palovarotene (Rx)

Brand and Other Names:Sohonos

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

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

Fibrodysplasia Ossificans Progressiva

Indicated for reduction in volume of new heterotopic ossification in adults with fibrodysplasia ossificans progressiva (FOP)

Chronic daily dose: 5 mg PO qDay

Modify/increase dose in the event of FOP flare-up symptoms (flare-up dose)

Flare-up dose

  • Initiate at onset of first symptom indicative of a FOP flare-up or substantial high-risk traumatic event 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
    • 20 mg PO qDay for 4 weeks, followed by
    • 10 mg PO qDay for 8 weeks
    • Complete 12 week of flare-up treatment even if symptoms resolve earlier, THEN
    • Return to 5 mg PO qDay
    • If during course of flare-up treatment, original flare-up site worsens or another flare-up starts at a new location, restart 12-week flare-up dosing at 20 mg qDay
    • If flare-up symptoms have not resolved after 12-week fare-up treatment period, extend 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 Modifications

Dose reductions for adverse reactions

  • If patients experience adverse reactions that require dosage reduction during either daily dosing or flare-up dosing, reduce daily dosage to next lower dose as shown below at the discretion of the healthcare provider
  • May further reduce dosage if adverse reactions do not improve
  • If already receiving lowest possible tolerated dose, then consider discontinuing temporarily or permanently
  • Initiate subsequent flare-up dosing at the same reduced dose that was tolerated previously
  • Dose reduction for flare-up and chronic treatment
    • Prescribed dose 20 mg qDay: Reduce to 15 mg qDay
    • Prescribed dose 15 mg qDay: Reduce to 12.5 mg qDay
    • Prescribed dose 12.5 mg qDay: Reduce to 10 mg qDay
    • Prescribed dose 10 mg qDay: Reduce to 7.5 mg qDay
    • Prescribed dose 7.5 mg qDay: Reduce to 5 mg qDay
    • Prescribed dose 6 mg qDay: Reduce to 4 mg qDay
    • Prescribed dose 5 mg qDay: Reduce to 2.5 mg qDay
    • Prescribed dose 4 mg qDay: Reduce to 2 mg qDay
    • Prescribed dose 3 mg qDay: Reduce to 1.5 mg qDay
    • Prescribed dose 2.5 mg qDay: Reduce to 1 mg qDay

Dosage modifications for strong or moderate CYP3A inhibitors

  • Strong CYP3A inhibitors: Avoid coadministration
  • Moderate CYP3A4 inhibitors: Avoid coadministration; if unavoidable, reduce dose by half as shown below when coadministered with moderate CYP3A inhibitors
  • ≥60 kg
    • Daily dose: Reduce to 2.5 mg qDay
    • Week 1-4 flare-up dosage: 10 mg qDay
    • Week 5-12 flare-up dosage: 5 mg qDay

Renal impairment

  • Mild or moderate: No dosage adjustment necessary
  • Severe: Pharmacokinetics are unknown

Hepatic impairment

  • Mild: No dosage adjustment necessary
  • Moderate or severe: Pharmacokinetics are unknown

Dosing Considerations

Obtain a negative pregnancy test within 1 week before initiating and periodically during therapy

If pregnancy occurs, stop treatment immediately and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity

Dosage Forms & Strengths

capsule

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

Fibrodysplasia Ossificans Progressiva

Indicated for reduction in volume of new heterotopic ossification in adults and pediatric patients aged ≥8 years for females and ≥10 years for males with fibrodysplasia ossificans progressiva (FOP)

Chronic daily dose

  • Females aged 8-13 years OR males aged 10-13 years
    • 10-19.9 kg: 2.5 mg PO qDay
    • 20-39.9 kg: 3 mg PO qDay
    • 30-59.9 kg: 4 mg PO qDay
    • ≥60 kg: 5 mg PO qDay
    • Modify/increase dose in the event of FOP flare-up symptoms (flare-up dose)
  • ≥14 years
    • 5 mg PO qDay
    • Modify/increase dose in the event of FOP flare-up symptoms (flare-up dose)

