Varuby 90 mg film-coated tablets

Each tablet contains 90 mg of rolapitant (as hydrochloride monohydrate).

Excipient(s) with known effect

This medicinal product contains 230 mg of lactose (as monohydrate) per dose (two tablets).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Tablets are blue, debossed with T0101 on one side and 100 on the other.

Prevention of delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in adults

Varuby is given as part of combination therapy (see section 4.2).

Posology

Adults

Varuby is given as part of a regimen that includes dexamethasone and a 5-HT₃ receptor antagonist.

180 mg (two tablets) should be administered within 2 hours prior to initiation of each chemotherapy cycle but at no less than 2-week intervals.

There is no medicinal product interaction between rolapitant and dexamethasone, so no dosage adjustment for dexamethasone is required.

The following regimens are recommended for the prevention of nausea and vomiting associated with emetogenic cancer therapy:

Highly emetogenic chemotherapy regimen

Moderately emetogenic chemotherapy regimen

Special populations

Elderly people (≥ 65 years)

No dose adjustment is necessary for the elderly. Limited data in patients aged 75 years and older are available. Varuby should be used with caution in these patients (see section 5.2).

Renal impairment

No dose adjustment is necessary for patients with mild or moderate renal impairment. There are limited data in patients with severe renal impairment and no data in patients with end stage renal disease undergoing haemodialysis. Varuby should be used with caution in these patients (see section 5.2).

Hepatic impairment

No dose adjustment is needed in patients with mild or moderate hepatic impairment. There are no data in patients with severe hepatic impairment. Varuby should be used with caution in these patients (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of rolapitant in children and adolescents below 18 years of age has not yet been established. No data are available.

Method of administration

The tablets should be swallowed whole, with some water and may be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

In combination with St John's wort (see section 4.5)

Patients with severe hepatic impairment

There are no data in patients with severe hepatic impairment (see section 5.2). Varuby should be used with caution in these patients. If use cannot be avoided, patients should be monitored for adverse reactions to Varuby (see section 4.8).

Patients with severe renal impairment

There are limited data in patients with severe renal impairment (see section 5.2). Varuby should be used with caution in these patients. If use cannot be avoided, patients should be monitored for adverse reactions to Varuby (see section 4.8).

Interactions

Varuby is not recommended in patients who require chronic administration of strong (e.g. rifampicin, carbamazepine, phenobarbital, enzalutamide, phenytoin) or moderate enzyme inducers (e.g. efavirenz, rifabutin) (see section 4.5)

The efficacy and safety of rolapitant with concurrent use of another NK₁ receptor antagonist (e.g. aprepitant and a combination of netupitant and palonosetron hydrochloride) is not established and therefore not recommended (see section 4.5).

Lactose

Varuby contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Effects of Varuby on the pharmacokinetics of other active substances

CYP2D6 substrates

Rolapitant is a moderate CYP2D6 inhibitor. Increased plasma concentration of CYP2D6 substrates may result in potential adverse reactions. A 3-fold increase in the exposure of dextromethorphan, a CYP2D6 substrate, was observed 7 days after a single oral dose of rolapitant and may last longer.

Therefore, caution should be taken when rolapitant is combined with a medicinal product metabolised by CYP2D6, notably those having a narrow therapeutic margin (e.g. propafenone, tamoxifen, metoprolol used in heart failure, thioridazine, pimozide).

BCRP substrates

Rolapitant is an inhibitor of Breast-Cancer-Resistance Protein (BCRP). Increased plasma concentrations of BCRP substrates (e.g. methotrexate, irinotecan, topotecan, mitoxantrone, rosuvastatin, sulfasalazine, doxorubicin, bendamustine) may result in potential adverse reactions. Co-administration of a single dose of 180 mg rolapitant with sulfasalazine, a BCRP substrate, resulted in an approximately 2-fold increase in C_max and AUC of sulfasalazine. If the combination cannot be avoided, clinical and biological monitoring for adverse reactions related to the concomitant medicinal product must be made. The lowest effective dose of rosuvastatin is to be used.

