OXBRYTA

5 WARNINGS 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 <1% of patients treated. Clinical manifestations may include generalized rash, urticaria, mild shortness of breath, mild facial swelling, and eosinophilia [see Adverse Reactions (6.1) ] . Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in postmarketing experience with OXBRYTA [see Adverse Reactions (6.2) ] . 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) [see Drug Interactions (7.3) ]. 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.

6 ADVERSE 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 [see Clinical Studies (14.1) ] . 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 <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 >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).

<table ID="_Reftable4" styleCode="Noautorules" width="75%"><caption>Table 4: Adverse Reactions (&#x2265;10%) in Patients Receiving OXBRYTA with a Difference Between Arms of &gt;3% Compared to Placebo in HOPE</caption><col width="22%"/><col width="31%"/><col width="34%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Adverse Reaction</content><footnote ID="_RefID0EI3AE">Adverse reactions were Grades 1 or 2 except for Grade 3 headache (2), diarrhea (1), nausea (1), rash (1), and rash generalized (3)</footnote></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">OXBRYTA</content> <content styleCode="bold">1,500 mg</content> <content styleCode="bold">(N=88)</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N=91)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>32%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>25%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>Abdominal Pain<footnote ID="_RefID0EL4AE">Abdominal pain (grouped PTs) includes the following PTs: abdominal pain, lower abdominal pain, and upper abdominal pain</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>16%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>19%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph>Rash<footnote ID="_RefID0E44AE">Rash (grouped PTs) includes the following PTs: rash, urticaria, generalized rash, macular rash, maculo-papular rash, pruritic rash, and papular rash</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph>8%</paragraph></td></tr></tbody></table>