SOHONOS

WARNING: EMBRYO-FETAL TOXICITY and PREMATURE EPIPHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS WARNING: EMBRYO-FETAL TOXICITY and PREMATURE EPIPHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS See full prescribing information for complete boxed warning. SOHONOS is contraindicated in pregnancy ( 5.1 , 8.1 ) Because of the risk of teratogenicity and to minimize fetal exposure, SOHONOS is to be administered only if conditions for pregnancy prevention are met ( 5.1 , 8.1 ) SOHONOS causes premature epiphyseal closure in growing pediatric patients with FOP, close monitoring is recommended ( 5.2 , 8.4 ) Embryo-Fetal Toxicity SOHONOS is contraindicated in pregnancy. SOHONOS may cause fetal harm. Because of the risk of teratogenicity and to minimize fetal exposure, SOHONOS is to be administered only if conditions for pregnancy prevention are met [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Premature Epiphyseal Closure Premature epiphyseal closure occurs in growing pediatric patients treated with SOHONOS, close monitoring is recommended [see Warnings and Precautions (5.2) and Use in Specific Populations (8.4) ] .

5 WARNINGS AND PRECAUTIONS Premature Epiphyseal Closure: Premature epiphyseal closure occurred with SOHONOS. Assess baseline skeletal maturity before SOHONOS therapy and monitor linear growth in growing pediatric patients ( 5.2 ) Mucocutaneous Adverse Reactions: Dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation, and dry eye occurred with SOHONOS. Prevent or treat with skin emollients, sunscreen, artificial tears. Dosage reduction may be required in some patients ( 2.4 , 5.3 ) Metabolic Bone Disorders: Decreased vertebral bone mineral content and bone density may occur. Assess for spinal fracture periodically using radiologic method ( 5.4 ) Psychiatric Disorders: Depression, anxiety, mood alterations and suicidal thoughts and behaviors occurred with SOHONOS. Contact healthcare provider if new or worsening symptoms develop in patients treated with SOHONOS ( 5.5 ) Night Blindness: May occur and make driving at night hazardous ( 5.6 ) 5.1 Embryo-Fetal Toxicity SOHONOS can cause fetal harm and is contraindicated during pregnancy. SOHONOS is a member of the retinoid class of drugs which is associated with birth defects in humans. In animal reproduction studies, palovarotene administered orally to pregnant rats during organogenesis was teratogenic and caused fetal malformations typical of retinoids including cleft palate, misshapen skull bones, and shortening of the long bones at clinically relevant exposures. For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment, periodically during the course of therapy and one month after treatment discontinuation. Advise females of reproductive potential to use an effective method of contraception at least one month prior to treatment, during treatment with SOHONOS and for 1 month after the last dose [see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.3) ]. If a pregnancy occurs during SOHONOS treatment, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Patients should be informed not to donate blood during SOHONOS therapy and for 1 week following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to palovarotene. 5.2 Premature Epiphyseal Closure in Growing Pediatric Patients SOHONOS can cause irreversible premature epiphyseal closure and potential adverse effects on growth. In clinical studies, premature epiphyseal closure occurred with SOHONOS treatment in growing pediatric patients with FOP [see Adverse Reactions (6.1) and Use in Specific Populations (8.4) ] . Monitoring of linear growth is recommended in growing pediatric patients [see Use in Specific Populations (8.4) ] . Prior to starting treatment with SOHONOS, all growing pediatric patients should undergo baseline assessment of skeletal maturity via hand/wrist and knee x-rays, standard growth curves and pubertal staging. Continued monitoring is recommended every 6 to 12 months until patients reach skeletal maturity or final adult height. If a patient exhibits signs of premature epiphyseal closure or adverse effects on growth based on clinical or radiologic evaluations, further evaluation may be required, including an assessment of the benefits and risks of continued treatment, or temporary or permanent discontinuation of SOHONOS until the patient achieves epiphyseal closure and skeletal maturity. 