Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Global Blood Therapeutics Netherlands B.V., Strawinskylaan 3051, 1077ZX Amsterdam, Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).
Serious hypersensitivity reactions have been observed in <1% of patients treated with voxelotor in clinical studies. Clinical manifestations may include generalised rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia (see section 4.8).
If hypersensitivity reactions occur, voxelotor must be discontinued and appropriate medical therapy must be administered. Voxelotor must not be reinitiated in patients who experience these symptoms with previous use.
Oxbryta 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 Oxbryta therapy in the immediately preceding 10 days.
No clinically significant differences in the pharmacokinetics of voxelotor were observed in subjects without SCD with mild to severe renal impairment (see section 5.2). No dose adjustment is recommended. Safety of voxelotor has not been evaluated in SCD patients with ESRD requiring dialysis.
There are limited data on the safety of voxelotor in patients with SCD with different degrees of hepatic impairment. Based on pharmacokinetic data in subjects without SCD, severe hepatic impairment increases voxelotor exposures (see section 5.2). The voxelotor dose in patients with severe hepatic impairment (Child Pugh C) should be adjusted (see section 4.2).
Concomitant use of strong CYP3A4 inducers with Oxbryta should be avoided due to the risk of decreased efficacy of voxelotor (see section 4.5).
Most patients (90.5%) in the pivotal Phase 3 study had SCD genotype HbSS (75.2%) or HbS/β0-thalassemia (15.3%). Therefore, safety and efficacy data on other SCD genotypes are limited.
Clinical studies of voxelotor did not include patients >65 years of age.
When Oxbryta is administered in combination with hydroxycarbamide, the prescribing information of hydroxycarbamide should be consulted.
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.
This medicinal product contains less than 1 mmol sodium (23 mg) per 1,500 mg (daily dose), that is to say essentially ‘sodium-free’.
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.
Itraconazole (a strong CYP3A4 inhibitor), omeprazole (acid reducing agent), and hydroxycarbamide had no effect on the pharmacokinetics of voxelotor.
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 Cmax 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 (see section 5.2). The clinical relevance is currently unknown, and caution is recommended when co-administering voxelotor with sensitive substrates of CYP2B6 such as bupropion and efavirenz.
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 Cmax 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 (see section 5.2). Therefore, caution is recommended when co-administering voxelotor with sensitive substrates of these transporters, especially for those substrates with a narrow therapeutic index.
Concomitant use of voxelotor with digoxin (a P-gp substrate) did not alter digoxin to a clinically relevant extent. Voxelotor is not an inhibitor of bile salt export pump (BSEP). It is not known if voxelotor affects the oral absorption of breast cancer resistance protein (BCRP) substrates.
Specific interaction studies with oral contraceptives have not been performed. However, based on the results of in vitro studies, a negative impact of voxelotor on contraceptive efficacy is not expected.
Voxelotor did not change the systemic exposure of caffeine (CYP1A2 substrate) and metoprolol (CYP2D6 substrate).
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 (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Oxbryta 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 (for details see section 5.3). A risk to the newborns/infants cannot be excluded. Voxelotor should not be used during breast-feeding.
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 (see section 5.3). Relevance to human is not known.
Oxbryta has no or negligible influence on the ability to drive and use machines.
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%).
Table 1 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.
Table 1. Adverse reactions:
| System organ class | Adverse reactionsa | Frequency category |
|---|---|---|
| Immune system disorders | Drug hypersensitivity | Uncommon |
| Nervous system disorders | Headache | Very common |
| Gastrointestinal disorders | Diarrhoea Abdominal painb Nausea | Very common |
| Skin and subcutaneous tissue disorders | Rashc | Very common |
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.
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.
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.
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.
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.
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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