Palovarotene (Monograph)

Drug class: Other Miscellaneous Therapeutic Agents

Medically reviewed by Drugs.com on Sep 10, 2024. Written by ASHP.

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Introduction

Orally bioavailable retinoid; retinoic acid receptor gamma (RARγ) agonist.

Uses for Palovarotene

Fibrodysplasia Ossificans Progressiva

Indicated for reduction of heterotopic ossification in adults and pediatric females ≥8 years of age and males ≥10 years of age with fibrodysplasia ossificans progressiva (FOP); designated as an orphan drug by the FDA for this use.

According to the International Clinical Council on FOP guidelines, the management of FOP is largely supportive and is aimed at managing chronic symptoms and disease flare-ups. The role of palovarotene in therapy is not specifically addressed in the current treatment guidelines; the drug was being studied in clinical trials at the time of their publication.

Palovarotene Dosage and Administration

General

Pretreatment Screening

• Obtain a pregnancy test in females of reproductive potential within 1 week prior to initiation of therapy.

• Perform baseline assessment of growth and skeletal maturity via hand/wrist and knee x-rays, standard growth curves, and pubertal staging in all growing pediatric patients.

Patient Monitoring

• Obtain a pregnancy test in females of reproductive potential periodically during treatment and 1 month after discontinuation.

• Monitor growth and skeletal maturity via hand/wrist and knee x-rays, standard growth curves, and pubertal staging in all growing pediatric patients every 6 to 12 months until skeletal maturity or final adult height is reached.

• Perform periodic radiological assessment of the spine to monitor for bone disorders.

• Monitor for development of new or worsening psychiatric symptoms during therapy.

Administration

Take capsules orally with food preferably at the same time every day.

Capsules should be swallowed whole. Alternatively, the capsules may be opened and contents emptied onto 5 mL of soft food (e.g., apple sauce, low-fat yogurt, warm oatmeal) and taken within 1 hour of opening provided it was maintained at room temperature and not exposed to direct sunlight.

Do not administer with grapefruit, pomelo, or juices containing these fruits.

If a dose is missed, take the missed dose as soon as possible. If the dose is missed by more than 6 hours, skip the missed dose and continue with the next scheduled dose. Do not take 2 doses at the same time or in the same day.

Dosage

Pediatric Patients

Chronic Management of Fibrodysplasia Ossificans Progressiva

Oral

Dosage is based on age and weight (see Table 1) and is given once daily.

Flare-up Treatment of Fibrodysplasia Ossificans Progressiva

Oral

Initiate flare-up treatment at onset of first symptom indicative of flare-up or substantial high-risk traumatic event likely to lead to flare-up (e.g., surgery, IM immunization, mandibular blocks for dental procedures, muscle fatigue, blunt muscle trauma from bumps, bruises, and falls, or influenza-like viral illnesses).

Dosage is based on age and weight (see Table 2) and is given once daily.

Administer initial flare-up dosage for 4 weeks, followed by lower flare-up dosage for 8 weeks, for a total duration of 12 weeks even if symptoms improve earlier. After 12 weeks, return to chronic management daily dosage.

If flare-up symptoms not resolved after 12 weeks, week 5–12 flare-up dosage may be extended in 4-week intervals and continued until flare-up symptoms resolve. If new flare-up symptoms occur after daily dosing is resumed, flare-up dosing may be restarted.

If flare-up symptoms worsen at original site or if a flare-up occurs at a new location, restart 12-week flare-up dosing with week 1–4 dosage.

Adults

Chronic Management of Fibrodysplasia Ossificans Progressiva

Oral

5 mg once daily.

Flare-up Treatment of Fibrodysplasia Ossificans Progressiva

Oral

Initiate flare-up treatment at onset of first symptom indicative of flare-up or substantial high-risk traumatic event likely to lead to flare-up (e.g., surgery, IM immunization, mandibular blocks for dental procedures, muscle fatigue, blunt muscle trauma from bumps, bruises, and falls, or influenza-like viral illnesses).

Initially, 20 mg once daily for 4 weeks, followed by 10 mg once daily for 8 weeks, for a total treatment duration of 12 weeks even if symptoms improve earlier. Return to 5 mg once daily after 12 weeks if flare-up symptoms resolve.

If flare-up symptoms not resolved at 12 weeks, continue 10 mg once daily in 4-week intervals until resolved.