P-gp substrates

Rolapitant is an inhibitor of P-glycoprotein (P-gp). A 70% increase in C_max and 30% increase in AUC of digoxin, a P-gp substrate, were observed when administered with a single dose of 180 mg rolapitant. Therefore, clinical monitoring of adverse reactions and, if possible, biological monitoring are recommended when rolapitant is combined with digoxin or with other P-gp substrates (e.g. dabigatran or colchicine), and in particular in patients with renal impairment.

OATP1B1 and 1B3 substrates

In vitro studies suggest that rolapitant is not expected to inhibit OATP1B1 at clinically relevant concentrations, whereas it is unknown whether it inhibits OATP1B3. Therefore, caution should be observed when rolapitant is combined with an OATP1B3 substrate (e.g. statins, bosentan, fexofenadine).

CYP3A4 substrates

In vivo, rolapitant is not expected to exhibit any inhibitory or inducing effect on CYP3A4. A single dose of 180 mg rolapitant had no significant effects on the pharmacokinetics of midazolam compared to oral midazolam 3 mg alone on Day 1, Day 8 and Day 11.

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.

Other CYPs

No clinically significant interaction is expected with the following medicinal products when administered with a single dose of 180 mg rolapitant on Day 1 and without rolapitant on Day 8: repaglinide 0.25 mg (a CYP2C8 substrate), efavirenz 600 mg (a CYP2B6 substrate), tolbutamide 500 mg (a CYP2C9 substrate) or omeprazole 40 mg (a CYP2C19 substrate).

The potential of rolapitant as a CYP1A2 inhibitor remains unknown.

Effects of other medicinal products on the pharmacokinetics of Varuby

Enzyme inducers

Concomitant administration of rifampicin, a strong enzyme inducer significantly decreased the systemic exposure to rolapitant and to its active metabolite. When 600 mg rifampicin was administered once daily for 7 days before and 7 days after administration of a single dose of 180 mg rolapitant, the mean AUC was reduced by 87% and its active metabolite by 89% compared to administration of rolapitant alone. Varuby in patients who require chronic administration of strong inducers (e.g. rifampicin, carbamazepine, enzalutamide, phenytoin) is not recommended (see section 4.4).

The effect of moderate inducers (e.g. efavirenz, rifabutin) is not established; therefore, the use of rolapitant in patients already given a moderate inducer is not recommended (see section 4.4).

Due to its strong inducing effect, St John's wort is contraindicated with rolapitant (see section 4.3).

CYP3A4 inhibitors

No clinically significant effect was seen on the pharmacokinetics of rolapitant when ketoconazole, a strong CYP3A4 inhibitor was administered with rolapitant. Concurrent administration of 400 mg ketoconazole once daily for 21 days following a single 90 mg dose of rolapitant, did not significantly affect the C_max of rolapitant while the AUC increased by 21%. This is not expected to be clinically relevant.

Other interactions

The efficacy and safety of rolapitant with concurrent use of another NK₁ receptor antagonist (e.g. aprepitant and a combination of netupitant and palonosetron hydrochloride) is not established and therefore not recommended (see section 4.4).

Pregnancy

There are no available data on rolapitant use in pregnant women. Studies in animals have shown no teratogenic or embryo-foetal effects. In the pre- and postnatal developmental study, at a dose equivalent to half of the recommended human dose, there was a decrease in memory in female pups in a maze test and a decrease in pup body weight (see section 5.3). Varuby should not be used during pregnancy unless clearly necessary.

Breast-feeding

There are no data on the presence of rolapitant in human milk. Rolapitant administered orally to lactating female rats was present in milk. Breast-feeding is not recommended during treatment with Varuby.

Fertility

Rolapitant did not affect the fertility or general reproductive performance of male rats. Decreases in the number of corpora lutea and implantation sites were observed in the female rat fertility and early embryonic development study (see section 5.3).

Varuby has minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of rolapitant (see section 4.8).