5.3 Mucocutaneous Adverse Reactions Mucocutaneous adverse reactions including dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation [skin peeling], and dry eye occurred in most (98%) patients treated with SOHONOS. SOHONOS may contribute to an increased risk of skin and soft tissue infections, particularly paronychia and decubitus ulcer, due to a decreased skin barrier from adverse reactions such as dry and peeling skin [see Adverse Reactions (6.1) ] . Some of these mucocutaneous adverse reactions led to dose reductions which occurred more frequently during flare-up dosing suggesting a dose response relationship. Prophylactic measures to minimize risk and/or treat the mucocutaneous adverse reactions are recommended (e.g., skin emollients, sunscreen, lip moisturizers, or artificial tears). Some patients may require dose reduction or drug discontinuation [see Dosage and Administration (2.4) ] . Photosensitivity Photosensitivity reactions, such as exaggerated sunburn reactions (e.g., burning, erythema, blistering) involving areas exposed to the sun have been associated with the use of retinoids and may occur with SOHONOS. Precautionary measures for phototoxicity are recommended. Excessive exposure to sun or artificial ultraviolet light should be avoided, and protection from sunlight should be used when exposure cannot be avoided (use of sunscreens, protective clothing, and use of sunglasses). 5.4 Metabolic Bone Disorders Bone mineral density and fracture Retinoids are associated with bone toxicity, including reductions in bone mass and spontaneous reports of osteoporosis and fracture. In FOP clinical trials, SOHONOS resulted in decreased vertebral bone mineral content and bone density, and an increased risk of radiologically observed vertebral (T4 to L4) fractures in treated adult and pediatric patients compared to untreated patients. Periodic radiological assessment of the spine is recommended. [see Adverse Reactions (6.1) ] . Hyperostosis Retinoids have been associated with hyperostotic changes (bone spurs) and calcification of tendons or ligaments and may occur with SOHONOS. These effects generally occur with long-term use, especially at high doses. 5.5 Psychiatric Disorders New or worsening psychiatric events were reported with SOHONOS use. These include depression, anxiety, mood alterations and suicidal thoughts and behaviors. There is a relatively high background prevalence of psychiatric disorders in untreated patients with FOP. Monitor for development of new or worsening psychiatric symptoms during treatment with SOHONOS [see Adverse Reactions (6.1) ]. Individuals with a history of psychiatric illness may be more susceptible to these adverse effects. Patients and/or caregivers should contact their healthcare provider if new or worsening psychiatric symptoms develop during treatment with SOHONOS. 5.6 Night Blindness Night blindness has been associated with systemic retinoids, including SOHONOS. This may be dose-dependent, making driving a vehicle at night potentially hazardous during treatment. Night blindness is generally reversible after cessation of treatment but can also persist in some cases. Advise patients to be cautious when driving or operating any vehicle at night and to seek medical attention in the event of vision impairment.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Premature Epiphyseal Closure in Growing Pediatric Patients [see Warnings and Precautions (5.2) ] Mucocutaneous Adverse Reactions [see Warnings and Precautions (5.3) ] Metabolic Bone Disorders [see Warnings and Precautions (5.4) ] Psychiatric Disorders [see Warnings and Precautions (5.5) ] Night Blindness [see Warnings and Precautions (5.6) ] Most common adverse reactions (incidence ≥10%) are dry skin, lip dry, arthralgia, pruritus, pain in extremity, rash, alopecia, erythema, headache, back pain, skin exfoliation, nausea, musculoskeletal pain, myalgia, dry eye, hypersensitivity, peripheral edema, and fatigue ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact IPSEN Biopharmaceuticals, Inc at 1-855-463-5127 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 SOHONOS was evaluated in clinical studies that enrolled a total of 164 subjects with FOP, including 139 subjects in the indicated population of ages 8 years and above for females and 10 years and above for males (8/10 years and older). Most of these subjects received open label treatment with the chronic daily/flare-up regimen, consisting of 5 mg daily dosage of oral SOHONOS with a 20/10 mg dosage as needed for 12 weeks at the time of flare-up (4 weeks of 20 mg once daily followed by 10 mg once daily for 8 weeks), with all doses reduced by weight in subjects who were less than 90% skeletally mature. The mean duration of exposure was 79 weeks for chronic dosing (N=131 subjects) and 35 weeks for flare-up dosing (N=105 subjects). The mean age of these subjects