Flare-up dose

  • Initiate at onset of first symptom indicative of a FOP flare-up or substantial high-risk traumatic event 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)
    • 10-19.9 kg: 10 mg PO qDay for Week 1-4, followed by 5 mg PO qDay for Week 5-12
    • 20-39.9 kg: 12.5 mg PO qDay for Week 1-4, followed by 6 mg PO qDay for Week 5-12
    • 30-59.9 kg: 15 mg PO qDay for Week 1-4, followed by 7.5 mg PO qDay for Week 5-12
    • ≥60 kg: 20 mg PO qDay for Week 1-4, followed by 10 mg PO qDay for Week 5-12
    • Complete 12 week of flare-up treatment even if symptoms resolve earlier, THEN
    • Return to chronic daily dosing as listed above
    • If during flare-up treatment, original flare-up site worsens or another flare-up starts at a new location, restart 12-week flare-up dosing with the Week 1-4 dose
    • If flare-up symptoms have not resolved after 12-week flare-up treatment period, extend Week 5-12 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 (aged ≥14 years)
    • 20 mg PO qDay for 4 weeks, followed by
    • 10 mg PO qDay for 8 weeks
    • Complete 12 week of flare-up treatment even if symptoms resolve earlier, THEN
    • Return to 5 mg PO qDay
    • If during course of flare-up treatment, original flare-up site worsens or another flare-up starts at a new location, restart 12-week flare-up dosing at 20 mg qDay
    • If flare-up symptoms have not resolved after 12-week fare-up treatment period, extend 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 Modifications

Dose reductions for adverse reactions

  • If patients experience adverse reactions that require dosage reduction during either daily dosing or flare-up dosing, reduce daily dosage to next lower dose as shown below at the discretion of the healthcare provider
  • May further reduce dosage if adverse reactions do not improve
  • If already receiving lowest possible tolerated dose, then consider discontinuing temporarily or permanently
  • Initiate subsequent flare-up dosing at the same reduced dose that was tolerated previously
  • Dose reduction for flare-up and chronic treatment
    • Prescribed dose 20 mg qDay: Reduce to 15 mg qDay
    • Prescribed dose 15 mg qDay: Reduce to 12.5 mg qDay
    • Prescribed dose 12.5 mg qDay: Reduce to 10 mg qDay
    • Prescribed dose 10 mg qDay: Reduce to 7.5 mg qDay
    • Prescribed dose 7.5 mg qDay: Reduce to 5 mg qDay
    • Prescribed dose 6 mg qDay: Reduce to 4 mg qDay
    • Prescribed dose 5 mg qDay: Reduce to 2.5 mg qDay
    • Prescribed dose 4 mg qDay: Reduce to 2 mg qDay
    • Prescribed dose 3 mg qDay: Reduce to 1.5 mg qDay
    • Prescribed dose 2.5 mg qDay: Reduce to 1 mg qDay

Dosage modifications for strong or moderate CYP3A inhibitors

  • Strong CYP3A inhibitors: Avoid coadministration
  • Moderate CYP3A inhibitors: Avoid coadministration; if unavoidable, reduce dose by half as shown below when coadministered with moderate CYP3A inhibitors
  • 10-19.9 kg
    • Daily dose: Reduce to 1 mg qDay
    • Week 1-4 flare-up dosage: 5 mg qDay
    • Week 5-12 flare-up dosage: 2.5 mg qDay
  • 20-39.9 kg
    • Daily dose: Reduce to 1.5 mg qDay
    • Week 1-4 flare-up dosage: 6 mg qDay
    • Week 5-12 flare-up dosage: 3 mg qDay
  • 40-59.9 kg
    • Daily dose: Reduce to 2 mg qDay
    • Week 1-4 flare-up dosage: 7.5 mg qDay
    • Week 5-12 flare-up dosage: 4 mg qDay
  • ≥60 kg or ≥14 years
    • Daily dose: Reduce to 2.5 mg qDay
    • Week 1-4 flare-up dosage: 10 mg qDay
    • Week 5-12 flare-up dosage: 5 mg qDay

