Rolapitant

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

Rolapitant is a neurokinin-1 (NK-1) receptor antagonist used in combination with other antiemetics for the prevention of delayed nausea and vomiting associated with emetogenic chemotherapy.

The plasma concentrations reached peak levels is about 4 hours. Rolapitant was highly protein bound to human plasma (99.8%). The apparent volume of distribution (Vd/F) was 460 L in healthy subjects, indicating an extensive tissue distribution of rolapitant. and Vd/F was 387 L in cancer patients. Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite, M19 (C4­ pyrrolidine-hydroxylated rolapitant). Among which the metabolite M19 was the major circulating metabolite. Excreted in Feces (73%) and urine (~14%; primarily as metabolites).

Rolapitant shows side effects like Hiccups, stomach pain, decreased appetite, dizziness, heartburn, mouth sores.

Rolapitant is available in the form of Oral Tablet and Intravenous emulsion.

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

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

Rolapitant is an orally active, highly selective Neurokinin-1 Receptor (NK1R) antagonist. NK1 receptors are located primarily in the gut and central nervous system and are activated by Substance P following chemotherapy administration. By binding to the NK1 receptor, rolapitant prevents binding of its ligand Substance P, which is released in the gut following chemotherapy administration.

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

The Tmax of Rolapitant is within 4 hours.

Rolapitant is available in the form of Oral Tablet and Intravenous emulsion.

Rolapitant Tablet is taken orally, Rolapitant emulsion is given via intravenous route.

Rolapitant is a neurokinin-1 (NK-1) receptor antagonist used in combination with other antiemetics for the prevention of delayed nausea and vomiting associated with emetogenic chemotherapy.

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

Rolapitant prevents delayed nausea and vomiting associated with emetogenic chemotherapy by selectively and competitively inhibiting the substance P/neurokinin 1 (NK₁) receptor.

Rolapitant is approved for use in the following clinical indications

• Chemotherapy-induced nausea and vomiting (prevention)

Rolapitant used in combination with other antiemetics for the prevention of delayed nausea and vomiting associated with emetogenic chemotherapy.

• Chemotherapy-induced nausea and vomiting (prevention)

Highly emetogenic chemotherapy (cisplatin-based)

Oral: 180 mg within 2 hours prior to initiation of chemotherapy on day 1 only (in combination with dexamethasone given on days 1 to 4 and a 5-HT₃ receptor antagonist on day 1).

Moderately emetogenic chemotherapy and anthracycline/cyclophosphamide combinations

Oral: 180 mg within 2 hours prior to initiation of chemotherapy on day 1 only (in combination with dexamethasone on day 1 and a 5-HT₃ receptor antagonist as appropriate based on the agent selected).

Rolapitant is available in various strengths as 90 mg and 166.5 mg/92.5 mL.

Rolapitant is available in the form of Oral Tablet and Intravenous emulsion.

• Dosage Adjustment in Kidney Patient

CrCl 30 to 90 mL/minute: There are no dosage adjustments provided.

CrCl <30 mL/minute: There are no dosage adjustments provided.

End-stage kidney disease requiring hemodialysis: There are no dosage adjustments provided.

• Dosage Adjustment in Hepatic impairment Patient

Child-Pugh classes A and B: No dosage adjustment is necessary.

Child-Pugh class C: Avoid use if possible (has not been studied); if use cannot be avoided, monitor closely for adverse reactions related to rolapitant.

Rolapitant is contraindicated in patients with

• Rolapitant is contraindicated in patients receiving thioridazine, a CYP2D6 substrate. A significant increase in plasma concentrations of thioridazine may result in QT prolongation and Torsades de Pointes.

• Narrow Therapeutic Index Drugs (Thioridazine and Pimozide)
• Rolapitant is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index such as thioridazine and pimozide. Increased plasma concentrations of thioridazine and pimozide are associated with serious and/or life-threatening events of QT prolongation and Torsades de Pointes.
• Before starting treatment with Rolapitant, consider whether patients require treatment with thioridazine or pimozide. If patients require these drugs, use an alternative antiemetic to Rolapitant or an alternative to thioridazine or pimozide that is not metabolized by CYP2D6.

There are no data on the presence of Rolapitant in human milk, the effects of Rolapitant in the breastfed infant, or the effects of Rolapitant on milk production. Rolapitant administered orally to lactating female rats was present in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rolapitant and any potential adverse effects on the breastfed infant from Rolapitant or from the underlying maternal condition or the use of concomitant chemotherapy.

