Voxelotor

Voxelotor is an in vitro inhibitor of CYP2C8, CYP2C9, and CYP2C19 at maximal systemic concentrations. There was no observed change on the exposures of S-warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 substrate) in healthy volunteers at a sub therapeutic voxelotor dose (observed voxelotor C_max 7.0-8.0 microgram/mL and AUC 126.3-148.9 microgramhr/mL). The effect at the full dose level of voxelotor is currently unknown. Caution is recommended when co-administering voxelotor with sensitive substrates of CYP enzymes.

In vitro studies indicated that voxelotor may act as an inhibitor of OATP1B1, OAT3 and MATE1 transporters. Therefore, caution is recommended when co-administering voxelotor with sensitive substrates of these transporters, especially for those substrates with a narrow therapeutic index.

Voxelotor increased the systemic exposure of midazolam (a sensitive CYP3A4 substrate). The observed exposure increase of the CYP3A4 substrate midazolam was 1.6-fold in healthy subjects at a voxelotor sub-therapeutic dose (observed voxelotor C_max 7.0-8.0 microgram/mL and AUC 126.3-148.9 microgramhr/mL). The effect at the full dose level of voxelotor is expected to be larger. Coadministration of voxelotor with sensitive CYP3A4 substrates with a narrow therapeutic index (i.e., alfentanil, sirolimus, and tacrolimus) should be avoided. If concomitant use is unavoidable, consider dose reduction of the sensitive CYP3A4 substrate(s).

In vitro studies indicated that voxelotor acts as an inhibitor and inducer of CYP2B6. The clinical relevance is currently unknown, and caution is recommended when co-administering voxelotor with sensitive substrates of CYP2B6 such as bupropion and efavirenz.

Coadministration of strong CYP3A4 inducers may decrease voxelotor exposures and may lead to reduced efficacy.

Coadministration of voxelotor with strong CYP3A4 inducers (i.e., rifampicin, phenobarbital, carbamazepine, phenytoin, and St John’s wort extract) should be avoided.

The recommended dose of voxelotor in patients with severe hepatic impairment (Child-Pugh C) is 1000 mg taken once daily.

Voxelotor decreased the humoral immune response to antigens in both rats and monkeys. Clinical relevance in already immunocompromised patients or in patients treated with immunosuppressive drugs cannot be excluded.

When voxelotor is administered in combination with hydroxycarbamide, the prescribing information of hydroxycarbamide should be consulted.

Voxelotor has not been evaluated in patients with end stage renal disease (ESRD) requiring dialysis.

Voxelotor administration may interfere with measurement of haemoglobin (Hb) subtypes (HbA, HbS, and HbF) by high-performance liquid chromatography (HPLC). If precise quantitation of Hb species is required, chromatography should be performed when the patient has not received voxelotor therapy in the immediately preceding 10 days.

There are no or limited amount of data from the use of voxelotor in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of voxelotor during pregnancy.

It is unknown whether voxelotor/metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of voxelotor in milk and subsequent uptake in pups. A risk to the newborns/infants cannot be excluded. Voxelotor should not be used during breast-feeding.

Fertility

No human data are available on the effect of voxelotor on fertility. In rats, effects on sperm motility and morphology were observed. These effects did not, however, affect the reproductive performance. Relevance to human is not known.

Voxelotor has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions include headache (31.8%), diarrhoea (22.7%) and abdominal pain (22.7%). Serious adverse reactions include headache (1.1%) and drug hypersensitivity (1.1%). Permanent discontinuation due to an adverse reaction occurred in 2.3% of patients.

Dose modifications (dose reduction or dosing interruption) due to an adverse reaction occurred in 13.6% of patients who received voxelotor in the pivotal study. The adverse reactions requiring dose modification included rash (4.5%), diarrhoea (3.4%), headache (2.3%), nausea (2.3%), abdominal pain (1.1%), and drug hypersensitivity (1.1%).

Tabulated list of adverse reactions

The table below lists adverse drug reactions that occurred in patients treated with voxelotor 1,500 mg during a 72-week, randomized, double-blind, placebo-controlled pivotal Phase 3 study (n=88).

Adverse reactions reported with voxelotor are listed by system organ class and preferred term. Within each system organ class, adverse reactions are listed under frequency categories. 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 (cannot be estimated from available clinical study data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions:

^aAdverse reactions were NCI Grades 1 or 2 except for Grade 3 diarrhoea (n=1), nausea (n=1), rash (n=1), rash generalized (n=3) and hypersensitivity (n=1).
^b Abdominal pain included abdominal pain, abdominal pain upper, and abdominal pain lower.
^c Rash included rash, urticaria, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash papular.

Description of selected adverse reactions

Gastrointestinal (GI) disorders

In the pivotal Phase 3 study, the most commonly reported GI adverse reactions were diarrhoea, abdominal pain and nausea with diarrhoea and nausea showing a dose-dependent effect. The majority of reported GI events were Grade 1 or 2 and were manageable without the need for dose interruption, reduction or treatment discontinuation and resolved with continued use. Gastrointestinal adverse reactions resulting in dose reductions occurred in 4.5% of patients. Diarrhoea was the most common adverse reaction and was reported in 22.7%, and 11.0% of patients in the voxelotor 1,500 mg, and placebo groups, respectively. There was 1 (1.1%) report of Grade 3 diarrhoea. A serious adverse reaction of nausea resulting in hospitalization occurred in 1 (1.1%) patient in the voxelotor 1,500 mg group.

Drug hypersensitivity

In the pivotal Phase 3 study, 1 patient (1.1%) experienced drug hypersensitivity on Study Day 40. Observed symptoms included generalized morbilliform rash, urticaria, mild shortness of breath, mild facial swelling, pyrexia, headache, and diarrhoea. Elevated eosinophils were noted. Symptoms abated after voxelotor was withheld, and recurrence was observed after reintroduction of voxelotor. Event resolved with antihistamine and oral corticosteroids.

Rash

In the pivotal Phase 3 Study, rash was reported in 14.8% and 11.0% of patients in the voxelotor 1,500 mg and placebo groups, respectively. The majority of rash events were similar in appearance (consistent with typical maculopapular drug eruptions) and distribution, were not associated with extradermal symptoms, and were clinically manageable with or without treatment including oral antihistamines or topical corticosteroids. Exposure-response analysis did not reveal a statistically significant dose- or exposure-response relationship.

Paediatric population

The safety profile observed in paediatric patients 12 to <18 years of age treated with voxelotor in the clinical studies was similar to that seen in adult patients.