23/15. Rolapitant- (VARUBI)- (Sept 2015)- to prevent phase chemotherapy-induced nausea and vomiting (emesis)
Drug Name:23/15. Rolapitant- (VARUBI)- (Sept 2015)- to prevent phase chemotherapy-induced nausea and vomiting (emesis)
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS-
• BCRP and P-gp Substrates with a Narrow Therapeutic Index: inhibition of BCRP and P-gp by VARUBI can increase plasma concentrations of the concomitant drug and potential for adverse reactions.
See full prescribing information for specific examples.
• Strong CYP3A4 Inducers (e.g., rifampin): significantly reduced plasma concentrations of rolapitant can decrease the efficacy of VARUBI; avoid use of VARUBI in patients who require chronic administration of such drugs.
Indication:
Novel Drug Approvals for 2015
1.Name - VARUBI
2. Active Ingredient- Rolapitant
3. Indication- To prevent delayed phase chemotherapy-induced nausea and vomiting (emesis)
Date of Approval Sept 2015
HIGHLIGHTS OF PRESCRIBING INFORMATION-
These highlights do not include all the information needed to use VARUBI safely and effectively.
See full prescribing information for VARUBI. VARUBI™ (rolapitant) tablets, for oral use
Initial U.S. Approval: 2015
INDICATIONS AND USAGE -
VARUBI™ is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.
Adverse Reaction:
ADVERSE REACTIONS -
Most common adverse reactions (= 5%) are:
• Cisplatin Based Highly Emetogenic Chemotherapy: neutropenia and hiccups
• Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide: decreased appetite, neutropenia and dizziness
Contra-Indications:
CONTRAINDICATIONS-
Concurrent use with thioridazine, a CYP2D6 substrate
WARNINGS AND PRECAUTIONS-
Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index: The inhibitory effect of a single dose of VARUBI on CYP2D6 lasts at least 7 days and may last longer.
Avoid use of pimozide; monitor for adverse reactions if concomitant use with other CYP2D6 substrates with a narrow therapeutic index cannot be avoided
Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index: The inhibitory effect of a single dose of VARUBI on CYP2D6 lasts at least 7 days and may last longer.
Avoid use of pimozide; monitor for adverse reactions if concomitant use with other CYP2D6 substrates with a narrow therapeutic index cannot be avoided
Dosages/ Overdosage Etc:
DOSAGE AND ADMINISTRATION-
• The recommended dosage is 180 mg rolapitant administered approximately 1 to 2 hours prior to the start of chemotherapy
• Administer in combination with dexamethasone and a 5-HT3 receptor antagonist, see full prescribing information for dosing information
• No dosage adjustment for dexamethasone is required.
DOSAGE FORMS AND STRENGTHS-
Tablets: 90 mg of rolapitant
Patient Information:
PATIENT COUNSELING INFORMATION-
Advise the patient to read the FDA-approved patient labeling (Patient Information). Drug Interactions
Advise patients to tell their healthcare provider when they start or stop taking any concomitant medications.
VARUBI is a moderate CYP2D6 inhibitor and can increase plasma concentrations of CYP2D6 substrates if they are co-administered.
The inhibitory effect of VARUBI on CYP2D6 lasts at least 7 days and may last longer than 7 days after a single dose
Manufactured for: TESARO Inc. 1000 Winter St., #3300, Waltham, MA 02451
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY-
1. Mechanism of Action- Rolapitant is a selective and competitive antagonist of human substance P/NK1 receptors.
Rolapitant does not have significant affinity for the NK2 or NK3 receptors or for a battery of other receptors, transporters, enzymes and ion channels. Rolapitant is also active in animal models of chemotherapy-induced emesis.
2. Pharmacodynamics-
NK1 Receptor Occupancy A human Positron Emission Tomography (PET) study with rolapitant demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK1 receptors.
A dose-dependent increase in mean NK1 receptor occupancy was observed in the dose range from 4.5 mg to 180 mg of rolapitant. At the 180 mg dose of rolapitant, the mean NK1 receptor occupancy was 73% in the striatum at 120 hours after a single dose administration in healthy subjects.
3. Pharmacokinetics Absorption - Following a single dose administration of 180 mg VARUBI under fasting conditions to healthy subjects, rolapitant was measurable in plasma between 30 minutes and the peak plasma concentration (Cmax) for rolapitant was reached in about 4 hours and mean Cmax was 968 ng/mL (%CV:28%).
With an increase in dose by four times from the recommended clinical dose of 180 mg, the Cmax and AUC of rolapitant increased by 3.1 fold and 3.7 fold, respectively.