There are no available data on Rolapitant use in pregnant women to inform any drug associated risks. In animal reproduction studies, there were no teratogenic or embryo-fetal effects observed with oral administration of rolapitant hydrochloride in rats and rabbits during the period of organogenesis at doses up to 1.2 times and 2.9 times, respectively, the maximum recommended human dose (MRHD). 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.

Common

• Abdominal pain, decreased appetite, dyspepsia, hiccups, stomatitis, Urinary tract infection, Anemia, Neutropenia, Dizziness.

Rare

• Anaphylactic shock, Anaphylaxis

Rolapitant is a substrate for CYP3A4.

• CYP2D6 Substrates with a Narrow Therapeutic Index

Increased plasma concentration of CYP2D6 substrates may result in potential adverse reactions. A three-fold increase in the exposure of dextromethorphan, a CYP2D6 substrate, was observed 7 days after a single dose of Rolapitant. The duration of CYP2D6 inhibition was not studied beyond 7 days and may last longer. Concomitant use with Thioridazine is contraindicated. Avoid use of Rolapitant with pimozide. Monitor for QT prolongation if concomitant use with pimozide cannot be avoided. Monitor for adverse reactions if concomitant use with CYP2D6 substrates with a narrow therapeutic index cannot be avoided.

• BCRP Substrates with a Narrow Therapeutic Index

(e.g., Methotrexate, topotecan, or irinotecan) Increased plasma concentrations of BCRP substrates may result in potential adverse reactions. Monitor for adverse reactions related to the concomitant drug if use of Rolapitant cannot be avoided. Use the lowest effective dose of rosuvastatin.

• P-gp Substrates with a Narrow Therapeutic Index

Increased plasma concentrations of digoxin, or other P-gp substrates, may result in potential adverse reactions. Monitor for increased digoxin concentrations. Monitor for adverse reactions if concomitant use of Rolapitant with other P-gp substrates with a narrow therapeutic index cannot be avoided.

• Effect of Other Drugs on Rolapitant

Strong CYP3A4 Inducers (e.g., rifampin): significantly reduced plasma concentrations of rolapitant can decrease the efficacy of Rolapitant; avoid use of Rolapitant in patients who require chronic administration of such drugs.

The common side effects of Rolapitant include the following

Common side effects

• Hiccups, Stomach pain, Decreased appetite, Dizziness, Heartburn, Mouth sores.

Rare side effects

• Fever, Chills, Sore throat, or Other signs of an Infection.

• Pregnancy

There are no available data on Rolapitant use in pregnant women to inform any drug associated risks. In animal reproduction studies, there were no teratogenic or embryo-fetal effects observed with oral administration of rolapitant hydrochloride in rats and rabbits during the period of organogenesis at doses up to 1.2 times and 2.9 times, respectively, the maximum recommended human dose (MRHD). 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.

• Nursing Mothers

There are no data on the presence of rolapitant in human milk, the effects of rolapitant in the breastfed infant, or the effects of rolapitant on milk production. Rolapitant administered orally to lactating female rats was present in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rolapitant and any potential adverse effects on the breastfed infant from Rolapitant or from the underlying maternal condition or the use of concomitant chemotherapy.

• Pediatric Use

Safety and efficacy of Rolapitant have not been established in pediatric patients.

• Geriatric Use

Of the 1294 subjects treated with Rolapitant, 25% were 65 years and over, while 5% were 75 and over. No overall differences in safety or efficacy were reported between the elderly subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Discontinue Rolapitant in the event of overdose, and institute general supportive measures and close observation.

Pharmacodynamic

Information is not available.

Pharmacokinetics

• Absorption

The plasma concentrations reached peak levels is about 4 hours.

• Distribution

Rolapitant was highly protein bound to human plasma (99.8%). The apparent volume of distribution (Vd/F) was 460 L in healthy subjects, indicating an extensive tissue distribution of rolapitant. and Vd/F was 387 L in cancer patients.

• Metabolism and Excretion

Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite, M19 (C4­ pyrrolidine-hydroxylated rolapitant). Among which the metabolite M19 was the major circulating metabolite. Excreted in Feces (73%) and urine (~14%; primarily as metabolites).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206500s000lbl.pdf
• https://www.uptodate.com/contents/rolapitant-drug-information?search=rolapitant&source=panel_search_result&selectedTitle=1~6&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://www.drugs.com/dosage/rolapitant.html
• https://go.drugbank.com/drugs/DB09291
• https://www.rxlist.com/Rolapitant -drug.htm#clinpharm
• https://medlineplus.gov/druginfo/meds/a615041.html
• https://reference.medscape.com/drug/Rolapitant -rolapitant-1000029