Sohonos Capsule
FDA Label NDC 15054-0100

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)].

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 experiences marked worsening of the original flare-up site or another flare-up at a new location, restart the 12-week flare-up dosing with the Week 1 to 4 dose.
    • For flare-up symptoms that have not resolved at the end of the 12-week period, the Week 5 to 12 flare-up dose may be extended in 4-week intervals and continued until the flare-up symptoms resolve. If new flare-up symptoms occur after daily dosing is resumed, flare-up dosing may be restarted.

    Table 1. Recommended SOHONOS Weight-Based Dosage for Pediatric Patients Aged 8 to 13 Years for Females and 10 to 13 Years for Males

    once daily

    Weight	Daily Dosage	Week 1 to 4 Flare-up Dosage	Week 5 to 12 Flare-up Dosage
    10 kg to 19.9 kg	2.5 mg	10 mg	5 mg
    20 kg to 39.9 kg	3 mg	12.5 mg	6 mg
    40 kg to 59.9 kg	4 mg	15 mg	7.5 mg
    ≥ 60 kg	5 mg	20 mg	10 mg

    Missed Dose

    If a dose of SOHONOS is missed, take the missed dose as soon as possible. If the dose has been missed by more than 6 hours, skip the missed dose, and continue with the next scheduled dose. Do not take two doses at the same time or in the same day.

    Moderate CYP3A Inhibitors:

    Avoid concomitant use of a moderate CYP3A inhibitor, if possible. If concomitant use will occur, reduce the dose of SOHONOS by half as shown in Table 3 when co-administered with moderate CYP3A inhibitors [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

    Table 3. Dose Reduction of SOHONOS for Use with Moderate CYP3A Inhibitors

    Weight	Daily Dosage	Week 1 to 4 Flare-up Dosage	Week 5 to 12 Flare-up Dosage
    10 kg to 19.9 kg	1 mg	5 mg	2.5 mg
    20 kg to 39.9 kg	1.5 mg	6 mg	3 mg
    40 kg to 59.9 kg	2 mg	7.5 mg	4 mg
    ≥ 60 kg All pediatric patients ≥14 years of age and adults should receive the dose in the ≥60 kg weight category.	2.5 mg	10 mg	5 mg

    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).

    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.

    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 1.5% 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)].

    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.

    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.

    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.

    CDC Effectiveness of Contraceptive Methods Chart, https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/contraceptive_methods_508.pdf

    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.

    Bone Safety

    In clinical studies with SOHONOS, assessments of growth and bone safety in growing children included linear and knee height, femur and tibia length measured by Whole-Body Computed Tomography (WBCT), and hand/wrist and knee radiographs. Premature epiphyseal closure has been identified as an irreversible serious risk associated with SOHONOS treatment. Premature epiphyseal closure was observed as early as 6 months after initiating therapy with the majority occurring at or after 12 months. In SOHONOS treated subjects there was a trend of declining height Z-scores in adolescent subjects, potentially due to a loss of linear height and/or increasing spinal deformity. The long-term effects on final height in subjects with FOP treated with SOHONOS have not been established. [see Adverse Reactions (6.1)].

    Monitoring Recommendation

    Prior to starting treatment with SOHONOS, all growing children should undergo baseline clinical and radiological assessments including but not limited to an assessment of skeletal maturity via hand/wrist and knee x-rays, standard growth curves and pubertal staging. Continued monitoring is recommended every 6-12 months until patients reach skeletal maturity (e.g., epiphyseal closure) or final adult height [see Warnings and Precautions (5.2)].

    Juvenile Animal Data

    A juvenile animal study was conducted in juvenile rats given daily oral doses of palovarotene at 0.1, 0.5 or 1.2 mg/kg/day from Week 3 to Week 9 of age (prior to epiphyseal fusion). Palovarotene adversely affected skeletal growth and development including, reduction in bone size, abnormal bone shape and/or geometry, diffuse bone loss, and growth in general were affected at ≥ 0.5 mg/kg/day (less than the clinical exposure). As expected, physes were either widened due to an expanded zone of cartilage hypertrophy/maturation (sometimes accompanied by chondrodysplasia), narrowed, or partially/completely closed. In the proximal femur, avascular necrosis of the femoral head was observed accompanied with malformations and microfractures of trabeculae in a few rats at 1.2 mg/kg/day (less than the clinical exposure). In vertebrae, palovarotene completely inhibited the endochondral ossification that normally occurs in the hyaline cartilage at the end of the vertebral body There also were tibial fractures in two high-dose females. The skeletal effects showed evidence of reversing after dosing discontinuation at 0.5 mg/kg/day, but not at highest dose of 1.2 mg/kg/day.

