Sohonos

• SOHONOS is contraindicated in pregnancy (

  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.

  ,

  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.

  ) 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 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.

  ,

  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.

  )
• SOHONOS causes premature epiphyseal closure in growing pediatric patients with FOP, close monitoring is recommended (

  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.

  ,

  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 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)]

  .

  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.

  )

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).

• Obtain a negative pregnancy test in females of reproductive potential before initiation of SOHONOS (
  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)].
  )
• Recommended dosage includes a chronic daily dose, which can be increased for flare-up symptoms (
  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 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 Malesonce 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.
  )
• 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 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 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 Malesonce 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.
  )
• 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 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 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 Malesonce 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.
  )
• Take SOHONOS with food preferably at same time each day (
  2.3 Administration Instructions

  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.
  ).
• Reduce the dose in the event of adverse reactions as appropriate (
  2.4 Dosage Reduction for Adverse Reactions

  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.

  Table 2. Dose Reduction of SOHONOS for Flare-Up and Chronic Treatment

  Dose Prescribed	Reduced Dose
  20 mg	15 mg
  15 mg	12.5 mg
  12.5 mg	10 mg
  10 mg	7.5 mg
  7.5 mg	5 mg
  6 mg	4 mg
  5 mg	2.5 mg
  4 mg	2 mg
  3 mg	1.5 mg
  2.5 mg	1 mg
  )
• See Full Prescribing Information for complete dosing instructions (
  2 DOSAGE AND ADMINISTRATION

  • Obtain a negative pregnancy test in females of reproductive potential before initiation of SOHONOS
  • Recommended dosage includes a chronic daily dose, which can be increased for flare-up symptoms
  • 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)
  • 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
  • Take SOHONOS with food preferably at same time each day .
  • Reduce the dose in the event of adverse reactions as appropriate
  • See Full Prescribing Information for complete dosing instructions

  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 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 Malesonce 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.

  2.3 Administration Instructions

  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.

  2.4 Dosage Reduction for Adverse Reactions

  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.

  Table 2. Dose Reduction of SOHONOS for Flare-Up and Chronic Treatment

  Dose Prescribed	Reduced Dose
  20 mg	15 mg
  15 mg	12.5 mg
  12.5 mg	10 mg
  10 mg	7.5 mg
  7.5 mg	5 mg
  6 mg	4 mg
  5 mg	2.5 mg
  4 mg	2 mg
  3 mg	1.5 mg
  2.5 mg	1 mg

  2.5 Dosage Modifications for Drug Interactions

  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 kgAll 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
  )

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.

• Pregnancy: May cause fetal harm (
  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)].
  ,
  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
  • Hypersensitivity to retinoids or any component of SOHONOS
  ,
  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.
  )
• 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 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.
  ,
  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 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)]

  .

  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.
  )