Rolapitant

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 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.

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 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.

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.

There are limited data in patients with severe renal impairment and no data in patients with end stage renal disease undergoing haemodialysis. Rolapitant should be used with caution in these patients.

There are no data in patients with severe hepatic impairment. Rolapitant should be used with caution in these patients.

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.

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. Rolapitant in patients who require chronic administration of strong inducers (e.g. rifampicin, carbamazepine, enzalutamide, phenytoin) is not recommended.

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. Rolapitant 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 rolapitant.

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.

Rolapitant has minor influence on the ability to drive and use machines. Dizziness and fatigue may occur following administration of rolapitant.

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.

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.

Infections and infestations

Uncommon: Oral fungal infection

Rare: Candidiasis, Oral candidiasis

Blood and lymphatic system disorders

Uncommon: Neutropenia

Rare: International Normalised Ratio increased, Leukopenia, Neutrophil count decreased, Thrombocytopenia

Immune system disorders

Rare: Hypersensitivity

Metabolism and nutrition disorders

Uncommon: Decreased appetite

Rare: Dehydration, Hypomagnesaemia

Psychiatric disorders

Uncommon: Insomnia

Rare: Anxiety, Bruxism

Nervous system disorders

Common: Headache

Uncommon: Dizziness, Disturbance in attention, Dysgeusia, Somnolence

Rare: Balance disorder, Movement disorder, Syncope

Ear and labyrinth disorders

Rare: Hypoacusis, Tinnitus

Eye disorders

Rare: Vision blurred

Cardiac disorders

Rare: Heart rate increased

Gastrointestinal disorders

Common: Constipation

Uncommon: Diarrhoea, Dyspepsia, Nausea, Abdominal distension, Abdominal pain, Stomatitis

Rare: Abdominal discomfort, Change of bowel habit, Dry mouth, Gastrooesophageal reflux disease, Retching

Vascular disorders

Rare: Hypertension

Respiratory, thoracic and mediastinal disorders

Uncommon: Hiccups

Rare: Dyspnoea

Skin and subcutaneous tissue disorders

Rare: Alopecia, Angioedema, Dermatitis acneiform, Dry skin

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia

Rare: Arthralgia, Back pain, Muscular weakness, Rhabdomyolysis

General disorders and administration site conditions

Common: Fatigue

Uncommon: Asthenia

Rare: Gait disturbance