, diarrhea, dyspepsia, abdominal pain, hiccups, decreased appetite, dysgeusia, eructation, flatulence, gastritis, gastroesophageal reflux disease, nausea, vomiting, xerostomia, Proteinuria, Decreased hemoglobin, decreased white blood cell count, anemia, febrile neutropenia, hematoma, thrombocytopenia, Increased serum alanine aminotransferase, increased serum alkaline phosphatase, increased serum aspartate aminotransferase, increased serum bilirubin, Candidiasis, postoperative infection, Induration at injection site, inflammation at injection site, infusion site reaction, Asthenia, musculoskeletal pain Increased blood urea nitrogen, Cough, dyspnea, hypoxia, oropharyngeal pain, pharyngitis, respiratory depression, Wound dehiscence.

Rare

• Abdominal distention, abnormal dreams, abnormal gait, acne vulgaris, anaphylaxis, angioedema, anxiety, cardiac disease, chest discomfort, chills, cognitive dysfunction, conjunctivitis, decreased neutrophils, disorientation, drowsiness, dysfunction, dysuria, edema, epigastric distress, euphoria, hematuria, hyperglycemia, hypersensitivity reaction, hyponatremia, increased thirst, lethargy, muscle cramps, myalgia, neutropenic enterocolitis, oily skin, perforated duodenal ulcer, pollakiuria, polyuria, polydipsia, post nasal drip, skin lesion, skin photosensitivity, sneezing, staphylococcal infection, Stevens-Johnson syndrome, stomatitis, throat irritation, tinnitus, toxic epidermal necrolysis, weight gain.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of Aprepitant. Consequently, concomitant administration of aprepitant 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) result in a 2-fold increase in plasma concentrations of Aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of aprepitant with drugs that strongly induce CYP3A4 activity (e.g., rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of Aprepitant that may result in decreased efficacy of Aprepitant.

• Ketoconazole

When a single 125-mg dose of aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of Aprepitant increased approximately 5-fold and the mean terminal half-life of Aprepitant increased approximately 3-fold. Concomitant administration of aprepitant with strong CYP3A4 inhibitors should be approached cautiously.

• Rifampin

When a single 375-mg dose of aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of Aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of aprepitant.

The common side effects of Aprepitant include the following

Common side effects

• Weakness, tiredness, dizziness, diarrhea, constipation, gas, stomach pain, heartburn, nausea, hiccups, loss of appetite, headache, fever, hair loss.

Rare side effects

• Hives, rash, itching, skin peeling or blisters, difficulty breathing or swallowing.

• Pregnancy

Pregnancy Category B

Teratogenic effects

Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0-24hr of 31.3 mcg hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses up to 25 mg/kg/day (plasma AUC0-24hr of 26.9 mcg hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed no evidence of impaired fertility or harm to the fetus due to Aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Nursing Mothers

Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from Aprepitant and because of the potential for tumorigenicity shown for Aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness of aprepitant in pediatric patients have not been established.

• Geriatric Use

In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with aprepitant, 31% were 65 and over, while 5% were 75 and over. In well controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with aprepitant, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.

Symptoms: Drowsiness, headache.

Management: Supportive treatment.

Pharmacodynamic

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).

Pharmacokinetics

• Absorption

Aprepitant is Absorbed in the GI tract. Bioavailability is Approximately 60%. Time taken to peak plasma concentration is Approximately 4 hr.

• Distribution

Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vdss) is approximately 70 L in humans.

• Metabolism and Excretion

Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, Aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-Aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of Aprepitant, which are only weakly active, have been identified in human plasma. Excreted mainly via urine and faeces.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021549s017lbl.pdf
• https://www.uptodate.com/contents/Aprepitant-drug-information?search=Aprepitant&selectedTitle=1~45&usage_type=panel&display_rank=1&kp_tab=drug_general&source=panel_search_result
• https://www.drugs.com/mtm/Aprepitant.html
• https://go.drugbank.com/drugs/DB00673
• https://www.rxlist.com/Aprepitant-drug.htm#warnings
• https://www.mims.com/india/drug/info/Aprepitant?type=full&mtype=generic
• https://medlineplus.gov/druginfo/meds/a604003.html