SOHONOS
Generic: PALOVAROTENE
Basic Information
Manufacturer
Ipsen Biopharmaceuticals, Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
67dce406-7cc4-4d66-92de-ad18b6df0625
Indications & Usage
1 INDICATIONS AND USAGE 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).
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) ( 1 ).
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) ( 1 ).
Adverse Reactions
6 ADVERSE REACTIONS 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) ] Most common adverse reactions (incidence ≥10%) are dry skin, lip dry, arthralgia, pruritus, pain in extremity, rash, alopecia, erythema, headache, back pain, skin exfoliation, nausea, musculoskeletal pain, myalgia, dry eye, hypersensitivity, peripheral edema, and fatigue ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact IPSEN Biopharmaceuticals, Inc at 1-855-463-5127 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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 (61) 60 (57) Lip dry includes lip dry, chapped lips, cheilitis 62 (47) 40 (38) Arthralgia 47 (36) 32 (31) Pruritus includes pruritus, pruritus generalized, and rash pruritic 45 (34) 50 (48) Pain in extremity 38 (29) 29 (28) Rash includes rash, rash generalized, rash maculo-papular 36 (28) 31 (30) Alopecia 32 (24) 31 (30) Erythema includes erythema, generalized erythema, flushing, rash erythematous 25 (19) 34 (32) Headache includes headache and migraine 25 (19) 20 (19) Back pain includes back pain, flank pain, sciatica 22 (17) 12 (11) Skin exfoliation [skin peeling] 20 (15) 30 (29) Nausea 20 (15) 14 (13) Musculoskeletal pain 18 (14) 14 (13) Myalgia includes myalgia, musculoskeletal discomfort 15 (12) 9 (9) Dry eye 13 (10) 23 (22) Hypersensitivity includes drug eruption, hypersensitivity, pruritus allergic, drug hypersensitivity 13 (10) 21 (20) Peripheral edema includes peripheral swelling, edema peripheral 12 (9) 20 (19) Fatigue includes fatigue, lethargy, asthenia, malaise 7 (5) 12 (11) 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% 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) ].
6.1 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 (61) 60 (57) Lip dry includes lip dry, chapped lips, cheilitis 62 (47) 40 (38) Arthralgia 47 (36) 32 (31) Pruritus includes pruritus, pruritus generalized, and rash pruritic 45 (34) 50 (48) Pain in extremity 38 (29) 29 (28) Rash includes rash, rash generalized, rash maculo-papular 36 (28) 31 (30) Alopecia 32 (24) 31 (30) Erythema includes erythema, generalized erythema, flushing, rash erythematous 25 (19) 34 (32) Headache includes headache and migraine 25 (19) 20 (19) Back pain includes back pain, flank pain, sciatica 22 (17) 12 (11) Skin exfoliation [skin peeling] 20 (15) 30 (29) Nausea 20 (15) 14 (13) Musculoskeletal pain 18 (14) 14 (13) Myalgia includes myalgia, musculoskeletal discomfort 15 (12) 9 (9) Dry eye 13 (10) 23 (22) Hypersensitivity includes drug eruption, hypersensitivity, pruritus allergic, drug hypersensitivity 13 (10) 21 (20) Peripheral edema includes peripheral swelling, edema peripheral 12 (9) 20 (19) Fatigue includes fatigue, lethargy, asthenia, malaise 7 (5) 12 (11) 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% 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) ].