Palovarotene

Palovarotene is a prescription medication indicated for reduction in volume of new heterotopic ossification in adults with fibrodysplasia ossificans progressiva (FOP).

• Palovarotene is available under the following different brand names: Sohonos

Common side effects of Palovarotene include:

• dry skin
• dry, scaly, or chapped lips
• hair loss
• itching
• redness of the skin
• rash
• skin shedding
• eczema

Serious side effects of Palovarotene include:

• dry eyes
• dry mouth
• diarrhea, upset stomach, or vomiting
• decreased appetite
• heartburn
• back, muscle, or joint pain
• joint swelling
• nosebleeds
• headache
• flushing

Rare side effects of Palovarotene include:

• none

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, coordination loss, unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out.

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult and pediatric dosage

Capsule

• 1 mg
• 1.5 mg
• 2.5 mg
• 5 mg
• 10 mg

FOP

Adult dosage

• Chronic daily dose: 5 mg orally once a day
• Modify/increase the dose in the event of FOP flare-up symptoms (flare-up dose)
• Flare-up dose
  • Initiate at the onset of the first symptom indicative of an FOP flare-up or following a substantial high-risk traumatic event that is likely to lead to a flare-up (e.g., surgery, intramuscular immunizatioZn, mandibular blocks for dental procedures, muscle fatigue, blunt muscle trauma from bumps, bruises, falls, or influenza-like viral illnesses)
  • Symptoms of an FOP flare-up include but are not limited to localized pain, soft tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness
  • 12-week flare-up treatment
    • 20 mg orally once a day for 4 weeks, followed by
    • 10 mg orally once a day for 8 weeks
    • Complete 12 weeks of flare-up treatment even if symptoms resolve earlier, and then
    • return to 5 mg orally once a day
    • If during the flare-up treatment, the original flare-up site worsens or another flare-up starts at a new location, restart the 12-week flare-up dosing at 20 mg once a day
    • If flare-up symptoms have not resolved after the 12-week fare-up treatment period, extend the 10 mg/day dosage in 4-week intervals and continue until flare-up symptoms resolve
    • If new flare-up symptoms occur after the 5 mg/day dosing is resumed, restart flare-up dosing

Pediatric dosage

Chronic daily dose

• Females aged 8-13 years or males aged 10-13 years
  • 10-19.9 kg: 2.5 mg orally once a day
  • 20-39.9 kg: 3 mg orally once a day
  • 30-59.9 kg: 4 mg orally once a day
  • Above 60 kg: 5 mg orally once a day
    • Modify/increase the dose in the event of FOP flare-up symptoms (flare-up dose)
• Females aged 14 years and older
  • 5 mg orally once a day
  • Modify/increase the dose in the event of FOP flare-up symptoms (flare-up dose)
  • Flare-up dose
    • Initiate at the onset of the first symptom indicative of an FOP flare-up or after a substantial high-risk traumatic event that is likely to lead to a flare-up (eg, surgery, intramuscular immunization, mandibular blocks for dental procedures, muscle fatigue, blunt muscle trauma from bumps, bruises, falls, or influenza-like viral illnesses)
    • Symptoms of FOP flare-up include but are not limited to, localized pain, soft tissue swelling/inflammation, redness, warmth, decreased joint range of motion, and stiffness
    • 12-week flare-up treatment (females aged 8-13 years or males aged 10-13 years)
    • Weighing between 10 kg and19.9 kg: 10 mg orally once a day for weeks 1-4, followed by 5 mg orally once a day for weeks 5-12
    • Weighing between 20 kg and 39.9 kg: 12.5 mg orally once a day for weeks 1-4, followed by 6 mg orally once a day for weeks 5-12
    • Weighing between 30 kg and 59.9 kg: 15 mg orally once a day for weeks 1-4, followed by 7.5 mg orally once a day for weeks 5-12
    • Weighing 60 kg and more: 20 mg orally once a day for weeks 1-4, followed by 10 mg orally once a day for weeks 5-12
    • Complete 12 weeks of flare-up treatment even if symptoms resolve earlier, then
    • return to chronic daily dosing as listed above
• If during flare-up treatment, the original flare-up site worsens or another flare-up starts at a new location, restart the 12-week flare-up dosing with the week 1-4 dose
• If flare-up symptoms have not resolved after the 12-week flare-up treatment period, extend week 5 to12 flare-up dose in 4-week intervals, and continue until flare-up symptoms resolve
• If new flare-up symptoms occur after daily dosing is resumed, restart flare-up dosing
• 12-week flare-up treatment (for children aged 14 years and above)
• 20 mg orally once a day for 4 weeks, followed by
• 10 mg orally once a day for 8 weeks
• Complete 12 weeks of flare-up treatment even if symptoms resolve earlier, then
• return to 5 mg orally once a day
• If during flare-up treatment, the original flare-up site worsens or another flare-up starts at a new location, restart the 12-week flare-up dosing at 20 mg once a day
• If flare-up symptoms have not resolved after the 12-week fare-up treatment period, extend the 10 mg/day dosage in 4-week intervals and continue until flare-up symptoms resolve
• If new flare-up symptoms occur after the 5 mg/day dosing is resumed, restart flare-up dosing

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, healthcare provider, or pharmacist first.

• Palovarotene has severe interactions with no other drugs.
• Palovarotene has serious interactions with at least 78 other drugs.
• Palovarotene has moderate interactions with at least 44 other drugs.
• Palovarotene has minor interactions with no other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all the products you use. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, health questions, or concerns.