Dosing Considerations

Obtain a negative pregnancy test within 1 week before initiating and periodically during therapy

If pregnancy occurs, stop treatment immediately and refer patient to an obstetrician/gynecologist experienced in reproductive toxicity

Next:

Interactions

Interaction Checker

and palovarotene

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            Contraindicated (0)

              Serious - Use Alternative (78)

              • acitretin

                acitretin, palovarotene. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids coadministered with palovarotene increases risk of hypervitaminosis A. .

              • alitretinoin topical

                alitretinoin topical, palovarotene. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids coadministered with palovarotene increases risk of hypervitaminosis A. .

              • amobarbital

                amobarbital will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • apalutamide

                apalutamide will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • armodafinil

                armodafinil will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • atazanavir

                atazanavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • belzutifan

                belzutifan will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • bexarotene

                bexarotene will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

                bexarotene, palovarotene. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids coadministered with palovarotene increases risk of hypervitaminosis A. .

              • bosentan

                bosentan will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • butabarbital

                butabarbital will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • butalbital

                butalbital will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • carbamazepine

                carbamazepine will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • cenobamate

                cenobamate will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • chloramphenicol

                chloramphenicol will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • clarithromycin

                clarithromycin will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • cobicistat

                cobicistat will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • conivaptan

                conivaptan will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • dabrafenib

                dabrafenib will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • darunavir

                darunavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • demeclocycline

                demeclocycline, palovarotene. Other (see comment). Avoid or Use Alternate Drug. Comment: Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines.

              • doxycycline

                doxycycline, palovarotene. Other (see comment). Avoid or Use Alternate Drug. Comment: Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines.

              • duvelisib

                duvelisib will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • efavirenz

                efavirenz will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • elagolix

                elagolix will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • elvitegravir/cobicistat/emtricitabine/tenofovir DF

                elvitegravir/cobicistat/emtricitabine/tenofovir DF will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • enzalutamide

                enzalutamide will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • eravacycline

                eravacycline, palovarotene. Other (see comment). Avoid or Use Alternate Drug. Comment: Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines.

              • eslicarbazepine acetate

                eslicarbazepine acetate will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • etravirine

                etravirine will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • fosphenytoin

                fosphenytoin will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • grapefruit

                grapefruit will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • idelalisib

                idelalisib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • indinavir

                indinavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • isotretinoin

                isotretinoin, palovarotene. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids coadministered with palovarotene increases risk of hypervitaminosis A. .

              • itraconazole

                itraconazole will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • ivosidenib

                ivosidenib will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • ketoconazole

                ketoconazole will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • levoketoconazole

                levoketoconazole will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • lonafarnib

                lonafarnib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of palovarotene, a CYP3A substrate, with strong CYP3A inhibitors

              • lopinavir

                lopinavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • lorlatinib

                lorlatinib will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • lumacaftor/ivacaftor

                lumacaftor/ivacaftor will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • mavacamten

                mavacamten will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • mifepristone

                mifepristone will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • minocycline

                minocycline, palovarotene. Other (see comment). Avoid or Use Alternate Drug. Comment: Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines.

              • mitapivat

                mitapivat will decrease the level or effect of palovarotene by affecting hepatic enzyme CYP2E1 metabolism. Avoid or Use Alternate Drug.

              • mitotane

                mitotane will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • mobocertinib

                mobocertinib will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • modafinil

                modafinil will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • nafcillin

                nafcillin will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • nefazodone

                nefazodone will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • nelfinavir

                nelfinavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • nirmatrelvir/ritonavir

                nirmatrelvir/ritonavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • olutasidenib

                olutasidenib will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • omadacycline

                omadacycline, palovarotene. Other (see comment). Avoid or Use Alternate Drug. Comment: Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines.