    Cardiac Electrophysiology

    At doses up to 2.5 times the maximum recommended dose, palovarotene does not prolong the QT interval to any clinically relevant extent.

    Absorption

    The median time to achieve peak concentration (T_max) of palovarotene was 3.0 to 4.0 hours across the chronic dose of 5 mg to flare-up dose of 10 and 20 mg.

    Effect of Food

    Palovarotene mean AUC and mean C_max increased by approximately 40% and 16%, respectively; T_max was delayed by approximately 2 hours with a high-fat, high-calorie meal (800 to 1000 calories, 15% protein, 25% carbohydrate, and 50 to 60% fat).

    No clinically significant differences in the AUC and C_max of palovarotene were observed when palovarotene was administered whole compared to the contents sprinkled onto one teaspoon of applesauce following a high-fat, high-caloric breakfast.

    Distribution

    The mean (SD) apparent volume of distribution (Vd/F) is 237 (± 90.1) L following administration of a single 20 mg dose with food. Protein binding of palovarotene is 97.9% to 99.6% in vitro.

    The mean blood-to-plasma ratio of palovarotene in humans is 0.62.

    Elimination

    The mean elimination half-life is 8.7 hours following administration of a 20 mg once daily dosage for 14 days with a standard breakfast (800 to 1000 calories, 15% protein, 25% carbohydrate, and 50 to 60% fat). The apparent total body clearance (CL/F) of palovarotene is estimated at 19.9 L/h.

    Metabolism

    Palovarotene is extensively metabolized by CYP3A4 and to a minor extent by CYP2C8 and CYP2C19.

    Following administration of [¹⁴-C]-radiolabeled palovarotene, the contribution of palovarotene and its four known major metabolites (M2, M3, M4a, and M4b) represented collectively 40% of the total exposure in plasma. The pharmacological activity of M3 and M4b is approximately 1.7% and 4.2% of the activity of the parent drug.

    Excretion

    Following administration of a 1 mg dose of [¹⁴C]-radiolabeled palovarotene in healthy subjects, 97.1% of the dose was recovered in the feces and 3.2% in the urine.

    Specific Populations

    There were no clinically significant differences in the pharmacokinetics of palovarotene based on age (2 to 85 years old), sex, race (Asian, black, white and others), smoking status, mild to moderate renal impairment, or mild hepatic impairment. The effect of severe renal impairment, or moderate to severe hepatic impairment on the pharmacokinetics of palovarotene is unknown.

    Body Weight

    Body weight (13 to 130 kg) was found to have a significant effect on the pharmacokinetics of palovarotene resulting in increasing exposure with decreasing weight at the same dose.

    Pediatric Patients

    The estimated steady-state AUC_0-τ and C_max,ss following weight-based dosing for 5, 10, and 20 mg (or dose equivalent) in pediatric patients <14 years old are comparable for the equivalent doses across the different weight groups.

    Drug Interaction Studies

    Clinical Studies and Model-Informed Approaches

    Strong CYP3A Inhibitor: Co-administration of palovarotene with ketoconazole (strong CYP3A4 inhibitor) increased the C_max and AUC of palovarotene by 2 and 3-fold, respectively.

    Moderate CYP3A Inhibitor: Co-administration of palovarotene with erythromycin (moderate CYP3A4 inhibitor) increased the C_max and AUC of palovarotene by 1.6 and 2.5-fold, respectively.

    Strong CYP3A Inducer: Co-administration of palovarotene with rifampicin (strong CYP3A4 inducer) decrease the C_max and AUC_0-t of palovarotene by 19% and 11%, respectively.

    Other Drugs: No clinically significant differences in the pharmacokinetics of palovarotene were observed when co-administered with prednisone 40 mg. No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate) were observed when co-administered with palovarotene.