Contraindications

• Pregnancy
• History of allergy or hypersensitivity to retinoids or any palovarotene components

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Palovarotene?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Palovarotene?”

Cautions

• Embryo-fetal toxicity
  • Can cause fetal harm and is contraindicated during pregnancy
  • Member of the retinoid class of drugs, which is associated with birth defects in humans
  • In animal reproduction studies, fetal malformations typical of retinoids were observed, including cleft palate, misshapen skull bones, and shortening of the long bones at clinically relevant exposures
  • For women of reproductive potential, verify that the patient is not pregnant before initiating the treatment, periodically during therapy, and 1 month after discontinuing palovarotene
  • Inform patients not to donate blood during therapy and for 1 week following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to this drug
• Premature epiphyseal closure in growing children
  • Can cause irreversible premature epiphyseal closure and potential adverse effects on growth
  • Monitor linear growth in growing pediatric patients
  • Before starting treatment, 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 to12 months until skeletal maturity or final adult height is reached
  • If clinical or radiologic evaluations reveal signs of premature epiphyseal closure or adverse effects on growth, further evaluation may be required, including an assessment of the benefits and risks of continued treatment, or temporary or permanent discontinuation until the patient achieves epiphyseal closure and skeletal maturity
• Mucocutaneous adverse effects
  • Mucocutaneous adverse reactions including dry skin, lip dryness, pruritus, rash, alopecia, erythema, skin exfoliation, and dry eye have been observed
  • This may contribute to an increased risk for skin and soft tissue infections, particularly paronychia and decubitus ulcer, owing to skin barrier damage from adverse reactions such as dry and peeling skin
  • Prophylactic measures are recommended to minimize risk and/or treat mucocutaneous adverse reactions (eg, skin emollients, sunscreen, lip moisturizers, artificial tears)
  • Some patients may require dose reduction or drug discontinuation
• Photosensitivity
  • Exaggerated sunburn reactions (eg, burning, erythema, blistering) affecting sun-exposed areas are associated with retinoid use
  • Avoid excessive sun or artificial UV light exposure; use sunscreen, protective clothing, and sunglasses
• Metabolic bone disorder
  • Retinoids are associated with bone toxicity, including reductions in bone mass and spontaneous reports of osteoporosis and fracture
  • Palovarotene resulted in decreased vertebral bone mineral content and bone density, and increased risk for radiologically observed vertebral (T4 to L4) fractures in treated adult and pediatric patients compared with untreated patients
  • Periodic radiological assessment of the spine recommended
• Hyperostosis
  • Retinoids are associated with hyperostotic changes (bone spurs) and calcification of tendons or ligaments
  • These effects generally occur with long-term use, especially at high doses
• Psychiatric disorders
  • New or worsening psychiatric events reported; including 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 the development of new or worsening psychiatric symptoms during treatment
  • Individuals with a history of psychiatric illness may be more susceptible to psychiatric adverse effects; patients and/or caregivers should contact their healthcare provider if new or worsening psychiatric symptoms develop during treatment
• Night blindness
  • Night blindness is associated with systemic retinoids
  • 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 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
• Drug interaction overview
  • Major substrate of CYP3A
    • Strong CYP3A inhibitors
    • Avoid coadministration
    • Coadministration with strong CYP3A4 inhibitors increases Palovarotene systemic exposure, which may increase the risk of adverse effects
  • Moderate CYP3A inhibitors
    • Avoid or reduce the palovarotene dose
    • Coadministration with moderate CYP3A4 inhibitors increases palovarotene systemic exposure, which may increase the risk for adverse effects
    • If unavoidable, reduce palovarotene dose by 50%
  • Strong or moderate CYP3A inducers
    • Avoid coadministration
    • Coadministration with strong or moderate CYP3A4 inducers decreases palovarotene systemic exposure, which may reduce efficacy
  • Vitamin A
    • Avoid coadministration
    • Palovarotene belongs to the same pharmacological class as vitamin A; coadministration may lead to additive effects
    • Vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids coadministered with palovarotene increases the risk for hypervitaminosis A
  • Tetracycline derivatives
    • Avoid coadministration
    • Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines

Pregnancy and Lactation

• Contraindicated during pregnancy; based on findings from animal studies and class effects of retinoids, the drug can cause fetal harm when administered during pregnancy
• Obtain a negative serum pregnancy test 1 week before initiating palovarotene; verify that the patient is not pregnant periodically, as needed, over the course of treatment, and 1 month after treatment discontinuation unless they are not at risk for pregnancy
• If pregnancy occurs during treatment, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for further evaluation and counseling
• Contraception
  • Women of reproductive potential: Use effective contraception at least 1 month before initiating treatment, during treatment, and for 1 month after the last dose (unless continuous abstinence is chosen)
  • Men
    • Palovarotene is present in semen (0.7 ng/mL) in amounts 100-fold lower than maternal plasma exposure at the no observed adverse effect level for fetal toxicity observed in animal studies
    • Administration to a male patient is considered unlikely to affect the development of an embryo or fetus carried by a pregnant female sexual partner exposed to palovarotene via the patient’s semen
• Lactation
  • There are no data available on the presence of the drug/metabolites in either animal or human milk, its effects on breastfed infants, or milk production
  • Advise women that breastfeeding is not recommended during treatment and for at least 1 month after the final dose