Concomitant administration of a high fat meal did not significantly affect the pharmacokinetics of rolapitant after administration of 180 mg VARUBI
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. In a population pharmacokinetic analysis of rolapitant, the Vd/F was 387 L in cancer patients.
Elimination - Following single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t1/2) of rolapitant ranged from 169 to 183 hours (approximately 7 days) and was independent of dose. In a population pharmacokinetic analysis the apparent total clearance (CL/F) of rolapitant was 0.96 L/hour in cancer patients.
Metabolism- Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite, M19 (C4 pyrrolidine-hydroxylated rolapitant).
The formation of M19 was significantly delayed with the median Tmax of 120 hours (range: 24-168 hours) and the mean half-life of M19 was 158 hours. The exposure ratio of M19 to rolapitant was approximately 50% in plasma.
Excretion- Rolapitant is eliminated primarily through the hepatic/biliary route. Following administration of a single oral 180-mg dose of [14C]-rolapitant, on average 14.2% (range 9% to 20%) and 73% (range 52% to 89%) of the dose was recovered in the urine and feces, respectively over 6 weeks.
Specific Populations Age, Sex and Race/Ethnicity Population pharmacokinetic analyses indicated that age, sex and race had no significant impact on the pharmacokinetics of rolapitan
Hepatic Impairment - Following administration of a single dose of 180 mg rolapitant to patients with mild hepatic impairment (Child-Pugh Class A), the pharmacokinetics of rolapitant were comparable with those of healthy subjects.
In patients with moderate hepatic impairment (Child-Pugh Class B), the mean Cmax was 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects.
Renal Impairment In population pharmacokinetic analyses, creatinine clearance (CLcr) at baseline did not show a significant effect on rolapitant pharmacokinetics in cancer patients with mild (CLcr: 60 to 90 mL/min) or moderate (CLcr: 30 to 60 mL/min) renal impairment compared to cancer patients with normal kidney function. Information is insufficient for the effect of severe renal impairment.
The pharmacokinetics of rolapitant was not studied in patients with end-stage renal disease requiring hemodialysis.
Drug Interaction Studies- Effect of Other Drugs on VARUBI Rolapitant is a substrate for CYP3A4. CYP3A4 inducers Concomitant administration of a CYP3A4 inducer significantly decreased the systemic exposure to rolapitant
When 600 mg rifampin was administered once daily for 7 days before and 7 days after administration of a single dose of 180 mg rolapitant , the mean Cmax of rolapitant was reduced by 30% and the mean AUC was reduced by 85% compared to administration of rolapitant alone.
Effect of VARUBI on Other Drugs - The effect of VARUBI on CYP450 enzymes and transporters is summarized below. See Table 4 for a summary of the effects of the clinical dose of VARUBI on the pharmacokinetics of coadministered drugs. CYP3A4 substrates Rolapitant is neither an inhibitor nor an inducer of CYP3A4.
Midazolam A single dose 180 mg rolapitant had no significant effects on the pharmacokinetics of midazolam when oral midazolam 3 mg was co-administered on Day 1 and administered alone on Days 6, and 9.
Ondansetron: Rolapitant had no significant effects on the pharmacokinetics of intravenous ondansetron when concomitantly administered with a single 180 mg dose of rolapitant on the same day
Dexamethasone: Rolapitant had no significant effects on the pharmacokinetics of dexamethasone when oral dexamethasone was administered on Days 1 to 3 after a single 180 mg dose of rolapitant was co-administered on Day 1
Administration (2]. CYP2D6 substrates Rolapitant is a moderate inhibitor of CYP2D6
Drug Interactions- BCRP transporter- Rolapitant is an inhibitor of BCRP transporter [see Drug Interactions (7)]. P-glycoprotein substrates 10 Reference ID: 3814176 Rolapitant is an inhibitor of P-gp transporter [see
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary- There are no available data on VARUBI use in pregnant women to inform any drug associated risks.
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.
2. Lactation Risk Summary- 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.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for B RAND N AME and any potential adverse effects on the breastfed infant from VARUBI or from the underlying maternal condition or the use of concomitant chemotherapy.
3. Pediatric Use - Safety and efficacy of VARUBI have not been established in pediatric patients.
4. Geriatric Use- Of the 1294 subjects treated with VARUBI, 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.
5.Hepatic Impairment- No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (ChildPugh Class B) hepatic impairment.
OVERDOSAGE - There are no data on overdose with VARUBI. There is no antidote for VARUBI overdose.
Discontinue VARUBI in the event of overdose, and institute general supportive measures and close observation.