              • pentobarbital

                pentobarbital will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • pexidartinib

                pexidartinib will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • phenobarbital

                phenobarbital will decrease the level or effect of palovarotene by affecting hepatic enzyme CYP2E1 metabolism. Avoid or Use Alternate Drug.

              • phenytoin

                phenytoin will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • posaconazole

                posaconazole will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • primidone

                primidone will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • rifabutin

                rifabutin will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • rifampin

                rifampin will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • rifapentine

                rifapentine will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • ritonavir

                ritonavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • rucaparib

                rucaparib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • saquinavir

                saquinavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • sarecycline

                sarecycline, palovarotene. Other (see comment). Avoid or Use Alternate Drug. Comment: Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines.

              • secobarbital

                secobarbital will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • sotorasib

                sotorasib will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • St John's Wort

                St John's Wort will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • stiripentol

                stiripentol will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • telotristat ethyl

                telotristat ethyl will decrease the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • tetracycline

                tetracycline, palovarotene. Other (see comment). Avoid or Use Alternate Drug. Comment: Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines.

              • tretinoin

                tretinoin, palovarotene. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids coadministered with palovarotene increases risk of hypervitaminosis A. .

              • tucatinib

                tucatinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              • vitamin A

                vitamin A, palovarotene. Either increases effects of the other by pharmacodynamic synergism. Avoid or Use Alternate Drug. Vitamin A in doses higher than the recommended daily allowance and/or other oral retinoids coadministered with palovarotene increases risk of hypervitaminosis A. .

              • voriconazole

                voriconazole will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              Monitor Closely (44)

              • adagrasib

                adagrasib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • amiodarone

                amiodarone will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • aprepitant

                aprepitant will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • bicalutamide

                bicalutamide will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • ceritinib

                ceritinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • crizotinib

                crizotinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • cyclosporine

                cyclosporine will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • diltiazem

                diltiazem will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • doxycycline

                doxycycline will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • dronedarone

                dronedarone will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • encorafenib

                encorafenib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • entacapone

                entacapone will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • erythromycin base

                erythromycin base will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • erythromycin ethylsuccinate

                erythromycin ethylsuccinate will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • erythromycin lactobionate

                erythromycin lactobionate will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • erythromycin stearate

                erythromycin stearate will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • fedratinib

                fedratinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • fexinidazole

                fexinidazole will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • fluconazole

                fluconazole will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • fluvoxamine

                fluvoxamine will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • fosamprenavir

                fosamprenavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • fosaprepitant

                fosaprepitant will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • fostamatinib

                fostamatinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • haloperidol

                haloperidol will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • ibrexafungerp

                ibrexafungerp will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • iloperidone

                iloperidone will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • imatinib

                imatinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • isavuconazonium sulfate

                isavuconazonium sulfate will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • isoniazid

                isoniazid will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • ivacaftor

                ivacaftor will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • lapatinib

                lapatinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • larotrectinib

                larotrectinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • lefamulin

                lefamulin will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • lenacapavir

                lenacapavir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • letermovir

                letermovir will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • metronidazole

                metronidazole will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • netupitant/palonosetron

                netupitant/palonosetron will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • quinupristin/dalfopristin

                quinupristin/dalfopristin will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • ribociclib

                ribociclib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • ritlecitinib

                ritlecitinib will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • sertraline

                sertraline will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • tetracycline

                tetracycline will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • verapamil

                verapamil will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              • voxelotor

                voxelotor will increase the level or effect of palovarotene by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Avoid coadministration of palovarotene, a CYP3A substrate, with moderate CYP3A inhibitors. If unavoidable, reduce palovarotene dose by 50%.

