Dosing & Uses
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
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
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)
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
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
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.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%
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
Images
Formulary
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