Dosage & Administration
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Sohonos Prescribing Information
Embryo-Fetal Toxicity
SOHONOS is contraindicated in pregnancy. SOHONOS may cause fetal harm. Because of the risk of teratogenicity and to minimize fetal exposure, SOHONOS is to be administered only if conditions for pregnancy prevention are met [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].
Premature Epiphyseal Closure
Premature epiphyseal closure occurs in growing pediatric patients treated with SOHONOS, close monitoring is recommended [see Warnings and Precautions (5.2) and Use in Specific Populations (8.4)].
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. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)].
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.
| 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.
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.
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.
| 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 |
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)].
| 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 kg * | 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.
| Strength (mg) | Imprint |
|---|---|
| 1 | PVO 1 |
| 1.5 | PVO 1.5 |
| 2.5 | PVO 2.5 |
| 5 | PVO 5 |
| 10 | PVO 10 |
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.
Lactation
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.
Females and Males of Reproductive Potential
SOHONOS can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]
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.
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.
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.
Geriatric Use
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.
Renal Impairment
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 (CLcr 60 to 89 mL/min) or moderate (CLcr 30 to 59 mL/min) renal impairment. Use of SOHONOS in patients with severe (CLcr 15 to 29 mL/min) renal impairment is not recommended.
Hepatic Impairment
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.
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)].