    In Vitro Studies

    Cytochrome P450 (CYP) Enzymes: Palovarotene is an inducer of CYP3A4 and CYP2B6, but not CYP1A2, CYP2C8, CYP2C9 and CYP2C19. Palovarotene is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

    Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Palovarotene is not an inhibitor or a substrate of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 or UGT2B7.

    Transporter Systems: Palovarotene is not an inhibitor of P-gp, OAT1, OAT3, OCT2, MATE1, MATE2 K, BCRP, OATP1B1, OATP1B3, OCT1, and BSEP. Palovarotene is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, or OCT1.

    Carcinogenesis and Mutagenesis

    Long term studies to assess the carcinogenic potential of palovarotene have not been conducted.

    Palovarotene and its metabolites were negative in the vitro bacterial reverse mutation (Ames) assay and an in vitro micronucleus assay in primary human lymphocyte. Palovarotene did not have any clastogenic effect in the in vivo mouse micronucleus study.

    Impairment of Fertility

    Palovarotene effects on fertility and reproductive function were assessed in male and female rats. In a female rat fertility study, palovarotene was orally administered to females for 14 days prior to mating with drug naïve males and up to GD 7 at the dose levels of 0.3, 1 and 3 mg/kg/day. Palovarotene caused prolonged periods of diestrous and reduced ovulation rate, resulting in lower numbers of implantation sites and live embryos at 3 mg/kg/day, a dose associated with maternal toxicity.

    In a male rat fertility study, palovarotene was orally administered prior to mating, during mating, and up to scheduled euthanasia (approximately 11 weeks in total) at 0.3, 1 and 3 mg/kg/day. Palovarotene did not cause adverse effects on mating, fertility indices, conception rate, reproductive organ weights or sperm parameters up to 1 mg/kg/day (less than the clinical exposure). Males did not tolerate 3 mg/kg/day, as it produced severe systemic toxicity including deaths, adverse skin and hair coat clinical signs, and substantially reduced body weight.

    Embryo-Fetal Toxicity:

    Advise patients that SOHONOS can cause fetal harm and is contraindicated during pregnancy. Advise patients to verify that they are not pregnant prior to initiating and periodically during SOHONOS treatment as well as one month after treatment discontinuation [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.3)].

    • Advise females of reproductive potential that they must avoid pregnancy while taking SOHONOS and for at least one month following discontinuation of therapy.
    • Advise females of childbearing potential to use at least one highly effective method of contraception (i.e. IUD) or two effective methods (i.e. combined hormonal contraception in combination with another method of contraception such as a barrier method) during treatment with SOHONOS [see Use in Specific Populations (8.3)].
    • Instruct patients to immediately stop taking SOHONOS if she becomes pregnant while taking SOHONOS and to rapidly consult her healthcare provider if there is a risk of pregnancy or if she might be pregnant.
    • Instruct patients to not donate blood during SOHONOS treatment and for 1 week following discontinuation to avoid blood donation to a pregnant patient and fetus.

    Lactation

    Because of the potential for serious adverse reactions from SOHONOS in a breastfed child, advise females not to breastfeed during treatment with SOHONOS, and for at least 1 month after the last dose of SOHONOS.

    Premature Epiphyseal Closure:

    Inform patients that SOHONOS has been shown to cause premature epiphyseal closure in growing pediatric patients with FOP and discuss the proposed monitoring plan with the patient and caregiver [see Warnings and Precautions (5.2)].

    Mucocutaneous Adverse Reactions:

    Advise patients that they may experience dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation, and dry eye. Discuss the plan to assess their symptoms and adjust the dose if needed [see Dosage and Administration (2.4) and Warning and Precautions (5.3)]. Recommend prophylactic measures to minimize risk and/or treat the mucocutaneous adverse reactions are recommended (e.g. skin emollients, sunscreen, lip moisturizers, artificial tears) [see Warnings and Precautions (5.3)].

    Photosensitivity:

    Advise patients of potential increased skin sensitivity to sunlight while taking SOHONOS and to minimize exposure to sunlight and artificial ultraviolet light [see Warnings and Precautions (5.3)].

    Radiological Vertebral Fractures:

    Inform patients that SOHONOS resulted in decreased vertebral bone mineral content, bone density and bone strength as well as an increased risk of radiologically observed vertebral fractures and that periodic radiological assessment of the spine is recommended [see Warnings and Precautions (5.4)].

