Pasatru

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: PASATRU can cause fetal harm. Verify females of reproductive potential are not pregnant prior to initiating PASATRU and advise of the potential risk to a fetus and to use effective contraception. Advise the patient to discontinue PASATRU immediately if pregnancy occurs during treatment and to contact their healthcare provider. ( 2.1 , 4 , 5.1 , 8.1 , 8.3 ) Skin and Soft Tissue Infections: Have occurred in patients treated with PASATRU. Advise patients to report signs or symptoms of infection to their healthcare provider. ( 5.2 ) Epistaxis: Spontaneous epistaxis, including serious cases requiring medical intervention, has been reported in patients receiving PASATRU. Advise patients to seek medical attention if they experience epistaxis that is severe, prolonged and does not resolve with standard first-aid measures. ( 5.3 ) 5.1 Embryo-Fetal Toxicity PASATRU is contraindicated during pregnancy. Based on its mechanism of action and findings from animal reproduction studies, PASATRU can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1) ] . Intravenous administration of garetosmab-grts to pregnant cynomolgus monkeys resulted in embryo-fetal toxicity, infant mortality, and post-natal malformations at exposures equivalent to or higher than those in patients at the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively. For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment. Advise females of reproductive potential to use effective contraception during treatment with PASATRU and for 6 months after the last dose. Advise the patient to discontinue PASATRU immediately if pregnancy occurs during treatment and to contact their healthcare provider [see Use in Specific Populations (8.1 , 8.3) ] . 5.2 Skin and Soft Tissue Infections Skin and soft tissue infections requiring treatment and/or hospitalization, including abscesses and cellulitis [see Adverse Reactions (6.1) ] , have occurred in patients receiving PASATRU in clinical trials. Advise patients to report signs or symptoms of skin infection, including erythema, pain, swelling, or fever, and to seek medical attention if these occur. 5.3 Epistaxis Spontaneous epistaxis, including serious cases requiring medical intervention, has been reported in patients receiving PASATRU. In clinical trials in the FOP population, one serious case of spontaneous epistaxis occurred that required hospitalization for nasal packing and application of a clotting agent. Advise patients to seek medical attention if they experience epistaxis that is severe, prolonged (e.g., lasting more than 20 minutes) and does not resolve with standard first-aid measures.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Skin and Soft Tissue Infections [see Warnings and Precautions (5.2) ] Epistaxis [see Warnings and Precautions (5.3) ] The most common adverse reactions (incidence ≥10%) are abscess, acne, increased hair growth, madarosis, oral ulcers, and epistaxis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-877-372-7287 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. The safety of PASATRU was evaluated in a randomized, double-blind, parallel-group, multicenter, placebo-controlled trial that enrolled a total of 63 adults with FOP. Patients received placebo or PASATRU 10 mg/kg or 3 mg/kg every 4 weeks in the 56-week double-blind treatment period then continued their originally assigned treatment in a double-blind extension phase [see Clinical Studies (14) ] . Table 1 summarizes the adverse reactions occurring in ≥10% of patients treated with PASATRU (10 mg/kg or 3 mg/kg) every 4 weeks and more frequently than placebo through Week 56. Table 1: Adverse Reactions Occurring in ≥10% of Adults with FOP Treated with PASATRU 10 mg/kg or 3 mg/kg and more Frequently than Placebo Through Week 56 Adverse Reaction Placebo PASATRU 10 mg/kg every 4 weeks PASATRU 3 mg/kg every 4 weeks N=21 n (%) N=23 n (%) N=19 n (%) Abscess Abscess includes abscess, abscess limb, subcutaneous abscess, and tooth abscess. 2 (10%) 8 (35%) 2 (11%) Acne 2 (10%) 7 (30%) 3 (16%) Increased hair growth Increased hair growth includes hirsutism, hypertrichosis, hair growth abnormal, and hair disorder. 0 6 (26%) 8 (42%) Madarosis 4 (19%) 6 (26%) 3 (16%) Oral ulcers Oral ulcers includes aphthous ulcer, lip ulceration, mouth ulceration, oral mucosal blistering, and stomatitis. 1 (5%) 6 (26%) 1 (5%) Epistaxis 5 (24%) 4 (17%) 10 (53%) Folliculitis 2 (10%) 2 (9%) 3 (16%) Paronychia 0 1 (4%) 2 (11%) Rash 0 1 (4%) 5 (26%) Clinically Significant Adverse Reactions Occurring in <10% of Adults with FOP Cellulitis was reported in 1 (4%) patient receiving PASATRU 10 mg/kg every 4 weeks and in none of the patients receiving PASATRU 3 mg/kg every 4 weeks or placebo.

<table width="75%"><caption>Table 1: Adverse Reactions Occurring in &#x2265;10% of Adults with FOP Treated with PASATRU 10 mg/kg or 3 mg/kg and more Frequently than Placebo Through Week 56</caption><col width="30%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule" rowspan="2" align="center">Adverse Reaction</th><th styleCode="Rrule">Placebo</th><th styleCode="Rrule">PASATRU 10 mg/kg every 4 weeks</th><th styleCode="Rrule">PASATRU 3 mg/kg every 4 weeks</th></tr><tr><th styleCode="Rrule" align="center" valign="bottom">N=21 n (%)</th><th styleCode="Rrule" valign="bottom">N=23 n (%)</th><th styleCode="Rrule" valign="bottom">N=19 n (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abscess<footnote>Abscess includes abscess, abscess limb, subcutaneous abscess, and tooth abscess. </footnote></td><td styleCode="Rrule">2 (10%)</td><td styleCode="Rrule">8 (35%)</td><td styleCode="Rrule">2 (11%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Acne</td><td styleCode="Rrule">2 (10%)</td><td styleCode="Rrule">7 (30%)</td><td styleCode="Rrule">3 (16%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased hair growth<footnote>Increased hair growth includes hirsutism, hypertrichosis, hair growth abnormal, and hair disorder.</footnote></td><td styleCode="Rrule">0</td><td styleCode="Rrule">6 (26%)</td><td styleCode="Rrule">8 (42%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Madarosis</td><td styleCode="Rrule">4 (19%)</td><td styleCode="Rrule">6 (26%)</td><td styleCode="Rrule">3 (16%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oral ulcers<footnote>Oral ulcers includes aphthous ulcer, lip ulceration, mouth ulceration, oral mucosal blistering, and stomatitis.</footnote></td><td styleCode="Rrule">1 (5%)</td><td styleCode="Rrule">6 (26%)</td><td styleCode="Rrule">1 (5%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epistaxis</td><td styleCode="Rrule">5 (24%)</td><td styleCode="Rrule">4 (17%)</td><td styleCode="Rrule">10 (53%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Folliculitis</td><td styleCode="Rrule">2 (10%)</td><td styleCode="Rrule">2 (9%)</td><td styleCode="Rrule">3 (16%)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Paronychia</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1 (4%)</td><td styleCode="Rrule">2 (11%)</td></tr><tr><td styleCode="Lrule Rrule">Rash</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1 (4%)</td><td styleCode="Rrule">5 (26%)</td></tr></tbody></table>