Summary of safety profile

Over 4,375 patients have been treated with Varuby or a comparator across Phase 1, 2, and 3 clinical studies. A total of 2,798 subjects received oral rolapitant at any dose, including 1,567 subjects in the CINV (chemotherapy-induced nausea and vomiting) studies.

The most common adverse reactions were fatigue (1.9%) and headache (1.5%). The safety profile in the multiple-cycle extensions of highly and moderately emetogenic chemotherapy studies for up to 6 cycles of chemotherapy is similar to the profile observed in Cycle 1.

Tabulated list of adverse reactions

The following adverse reactions were observed in a pooled analysis of the Highly Emetogenic Chemotherapy (HEC) and Moderately Emetogenic Chemotherapy (MEC) studies.

Frequencies are defined as: Very common (≥1/10); common (≥1/100 to < 1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known: frequency cannot be estimated from the available data.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Rolapitant doses up to 720 mg have been used in clinical studies without any safety concerns. In case of overdose, the medicinal product should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of rolapitant, emesis induced by a medicinal product may not be effective. Dialysis studies have not been performed.

Pharmacotherapeutic group: Antiemetics and antinauseants, other antiemetics, ATC code: A04AD14

Mechanism of action

Rolapitant is a selective antagonist of human substance P/neurokinin 1 (NK₁) receptors.

Clinical efficacy and safety

Cisplatin-Based Highly Emetogenic Chemotherapy (HEC)

Study 1 and Study 2 (HEC)

In two multicentre, randomised, double-blind, parallel group, controlled clinical studies (Study 1 and Study 2), the rolapitant regimen (180 mg rolapitant, 10 mcg/kg intravenous granisetron and 20 mg oral dexamethasone) was compared with control therapy (placebo, 10 mcg/kg intravenous granisetron and 20 mg oral dexamethasone) on Day 1 in patients receiving a chemotherapy regimen that included cisplatin ≥60 mg/m². On Day 2 to 4, patients received 8 mg twice daily of oral dexamethasone. Study medicinal products were administered prior to chemotherapy on Day 1 at the following intervals: rolapitant (1 to 2 hours prior); granisetron and dexamethasone (30 minutes prior).

A total of 1087 patients were randomised to either the rolapitant regimen (N=544) or control therapy (N=543) across Study 1 and Study 2; 1070 patients were included in the eva luation of efficacy; 37% were women and 63% were men. Of the 1070 patients, 26% were greater than 65 years of age and 3% were greater than 75 years of age.

The primary endpoint in both studies was complete response (defined as no emetic episodes and no rescue medicinal product) in the delayed phase (>24 to 120 hours) of chemotherapy-induced nausea and vomiting. The following additional pre-specified endpoints were also eva luated: complete response in the acute phase (0 to 24 hours) and overall phase (0 to 120 hours); no emesis in each CINV phase, no significant nausea in each CINV phase, and time to first emesis or use of rescue medicinal product.

The results were eva luated for each individual study and for the two studies combined. Individual results from Studies 1 and 2 as well as a summary of the key results from the combined analysis are shown in Table 1 below.

The estimated time to first emesis in the combined analysis is depicted by the Kaplan-Meier plot in Figure 1.

Figure 1: Kaplan-Meier Plot of Proportions of Patients without Emesis or Use of Rescue Medication (Study 1 and Study 2 Combined – HEC)

Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide Chemotherapy

Study 3 (MEC)

In Study 3, a multicentre, randomised, double-blind, parallel group, controlled clinical study in moderately emetogenic chemotherapy, the rolapitant regimen (180 mg rolapitant, 2 mg oral granisetron and 20 mg oral dexamethasone) was compared with control therapy (placebo, 2 mg oral granisetron and 20 mg oral dexamethasone) on Day 1 in patients receiving a moderately emetogenic chemotherapy regimen that included 53% of patients receiving a combination of anthracycline and cyclophosphamide (AC). On Day 2 to 3, patients received 2 mg once daily of oral granisetron. Study medicinal products were administered prior to chemotherapy on Day 1 at the following intervals: rolapitant (1 to 2 hours prior); granisetron and dexamethasone (30 minutes prior). At the time the study was designed, AC containing chemotherapy regimens were considered to be moderately emetogenic. Recent guidance has updated these regimens to highly emetogenic. The percentage of patients who received carboplatin in Cycle 1 was 30%.