    Psychiatric Disorders:

    Advise patients of the possibility of experiencing new or worsening psychiatric effects, including suicidal thoughts and behaviors, depression, depression aggravated, anxiety, and mood alterations. Particular care should be taken in patients with history of psychiatric illness. Patients should be monitored for signs of depression and referred for appropriate treatment if necessary [see Warnings and Precautions (5.5)].

    Night Blindness:

    Advise patients of the risk of experiencing night blindness [see Warnings and Precautions (5.6)].

    Drug Interactions:

    Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products [see Dosage and Administration (2.5) and Drug Interactions (7)].

    Dosing Instructions:

    Advise the patient to take SOHONOS capsules with food. If the patient is unable to swallow the capsule, the capsule contents may be emptied onto soft food [see Dosage and Administration (2.3)].

    Missed dose:

    If a dose is missed, it should be taken as soon as the patient remembers. If the dose has been missed by more than 6 hours, advise the patient to skip the missed dose and continue with the next scheduled dose. Advise the patient to not take two doses at the same time or in the same day.

    Distributed by: Ipsen Biopharmaceuticals, Inc. Cambridge, MA; 02142.

    SOHONOS is a trademark of Clementia Pharmaceuticals Inc.
    ©2023. Ipsen Biopharmaceuticals, Inc. All rights reserved.

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).

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)].

Take SOHONOS with food preferably at the same time each day. SOHONOS may be swallowed whole, or capsules may be opened and the contents emptied onto one teaspoon (5 mL) of soft food (such as apple sauce, low-fat yogurt, or warm oatmeal) and taken within 1 hour of opening provided it was maintained at room temperature and not exposed to direct sunlight [see Clinical Pharmacology (12.3)]. Do not administer with grapefruit, pomelo, or juices containing these fruits.

If patients experience adverse reactions that require dosage reduction during either the SOHONOS daily dosing or flare-up dosing, reduce the daily dosage to the next lower dose as shown in Table 2 at the discretion of the healthcare provider; reduce the dosage further if adverse reactions do not improve. If the patient is already receiving the lowest possible tolerated dose, then consider discontinuing SOHONOS temporarily or permanently. Initiate subsequent flare-up dosing at the same reduced dose that was tolerated previously.

SOHONOS is available in 5 strengths as an opaque white elongated size "0" hard-gelatin capsule, containing white to off-white powder. Table 4 shows capsules' strengths and imprints.

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)].

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.

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.

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)].

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.

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.

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)]

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.

Clinically significant drug interactions affecting the exposure of SOHONOS are listed in Table 6.

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.

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)].

No clinically significant drug-drug interaction is expected when SOHONOS is co-administered with prednisone [see Clinical Pharmacology (12.3)].

SOHONOS can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]

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 clinical studies in adults and pediatric subjects [see Clinical Studies (14)]. The safety and effectiveness of SOHONOS for the treatment of FOP have not been established in pediatric patients less than 8 years of age in females and less than 10 years of age for males. SOHONOS is not recommended for use in patients younger than 8 years of age for females and 10 years of age for males because of the potential for premature epiphyseal closure. Clinical studies have shown that growing patients with open epiphyses are at risk of developing premature epiphyseal closure when treated with SOHONOS [see Warnings and Precautions (5.2), Adverse Reactions (6.1) and Clinical Studies (14.1)].

Clinical studies of SOHONOS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The effect of renal impairment on the pharmacokinetics of palovarotene has not been evaluated. Given that palovarotene is hepatically eliminated, no dose adjustment of SOHONOS is recommended in patients with mild (CL_cr 60 to 89 mL/min) or moderate (CL_cr 30 to 59 mL/min) renal impairment. Use of SOHONOS in patients with severe (CL_cr 15 to 29 mL/min) renal impairment is not recommended.

The effect of moderate or severe hepatic impairment on the pharmacokinetics of palovarotene has not been evaluated. SOHONOS undergoes extensive hepatic metabolism. No dose adjustment is recommended in patients with mild (Child-Pugh A) hepatic impairment. Use of SOHONOS in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment is not recommended.

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.

