Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: TESARO Bio Netherlands B.V., Joop Geesinkweg 901, 1114 AB Amsterdam-Duivendrecht, Netherlands
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).
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).
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).
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).
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.
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).
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.
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 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.
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.
In vitro studies suggest that rolapitant is not expected to inhibit OATP1B1 at clinically relevant concentrations and rolapitant is not an inhibitor of OATP1B3 at the tested concentrations up to 20 μM.
In vitro, rolapitant is not an inhibitor of OCT1 at the tested concentrations up to 20 μM.
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.
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.
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.
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.
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).
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.
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).
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.
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.
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).
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.
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:
Uncommon: Oral fungal infection
Rare: Candidiasis, Oral candidiasis
Uncommon: Neutropenia
Rare: International Normalised Ratio increased, Leukopenia, Neutrophil count decreased, Thrombocytopenia
Rare: Hypersensitivity
Uncommon: Decreased appetite
Rare: Dehydration, Hypomagnesaemia
Uncommon: Insomnia
Rare: Anxiety, Bruxism
Common: Headache
Uncommon: Dizziness, Disturbance in attention, Dysgeusia, Somnolence
Rare: Balance disorder, Movement disorder, Syncope
Rare: Hypoacusis, Tinnitus
Rare: Vision blurred
Rare: Heart rate increased
Common: Constipation
Uncommon: Diarrhoea, Dyspepsia, Nausea, Abdominal distension, Abdominal pain, Stomatitis
Rare: Abdominal discomfort, Change of bowel habit, Dry mouth, Gastrooesophageal reflux disease, Retching
Rare: Hypertension
Uncommon: Hiccups
Rare: Dyspnoea
Rare: Alopecia, Angioedema, Dermatitis acneiform, Dry skin
Uncommon: Myalgia
Rare: Arthralgia, Back pain, Muscular weakness, Rhabdomyolysis
Common: Fatigue
Uncommon: Asthenia
Rare: Gait disturbance
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 Appendix V.
Not applicable.
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