A total of 1369 patients were randomised to either the rolapitant regimen (N=684) or control therapy (N=685). A total of 1332 patients were included in the eva luation of efficacy, 80% were women and 20% were men. Of these 1332 patients, 28% were greater than 65 years of age and 6% were greater than 75 years of age. Of these 1332 patients, 629 received non-AC chemotherapy.

The primary endpoint was complete response (defined as no emetic episodes and no rescue medicinal product) in the delayed phase (>24 to 120 hours) of chemotherapy-induced nausea and vomiting. The following additional pre-specified endpoints were also eva luated: complete response in the acute phase (0 to 24 hours) and overall phase (0 to 120 hours); no emesis in each CINV phase, no significant nausea in each CINV phase and time to first emesis or use of rescue medicinal product.

A summary of the study results from the MEC Study (Study 3) is shown in Table 2 below. A summary of the results from the non-AC and AC subsets are provided in Table 3.

The estimated time to first emesis or use of rescue medicinal product in patients receiving a MEC regimen is depicted by the Kaplan-Meier plot in Figure 2.

Figure 2: Kaplan-Meier Plot of Proportions of Patients without Emesis or Use of Rescue Medication (Study 3--MEC)

The impact of nausea and vomiting on patients' daily lives was assessed using the Functional Living Index-Emesis (FLIE). The proportion of patients with no impact on daily life was higher in the Varuby group than in the control group (MEC: 73.2% vs. 67.4%; p=0.027).

Multiple-Cycle Extension: In each study, patients had the option of continuing into a multiple-cycle extension for up to 5 additional cycles of chemotherapy receiving the same treatment as assigned in cycle 1. At Day 6 to 8 following initiation of chemotherapy, patients were asked to recall whether they had any episode of vomiting or retching or nausea that interfered with normal daily life. Antiemetic activity of rolapitant was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with rolapitant in all subsets of the paediatric population in prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cisplatin-based cancer therapy and moderately emetogenic cancer therapy (see section 4.2 for information on paediatric use).

Rolapitant displays linear PK with exposures increased in a dose-proportional manner. Rolapitant is slowly eliminated with mean terminal half-life of approximately 7 days. Rolapitant is eliminated mainly through the hepatic/biliary route, with minor contributions from renal elimination. Rolapitant is metabolised by CYP3A4 to form a major active metabolite, M19. In vitro studies suggest that rolapitant is not an inhibitor of CYP2E1.

Absorption

Following a single dose administration of 180 mg rolapitant under fasting conditions to healthy subjects, rolapitant was measurable in plasma between 30 minutes and the peak plasma concentration (C_max) for rolapitant which was reached in about 4 hours and mean C_max was 968 ng/mL (%CV:28%). Following multiple oral doses 9 to 45 mg once daily of rolapitant; accumulation of rolapitant was approximately 5-fold.

The systemic exposures (C_max and AUC) to rolapitant increased in a dose-proportional manner when the dose of rolapitant increased from 4.5 mg to 180 mg. With an increase in dose by 4 times from the recommended clinical dose of 180 mg, the C_max and AUC of rolapitant increased by 3.1 fold and 3.7 fold, respectively.

The absolute bioavailability of rolapitant is approximately 100%, indicating minimal first pass effect.

Concomitant administration of a high fat meal did not significantly affect the pharmacokinetics of rolapitant after administration of 180 mg rolapitant.

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.

Biotransformation

Rolapitant is metabolised by CYP3A4 to form a major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant). In a mass balance study, the metabolite M19 was the major circulating metabolite. The formation of M19 was significantly delayed with the median T_max 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.

