VOXELOTOR: 21,940 Adverse Event Reports & Safety Profile

OXBRYTA contains voxelotor, a hemoglobin S polymerization inhibitor. The chemical name of voxelotor is 2-hydroxy-6-((2-(1-isopropyl-1 H -pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde with a molecular formula of C 19 H 19 N 3 O 3 and a molecular weight of 337.4. The chemical structure of voxelotor is: Voxelotor is a white-to-yellow-to-beige compound in crystalline Form II of its free base. It is non-hygroscopic and highly soluble in common organic solvents such as acetone and toluene and insoluble in water. OXBRYTA film-coated tablets for oral use contain either 300 mg or 500 mg of voxelotor. Both strengths of OXBRYTA film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. In addition, the 500 mg tablet film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.

The

300 mg tablet film coating contains: black and red iron oxide, polyethylene glycol 3350, polyvinyl alcohol, talc, and titanium dioxide. Each OXBRYTA tablet for oral suspension contains 300 mg of voxelotor with the following inactive ingredients: artificial grape flavor, colloidal silicon dioxide, croscarmellose sodium, iron oxide pigment, magnesium stearate, microcrystalline cellulose, and sucralose.

Chemical

Structure

AND USAGE OXBRYTA is indicated for the treatment of sickle cell disease (SCD) in adults and pediatric patients 4 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin (Hb) [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). OXBRYTA is a hemoglobin S polymerization inhibitor indicated for the treatment of sickle cell disease in adults and pediatric patients 4 years of age and older. This indication is approved under accelerated approval based on increase in hemoglobin (Hb). Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1 )

AND ADMINISTRATION OXBRYTA can be taken with or without food. ( 2.7 ) Recommended dosage:

• Adults and pediatric patients 12 years and older: 1,500 mg orally once daily. ( 2.1 )
• Pediatric patients 4 to less than 12 years: Dosing with OXBRYTA is based on body weight.

See Table

1 for complete dosing recommendations. ( 2.2 ) Recommended dosage for severe hepatic impairment (Child Pugh C) :

• Adults and pediatric patients 12 years and older: 1,000 mg orally once daily. ( 2.3 )
• Pediatric patients 4 to less than 12 years: Reduce the dose of OXBRYTA based on body weight.

See Table

2 for complete dosing recommendations. ( 2.4 )

2.1 Recommended Dosage for Adults and Pediatric Patients 12 Years and Older The recommended dosage of OXBRYTA is 1,500 mg orally once daily.

2.2 Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years For pediatric patients 4 years to less than 12 years, select the appropriate product (OXBRYTA tablets or OXBRYTA tablets for oral suspension) based on patient's ability to swallow tablets and patient's weight. The recommended dosage of OXBRYTA for pediatric patients 4 years to less than 12 years is shown in Table 1.

Table

1: Recommended OXBRYTA Dosage in Pediatric Patients 4 Years to Less Than 12 Years Body Weight Recommended Dose (once daily) 40 kg or greater 1,500 mg 20 kg to less than 40 kg 900 mg 10 kg to less than 20 kg 600 mg

2.3 Recommended Dosage for Adults and Pediatric Patients 12 Years and Older with Hepatic Impairment The recommended dosage of OXBRYTA in adults and pediatric patients 12 years and older with severe hepatic impairment (Child Pugh C) is 1,000 mg orally once daily. No dosage adjustment of OXBRYTA is required for patients with mild or moderate hepatic impairment [ see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

2.4 Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years with Hepatic Impairment The recommended dosage of OXBRYTA in pediatric patients 4 years to less than 12 years with severe hepatic impairment (Child Pugh C) is described in Table 2. No dosage adjustment of OXBRYTA is required for patients with mild or moderate hepatic impairment <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]</span> .

Table

2: Recommended OXBRYTA Dosage in Pediatric Patients 4 Years to Less Than 12 Years with Severe Hepatic Impairment (Child Pugh C)

Body Weight Recommended

Dose (once daily) 40 kg or greater 1,000 mg (two 500 mg tablets) or 900 mg (three 300 mg tablets for oral suspension or three 300 mg tablets) 20 kg to less than 40 kg 600 mg 10 kg to less than 20 kg 300 mg

2.5 Recommended Dosage of OXBRYTA for Adults and Pediatric Patients 12 Years and Older When Used with Concomitant Strong or Moderate CYP3A4 Inducers CYP3A4 Inducers Avoid concomitant use of strong or moderate CYP3A4 inducers with OXBRYTA <span class="opacity-50 text-xs">[see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]</span> . If concomitant use of strong CYP3A4 inducers is unavoidable, the recommended dosage of OXBRYTA is 2,500 mg orally once daily. If concomitant use of moderate CYP3A4 inducers is unavoidable, the recommended dosage of OXBRYTA is 2,000 mg orally once daily.