was 19 years (range 8 to 61 years); 51% were male. Serious adverse reactions occurred in 21 (15%) SOHONOS treated subjects in the 8/10 years or older population with the most common serious adverse reaction being premature epiphyseal closure. Adverse reactions leading to permanent discontinuation occurred in 11 (8%) SOHONOS treated subjects with dry skin being the most common in 2 (1%) subjects. Mucocutaneous adverse reactions leading to dose reductions were more common during SOHONOS 20/10 mg flare-up treatment (37%) than during chronic treatment (4%). Table 5 below presents adverse reactions which occurred in at least 10% of FOP subjects 8/10 years and older during treatment with chronic or flare-up dosing. Table 5. Summary of Adverse Reactions Reported at greater than 10% Frequency in FOP Subjects 8/10 years and older in Clinical Trials Adverse Reaction Chronic 5 mg N=131 n (%) Flare-up dosing 20/10 mg N=105 n (%) Doses were reduced according to body weight in subjects who were less than 90% skeletally mature Dry skin 80 (61) 60 (57) Lip dry includes lip dry, chapped lips, cheilitis 62 (47) 40 (38) Arthralgia 47 (36) 32 (31) Pruritus includes pruritus, pruritus generalized, and rash pruritic 45 (34) 50 (48) Pain in extremity 38 (29) 29 (28) Rash includes rash, rash generalized, rash maculo-papular 36 (28) 31 (30) Alopecia 32 (24) 31 (30) Erythema includes erythema, generalized erythema, flushing, rash erythematous 25 (19) 34 (32) Headache includes headache and migraine 25 (19) 20 (19) Back pain includes back pain, flank pain, sciatica 22 (17) 12 (11) Skin exfoliation [skin peeling] 20 (15) 30 (29) Nausea 20 (15) 14 (13) Musculoskeletal pain 18 (14) 14 (13) Myalgia includes myalgia, musculoskeletal discomfort 15 (12) 9 (9) Dry eye 13 (10) 23 (22) Hypersensitivity includes drug eruption, hypersensitivity, pruritus allergic, drug hypersensitivity 13 (10) 21 (20) Peripheral edema includes peripheral swelling, edema peripheral 12 (9) 20 (19) Fatigue includes fatigue, lethargy, asthenia, malaise 7 (5) 12 (11) Premature epiphyseal closure Subjects under 18 years with open epiphyses were assessed for growth during the clinical studies. Premature epiphyseal closure was identified by scheduled imaging in 27% of subjects who were less than 18 years of age at enrollment and was more common in younger compared with older subjects (31% in subjects between 8/10 years to 14 years and no subjects 14 years or older). Many of the affected subjects exhibited slowing of growth in height. [see Use in Specific Populations (8.4) and Clinical Studies (14) ] . Mucocutaneous Adverse Reactions Mucocutaneous adverse reactions observed in over 10% of subjects (N=134) were dry skin (78%), lip dry (66%), pruritus (55%), alopecia (44%), rash (42%), erythema (37%), skin exfoliation [skin peeling] (31%), and skin irritation (11%). In addition, dry eye occurred in 25% of subjects. Bone Mineral Density and Fractures Loss of bone mineral density and radiological vertebral fractures (PT: Spinal fracture) were identified as a risk associated with SOHONOS based on novel analyses performed on whole body CT data in FOP subjects in the Phase 3 study [see Warnings and Precautions (5.4) ] . Hepatotoxicity Retinoids have been associated with dose dependent elevations of liver enzymes and isolated cases of severe hepatitis. In SOHONOS studies of FOP, elevated ALT was observed in 7.0% of subjects during 20/10 mg flare-up dosing and 1% of subjects during 5 mg chronic dosing. There were no subjects who required dose reduction or treatment discontinuation due to liver enzyme elevations. Hypertriglyceridemia Systemic retinoids may cause marked elevations of serum triglycerides. In FOP studies, hypertriglyceridemia was reported in 2 subjects during chronic SOHONOS treatment (2%) and in 4 subjects during flare-up dosing (4%). Pancreatitis Pancreatitis has been reported with other systemic retinoids, both with and without elevated triglycerides, including fatal cases. In palovarotene studies, one healthy subject developed acute pancreatitis, possibly related to concomitant use of ketoconazole in a drug-drug interaction study. There were no reports of pancreatitis in the FOP clinical studies. Night Blindness One reaction of night blindness was observed in SOHONOS treated subjects. Intracranial Hypertension (Pseudotumor Cerebri) Systemic retinoid use has been associated with cases of benign intracranial hypertension (also called pseudotumor cerebri), some of which involved the concomitant use of tetracyclines. There were no reports of benign intracranial hypertension in the FOP clinical studies [see Drug Interactions (7.3) ].

