Introduction

Palovarotene is an orally bioavailable retinoid that acts as a retinoic acid receptor (RAR) agonist.

Uses for Palovarotene (Systemic)

Palovarotene has the following uses:

Palovarotene is indicated for reduction in the volume of new heterotopic ossification in adults and pediatric patients 8 years of age and older for females and 10 years of age and older for males with fibrodysplasia ossificans progressiva (FOP).

Palovarotene (Systemic) Dosage and Administration

General

Palovarotene is available in the following dosage form(s) and strength(s):

Capsules: 1, 1.5, 2.5, 5, 10 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Obtain a negative pregnancy test in females of reproductive potential before initiation of palovarotene.

Take palovarotene with food, preferably at same time each day.

Pediatric Patients

Dosage and Administration

• Recommended dosage includes a chronic daily dosage, which can be increased for flare-up symptoms.

• Recommended dosage for pediatric patients ≥14 years of age: 5 mg once daily, with an increase in dosage 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).

• Recommended dosage for pediatric patients <14 years of age: Weight-based dosage ranging from 2.5 to 5 mg daily for daily and flare-up dosing. See Full Prescribing Information for complete dosing instructions.

• Reduce the dose in the event of adverse reactions as appropriate.

Adults

Dosage and Administration

• Recommended dosage includes a chronic daily dosage, which can be increased for flare-up symptoms.

• Recommended dosage for adults: 5 mg once daily, with an increase in dosage 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).

• Reduce the dose in the event of adverse reactions as appropriate.

• See Full Prescribing Information for complete dosing instructions.

Contraindications

• Pregnancy.

• Hypersensitivity to retinoids or any component of palovarotene.

Warnings/Precautions

Embryo-fetal Toxicity

Palovarotene can cause fetal harm and is contraindicated during pregnancy. Palovarotene 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 1 month after treatment discontinuation. Advise females of reproductive potential to use an effective method of contraception at least 1 month prior to treatment, during treatment with palovarotene, and for 1 month after the last dose. If a pregnancy occurs during palovarotene 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 palovarotene 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.

Premature Epiphyseal Closure in Growing Pediatric Patients

Palovarotene can cause irreversible premature epiphyseal closure and potential adverse effects on growth. In clinical studies, premature epiphyseal closure occurred with palovarotene treatment in growing pediatric patients with fibrodysplasia ossificans progressiva (FOP).

Monitoring of linear growth is recommended in growing pediatric patients. Prior to starting treatment with palovarotene, 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 palovarotene until the patient achieves epiphyseal closure and skeletal maturity.

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 palovarotene. Palovarotene 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. 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.

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 palovarotene. 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).

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 clinical trials, palovarotene 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.

Hyperostosis

Retinoids have been associated with hyperostotic changes (bone spurs) and calcification of tendons or ligaments and may occur with palovarotene. These effects generally occur with long-term use, especially at high doses.

Psychiatric Disorders

New or worsening psychiatric events were reported with palovarotene 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 palovarotene. 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 palovarotene.

Night Blindness

Night blindness has been associated with systemic retinoids, including palovarotene. 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.

Specific Populations

Pregnancy

Palovarotene is contraindicated during pregnancy. Based on the findings in animal studies and class effects of retinoids, palovarotene can cause fetal harm when administered during pregnancy. 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). There are no available human data on palovarotene use in pregnant women. If pregnancy occurs during treatment with palovarotene, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for further evaluation and counseling.

Lactation

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 palovarotene, and for at least 1 month after the final dose.

Females and Males of Reproductive Potential

Palovarotene can cause fetal harm when administered during pregnancy.

Obtain a negative serum pregnancy test within 1 week prior to palovarotene therapy. Verify that patient is not pregnant periodically, as needed, over the course of treatment with palovarotene and 1 month after treatment discontinuation unless they are not at risk of pregnancy.

Palovarotene can cause embryo-fetal harm when administered during pregnancy. Advise females of reproductive potential to use effective contraception at least 1 month prior to treatment, during treatment with palovarotene and for 1 month after the last dose, unless continuous abstinence is chosen.

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 palovarotene to a male patient is considered unlikely to affect development of an embryo or fetus carried by a pregnant female sexual partner exposed to palovarotene via the patient's semen.

Pediatric Use

The safety and effectiveness of palovarotene for the treatment of FOP have been established in pediatric patients 8 years of age and older for females and 10 years of age and older for males. Use of palovarotene for this indication is supported by evidence from clinical studies in adults and pediatric subjects. The safety and effectiveness of palovarotene 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. Palovarotene 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 palovarotene.

In clinical studies with palovarotene, 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 palovarotene treatment. Premature epiphyseal closure was observed as early as 6 months after initiating therapy with the majority occurring at or after 12 months. In palovarotene 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 palovarotene have not been established.

Prior to starting treatment with palovarotene, 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.

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 palovarotene did not include sufficient numbers of subjects 65 years of age 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 palovarotene is recommended in patients with mild (CL_cr 60 to 89 mL/minute) or moderate (CL_cr30 to 59 mL/minute) renal impairment. Use of palovarotene in patients with severe (CL_cr 15 to 29 mL/minute) renal impairment is not recommended.

Hepatic Impairment

The effect of moderate or severe hepatic impairment on the pharmacokinetics of palovarotene has not been evaluated. Palovarotene undergoes extensive hepatic metabolism. No dose adjustment is recommended in patients with mild (Child-Pugh A) hepatic impairment. Use of palovarotene in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment is not recommended.

Common Adverse Effects

Most common adverse reactions (incidence ≥10%) are dry skin, dry lip, arthralgia, pruritus, pain in extremity, rash, alopecia, erythema, headache, back pain, skin exfoliation, nausea, musculoskeletal pain, myalgia, dry eye, hypersensitivity, peripheral edema, and fatigue.

General

Palovarotene is available in the following dosage form(s) and strength(s):

Capsules: 1, 1.5, 2.5, 5, 10 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Obtain a negative pregnancy test in females of reproductive potential before initiation of palovarotene.

Take palovarotene with food, preferably at same time each day.

Pediatric Patients

Dosage and Administration

• Recommended dosage includes a chronic daily dosage, which can be increased for flare-up symptoms.

• Recommended dosage for pediatric patients ≥14 years of age: 5 mg once daily, with an increase in dosage 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).

• Recommended dosage for pediatric patients <14 years of age: Weight-based dosage ranging from 2.5 to 5 mg daily for daily and flare-up dosing. See Full Prescribing Information for complete dosing instructions.

• Reduce the dose in the event of adverse reactions as appropriate.

Adults

Dosage and Administration

• Recommended dosage includes a chronic daily dosage, which can be increased for flare-up symptoms.

• Recommended dosage for adults: 5 mg once daily, with an increase in dosage 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).

• Reduce the dose in the event of adverse reactions as appropriate.

• See Full Prescribing Information for complete dosing instructions.