Sohonos Drug Information

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).

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.

Recommended Dosage and Duration Dosage Overview Take SOHONOS with food preferably at the same time each day. 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.

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.

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. 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 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.

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. Do not administer with grapefruit, pomelo, or juices containing these fruits.

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

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. Table 3.

Dose Reduction of SOHONOS for Use with Moderate CYP3A Inhibitors

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). 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. 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. Many of the affected subjects exhibited slowing of growth in height.

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. Hepatotoxicity Retinoids have been associated with dose dependent elevations of liver enzymes and isolated cases of severe hepatitis.

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. 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.

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, which may increase the risk of SOHONOS adverse reactions. Prevention or Management Avoid concomitant use of a strong CYP3A4 inhibitor during SOHONOS treatment. 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. Strong CYP3A Inducers Clinical Impact Co-administration of SOHONOS with strong CYP3A4 inducers decreased the exposure of palovarotene, which may reduce the effectiveness of SOHONOS. Prevention or Management Avoid concomitant use of strong CYP3A4 inducers with SOHONOS.

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.

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.

Systemic Corticosteroids

No clinically significant drug-drug interaction is expected when SOHONOS is co-administered with prednisone.

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. 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. 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.

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. 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. 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. 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.

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 contraindicated in the following patients: During Pregnancy. A history of allergy or hypersensitivity to retinoids, or to any component of SOHONOS. Anaphylaxis and other allergic reactions have occurred with other retinoids.

Pregnancy Hypersensitivity to retinoids or any component of SOHONOS

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.