<table width="95%"><caption>Table 5. Summary of Adverse Reactions Reported at greater than 10% Frequency in FOP Subjects 8/10 years and older in Clinical Trials</caption><col width="40%" align="left" valign="bottom"/><col width="30%" align="center" valign="bottom"/><col width="30%" align="center" valign="bottom"/><thead><tr><th styleCode="Lrule Rrule">Adverse Reaction</th><th styleCode="Rrule">Chronic 5 mg N=131 n (%)</th><th styleCode="Rrule">Flare-up dosing 20/10 mg N=105 n (%)</th></tr></thead><tfoot><tr><td colspan="3" align="left">Doses were reduced according to body weight in subjects who were less than 90% skeletally mature</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry skin</td><td styleCode="Rrule">80 (61)</td><td styleCode="Rrule">60 (57)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Lip dry <footnote>includes lip dry, chapped lips, cheilitis</footnote></td><td styleCode="Rrule">62 (47)</td><td styleCode="Rrule">40 (38)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">47 (36)</td><td styleCode="Rrule">32 (31)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pruritus <footnote>includes pruritus, pruritus generalized, and rash pruritic</footnote></td><td styleCode="Rrule">45 (34)</td><td styleCode="Rrule">50 (48)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain in extremity</td><td styleCode="Rrule">38 (29)</td><td styleCode="Rrule">29 (28)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Rash <footnote>includes rash, rash generalized, rash maculo-papular</footnote></td><td styleCode="Rrule">36 (28)</td><td styleCode="Rrule">31 (30)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Alopecia</td><td styleCode="Rrule">32 (24)</td><td styleCode="Rrule">31 (30)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Erythema <footnote>includes erythema, generalized erythema, flushing, rash erythematous</footnote></td><td styleCode="Rrule">25 (19)</td><td styleCode="Rrule">34 (32)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache <footnote>includes headache and migraine</footnote></td><td styleCode="Rrule">25 (19)</td><td styleCode="Rrule">20 (19)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain <footnote>includes back pain, flank pain, sciatica</footnote></td><td styleCode="Rrule">22 (17)</td><td styleCode="Rrule">12 (11)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Skin exfoliation [skin peeling]</td><td styleCode="Rrule">20 (15)</td><td styleCode="Rrule">30 (29)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">20 (15)</td><td styleCode="Rrule">14 (13)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain</td><td styleCode="Rrule">18 (14)</td><td styleCode="Rrule">14 (13)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Myalgia <footnote>includes myalgia, musculoskeletal discomfort</footnote></td><td styleCode="Rrule">15 (12)</td><td styleCode="Rrule">9 (9)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dry eye</td><td styleCode="Rrule">13 (10)</td><td styleCode="Rrule">23 (22)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypersensitivity <footnote>includes drug eruption, hypersensitivity, pruritus allergic, drug hypersensitivity</footnote></td><td styleCode="Rrule">13 (10)</td><td styleCode="Rrule">21 (20)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Peripheral edema <footnote>includes peripheral swelling, edema peripheral</footnote></td><td styleCode="Rrule">12 (9)</td><td styleCode="Rrule">20 (19)</td></tr><tr><td styleCode="Lrule Rrule">Fatigue <footnote>includes fatigue, lethargy, asthenia, malaise</footnote></td><td styleCode="Rrule">7 (5)</td><td styleCode="Rrule">12 (11)</td></tr></tbody></table>