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 C₂₇H₃₀N₂O₂ and has a molecular weight of 414.54 g/mol.

The structural formula is represented below:

Chemical Structure (Sohonos 01)

SOHONOS capsules are supplied in 1 mg, 1.5 mg, 2.5 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.

In patients with FOP, abnormal bone formation, including heterotrophic 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.

Palovarotene exposure (AUC) increases proportionally from 0.02 to 50 mg (0.001 to 2.5 times the maximum recommended dosage). Steady-state is achieved by Day 3 following once daily dosing. Palovarotene exposure in patients with FOP are listed in the Table 7.

Study PVO-1A-301 (NCT03312634, Study 301) was a single arm study in 97 subjects with FOP with R206H mutation aged 4 years and older utilizing the Natural History Study (NHS, PVO-1A-001) as an external control (n=101). The primary efficacy endpoint was annualized volume of new heterotopic ossification (HO) as assessed by low-dose, whole body CT (WBCT) imaging (excluding head). All WBCT images from treated subjects in the 301 study and untreated subjects in the NHS were read in a manner blinded to study origination.

Study 301 subjects received SOHONOS 5 mg daily with increased dosing at the time of a flare-up defined as at least one symptom (e.g. pain, swelling, redness) consistent with a previous flare-up or a substantial high-risk traumatic event likely to lead to a flare-up, to 20 mg once daily for 4 weeks followed by 10 mg once daily for 8 weeks (denoted as the chronic/flare-up regimen), with flare-up treatment extension in 4-week increments for persistent symptoms. Anytime during flare-up treatment, the 12-week treatment restarted if the subject had another flare-up or substantial high-risk traumatic event. The dosing was adjusted according to body weight in skeletally immature children (children who had not reached at least 90% skeletal maturity defined as a bone age of ≥12 years 0 months for girls and ≥14 years 0 months for boys).

The mean age of subjects in the SOHONOS group (N=97) was 15.1 years; and 17.8 years in the untreated group (N=101). There were more male than female subjects in both the SOHONOS (53% and 47%, respectively) and untreated (55% and 45%, respectively) groups.

The mean annualized new HO was 9.4 cm³/year in subjects receiving the chronic/flare-up SOHONOS treatment and 20.3 cm³/year in untreated subjects in the NHS based on a linear mixed effect model. The treatment effect was about 10.9 cm³/year with 95% confidence interval (-21.2 cm³/year, -0.6 cm³/year).

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.

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.

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

NDC 15054-0010-1
Rx Only

sohonos™
(palovarotene) capsules

1 mg
per capsule

For Oral Use
14 capsules

CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT

LIFT OPEN HERE

PHARMACIST:
Dispense in the original
carton with the enclosed
Medication Guide.

IPSEN
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Principal Display Panel (1 mg Capsule Blister Pack Carton)

NDC 15054-0015-1
Rx Only

sohonos™
(palovarotene) capsules

1.5 mg
per capsule

For Oral Use
14 capsules

CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT

LIFT OPEN HERE

PHARMACIST:
Dispense in the original
carton with the enclosed
Medication Guide.

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Principal Display Panel (1.5 mg Capsule Blister Pack Carton)

NDC 15054-0025-1
Rx Only

sohonos™
(palovarotene) capsules

2.5 mg
per capsule

For Oral Use
14 capsules

CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT

LIFT OPEN HERE

PHARMACIST:
Dispense in the original
carton with the enclosed
Medication Guide.

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Principal Display Panel (2.5 mg Capsule Blister Pack Carton)

NDC 15054-0050-1
Rx Only

sohonos™
(palovarotene) capsules

5 mg
per capsule

For Oral Use
14 capsules

CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT

LIFT OPEN HERE

PHARMACIST:
Dispense in the original
carton with the enclosed
Medication Guide.

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Principal Display Panel (5 mg Capsule Blister Pack Carton)

NDC 15054-0100-1
Rx Only

sohonos™
(palovarotene) capsules

10 mg
per capsule

For Oral Use
14 capsules

CAUSES BIRTH DEFECTS
DO NOT GET PREGNANT

LIFT OPEN HERE

PHARMACIST:
Dispense in the original
carton with the enclosed
Medication Guide.

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Principal Display Panel (10 mg Capsule Blister Pack Carton)