              Minor (0)

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                Adverse Effects

                >10%

                Premature epiphyseal closure, <18 years (27%)

                Chronic dosing

                • Dry skin (61%)
                • Dry lips (47%)
                • Arthralgia (36%)
                • Pruritus (34%)
                • Pain in extremity (29%)
                • Rash (28%)
                • Alopecia (24%)
                • Erythema (19%)
                • Headache (19%)
                • Back pain (17%)
                • Skin exfoliation (15%)
                • Nausea (15%)
                • Musculoskeletal pain (14%)
                • Myalgia (12%)

                Flare-up dosing

                • Dry skin (57%)
                • Pruritus (48%)
                • Dry lips (38%)
                • Erythema (32%)
                • Arthralgia (31%)
                • Rash (30%)
                • Alopecia (30%)
                • Skin exfoliation (29%)
                • Pain in extremity (28%)
                • Dry eye (22%)
                • Hypersensitivity (20%)
                • Peripheral edema (19%)
                • Headache (19%)
                • Nausea (13%)
                • Musculoskeletal pain (13%)
                • Back pain (11%)
                • Fatigue (11%)

                1-10%

                Chronic dosing

                • Dry eye (10%)
                • Hypersensitivity (10%)
                • Peripheral edema (9%)
                • Fatigue (5%)
                • Hypertriglyceridemia (2%)
                • Elevated ALT, 5-mg dose (1.5%)

                Flare-up dosing

                • Myalgia (9%)
                • Elevated ALT, 20/10 mg flare-up dose (7%)
                • Hypertriglyceridemia (4%)

                Frequency Not Defined

                Loss of bone mineral density and radiological vertebral fractures were identified as a risk

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                Warnings

                Black Box Warnings

                Embryo-fetal toxicity

                • Contraindicated in pregnancy
                • Palovarotene may cause fetal harm
                • Because of risk of teratogenicity and to minimize fetal exposure, administered only if conditions for pregnancy prevention are met

                Premature epiphyseal closure

                • Premature epiphyseal closure occurs in growing pediatric patients treated with palovarotene, close monitoring is recommended

                Contraindications

                Pregnancy

                History of allergy or hypersensitivity to retinoids or any palovarotene components

                Cautions

                Embryo-fetal toxicity

                • Can cause fetal harm and is contraindicated during pregnancy
                • Member of 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 females of reproductive potential, verify that patient is not pregnant before initiating 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 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 6-12 months until skeletal maturity or final adult height is reached
                • If signs of premature epiphyseal closure or adverse effects on growth are exhibited based on clinical or radiologic evaluations, further evaluation may be required, including an assessment of benefits and risks of continued treatment, or temporary or permanent discontinuation until patient achieves epiphyseal closure and skeletal maturity

                Mucocutaneous adverse effects

                • Mucocutaneous adverse reactions including dry skin, lip dry, pruritus, rash, alopecia, erythema, skin exfoliation, and dry eye occurred
                • This 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
                • 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) involving areas exposed to sun 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 of radiologically observed vertebral (T4 to L4) fractures in treated adult and pediatric patients compared to 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 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 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 risk of adverse effects
                • Moderate CYP3A inhibitors
                  • Avoid or reduce palovarotene dose
                  • Coadministration with moderate CYP3A4 inhibitors increases palovarotene systemic exposure, which may increase risk of adverse effects
                  • If unavoidable, reduce palovarotene dose by 50%
                • Strong or moderate CYP3A inducers
                  • Avoid coadministration
                  • Coadministration with strong or moderate CYP3A4 inducers decreased palovarotene systemic exposure, which may reduce efficacy
                • Vitamin A
                  • Avoid
                  • 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 risk of hypervitaminosis A
                • Tetracycline derivatives
                  • Avoid
                  • Systemic retinoid use has been associated with cases of benign intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines
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                Pregnancy & Lactation

                Pregnancy

                Contraindicated during pregnancy; based on findings in animal studies and class effects of retinoids, can cause fetal harm when administered during pregnancy

                Obtain a negative serum pregnancy test within 1 week before initiating palovarotene; verify that patient is not pregnant periodically, as needed, over the course of treatment, and 1 month after treatment discontinuation unless they are not at risk of pregnancy

                If pregnancy occurs during treatment, discontinue treatment immediately and refer patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for further evaluation and counseling

