SOHONOS Dosage & Rx Info | Uses, Side Effects

Sohonos Generic Name & Formulations

Legal Class

General Description

Palovarotene 1mg, 1.5mg, 2.5mg, 5mg, 10mg; caps.

Pharmacological Class

Retinoid.

How Supplied

Caps—14

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room temperature]. Sohonos must be kept in the original carton to protect from light.

Manufacturer

Ipsen Biopharmaceuticals, Inc.

Generic Availability

Mechanism of Action

Palovarotene is an orally bioavailable retinoic acid receptor (RAR) agonist, with particular selectivity at the gamma subtype of RAR. Through binding to RARγ, palovarotene decreases the BMP/ALK2 downstream signaling pathway by inhibiting the phosphorylation of SMAD1/5/8, which reduces ALK2/SMAD-dependent chondrogenesis and osteocyte differentiation resulting in reduced endochondral bone formation.

Sohonos Indications

Indications

For reduction in the volume of new heterotopic ossification in adults and children aged ≥8yrs (females) and aged ≥10yrs (males) with fibrodysplasia ossificans progressiva (FOP).

Sohonos Dosage and Administration

Prior to Treatment Evaluations

Females of reproductive potential: obtain a negative pregnancy test within 1 week prior to starting and periodically during treatment. If pregnancy occurs, discontinue treatment immediately and refer patient to an ob/gyn experienced in reproductive toxicity.

Prior to starting treatment, 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.

Adults and Children

<8yrs (females) and <10yrs (males): not established. Take with food. Swallow caps whole, or may be opened and the contents emptied onto 1 tsp of soft food (eg, apple sauce, low-fat yogurt, warm oatmeal); consume within 1hr of opening. 8–13yrs (females) and 10–13yrs (males): weight-based dose ranging from 2.5–5mg once daily (see full labeling); stop daily dosing when flare-up dosing begins. Flare-up: give initial flare-up dose (weight-based; see full labeling) once daily for 4 weeks, followed by lower flare-up dose once daily for 8 weeks (for total of 12 weeks of flare-up treatment), then return to daily dosing. Restart the 12-week flare-up dosing (Week 1–4), if marked worsening of the original flare-up site or another flare-up at a new location occurs during the course of the flare-up treatment. May extend the Week 5–12 flare-up dose in 4-week intervals for flare-up symptoms that have not resolved at the end of the 12-week period, and continued until resolved. If new flare-up symptoms occur after daily dosing is resumed, flare-up dosing may be restarted. ≥14yrs: 5mg once daily; stop daily dosing when flare-up dosing begins. Flare-up: 20mg once daily for 4 weeks, followed by 10mg once daily for 8 weeks (for total of 12 weeks of flare-up treatment), then return to 5mg daily. Restart the 12-week flare-up dosing at 20mg once daily, if marked worsening of the original flare-up site or another flare-up at a new location occurs during the course of the flare-up treatment. May extend the 10mg once daily dose in 4-week intervals for flare-up symptoms that have not resolved at the end of the 12-week period, and continued until resolved. If new flare-up symptoms occur after the 5mg once daily dosing is resumed, flare-up dosing may be restarted. Dosage modifications for adverse reactions, drug interactions: see full labeling.

Other Modifications

Dose Reduction for Flare-Up and Chronic Treatment

If adverse reactions occur during daily dosing or flare-up dosing that require dosage reduction, reduce the daily dose to the next lower dose at the discretion of the health care provider; reduce further if reactions do not improve. If patient is already receiving the lowest possible tolerated dose, consider discontinuing temporarily or permanently. Initiate subsequent flare-up dosing at the same reduce dose that was previously tolerated.

Dose Prescribed: 20mg; reduce dose to 15mg.
Dose Prescribed: 15mg; reduce dose to 12.5mg.
Dose Prescribed: 12.5mg; reduce dose to 10mg.
Dose Prescribed: 10mg; reduce dose to 7.5mg.
Dose Prescribed: 7.5mg; reduce dose to 5mg.
Dose Prescribed: 6mg; reduce dose to 4mg.
Dose Prescribed: 5mg; reduce dose to 2.5mg.
Dose Prescribed: 4mg; reduce dose to 2mg.
Dose Prescribed: 3mg; reduce dose to 1.5mg.
Dose Prescribed: 2.5mg; reduce dose to 1mg.

Moderate CYP3A Inhibitors

Avoid concomitant moderate CYP3A inhibitor, if possible. If concomitant use is unavoidable, reduce the dose of Sohnos by half.