If flare-up symptoms markedly worsen in original site or if another flare-up occurs at a new location, restart 12-week flare-up dosage of 20 mg daily.

Dosage Modification for Toxicity

Reduce to next lower dosage if adverse reactions require dosage reduction during either chronic management or flare-up treatment (see Table 3). Reduce dosage further if adverse reactions do not improve. If patient is already receiving the lowest possible tolerated dosage, consider temporary interruption or permanent discontinuance of therapy. Initiate subsequent flare-up dosing at the same reduced dosage that was tolerated previously.

Dosage Modification for Drug Interactions

Avoid concomitant use of moderate CYP3A inhibitors, if possible. If concomitant use will occur, reduce palovarotene dosage by 50% (see Table 4).

Special Populations

Hepatic Impairment

No dosage adjustments for mild hepatic impairment (Child-Pugh class A); use in moderate or severe (Child-Pugh class B or C) hepatic impairment not recommended.

Renal Impairment

No dosage adjustments recommended for mild (Cl_cr 60 to 89 mL/minute) or moderate (Cl_cr 30 to 59 mL/minute) renal impairment; use in severe renal impairment (Cl_cr 15-29 mL/minute) not recommended.

Geriatric Patients

No specific dosage recommendations at this time; use with caution and generally start 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.

Cautions for Palovarotene

Contraindications

• Pregnancy.

• History of allergy or hypersensitivity to retinoids or to any component of the palovarotene formulation. Anaphylaxis and other allergic reactions have occurred with other retinoids.

Warnings/Precautions

Warnings

Embyrofetal Toxicity

Palovarotene can cause fetal harm and is contraindicated during pregnancy. (See Boxed Warning.)

For females of reproductive potential, verify 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, discontinue treatment immediately and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Inform patients 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. (See Boxed Warning.)

Monitoring of linear growth is recommended in growing pediatric patients. Conduct baseline assessment of skeletal maturity via hand/wrist and knee x-rays, standard growth curves, and pubertal staging in all growing pediatric patients prior to starting treatment. Continued monitoring is recommended every 6 to 12 months until skeletal maturity or final adult height is reached.

Signs of premature epiphyseal closure or adverse effects on growth require further evaluation, including assessment of benefits and risks of continued treatment, or temporary or permanent discontinuation of palovarotene until epiphyseal closure and skeletal maturity are reached.

Other Warnings/Precautions

Mucocutaneous Adverse Reactions

Mucocutaneous adverse reactions (e.g., dry skin, dry lips, pruritus, rash, alopecia, erythema, skin exfoliation [skin peeling], dry eyes) occurred in most (98%) palovarotene-treated patients. An increased risk of skin and soft tissue infections (particularly paronychia and decubitus ulcer) also reported. Some of these adverse reactions led to dose reduction or drug discontinuation.

Prophylactic measures to minimize risk and/or treat the mucocutaneous adverse reactions recommended (e.g., skin emollients, sunscreen, lip moisturizers, artificial tears).

Photosensitivity reactions reported. Precautionary measures for phototoxicity are recommended, including avoidance of excessive exposure to sun or artificial ultraviolet light and use of protection (e.g., sunscreens, sunglasses, protective clothing) when exposure to sunlight cannot be avoided.

Metabolic Bone Disorders

Retinoids are associated with bone toxicity, including reductions in bone mass and spontaneous reports of osteoporosis and fracture. Periodic radiological assessment of the spine is recommended during therapy.

Retinoids are also associated with hyperostotic changes (bone spurs) and calcification of tendons or ligaments; these effects generally occur during long-term use, particularly at high doses.

Psychiatric Disorders

New or worsening psychiatric events reported, including depression, anxiety, mood alterations, and suicidal thoughts and behaviors. Individuals with a history of psychiatric illness may be more susceptible to these adverse effects. Monitor for development of new or worsening psychiatric symptoms during therapy.

Night Blindness

Night blindness associated with systemic retinoids, including palovarotene. Advise patients to use caution when driving or operating any vehicle at night and to seek medical attention in the event of vision impairment.

Specific Populations

Pregnancy

Contraindicated during pregnancy. No available human data in pregnant women.

Based on findings in animal studies and class effects of retinoids, palovarotene can cause fetal harm when administered during pregnancy.

If pregnancy occurs during treatment, discontinue treatment immediately and refer patient to a specialist experienced in reproductive toxicity for further evaluation and counseling.

Lactation

No data available on the presence of palovarotene or its main metabolites in animal or human milk, the effects on the breast-fed infant, or on milk production.

