SOHONOS

1 INDICATIONS AND USAGE SOHONOS is indicated for the reduction in volume of new heterotopic ossification in adults and pediatric patients aged 8 years and older for females and 10 years and older for males with fibrodysplasia ossificans progressiva (FOP). SOHONOS is a retinoid indicated for reduction in the volume of new heterotopic ossification in adults and children aged 8 years and older for females and 10 years and older for males with fibrodysplasia ossificans progressiva (FOP) ( 1 ).

2 DOSAGE AND ADMINISTRATION Obtain a negative pregnancy test in females of reproductive potential before initiation of SOHONOS ( 2.1 ) Recommended dosage includes a chronic daily dose, which can be increased for flare-up symptoms ( 2.2 ) For adults and pediatric patients 14 years and older: Recommended dosage is 5 mg once daily, with an increase in dose at the time of a flare-up to 20 mg once daily for 4 weeks, followed by 10 mg once daily for 8 weeks for a total of 12 weeks (20/10 mg flare-up treatment) ( 2.2 ) For pediatric patients under 14 years: Weight-adjusted for daily and flare-up dosing. Recommended daily dosage range from 2.5 to 5 mg. Refer to Table 1 in Full Prescribing Information for complete pediatric dosing ( 2.2 ) Take SOHONOS with food preferably at same time each day ( 2.3 ). Reduce the dose in the event of adverse reactions as appropriate ( 2.4 ) See Full Prescribing Information for complete dosing instructions ( 2 ) 2.1 Pregnancy Testing Prior to Treatment with SOHONOS For females of reproductive potential, obtain a negative pregnancy test within one week prior to initiating and periodically during SOHONOS therapy . If pregnancy occurs, stop SOHONOS treatment immediately and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1 , 8.3) ]. 2.2 Recommended Dosage and Duration Dosage Overview Take SOHONOS with food preferably at the same time each day [see Dosage and Administration (2.3) ] . The recommended dosing for SOHONOS includes a chronic daily dosage (daily dose) which can then be modified/increased in the event of FOP flare-up symptoms (flare-up dose). Initiate flare-up treatment at the onset of the first symptom indicative of a FOP flare-up or substantial high-risk traumatic event likely to lead to a flare-up (e.g., surgery, intramuscular immunization, mandibular blocks for dental procedures, muscle fatigue, blunt muscle trauma from bumps, bruises, falls, or influenza-like viral illnesses). Symptoms of a FOP flare-up typically include but are not limited to localized pain, soft tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness. Recommended Dosage for Adults and Pediatric Patients 14 Years and Older Daily Dose: The recommended SOHONOS daily dosage for adults and pediatric patients 14 years and older is 5 mg daily. Stop daily dosing when flare-up dosing begins. Flare-up Dose: The recommended SOHONOS flare-up dosage for adults and pediatric patients 14 years and older is 20 mg daily for 4 weeks, followed by 10 mg daily for 8 weeks (for a total of 12 weeks of flare-up treatment), even if symptoms resolve earlier, then return to daily dosing of 5 mg. If during the course of flare-up treatment, the patient experiences marked worsening of the original flare-up site or another flare-up at a new location, restart the 12-week flare-up dosing at 20 mg daily. For flare-up symptoms that have not resolved at the end of the 12-week period, the 10 mg daily dosage may be extended in 4-week intervals and continued until the flare-up symptoms resolve. If new flare-up symptoms occur after the 5 mg daily dosing is resumed, flare-up dosing may be restarted. Recommended Dosage for Pediatric Patients Aged 8 to 13 Years for Females and Aged 10 to 13 Years for Males Daily Dose: The recommended SOHONOS daily dosage for patients under 14 years of age is weight-based ranging from 2.5 mg to 5 mg daily (see Table 1 ). Stop daily dosing when flare-up dosing begins. Flare-up Dose: The recommended flare-up SOHONOS dosage for patients under 14 years of age is weight-based (see Table 1 ). Administer the initial flare-up dosage once daily for 4 weeks, then administer the lower flare-up dosage once daily for 8 weeks (for a total of 12 weeks of flare-up treatment), even if symptoms resolve earlier, then return to daily dosing (see Table 1 ). If during the course of flare-up treatment, the patient …

3 DOSAGE FORMS AND STRENGTHS SOHONOS is available in 4 strengths as an opaque white elongated size "0" hard-gelatin capsule, containing white to off-white powder. Table 4 shows capsules' strengths and imprints. Table 4. SOHONOS Capsules' Strengths and Imprints Strength (mg) Imprint 1 PVO 1 1.5 PVO 1.5 5 PVO 5 10 PVO 10 Capsules: 1, 1.5, 5, 10 mg ( 3 )

