Sohonos Drug Information

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

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of SOHONOS was evaluated in clinical studies that enrolled a total of 164 subjects with FOP, including 139 subjects in the indicated population of ages 8 years and above for females and 10 years and above for males (8/10 years and older). Most of these subjects received open label treatment with the chronic daily/flare-up regimen, consisting of 5 mg daily dosage of oral SOHONOS with a 20/10 mg dosage as needed for 12 weeks at the time of flare-up (4 weeks of 20 mg once daily followed by 10 mg once daily for 8 weeks), with all doses reduced by weight in subjects who were less than 90% skeletally mature. The mean duration of exposure was 79 weeks for chronic dosing (N=131 subjects) and 35 weeks for flare-up dosing (N=105 subjects). The mean age of these subjects was 19 years (range 8 to 61 years); 51% were male.

Serious adverse reactions occurred in 21 (15%) SOHONOS treated subjects in the 8/10 years or older population with the most common serious adverse reaction being premature epiphyseal closure. Adverse reactions leading to permanent discontinuation occurred in 11 (8%) SOHONOS treated subjects with dry skin being the most common in 2 (1%) subjects. Mucocutaneous adverse reactions leading to dose reductions were more common during SOHONOS 20/10 mg flare-up treatment (37%) than during chronic treatment (4%). Table 5 below presents adverse reactions which occurred in at least 10% of FOP subjects 8/10 years and older during treatment with chronic or flare-up dosing.

Table 5. Summary of Adverse Reactions Reported at greater than 10% Frequency in FOP Subjects 8/10 years and older in Clinical Trials Adverse Reaction Chronic 5 mg N=131 n (%) Flare-up dosing 20/10 mg N=105 n (%) Doses were reduced according to body weight in subjects who were less than 90% skeletally mature Dry skin 80 60 Lip dry includes lip dry, chapped lips, cheilitis 62 40 Arthralgia 47 32 Pruritus includes pruritus, pruritus generalized, and rash pruritic 45 50 Pain in extremity 38 29 Rash includes rash, rash generalized, rash maculo-papular 36 31 Alopecia 32 31 Erythema includes erythema, generalized erythema, flushing, rash erythematous 25 34 Headache includes headache and migraine 25 20 Back pain includes back pain, flank pain, sciatica 22 12 Skin exfoliation 20 30 Nausea 20 14 Musculoskeletal pain 18 14 Myalgia includes myalgia, musculoskeletal discomfort 15 9 Dry eye 13 23 Hypersensitivity includes drug eruption, hypersensitivity, pruritus allergic, drug hypersensitivity 13 21 Peripheral edema includes peripheral swelling, edema peripheral 12 20 Fatigue includes fatigue, lethargy, asthenia, malaise 7 12 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. . 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 (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 . Hepatotoxicity Retinoids have been associated with dose dependent elevations of liver enzymes and isolated cases of severe hepatitis.

In SOHONOS studies of FOP, elevated ALT was observed in 7.0% of subjects during 20/10 mg flare-up dosing and 1% of subjects during 5 mg chronic dosing. There were no subjects who required dose reduction or treatment discontinuation due to liver enzyme elevations. Hypertriglyceridemia Systemic retinoids may cause marked elevations of serum triglycerides.

In FOP studies, hypertriglyceridemia was reported in 2 subjects during chronic SOHONOS treatment (2%) and in 4 subjects during flare-up dosing (4%). Pancreatitis Pancreatitis has been reported with other systemic retinoids, both with and without elevated triglycerides, including fatal cases. In palovarotene studies, one healthy subject developed acute pancreatitis, possibly related to concomitant use of ketoconazole in a drug-drug interaction study. There were no reports of pancreatitis in the FOP clinical studies.

Night Blindness One reaction of night blindness was observed in SOHONOS treated subjects. Intracranial Hypertension (Pseudotumor Cerebri) Systemic retinoid use has been associated with cases of benign intracranial hypertension (also called pseudotumor cerebri), some of which involved the concomitant use of tetracyclines. There were no reports of benign intracranial hypertension in the FOP clinical studies.

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 . Moderate CYP3A Inhibitors Clinical Impact Co-administration of SOHONOS with moderate CYP3A4 inhibitors may increase the exposure of palovarotene , which may increase the risk of SOHONOS adverse reactions. Prevention or Management Avoid concomitant use of a moderate CYP3A4 inhibitor with SOHONOS, if possible.

If co-administration will occur, reduce the SOHONOS dose by half when co-administered with moderate CYP3A inhibitors . 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. . Moderate CYP3A Inducers Clinical Impact Co-administration of moderate CYP3A4 inducers with palovarotene may decrease palovarotene exposure, which may reduce the effectiveness of SOHONOS. Prevention or Management Avoid concomitant use of moderate 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.

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.

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 . 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.

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.