2.6 Recommended Dosage of OXBRYTA for Pediatric Patients 4 Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers CYP3A4 Inducers Avoid concomitant use of strong or moderate CYP3A4 inducers with OXBRYTA <span class="opacity-50 text-xs">[see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]</span> . If concomitant use of strong or moderate CYP3A4 inducers is unavoidable, see Table 3 for dosage.

Table

3: OXBRYTA Recommended Dosage for Pediatric Patients 4 Years to Less Than 12 Years When Used with Concomitant Strong or Moderate CYP3A4 Inducers Body Weight Recommended Dose (once daily)

Concomitant

Use of Strong CYP3A4 Inducers Concomitant Use of Moderate CYP3A4 Inducers 40 kg or greater 2,500 mg (five 500 mg tablets) or 2,400 mg (eight 300 mg tablets for oral suspension or eight 300 mg tablets) 2,000 mg (four 500 mg tablets) or 2,100 mg (seven 300 mg tablets for oral suspension or seven 300 mg tablets) 20 kg to less than 40 kg 1,500 mg 1,200 mg 10 kg to less than 20 kg 900 mg 900 mg

2.7 Important Administration Instructions Administer OXBRYTA orally, once daily with or without food. If a dose is missed, or not administered entirely, resume dosing the following day. OXBRYTA may be given with or without hydroxyurea. OXBRYTA 300 mg and 500 mg Tablets Patients should swallow OXBRYTA tablets whole. Do not cut, crush, or chew the tablets. OXBRYTA 300 mg Tablets for Oral Suspension Patients should disperse tablets for oral suspension immediately before administration in a cup and in room temperature clear liquid (such as drinking water, clear soda, apple juice, clear electrolyte drinks, clear flavored drinks, or clear sports drinks) before swallowing. Do not swallow whole, cut, crush, or chew the tablets for oral suspension.

Recommended Daily Dose

Number of Tablets for Oral Suspension Minimum Recommended Volume of Clear Drink 300 mg 1 5 mL (1 teaspoon) 600 mg 2 10 mL (2 teaspoons) 900 mg 3 15 mL (3 teaspoons) 1,200 mg 4 20 mL (4 teaspoons) 1,500 mg 5 25 mL (5 teaspoons) 2,100 mg 7 35 mL (7 teaspoons) 2,400 mg 8 40 mL (8 teaspoons)

• After the tablets start to disintegrate, swirl the contents of the cup until the tablets are dispersed, wait 1 to 5 minutes, swirl the contents of the cup again, and then orally administer the contents of the cup. The tablet(s) will not completely dissolve; there will still be small tablet clumps in the mixture.
• Resuspend any residue left in the cup in more clear drink and administer. Repeat until no tablet residue is left in the cup. Tablets for oral suspension may be substituted for tablets in adults and pediatric patients 12 years and older with difficulty swallowing the tablets. Use the number of tablets for oral suspension needed to achieve the recommended dose.

OXBRYTA is contraindicated in patients with a history of serious drug hypersensitivity reaction to voxelotor or excipients. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ]. Prior drug hypersensitivity to voxelotor or excipients. ( 4 )

REACTIONS The following clinically significant adverse reaction is discussed in other sections of the labeling:

• Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.1) ]. Most common adverse reactions (incidence ≥10% with a difference of >3% compared to placebo) are headache, diarrhea, abdominal pain, nausea, rash, and pyrexia. ( 6.1 ) Most common adverse reactions (incidence >10%) reported in pediatric patients 4 to <12 years are pyrexia, vomiting, rash, abdominal pain, diarrhea, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults and Pediatric Patients 12 Years and Older The safety of OXBRYTA was evaluated in the HOPE trial based on data from 88 patients with SCD who received OXBRYTA 1,500 mg and 91 patients who received placebo orally once daily <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . Seventy-four patients received OXBRYTA 1,500 mg once daily for ≥24 weeks, 65 patients for ≥48 weeks, and 63 patients completed the 72-week treatment period. In patients who received OXBRYTA 1,500 mg once daily the median age was 24 years (range:12 to 59 years); 65% female; 66% Black or African American and 23% Arab/Middle Eastern; and 65% receiving hydroxyurea at baseline. Serious adverse reactions occurred in 3% (3/88) of patients receiving OXBRYTA 1,500 mg, which included headache, drug hypersensitivity, and pulmonary embolism occurring in 1 patient each. Permanent discontinuation due to an adverse reaction (Grades 1-4) occurred in 5% (4/88) of patients who received OXBRYTA 1,500 mg. Dosage modifications (dose reduction or dosing interruption) due to adverse reactions occurred in 14% (12/88) of patients who received OXBRYTA 1,500 mg. The adverse reactions requiring dosage modification included rash (4.5%), diarrhea (3.4%), headache (2.3%), nausea (2.3%), abdominal pain (1.1%), and drug hypersensitivity (1.1%). The safety profile observed in pediatric patients 12 to &lt;17 years treated with OXBRYTA in the HOPE trial was similar to that seen in adult patients. The most common adverse reactions occurring in ≥10% of patients treated with OXBRYTA 1,500 mg with a difference of &gt;3% compared to placebo are summarized in Table 4.