4 CONTRAINDICATIONS SOHONOS is contraindicated in the following patients: During Pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ] . A history of allergy or hypersensitivity to retinoids, or to any component of SOHONOS. Anaphylaxis and other allergic reactions have occurred with other retinoids. [see Description (11) ]. Pregnancy ( 4 , 5.1 , 8.1 ) Hypersensitivity to retinoids or any component of SOHONOS ( 4 , 11 )

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 ( …

7 DRUG INTERACTIONS CYP3A4 Inhibitors: May increase SOHONOS exposure. Avoid concomitant use of strong/moderate CYP3A4 inhibitors. If concomitant use of moderate CYP3A4 inhibitors is unavoidable, reduce the dose of SOHONOS by half ( 2.5 , 7.1 ) CYP3A4 Inducers: May decrease SOHONOS exposure. Avoid concomitant use of strong/moderate CYP3A4 inducers ( 7.1 ) Vitamin A: May cause additive effects ( 7.2 ) Tetracyclines: Avoid concomitant use with SOHONOS ( 7.3 ) Systemic Corticosteroids: No clinically significant drug interaction is expected with concomitant use of SOHONOS ( 7.4 ) 7.1 Effect of Other Drugs on SOHONOS Clinically significant drug interactions affecting the exposure of SOHONOS are listed in Table 6. Table 6. Drugs that affect exposure of SOHONOS. Strong CYP3A Inhibitors Clinical Impact Co-administration of SOHONOS with strong CYP3A4 inhibitors increased the exposures of palovarotene [see Clinical Pharmacology (12.3) ] , which may increase the risk of SOHONOS adverse reactions. Prevention or Management Avoid concomitant use of a strong CYP3A4 inhibitor during SOHONOS treatment [see Dosage and Administration (2.5) ] . Moderate CYP3A Inhibitors Clinical Impact Co-administration of SOHONOS with moderate CYP3A4 inhibitors may increase the exposure of palovarotene [see Clinical Pharmacology (12.3) ] , which may increase the risk of SOHONOS adverse reactions. Prevention or Management Avoid concomitant use of a moderate CYP3A4 inhibitor with SOHONOS, if possible. If co-administration will occur, reduce the SOHONOS dose by half when co-administered with moderate CYP3A inhibitors [see Dosage and Administration (2.5) ] . Strong CYP3A Inducers Clinical Impact Co-administration of SOHONOS with strong CYP3A4 inducers decreased the exposure of palovarotene [see Clinical Pharmacology (12.3) ] , which may reduce the effectiveness of SOHONOS. Prevention or Management Avoid concomitant use of strong CYP3A4 inducers with SOHONOS. [see Dosage and Administration (2.5) ] . Moderate CYP3A Inducers Clinical Impact Co-administration of moderate CYP3A4 inducers with palovarotene may decrease palovarotene exposure [see Clinical Pharmacology (12.3) ], which may reduce the effectiveness of SOHONOS. Prevention or Management Avoid concomitant use of moderate CYP3A4 inducers with SOHONOS. 7.2 Vitamin A Palovarotene belongs to the same pharmacological class as vitamin A. Therefore, the use of both vitamin A and SOHONOS at the same time may lead to additive effects. Concomitant administration of vitamin A in doses higher than the recommended daily allowance (RDA) and/or other oral retinoids with SOHONOS must be avoided because of the risk of hypervitaminosis A. 7.3 Tetracyclines 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. Avoid coadministration of SOHONOS with tetracycline derivatives [see Adverse Reactions (6.1) ] . 7.4 Systemic Corticosteroids No clinically significant drug-drug interaction is expected when SOHONOS is co-administered with prednisone [see Clinical Pharmacology (12.3) ] .

