SCD medical experts discuss Oxbryta and appropriate patient cases

Managing Side Effects During Oxbryta Treatment

While not necessary for all patients, dose modifications may be appropriate to help manage adverse reactions in some cases. Watch Dr. Alan Anderson describe the dose adjustment protocols utilized during the Phase 3 HOPE trial.

INDICATIONS AND USAGE

Oxbryta is indicated for the treatment of sickle cell disease in adults and pediatric patients 12 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

CONTRAINDICATIONS

Oxbryta is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients.

Hello. My name is Dr. Alan Anderson, and I’m the medical director of a comprehensive lifespan sickle cell disease program and a practicing hematologist, oncologist and during this presentation I’d like to talk to you about how we managed side effects seen in patients in the HOPE clinical trial. This information may help guide management of patients on Oxbryta in your clinical practice.

This table illustrates the adverse reactions that were observed in at least 10% of patients and with a difference of more than 3% in the Oxbryta vs placebo arms at Week 24 or Week 72.

These reactions included headache, diarrhea, abdominal pain, nausea, arthralgia, fatigue, rash, pyrexia, and back pain.

Serious adverse reactions that occurred in 3% of patients receiving 1,500 mg of Oxbryta included headache, drug hypersensitivity, and pulmonary embolism, occurring in one patient each at 24 weeks. No new events occurred after 24 weeks.

The safety profile observed in pediatric patients between the ages of 12 and 17 was similar to adult patients enrolled in the phase 3 trial through Weeks 24 and 72.

Clinically relevant adverse reactions occurring in <10% of patients through Week 24 included drug hypersensitivity. No new events occurred after 24 weeks.

While not needed for all patients, dose modification may be warranted to help manage adverse events.

Less than half of patients who received Oxbryta, or 41% of patients at Week 24 and 48% of patients at Week 72, required a dose modification. This was either a dose reduction or interruption.

The most frequent adverse reactions requiring dosage interruption occurring in more than 1 patient who received Oxbryta 1,500 mg included diarrhea, headache, rash, and vomiting.

In the HOPE trial, patients needing a temporary modification based on physician discretion or adverse reaction severity could be lowered to 1,200 mg/day, which was a reduction of 1 pill in the HOPE trial based on the clinical formulation at that time, until the event subsided and patients could return to 1,500 mg/day.

During the first 24 weeks of the HOPE trial, 5% of patients permanently discontinued therapy due to a treatment-related adverse reaction; however, there were no additional discontinuations through Week 72.

There were no discontinuations due to diarrhea, headache, rash, fatigue, arthralgia, or pyrexia.

Most diarrhea events reported were mild and self-limiting. Median time to onset was 15 days, and median time from onset to resolution was 30 days.

Lastly, patients experiencing a Grade 1 or 2 rash were allowed oral antihistamines and/or topical steroids.

Thank you very much for listening to this presentation. I hope this information helps you manage side effects your patients may experience while on Oxbryta. Please see important safety information at the end of this video.

Important Safety Information and Indication

INDICATIONS AND USAGE

Oxbryta is indicated for the treatment of sickle cell disease in adults and pediatric patients 12 years of age and older.

This indication is approved under accelerated approval based on increase in hemoglobin. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS

Oxbryta is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients.

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions Serious hypersensitivity reactions after administration of Oxbryta have occurred in <1% of patients treated. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia.

If hypersensitivity reactions occur, discontinue Oxbryta and administer appropriate medical therapy. Do not reinitiate Oxbryta in patients who experience these symptoms with previous use.

Laboratory Test Interference

Oxbryta administration may interfere with measurement of hemoglobin subtypes A, S, and F by HPLC. If precise quantitation of hemoglobin species is required, chromatography should be performed when the patient is not receiving Oxbryta therapy.

ADVERSE REACTIONS

Clinical Trials Experience

Serious adverse reactions occurred in 3% (3 out of 88) of patients receiving Oxbryta 1,500 mg, which included headache, drug hypersensitivity, and pulmonary embolism occurring in 1 patient each.