Dose reduction of Sohonos for use with moderate CYP3A inhibitors:

If weight is 10–19.9kg, daily dose should be 1mg; week 1 to 4 flare-up dose should be 5mg; and week 5 to 12 flare-up dose should be 2.5mg.
If weight is 20–39.9kg, daily dose should be 1.5mg; week 1 to 4 flare-up dose should be 6mg; and week 5 to 12 flare-up dose should be 3mg.
If weight is 40–59.9kg, daily dose should be 2mg; week 1 to 4 flare-up dose should be 7.5mg; and week 5 to 12 flare-up dose should be 4mg.
If weight is ≥60kg, daily dose should be 2.5mg; week 1 to 4 flare-up dose should be 10mg; and week 5 to 12 flare-up dose should be 5mg. All pediatric patients aged ≥14 years and adults should receive the dose in the ≥60kg weight category.

Administration

Take with food preferably at the same time each day. Each capsule may be swallowed whole, or may open and empty the contents onto one teaspoon (5mL) of soft food (eg, apple sauce, low-fat yogurt, or warm oatmeal) and take within 1 hour of opening provided it was kept at room temperature and not exposed to direct sunlight. Do not administer with grapefruit, pomelo, or juices containing these fruits.

Sohonos Contraindications

Contraindications

Pregnancy.

Sohonos Boxed Warnings

Boxed Warning

Embryo-fetal toxicity. Premature epiphyseal closure in growing pediatric patients.

Sohonos Warnings/Precautions

Warnings/Precautions

Embryo-fetal toxicity. Females of reproductive potential: obtain a negative pregnancy test within 1 week prior to initiation and periodically during therapy. Discontinue immediately if pregnancy occurs; refer to ob/gyn. Advise females of reproductive potential to use effective contraception at least 1 month prior to therapy, during, and for 1 month after the last dose. Do not donate blood during and for 1 week after discontinuation. Risk for premature epiphyseal closure in growing pediatric patients; monitor linear growth. Assess baseline skeletal maturity in all growing children prior to initiation and continue monitoring every 6–12 months until skeletal maturity or final adult height is reached. Increased risk for mucocutaneous adverse reactions, skin/soft tissue infections, paronychia and decubitus ulcer. Phototoxicity. Avoid excessive exposure to sun or artificial UV light. Metabolic bone disorders (eg, bone mineral density and fracture, hyperostosis). Obtain periodic radiological assessment of the spine. Monitor for new or worsening psychiatric symptoms during treatment. History of psychiatric illness. Severe renal impairment (CrCl 15–29mL/min): not recommended. Moderate or severe hepatic impairment: not recommended. Elderly. Nursing mothers: not recommended (during and for at least 1 month after the last dose).

Pregnancy Considerations

Risk Summary

The use of Sohonos is contraindicated during pregnancy. Sohonos may cause fetal harm if administered during pregnancy.

Nursing Mother Considerations

Risk Summary

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.
Advise females not to breastfeed during treatment and for at least 1 month after the final dose.

Pediatric Considerations

Safety and efficacy 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 this patient population due to the risk for premature epiphyseal closure.

Bone Safety

Prior to starting treatment, 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 to 12 months until patients reach skeletal maturity (eg, epiphyseal closure) or final adult height.

Geriatric Considerations

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 Considerations

Severe renal impairment (CrCl 15 to 29 mL/min): not recommended.

Hepatic Impairment Considerations

Moderate to severe hepatic impairment (Child-Pugh B or C): not recommended.

Other Considerations for Specific Populations

Females and Males of Reproductive Potential

Pregnancy Testing:

Obtain a negative serum pregnancy test within 1 week prior to therapy. Periodically verify that the patient is not pregnancy during treatment and 1 month after treatment discontinuation.

Contraception:

Females – Sohonos may cause embryo-fetal harm during pregnancy. Advise females of reproductive potential to use effective contraception at least 1 month prior to treatment, during and for 1 month after the last dose unless continuous abstinence is chosen.
Males – Sohonos is present in semen in amounts 100-fold lower than the maternal plasma exposure. 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.

Sohonos Pharmacokinetics

Absorption

Median time to achieve peak concentration (T_max): 3.0–4.0 hours, across the chronic dose of 5 mg to flare-up dose of 10 and 20 mg. Palovarotene mean AUC and mean C_max increased by approximately 40% and 16%, respectively; T_max was delayed by approximately 2 hours with a high-fat, high-calorie meal (800–1000 calories, 15% protein, 25% carbohydrate, and 50–60% fat).

Distribution

Mean (SD) apparent volume of distribution (Vd/F): 237 (± 90.1) L. Protein bound: 97.9–99.6% in vitro. Mean blood-to-plasma ratio: 0.62.