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm ( 2.1 , 4 , 8.1 ) Growing pediatric patients are recommended to undergo baseline assessment of growth and skeletal maturity before starting treatment and continued clinical and radiographic monitoring every 6 to 12 months until patients reach skeletal maturity or final adult height ( 5.2 , 8.4 ) 8.1 Pregnancy Risk Summary SOHONOS is contraindicated during pregnancy. Based on the findings in animal studies and class effects of retinoids, SOHONOS can cause fetal harm when administered during pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ] . In animal reproduction studies, oral administration of palovarotene to pregnant rats during the period of organogenesis resulted in multiple fetal malformations typical of retinoids (e.g., cleft palate, malformed skull bone, shortening of the long bones) at doses ≥0.25 mg/kg/day (less than the clinical exposure) (see Data ) . There are no available human data on SOHONOS use in pregnant women. If pregnancy occurs during treatment with SOHONOS, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for further evaluation and counseling. Data Animal Data Palovarotene oral administration to pregnant rats during the period of organogenesis (gestation day 6 to 17) at doses of 0.01, 0.25 and 1.25 mg/kg/day resulted in fetal malformations consistent with retinoid-mediated embryopathy. Palovarotene exposure resulted in fetal external, visceral and skeletal malformations typical of retinoids, including defects in the mouth (cleft palate, protruding tongue), eye (anophthalmia, microphthalmia), skull (dilated cerebral ventricle, misshapen brain), skeleton (shortening of the long bones), blood vessels, kidney, and ureters at doses ≥ 0.25 mg/kg/day (less than the clinical exposure). The fetal toxicity was observed at maternal rat exposures well below the range of clinically relevant exposures. 8.2 Lactation Risk Summary There are no data available on the presence of palovarotene or its main metabolites in either animal or human milk, the effects on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions in breastfed infants exposed to palovarotene through breastmilk, advise females that breastfeeding is not recommended during treatment with SOHONOS, and for at least 1 month after the final dose of SOHONOS. 8.3 Females and Males of Reproductive Potential SOHONOS can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1) ] Pregnancy Testing Obtain a negative serum pregnancy test within one week prior to SOHONOS therapy . Verify that patient is not pregnant periodically, as needed, over the course of treatment with SOHONOS and one month after treatment discontinuation unless they are not at risk of pregnancy. Contraception Females SOHONOS can cause embryo-fetal harm when administered during pregnancy [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ]. Advise females of reproductive potential to use effective contraception at least one month prior to treatment, during treatment with SOHONOS and for 1 month after the last dose, unless continuous abstinence is chosen. Males Palovarotene is present in semen (0.7 ng/mL) in amounts 100-fold lower than the maternal plasma exposure at the no observed adverse effect level (NOAEL) for fetal toxicity observed in animal studies. Administration of SOHONOS to a male patient is considered unlikely to affect development of an embryo or fetus carried by a pregnant female sexual partner exposed to SOHONOS via the patient's semen. 8.4 Pediatric Use The safety and effectiveness of SOHONOS for the treatment of FOP have been established in pediatric patients aged 8 years and older for females and 10 years and older for males. Use of SOHONOS for this indication is supported by evidence from cli …

12.1 Mechanism of Action In patients with FOP, abnormal bone formation, including heterotopic ossification (HO), is driven by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1). Palovarotene is an orally bioavailable retinoic acid receptor agonist, with particular selectivity at the gamma subtype of RAR. Through binding to RARγ, palovarotene decreases the BMP/ALK2 downstream signaling pathway by inhibiting the phosphorylation of SMAD1/5/8, which reduces ALK2/SMAD-dependent chondrogenesis and osteocyte differentiation resulting in reduced endochondral bone formation.

11 DESCRIPTION Palovarotene is an orally bioavailable retinoid that acts as a retinoic acid receptor (RAR) agonist with particular selectivity at the gamma subtype of RAR. Palovarotene is chemically described as 4-[( E )-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic acid with an empirical formula of C 27 H 30 N 2 O 2 and has a molecular weight of 414.54 g/mol. The structural formula is represented below: SOHONOS capsules are supplied in 1 mg, 1.5 mg, 5 mg and 10 mg strengths. Each capsule contains palovarotene as the active ingredient and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate. The capsule consists of gelatin and titanium dioxide. The black printing ink consists of black iron oxide, potassium hydroxide, propylene glycol and Shellac. Chemical Structure

10 OVERDOSAGE No clinical experience with an overdose of SOHONOS has been reported. SOHONOS is a derivative of vitamin A. In case of accidental overdose, signs of hypervitaminosis A could appear, including severe headache, nausea or vomiting, drowsiness, irritability and pruritus. Any overdose should be treated with supportive care according to the signs and symptoms exhibited by the patient.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied SOHONOS is an opaque white elongated hard-gelatin capsule. SOHONOS is available in size "0" capsule and supplied as a blister strip containing 14 capsules in a child resistant carton. Capsule contains white to off-white powder. Table 8 shows capsules' strengths, imprints, and NDC numbers. Table 8. Capsules' Strengths, Imprints, and NDC numbers Strength (mg) Imprint NDC 1 PVO 1 15054-0010-1 1.5 PVO 1.5 15054-0015-1 5 PVO 5 15054-0050-1 10 PVO 10 15054-0100-1 Storage and Handling This package is child-resistant. Keep out of reach of children. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room temperature]. SOHONOS must be kept in the original carton to protect from light. SOHONOS capsules may be opened and the contents emptied on a teaspoon of soft food and taken immediately. If not taken immediately, it can be taken after a maximum of one hour after the sprinkling, provided it was maintained at room temperature and not exposed to direct sunlight.

How Supplied SOHONOS is an opaque white elongated hard-gelatin capsule. SOHONOS is available in size "0" capsule and supplied as a blister strip containing 14 capsules in a child resistant carton. Capsule contains white to off-white powder. Table 8 shows capsules' strengths, imprints, and NDC numbers. Table 8. Capsules' Strengths, Imprints, and NDC numbers Strength (mg) Imprint NDC 1 PVO 1 15054-0010-1 1.5 PVO 1.5 15054-0015-1 5 PVO 5 15054-0050-1 10 PVO 10 15054-0100-1