Adverse Reactions (≥10%) in patients receiving Oxbryta with a difference of >3% compared to placebo: Headache (26% vs. 22%), Diarrhea (20% vs. 10%), Abdominal Pain (19% vs. 13%), Nausea (17% vs. 10%), Fatigue (14% vs. 10%), Rash (14% vs. 10%), and Pyrexia (12% vs. 7%).

DRUG INTERACTIONS

Sensitive CYP3A4 Substrates Voxelotor increased the systemic exposure of midazolam (a sensitive CYP3A4 substrate). Avoid co- administration with sensitive CYP3A4 substrates with a narrow therapeutic index. If unavoidable, consider dose reduction of the CYP3A4 substrates.

Strong CYP3A4 Inhibitors or Fluconazole

Co-administration of strong CYP3A4 inhibitors or fluconazole may increase voxelotor plasma concentrations and may lead to increased toxicity. Avoid co-administration of strong CYP3A4 inhibitors or fluconazole. Decrease Oxbryta dosage if unavoidable.

Strong or Moderate CYP3A4 Inducers Co-administration of strong or moderate CYP3A4 inducers may decrease voxelotor plasma concentrations and may lead to reduced efficacy. Avoid co- administration of strong or moderate CYP3A4 inducers. Increase the Oxbryta dosage if unavoidable.

USE IN SPECIFIC POPULATIONS

Lactation

Because of the potential for serious adverse reactions in the breastfed child, including changes in the hematopoietic system, advise patients not to breastfeed while taking Oxbryta and for at least 2 weeks after the last dose.

Recommended Dosage for Hepatic Impairment

Severe hepatic impairment increases voxelotor exposures. Reduce dose to 1,000 mg orally once daily for severe hepatic (Child Pugh C) impairment.

Please see Full Prescribing Information for Oxbryta by clicking below for more information.

Additional Videos
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How Oxbryta Works

Listen to Dr. Nirmish Shah discuss the mechanism of action of Oxbryta, how it was designed to target HbS polymerization, and its proposed effect on red blood cell morphology.

For more information about the Oxbryta MOA, watch an additional video How oxbryta intervenes
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Understanding the HOPE Trial

Dr. Santosh L. Saraf explores the Phase 3 HOPE trial, including the trial’s design, study endpoints, and baseline demographics. Go to Video >>

Efficacy & Safety of Oxbryta in the HOPE Trial

Dr. Alan Anderson describes the safety and efficacy results from the pivotal Phase 3 HOPE trial, including the impact of Oxbryta on anemia and hemolysis at 72 weeks. Go to Video >>

Dosing and Management of Your Patient on Oxbryta Therapy

Dr. Santosh L. Saraf reviews the convenient, once-daily oral dosing of Oxbryta, dose adjustment protocols utilized during the Phase 3 HOPE trial, and topics to discuss with patients when initiating Oxbryta therapy. Go to Video >>

Managing Side Effects During Oxbryta Treatment

While not necessary for all patients, dose modifications may be appropriate to help manage adverse reactions in some cases. Watch Dr. Alan Anderson describe the dose adjustment protocols utilized during the Phase 3 HOPE trial. Go to Video >>

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Dr. Santosh L. Saraf discusses Henry who has an Hb level of 6.5 g/dL and has had 3 VOCs and 2 episodes of acute chest syndrome in the past year. Go to Video >>

Jamie, Age 12, Female With SCD Genotype HbSS

Dr. Alan Anderson discusses Jamie who has an Hb level of 7.5 g/dL and has had 1 VOC in the past year. Go to Video >>

Gabriel, Age 14, Male With SCD Genotype HbSS

Dr. Alan Anderson discusses Gabriel who has an Hb level of 6.0 g/dL, has had 3 VOCs in the past year, has established microalbuminuria, and complains of yellowing eyes. Go to Video >>

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