Breastfeeding not recommended during treatment and for at least 1 month after the final dose.

Females and Males of Reproductive Potential

Can cause fetal harm when administered during pregnancy. Obtain negative serum pregnancy test within 1 week prior to initiation of therapy. Verify negative pregnancy test periodically over the course of treatment and 1 month after discontinuation unless not at risk of pregnancy. Advise females of reproductive potential to use effective contraception at least 1 month prior to treatment, during treatment, and for 1 month after the last dose, unless continuous abstinence is chosen.

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

Pediatric Use

Safety and effectiveness of palovarotene for treatment of fibrodysplasia ossificans progressiva (FOP) established in pediatric female patients ≥8 years of age and male patients ≥10 years of age. Safety and effectiveness of palovarotene for treatment of FOP not established in pediatric female patients <8 years of age and male patients <10 years of age; palovarotene is not recommended in these patients because of potential for premature epiphyseal closure. Clinical studies have shown that growing patients with open epiphyses are at serious risk of developing irreversible premature epiphyseal closure when treated with palovarotene.

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.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65 years and older to determine whether they respond differently from younger patients. Dosage selection for geriatric patients 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.

Hepatic Impairment

Undergoes extensive hepatic metabolism. No dosage adjustment is recommended in patients with mild (Child-Pugh class A) hepatic impairment. Effect of moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment on pharmacokinetics has not been evaluated; use is not recommended.

Renal Impairment

Effect of renal impairment on pharmacokinetics has not been evaluated. No dosage adjustment recommended in mild (Cl_cr 60 to 89 mL/minute) or moderate (Cl_cr 30 to 59 mL/minute) renal impairment. Use in severe (Cl_cr 15 to 29 mL/minute) renal impairment not recommended.

Common Adverse Effects

Most common adverse reactions (≥10% of patients): Dry skin, dry lips, arthralgia, pruritus, extremity pain, rash, alopecia, erythema, headache, back pain, skin exfoliation, nausea, musculoskeletal pain, myalgia, dry eyes, hypersensitivity, peripheral edema, fatigue.

Drug Interactions

Extensively metabolized by CYP3A4 and to a minor extent by CYP2C8 and CYP2C19.

Inducer of CYP3A4 and CYP2B6 but not CYP1A2, CYP2C8, CYP2C9, and CYP2C19.

Not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

Not an inhibitor or substrate of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.

Not an inhibitor of breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter (OAT) 1 or OAT3, organic anion transporter polypeptide (OATP) 1B1 or OATP1B3, organic cation transporter (OCT) 1 or OCT2, multidrug and toxin extrusion (MATE) 1, MATE2 K, or P-glycoprotein (P-gp).

Not a substrate of BCRP, OATP1B1, OATP1B3, OCT1, or P-gp.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors: Concurrent use increases palovarotene exposure, which may increase risk of adverse effects. Avoid concomitant use.

Moderate CYP3A4 inhibitors: Concurrent use may increase palovarotene exposure, which may increase risk of adverse effects. Avoid concomitant use, if possible. If concomitant use will occur, reduce palovarotene dosage by 50%.

Strong CYP3A4 inducers: Concurrent use decreases palovarotene exposure, which may reduce efficacy. Avoid concomitant use.

Moderate CYP3A4 inducers: Concurrent use may decrease palovarotene exposure, which may reduce efficacy. Avoid concomitant use.

Specific Drugs and Foods

Palovarotene Pharmacokinetics

Absorption

Bioavailability

AUC increases proportionally from 0.02 to 50 mg (0.001 to 2.5 times the maximum recommended dosage).

Food

Mean AUC and C_max increased approximately 40 and 16%, respectively, when administered with food.

Mean T_max occurs at 3—4 hours when administered without food; a delay in T_max of approximately 2 hours observed when administered with a high-fat, high-calorie meal (800-1000 calories, 50-60% fat).

No clinically significant differences in AUC and C_max when capsules are administered whole compared to when contents are sprinkled onto 5 mL of applesauce following a high-fat, high-calorie breakfast.

Special Populations

Body weight (range: 13 to 130 kg) found to have a significant effect on pharmacokinetics, resulting in increasing exposure with decreasing weight at the same dose.

Distribution

Plasma Protein Binding

97.9-99.6% bound to plasma proteins

Elimination

Metabolism

Extensively metabolized by CYP3A4 and to a minor extent by CYP2C8 and 2C19.