Metabolism

Hepatic: CYP3A4 (major), CYP2C8, CYP2C19.

Elimination

Fecal (97.1%), renal (3.2%). Mean elimination half-life: 8.7 hours with a standard breakfast (800–1000 calories, 15% protein, 25% carbohydrate, and 50–60% fat). Apparent total body clearance: 19.9 L/h.

Sohonos Interactions

Interactions

Avoid concomitant grapefruit, pomelo, or juices containing these fruits. Potentiated by moderate or strong CYP3A4 inhibitors; avoid concomitant use. If moderate CYP3A4 inhibitor is unavoidable, reduce Sohonos dose by half. Antagonized by moderate or strong CYP3A4 inducers; avoid concomitant use. Avoid concomitant Vit. A (w. doses > recommended daily allowance) and/or other oral retinoids due to the risk for hypervitaminosis A. Avoid concomitant tetracycline derivatives (increased risk for pseudotumor cerebri).

Sohonos Adverse Reactions

Adverse Reactions

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, fatigue; premature epiphyseal closure, hepatotoxicity, night blindness.

Sohonos Clinical Trials

Clinical Trials

The approval was based on data from the phase 3 MOVE trial (ClinicaTrials.gov Identifier: NCT03312634), an open-label study that enrolled patients with FOP with R206H mutation aged 4 years and older. Patients (N=97) received oral palovarotene 5mg once daily, increased at the time of flare-up symptoms to 20mg once daily for 4 weeks, followed by 10mg once daily for 8 weeks (chronic/flare-up regimen), with flare-up treatment extension in 4-week increments for persistent symptoms. The 12-week treatment restarted if the patient had another flare-up or substantial high-risk traumatic event anytime during flare-up treatment.

The primary endpoint was annualized change in new HO volume measured by low-dose whole-body computed tomography. Efficacy data were compared with data from FOP Natural History Study (NHS) participants (untreated beyond standard of care; ClinicalTrials.gov Identifier: NCT02322255).

Based on a linear mixed effect model, mean annualized new HO was reported to be 9.4 cm³/year in patients receiving the chronic/flare-up palovarotene treatment and 20.3 cm³/year in untreated patients in the NHS. The treatment effect was about 10.9 cm³/year (95% CI, -21.2, -0.6).

Sohonos Note

Not Applicable

Sohonos Patient Counseling

Patient Counseling

Embryo-Fetal Toxicity

Advise patients that Sohonos may cause fetal harm and is contraindicated during pregnancy. Verify that patients are not pregnant prior to initiating, periodically during treatment, and for 1 month after treatment discontinuation.
Advise females of reproductive potential to avoid pregnancy during treatment and for at least 1 month after discontinuation.
Advise females of childbearing potential to use at least 1 highly effective method of contraception (eg, IUD) or 2 effective methods (eg, combined hormonal contraception in combination with another method of contraception such as a barrier method) during treatment.
Discontinue Sohonos if patient becomes pregnant during and to rapidly consult your health care provider if there is a risk for pregnancy or if the patient might be pregnant.
Do not donate blood during treatment and for 1 week after discontinuation.

Lactation

Do not breastfeed during and for at least 1 month after the last dose.

Premature Epiphyseal Closure

May cause premature epiphyseal closure in growing pediatric patients with FOP and discuss the monitoring plan with the patient and caregiver.

Mucocutaneous Adverse Reactions

May cause dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation, and dry eye. Recommend prophylactic measures to minimize risk and/or treat the mucocutaneous adverse reactions are recommended (eg, skin emollients, sunscreen, lip moisturizers, artificial tears).

Photosensitivity

Advise patients of the increased risk for skin sensitivity to sunlight during treatment and to minimize exposure to sunlight and artificial UV light.

Radiological Vertebral Fractures

Advise patients of the risk for decreased vertebral bone mineral content, bone density and bone strength as well as an increased risk for radiologically observed vertebral fractures and that periodic radiological assessment of the spine is recommended.

Psychiatric Disorders

Advise patients of the risk for new or worsening psychiatric effects, including suicidal thoughts and behaviors, depression, depression aggravated, anxiety, and mood alterations. Monitor closely in patients with a history of psychiatric illness. Monitor for signs of depression and referred for appropriate treatment if necessary.

Night Blindness

Advise patients of the risk for experiencing night blindness.

Drug Interactions

Inform a health care provider of all concomitant medications.

Dosing Instructions

Swallow capsules whole with food. May empty the contents of each capsule onto soft food.

Cost Savings Program

IPSEN CARES

Sohonos

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