SOHONOS Capsule Ref.[107414] Active ingredients: Palovarotene

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.

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.

5.3 Mucocutaneous Adverse Reactions

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)].

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).

5.4 Metabolic Bone Disorders

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.

5.5 Psychiatric Disorders

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.

5.6 Night Blindness

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.

Table 5. Summary of Adverse Reactions Reported at greater than 10% Frequency in FOP Subjects 8/10 years and older in Clinical Trials:

Doses were reduced according to body weight in subjects who were less than 90% skeletally mature.
^* includes lip dry, chapped lips, cheilitis
^† includes pruritus, pruritus generalized, and rash pruritic
^‡ includes rash, rash generalized, rash maculo-papular
^§ includes erythema, generalized erythema, flushing, rash erythematous
^¶ includes headache and migraine
^# includes back pain, flank pain, sciatica
^Þ includes myalgia, musculoskeletal discomfort
^ß includes drug eruption, hypersensitivity, pruritus allergic, drug hypersensitivity
^à includes peripheral swelling, edema peripheral
^è includes fatigue, lethargy, asthenia, malaise

Doses were reduced according to body weight in subjects who were less than 90% skeletally mature

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)].

7.1 Effect of Other Drugs on SOHONOS

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

Table 6. Drugs that affect exposure of SOHONOS:

7.2 Vitamin A

Palovarotene belongs to the same pharmacological class as vitamin A. Therefore, the use of both vitamin A and SOHONOS at the same time may lead to additive effects. Concomitant administration of vitamin A in doses higher than the recommended daily allowance (RDA) and/or other oral retinoids with SOHONOS must be avoided because of the risk of hypervitaminosis A.

7.3 Tetracyclines

Systemic retinoid use has been associated with cases of benign intracranial hypertension (also called pseudotumor cerebri), some of which involved the concomitant use of tetracyclines. Avoid coadministration of SOHONOS with tetracycline derivatives [see Adverse Reactions (6.1)].

7.4 Systemic Corticosteroids

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

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.

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

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.

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.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)].

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.

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.