4.1. Therapeutic indications

Oxbryta is indicated for the treatment of haemolytic anaemia due to sickle cell disease (SCD) in adults and paediatric patients 12 years of age and older as monotherapy or in combination with hydroxycarbamide.

4.2. Posology and method of administration

Treatment should be initiated by physicians experienced in the management of SCD.

Posology

The recommended dose of Oxbryta is 1500 mg (three 500 mg film-coated tablets) taken orally once daily.

If a dose is missed, treatment should be continued on the day following the missed dose.

Paediatric population

The recommended dose of Oxbryta in patients 12 to < 18 years of age is the same as for adults.

The safety and efficacy of Oxbryta in paediatric patients below the age of 12 years have not been established yet. No data are available.

Special populations

Renal impairment

No dose adjustment is recommended in patients with mild to severe renal impairment. Oxbryta has not been evaluated in patients with end stage renal disease (ESRD) requiring dialysis (see section 4.4).

Hepatic impairment

No dose adjustment of Oxbryta is recommended for patients with mild or moderate hepatic impairment. The recommended dose of voxelotor in patients with severe hepatic impairment (Child Pugh C) is 1000 mg (two 500 mg film-coated tablets) taken once daily (see section 4.4).

Method of administration

Oxbryta film-coated tablets should be swallowed whole with water. Oxbryta can be taken with or without food (see section 5.2). Tablets should not be cut, crushed, or chewed because of the unpleasant taste.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

4.4. Special warnings and precautions for use

Hypersensitivity reactions

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.

Severe cutaneous adverse reactions (SCARs)

Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity, which can be life-threatening or fatal, has been reported in association with Oxbryta (see section 4.8).

At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, Oxbryta should be withdrawn immediately and an alternative treatment considered. If the patient has developed a serious reaction such as DRESS with the use of Oxbryta, treatment with Oxbryta must not be restarted in this patient at any time.

Laboratory test interference

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.

Renal impairment

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.

Hepatic impairment

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 strong CYP3A4 inducers

Concomitant use of strong CYP3A4 inducers with Oxbryta should be avoided due to the risk of decreased efficacy of voxelotor (see section 4.5).

SCD genotypes

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.

Elderly

Clinical studies of voxelotor did not include patients > 65 years of age.

Combination therapy with hydroxycarbamide

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

Immunosuppressive effects

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.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per 1500 mg (daily dose), that is to say essentially “sodium-free”.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on voxelotor

Strong CYP3A4 inducers

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.

Other interactions studied

Itraconazole (a strong CYP3A4 inhibitor), omeprazole (acid reducing agent), and hydroxycarbamide had no effect on the pharmacokinetics of voxelotor.

Effect of voxelotor on other medicinal products

CYP3A4 substrates

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 microgram•hr/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).

CYP2B6 substrates

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.

CYP2C8, CYP2C9, and CYP2C19 substrates

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 microgram•hr/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.

Transporter-mediated drug interactions

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.

Oral contraceptives and other steroidal agents

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.

Other interactions studied

Voxelotor did not change the systemic exposure of caffeine (CYP1A2 substrate) and metoprolol (CYP2D6 substrate).

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Breastfeeding

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.

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 (see section 5.3). Relevance to human is not known.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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%).

Severe cutaneous adverse reactions (SCARs): drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in association with Oxbryta treatment (see section 4.4).

Tabulated list of adverse reactions

Table 1 lists adverse drug reactions that occurred in patients treated with voxelotor 1500 mg during a 72-week, randomized, double-blind, placebo-controlled pivotal Phase 3 study (n=88), as well as adverse reactions from postmarketing experience.

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

DiarrhoeaAbdominal painbNausea

Very common

Skin and subcutaneous tissue disorders

Rashc

Very common

Pruritus

Common

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Angioedemad

Not known

a. Adverse 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 includes abdominal pain, abdominal pain upper, and abdominal pain lower.

c. Rash includes rash, urticaria, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash papular.

d. Angioedema includes swelling of eyelid, face oedema, lip swelling, and periorbital swelling.

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 1500 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 1500 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 1500 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.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There was one report of overdose in the pivotal Phase 3 study where a patient took a total of 3000 mg of voxelotor at one time. There were no adverse reactions associated with this event.

In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.