                Contraception

                • Females of reproductive potential: Use effective contraception at least 1 month before initiating treatment, during treatment, and for 1 month after last dose (unless continuous abstinence is chosen)
                • Males
                  • Present in semen (0.7 ng/mL) in amounts 100-fold lower than maternal plasma exposure at the no observed adverse effect level (NOAEL) for fetal toxicity observed in animal studies
                  • 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

                Animal studies

                • Oral administration to pregnant rats during organogenesis resulted in multiple fetal malformations typical of retinoids (eg, cleft palate, malformed skull bone, shortening of long bones) at doses ≥0.25 mg/kg/day (less than the clinical exposure)

                Lactation

                There are no data available on drug/metabolites presence in either animal or human milk, effects on breastfed infants, or on milk production

                Advise females that breastfeeding is not recommended during treatment and for at least 1 month after final dose

                Pregnancy Categories

                A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

                B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

                C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

                D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

                X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

                NA: Information not available.

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                Pharmacology

                Mechanism of Action

                In patients with 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 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 phosphorylation of SMAD1/5/8, which reduces ALK2/SMAD-dependent chondrogenesis and osteocyte differentiation resulting in reduced endochondral bone formation

                Absorption

                Peak plasma time: 3-4 hr

                Accumulation ratio: 1.04-1.16

                Peak plasma concentration (steady-state)

                • Chronic dose 5 mg or weight-based equivalent: 40.6 ng/mL
                • Flare-up dose 10 mg or weight-based equivalent: 78.4 ng/mL
                • Flare-up dose 20 mg or weight-based equivalent: 165 ng/mL

                AUC

                • Chronic dose 5 mg or weight-based equivalent: 264 ng⋅hr/mL
                • Flare-up dose 10 mg or weight-based equivalent: 540 ng⋅hr/mL
                • Flare-up dose 20 mg or weight-based equivalent: 1,060 ng⋅hr/mL

                Effect of food

                • Mean AUC and mean peak plasma concentration increased by ~40% and 16%, respectively
                • Peak plasma time was delayed by ~2 hr with a high-fat, high-calorie meal (800-1000 calories, 15% protein, 25% carbohydrate, and 50 to 60% fat)
                • No clinically significant differences in AUC and peak plasma concentration were observed when capsule administered whole compared to the contents sprinkled onto 1 teaspoon of applesauce following a high-fat, high-caloric breakfast

                Distribution

                Protein bound: 97.9-99.6%

                Vd: 237 L

                Metabolism

                Extensively metabolized by CYP3A4

                Minor extent by CYP2C8 and CYP2C19

                4 major metabolites (ie, M2, M3, M4a, M4b); M3 and M4b are ~1.7% and 4.2% of the activity of the parent drug

                Elimination

                Half-life: 8.7 hr

                Clearance: 19.9 L/hr

                Excretion: Feces 97.1%; urine 3.2%

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                Administration

                Oral Administration

                Take with food, preferably at same time each day

                Swallowed capsule whole

                Unable to swallow capsule

                • Open capsule and empty onto 1 teaspoon (5 mL) of soft food (eg, applesauce, low-fat yogurt, warm oatmeal) and take within 1 hr 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 fruit

                Missed dose

                • Missed dose 6 hr: Take as soon as possible
                • Missed dose >6 hr: Skip missed dose, and continue with next scheduled dose; do not take 2 doses at the same time or in the same day

                Storage

                Capsules

                • Keep out of reach of children
                • Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
                • Keep in original carton to protect from light

                Extemporaneous preparation

                • If not taken immediately, it can be taken after a maximum of 1 hr after sprinkling on food, provided it was stored at room temperature and not exposed to direct sunlight
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                Images

                No images available for this drug.
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                Patient Handout

                A Patient Handout is not currently available for this monograph.
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                Formulary

                FormularyPatient Discounts

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                The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                Tier Description
                1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                NC NOT COVERED – Drugs that are not covered by the plan.
                Code Definition
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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.