Overview
11 DESCRIPTION Palovarotene is an orally bioavailable retinoid that acts as a retinoic acid receptor (RAR) agonist with particular selectivity at the gamma subtype of RAR. Palovarotene is chemically described as 4-[( E )-2-(5,5,8,8-tetramethyl-3-pyrazol-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoic acid with an empirical formula of C 27 H 30 N 2 O 2 and has a molecular weight of...
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action In patients with FOP, abnormal bone formation, including heterotopic ossification (HO), is driven by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1). Palovarotene is an orally bioavailable retinoic acid receptor 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. 12.2 Pharmacodynamics Cardiac Electrophysiology At doses up to 2.
Indications
- 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 ).
Common Doses
- 5 mg
- 20 mg
- 10 mg
- 2.5 mg
Dosage
2 DOSAGE AND ADMINISTRATION Obtain a negative pregnancy test in females of reproductive potential before initiation of SOHONOS ( 2.1 ) Recommended dosage includes a chronic daily dose, which can be increased for flare-up symptoms ( 2.2 ) For adults and pediatric patients 14 years and older: Recommended dosage is 5 mg once daily, with an increase in dose at the time of a flare-up to 20 mg once daily for 4 weeks, followed by 10 mg once daily for 8 weeks for a total of 12 weeks (20/10 mg flare-up treatment) ( 2.
Black Box Warning
WARNING: EMBRYO-FETAL TOXICITY and PREMATURE EPIPHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS WARNING: EMBRYO-FETAL TOXICITY and PREMATURE EPIPHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS See full prescribing information for complete boxed warning. SOHONOS is contraindicated in pregnancy ( 5.1 , 8.1 ) Because of the risk of teratogenicity and to minimize fetal exposure, SOHONOS is to be administered only if conditions for pregnancy prevention are met ( 5.1 , 8.1 ) SOHONOS causes premature epiphyseal closure in growing pediatric patients with FOP, close monitoring is recommended ( 5.2 , 8.
Contraindications
- 4 CONTRAINDICATIONS 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) ]. Pregnancy ( 4 , 5.1 , 8.1 ) Hypersensitivity to retinoids or any component of SOHONOS ( 4 , 11 )
Side Effects
- 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.
Interactions
- 7 DRUG INTERACTIONS CYP3A4 Inhibitors: May increase SOHONOS exposure. Avoid concomitant use of strong/moderate CYP3A4 inhibitors. If concomitant use of moderate CYP3A4 inhibitors is unavoidable, reduce the dose of SOHONOS by half ( 2.5 , 7.1 ) CYP3A4 Inducers: May decrease SOHONOS exposure. Avoid concomitant use of strong/moderate CYP3A4 inducers ( 7.1 ) Vitamin A: May cause additive effects ( 7.2 ) Tetracyclines: Avoid concomitant use with SOHONOS ( 7.3 ) Systemic Corticosteroids: No clinically significant drug interaction is expected with concomitant use of SOHONOS ( 7.4 ) 7.