Elimination

Following single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t_1/2) 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.

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. In pooled samples collected over 2 weeks, 8.3% of the dose was recovered in the urine primarily as metabolites and 37.8% of the dose was recovered in the feces primarily as unchanged rolapitant. Unchanged rolapitant or M19 were not found in pooled urine sample. Drug metabolising enzymes (and drug transporters) other than CYP3A4 involved in rolapitant hepatic/biliary elimination remain to be elucidated.

Pharmacokinetics in special populations

Age, Sex and Race/Ethnicity

Population pharmacokinetic analyses indicated that age, sex and race had no significant impact on the pharmacokinetics of Varuby. There are limited data in patients aged 75 years and older.

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 C_max was 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects. The median T_max for M19 was delayed to 204 hours in patients with mild or moderate hepatic impairment compared to 168 hours in healthy subjects. The pharmacokinetics of Varuby was not studied in patients with severe hepatic impairment (Child-Pugh Class C).

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 Varuby was not studied in patients with end-stage renal disease requiring haemodialysis.

Relationship between concentration and effect

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 rolapitant plasma concentrations of >15 ng/mL and 348 ng/mL, the NK₁ receptor occupancies in the cortical regions were approximately >50% and 90% respectively. At the 180 mg dose of rolapitant, the mean NK₁ receptor occupancy in the cortical regions was greater than 90% for at least 120 hours.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, teratogenic potential, and carcinogenic potential.

The mechanism of the significant difference of half-lives observed between the rat and monkey (6-8 h) and human (7 days) is not elucidated.

In rodents, rolapitant was tested in repeated dose oral toxicity studies up to 26 weeks in duration, and the liver, thyroid, kidneys, epididymis and uterus were identified as target organs. In a three-month rat study, clonic convulsions were observed in a single animal at 125 mg/kg/day (approximately 6 times the recommended human dose on a body surface area basis). In the one-month monkey study, convulsions were observed at 60 mg/kg/day (approximately 5.8 times the recommended human dose on a body surface area basis). The relevance of convulsions for humans is unknown.

In a fertility and early embryonic development study in female rats, rolapitant hydrochloride at an oral dose equivalent to 9 mg/kg per day free base (approximately 0.5 times the recommended human dose on a body surface area basis) caused a transient decrease in maternal body weight gain and increases in the incidence of pre- and post-implantation loss. At a dose equivalent to 4.5 mg/kg per day free base (approximately 0.2 times the recommended human dose on a body surface area basis), there were decreases in the number of corpora lutea and implantation sites.

In a pre- and post-natal development rat study, maternal toxicity was evident based on mortality/moribund condition, decreased body weight and food consumption, total litter loss, prolonged parturition, decreased length of gestation, and increased number of unaccounted for implantation sites at a dose equivalent to 22.5 mg/kg per day free base (approximately 1.2 times the recommended human dose on a body surface area basis). Effects on offspring at this dose included decreased postnatal survival, and decreased body weights and body weight gain, and may be related to the maternal toxicity observed. At a maternal dose equivalent to 9 mg/kg per day rolapitant free base (approximately 0.5 times the recommended human dose on a body surface area basis), there was a decrease in memory in female pups in a maze test and a decrease in pup body weight.

Tablet content

Lactose monohydrate

Pregelatinised starch

Microcrystalline cellulose (E460)

Povidone (K-30)

Croscarmellose sodium

Colloidal silicon dioxide

Magnesium stearate

Tablet coating

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol

Talc

Indigo carmine (E132)

Polysorbate 80

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Polyvinyl chloride/polychlorotrifluoroethylene/aluminium foil twinned blister.

Pack size of two tablets.

Any unused medicinal product or waste material should be disposed of in accordance with local requirement.

TESARO UK LIMITED

55 Baker Street

London W1U 7EU

United Kingdom

EU/1/17/1180/001

Date of first authorisation: 20 April 2017

20 April 2017

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.