Table

4: Adverse Reactions (≥10%) in Patients Receiving OXBRYTA with a Difference Between Arms of >3% Compared to Placebo in HOPE Adverse Reaction Adverse reactions were Grades 1 or 2 except for Grade 3 headache (2), diarrhea (1), nausea (1), rash (1), and rash generalized (3) OXBRYTA 1,500 mg (N=88) Placebo (N=91)

Headache

32% 25% Diarrhea 23% 11% Abdominal Pain Abdominal pain (grouped PTs) includes the following PTs: abdominal pain, lower abdominal pain, and upper abdominal pain 23% 16% Nausea 19% 10% Rash Rash (grouped PTs) includes the following PTs: rash, urticaria, generalized rash, macular rash, maculo-papular rash, pruritic rash, and papular rash 15% 11% Pyrexia 15% 8% Clinically relevant adverse reactions occurring in <10% of patients included:

• Drug hypersensitivity Pediatric Patients 4 to <12 Years The safety of OXBRYTA in pediatric patients 4 to <12 years with SCD was evaluated in an open-label, Phase 2 study [see Clinical Studies (14.2) ] . In this study, 45 patients 4 to <12 years of age received doses of OXBRYTA tablets for oral suspension based on weight at baseline. Thirty-five patients received OXBRYTA for 24 weeks and 26 patients for 48 weeks. The most common adverse reactions (>10%) reported in pediatric patients 4 to <12 years were pyrexia (36%), vomiting (33%), rash (20%), abdominal pain (18%), diarrhea (18%), and headache (18%). The overall safety profile of OXBRYTA in pediatric patients 4 to <12 years was similar to that seen in adults and pediatric patients 12 years and older.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of OXBRYTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

• Drug reaction with eosinophilia and systemic symptoms (DRESS), Pruritis, Angioedema (including swelling of eyelid, face edema, lip swelling, and periorbital swelling).

AND PRECAUTIONS

• Hypersensitivity Reactions: Observe for signs and symptoms and manage promptly. ( 5.1 )
• Laboratory Test Interference: Perform quantification of hemoglobin species when patient is not receiving OXBRYTA. ( 5.2 )

5.1 Hypersensitivity Reactions Serious hypersensitivity reactions after administration of OXBRYTA have occurred in &lt;1% of patients treated. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in postmarketing experience with OXBRYTA <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Patients who develop a combination of skin rash, fever, peripheral eosinophilia, and internal systemic organ involvement (e.g., hepatic, renal, pulmonary) while receiving OXBRYTA should undergo medical evaluation. Advise patients of the signs and symptoms of severe hypersensitivity reactions, including DRESS. If hypersensitivity reactions occur, discontinue OXBRYTA and administer appropriate medical therapy. Do not reinitiate OXBRYTA in patients who experience these symptoms with previous use.

5.2 Laboratory Test Interference OXBRYTA administration may interfere with measurement of Hb subtypes (HbA, HbS, and HbF) by high-performance liquid chromatography (HPLC) <span class="opacity-50 text-xs">[see Drug Interactions (7.3) ]</span>. 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.

INTERACTIONS

• Sensitive CYP3A4 Substrates: Avoid coadministration of sensitive CYP3A4 substrates with a narrow therapeutic index. ( 7.2 )
• Strong or moderate CYP3A4 Inducers: Avoid coadministration with strong or moderate CYP3A4 inducers. If unavoidable, increase the dose of OXBRYTA. ( 2.5 , 2.6 , 7.1 )

7.1 Effect of Other Drugs on Voxelotor Strong or Moderate CYP3A4 Inducers Coadministration of strong or moderate CYP3A4 inducers may decrease voxelotor plasma and whole blood concentrations and may lead to reduced efficacy. Avoid coadministration of OXBRYTA with strong or moderate CYP3A4 inducers. Increase the OXBRYTA dosage when coadministration with a strong or moderate CYP3A4 inducer is unavoidable <span class="opacity-50 text-xs">[see Dosage and Administration (2.5 , 2.6) and Clinical Pharmacology (12.3) ]</span>.

7.2 Effect of Voxelotor on Other Drugs Voxelotor increased the systemic exposure of midazolam (a sensitive CYP3A4 substrate) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. Avoid coadministration of OXBRYTA with sensitive CYP3A4 substrates with a narrow therapeutic index. If concomitant use is unavoidable, consider dose reduction of the sensitive CYP3A4 substrate(s).

7.3 Laboratory Test Interference OXBRYTA administration may interfere with measurement of Hb subtypes (HbA, HbS, and HbF) by HPLC <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span>. 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.