Varuby - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Varuby 90 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient(s) with known effect

3. PHARMACEUTICAL FORM

4.   CLINICAL PARTICULARS

4.1 Therapeutic indications

Day 1

180 mg orally;

Within 2 hours prior to chemotherapy

20 mg orally;

30 min prior to chemotherapy __________

Standard dose of 5-HTs receptor antagonist. See the Summary of Product । Characteristics for the co-administered 5-HTs receptor antagonist for appropriate dosing information.

Elderly people (> 65 years)

No dose adjustment is necessary fo 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.

4.3 Contraindications

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)

4.4 Special warnings and precautions for use

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 carbamazepine, phenobarbital, enzalutamide, phenytoin) o 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.

4.5 Interaction with other medicinal products and other forms of interactionEffects of Varuby

pharmacokinetics of other active substances

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).

UGT1A1 and UGT2B7 substrates (e.g. irinotecan and morphine, respectively)

Rolapitant modestly inhibited UGT1A1 and UGT2B7 in vitro. Therefore, the potential interactions associated with the inhibition of these UGT enzymes in the intestine cannot be excluded.

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. Coadministration of a single dose of 180 mg rolapitant with sulfasalazine, a BCRP substrate, resulted in an approximately 2-fold increase in Cmax 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 Cmax 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 clini concentrations and rolapitant is not an inhibitor of OATP1B3 at the tested concen

OCT1 substrates

In vitro , rolapitant is not an inhibitor of OCT1 at the tested concentrations up to 20 ^M.

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 administere Days 1 to 3 after a single 180 mg dose of rolapitant was coadministered on Day 1.

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).

Rolapitant had no effects on the pharmacokinetics of caffeine (a CYP1A2 substrate) when an oral dose of 200 mg caffeine was administered with a single dose of 180 mg rolapitant on Day 1, and without rolapitant on Day 8 and Day 15.

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 Cmax 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).

4.6 Fertility, pregnancy and lactation

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).

4.7 Effects on ability to drive and use machines

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).

4.8 Undesirable effects

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.

Adverse reactions per system organ class

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 national reporting system listed in

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 evaluation 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 evaluated: 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 evaluated 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.

a Primary endpoint was complete response in the delayed phase. Delayed phase: >24 to 120 hours postcisplatin treatment; Acute phase: 0 to 24 hours post-cisplatin treatment; Overall phase: 0 to 120 hours postcisplatin treatment

b Unadjusted P-values are obtained from Cochran-Mantel Haenszel test, stratified for sex.

c Unadjusted P-values are obtained from Cochran-Mantel-Haenszel test, stratified by study and sex. N.S.=Not significant (p> 0.05)

Not significant after applying pre-specified multiplicity adjustment. _____________­________________________­__

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

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, 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 evaluation 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 evaluated: 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.

a Primary endpoint was complete response in the delayed phase. A AC or non-AC regimen; Delayed phase: >24 to 120 hours after A phase: 0 to 120 hours after AC or non-AC regimen b Unadjusted P-values are obtained from Cochran-Mantel-Haenszel test, stratified by sex. N.S.=Not significant (p>0.05)

* N.S. after pre-specified multiplicity adjustment.

Table 3: Proportion of Patients Receiving AC or non-AC Chemotherapy Achieving

hran-Mantel-Haenszel test.

a Unadjusted P-values are obtained from Coc

N.S.=Not significant (p>0.05) ______________

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)

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).

5.2 Pharmacokinetic properties

Rolapitant displays linear PK with exposures increased in a dose-proportional manner. Rolapitant is slowly eliminated with a mean terminal half-life of approximately 7 days. Rolapitant is eliminated mainly through the hepatobiliary 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 (Cmax) for rolapitant which was reached in about 4 hours and mean Cmax 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 (Cmax 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 Cmax 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 (Vd/F) was 460 L in healthy subjects, indicating an extensive tissue distribution o population pharmacokinetic analysis of rolapitant, the Vd/F was 387 L in cance

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 Tmax of 120 hours (range:

24–168 hours) and the mean half-life of M19 was 158 hou was approximately 50% in plasma.

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. rSr

ough the hepatobiliary 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 transport     ther than CYP3A4 involved in rolapitant hepatobiliary elimination remain to be

elucidate

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 Cmax was 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects. The median Tmax 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

NK 1 Receptor Occupancy

A human Positron Emission Tomography (PET) study with rolapitant demonstrated that rol nt

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.

5.3 Preclinical safety data

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.

Based on the environmental risk assessment, rolapitant is considered as very persistent, bioaccumulative and not readily biodegradable.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

6.2 Incompatibilities

6.3 Shelf life

6.4 Special precautions for storage

Polyvinyl chloride/polychlo­rotrifluoroet­hylene/alumini­um foil twinned blister. Pack size of t blets.

6.6 Special precautions for disposal ed medicinal product or waste material should be disposed of in accordance with local nts.req

7. MARKETING AUTHORISATION HOLDER

TESARO Bio Netherlands B.V.

Joop Geesinkweg 901

1114 AB Amsterdam-Duivendrecht

Netherlands

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1180/001