Major metabolites M3 and M4B retain approximately 1.7 and 4.2% of the activity of the parent drug, respectively.

Elimination Route

Recovered in the feces (97.1%) and urine (3.2%).

Half-life

8.7 hours following chronic administration with a standard breakfast.

Special Populations

No clinically significant differences in pharmacokinetics based on age (range: 2 to 85 years), sex, race, smoking status, mild to moderate (Cl_cr 30 to 89 mL/minute) renal impairment, or mild (Child-Pugh class A) hepatic impairment.

Effect of severe renal impairment (Cl_cr 15 to 29 mL/minute) or moderate to severe (Child-Pugh class B or C) hepatic impairment on pharmacokinetics unknown.

Stability

Storage

Oral

Capsules

Store in original carton to protect from light at 20–25°C; excursions permitted to 15–30°C.

Actions

• In fibrodysplasia ossificans progressiva (FOP), abnormal bone formation, including heterotrophic ossification, is driven by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor activin receptor-like kinase-2 (ALK2).

• Palovarotene is an orally bioavailable retinoic acid receptor (RAR) agonist with selectivity at the gamma subtype of RAR (RARγ).

• 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.

Advice to Patients

• Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

• Advise patients that palovarotene can cause fetal harm and is contraindicated during pregnancy. Advise patients to verify that they are not pregnant prior to initiation and periodically during palovarotene treatment, as well as 1 month after treatment discontinuation. Advise females of reproductive potential to use at least 1 highly effective method (i.e., intrauterine device) or 2 effective methods of contraception (i.e., combined hormonal contraception in combination with another method such as a barrier method) at least 1 month prior to treatment, during treatment, and for 1 month after the last dose of palovarotene, unless continuous abstinence is chosen. Inform patients that if pregnancy occurs during treatment with palovarotene, they should immediately discontinue treatment and rapidly consult a clinician if there is a risk of pregnancy.

• Inform patients not to donate blood during treatment with palovarotene and for 1 week following discontinuation to avoid the blood being given to a pregnant patient and fetus.

• Advise females not to breastfeed during treatment with palovarotene and for at least 1 month after the last dose due to the potential for serious adverse reactions from palovarotene in a breast-fed child.

• Inform patients that palovarotene has been shown to cause premature epiphyseal closure in growing pediatric patients with fibrodysplasia ossificans progressiva (FOP) and discuss the recommended monitoring plan with the patient and caregiver.

• Advise patients that they may experience dry skin, dry lips, pruritus, rash, alopecia, erythema, skin exfoliation, and dry eyes. Advise patients of an appropriate plan to assess their symptoms and inform them that an adjustment to the dosage may be needed. Advise patients on appropriate prophylactic measures to minimize risk and/or treat mucocutaneous adverse reactions (e.g., skin emollients, sunscreen, lip moisturizers, artificial tears).

• Advise patients of potential increased skin sensitivity to sunlight while taking palovarotene and to minimize exposure to sunlight and artificial ultraviolet light. Advise patients that the use of protection from sunlight (e.g., sunscreen, sunglasses, protective clothing) is recommended when exposure cannot be avoided.

• Inform patients that palovarotene can cause decreased vertebral bone mineral content, bone density, and bone strength as well as an increased risk of radiologically-observed vertebral fractures, and that periodic radiological assessment of the spine is recommended.

• Advise patients of the possibility of experiencing new or worsening psychiatric effects, including suicidal thoughts and behaviors, depression, aggravated depression, anxiety, and mood alterations. Particular care should be taken in patients with a history of psychiatric illness. Patients should be monitored for new or worsening psychiatric symptoms and patients and/or caregivers should contact their clinician if new or worsening psychiatric symptoms develop during treatment with palovarotene.

• Advise patients of the risk of experiencing night blindness. Advise patients to be cautious when driving or operating any vehicle at night and to seek medical attention in the event of vision impairment.

• Advise patients to take palovarotene capsules with food. Inform the patient that if they are unable to swallow the capsules, the contents of the capsule may be emptied onto 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.

• If a dose of palovarotene is missed, advise the patient to take it as soon as possible. If the dose is missed by more than 6 hours, advise the patient to skip the missed dose and continue with the next scheduled dose. Advise the patient not to take 2 doses at the same time or in the same day.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Palovarotene is available through specialty pharmacies. Contact manufacturer for availability information.

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