Sohonos (palovarotene)

Avoid concomitant use of palovarotene with moderate cytochrome P-450 (CYP) 3A inhibitors, if possible. If concomitant use with a moderate CYP3A inhibitor will occur, reduce the dosage of palovarotene by 50% (see Table 4).

Table 4. Dosage Reduction of Palovarotene during Concurrent Use of Moderate CYP3A Inhibitors

Weight Daily Dosage Week 1-4 Flare-up Week 5-12 Dosage Flare-up Dosage 10-19.9 kg 1 mg 5 mg 2.5 mg 20-39.9 kg 1.5 mg 6 mg 3 mg 40-59.9 kg 2 mg 7.5 mg 4 mg >=60 kg (also 2.5 mg 10 mg 5 mg includes all pediatric patients >=14 years of age and adults)

Patients that experience adverse reactions that require a dosage reduction during either chronic daily dosing or flare-up dosing should have their daily dosage reduced to the next lower dosage at the discretion of the clinician (see Table 3). Palovarotene dosage should be further reduced if the adverse reaction does not improve. If the patient is already receiving the lowest possible tolerated dosage, consider temporary interruption or permanent discontinuation of therapy. Subsequent flare-up dosing should be initiated at the same reduced dosage that was previously tolerated.

Table 3. Palovarotene Dosage Reduction for Toxicity

Dosage Prescribed Reduced Dosage 20 mg 15 mg 15 mg 12.5 mg 12.5 mg 10 mg 10 mg 7.5 mg 7.5 mg 5 mg 6 mg 4 mg 5 mg 2.5 mg 4 mg 2 mg 3 mg 1.5 mg 2.5 mg 1 mg

Palovarotene capsules should be taken orally with food preferably at the same time every day.

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

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

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

Store palovarotene capsules in the original carton to protect from light at 20-25oC; excursions are permitted to 15-30oC.

No dosing information is available for this tab.

No dosing information is available for this tab.

Palovarotene is extensively metabolized by cytochrome P-450 (CYP) 3A4 and to a minor extent by CYP2C8 and CYP2C19. In vitro, palovarotene is an inducer of CYP3A4 and CYP2B6 but not CYP1A2, CYP2C8, CYP2C9, and CYP2C19. Palovarotene is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.

In vitro, palovarotene is not an inhibitor or substrate of uridine diphosphate-glucuronosyltransferase (UGT) enzymes 1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, or UGT2B7. Palovarotene is not an inhibitor of breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter (OAT) 1 or OAT3, organic anion transporter polypeptide (OATP) 1B1 or OATP1B3, organic cation transporter (OCT) 1 or OCT2, multidrug and toxin extrusion (MATE) 1, MATE2 K, or P-glycoprotein (P-gp). Palovarotene is not a substrate of BCRP, OATP1B1, OATP1B3, OCT1, or P-gp.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Palovarotene/Strong And Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Palovarotene is extensively metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of palovarotene.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of palovarotene.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid concomitant use of palovarotene with strong and moderate CYP3A4 inducers.(1)

DISCUSSION: In a clinical trial, rifampin, a strong CYP3A4 inducer, decreased the maximum concentration (Cmax) and area-under-curve (AUC) of palovarotene by 81% and 89%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2)

Palovarotene/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of palovarotene.(1,2)

CLINICAL EFFECTS: Concurrent use of a strong CYP3A4 inhibitor may result in increased levels of and effects from palovarotene including rash, alopecia, skin exfoliation, photosensitivity, reduction in bone mass, hyperostosis, and night blindness.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of strong CYP3A4 inhibitors with palovarotene should be avoided.(1,2)

DISCUSSION: In a clinical trial, ketoconazole, a strong CYP3A4 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of palovarotene by 121% and 212%, respectively.(1,2) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, grapefruit, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(3)

Selected Retinoids (Systemic)/Tetracyclines

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both systemic tetracyclines(1-4,14) and systemic retinoids(5-14) have been independently associated with medication-induced intracranial hypertension.

CLINICAL EFFECTS: The concurrent use of oral retinoids(5-12) with tetracyclines has been associated with pseudotumor cerebri (benign intracranial hypertension). Early signs of pseudotumor cerebri include papilledema (inflammation of the optic nerve), headache, nausea, vomiting, and visual disturbances such as blurred vision, double vision, and loss of vision.(15)

PREDISPOSING FACTORS: Women of childbearing age who are overweight or have a previous history of intracranial hypertension are at a greater risk of developing intracranial hypertension.(15)

PATIENT MANAGEMENT: The UK(5) and US(6) manufacturers of acitretin state state that concurrent use with tetracyclines is contraindicated. The UK manufacturer of isotretinoin states that concurrent use with tetracyclines is contraindicated.(7) The US manufacturer of isotretinoin states that the concurrent use of tetracyclines should be avoided.(8) The US manufacturer of minocycline states that the administration of isotretinoin should be avoided shortly before, during and shortly after minocycline therapy.(2) The UK manufacturers of oral tretinoin and alitretinoin states that concurrent use with tetracyclines is contraindicated.(9,11) The Canadian manufacturer of palovarotene states that coadministration of tetracycline derivatives should be avoided.(12) Patients who present with symptoms of pseudotumor cerebri should be screened for papilledema. If papilledema is present, they should discontinue the drug and be referred to a neurologist for further treatment.(5-13)

DISCUSSION: The concurrent use of isotretinoin and tetracyclines has been associated with pseudotumor cerebri.(5-13) A review of ocular side effects from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, the Food and Drug Administration, and medical journals from 1979 to 2003 found 6 patients who developed intracranial hypertension while taking concurrent minocycline or tetracycline with tretinoin, acitretin, or etretinate.(13)

Selected Retinoids/Vitamin A

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The retinoids are structurally related to vitamin A. (1-6)

CLINICAL EFFECTS: Concurrent use of retinoids with vitamin A supplements may result in signs of vitamin A toxicity.(1-6) Symptoms of vitamin A toxicity include nausea, vomiting, loss of appetite, weakness, dry or itchy skin or lips, irritability, and hair loss.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of acitretin states that concomitant use of vitamin A supplements should be avoided.(1) The manufacturer of bexarotene states that patients should be advised to limit vitamin A supplements. In clinical studies, patients were advised to limit their vitamin A intake to less than or equal to 15,000 International Units/day.(2) The manufacturer of isotretinoin states that patients should be advised against taking vitamin A supplements.(3) The manufacturer of palovarotene states that concomitant use of vitamin A must be avoided.(4) The manufacturer of tretinoin states that tretinoin must not be administered in combination with vitamin A.(5) The UK manufacturer of alitretinoin states that tretinoin must not be administered in combination with vitamin A.(6)

DISCUSSION: The retinoids are structurally related to vitamin A. The concurrent use of retinoids with vitamin A may result in signs and symptoms of vitamin A toxicity.(1-6)

There are no severe interactions for this drug.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Palovarotene/Moderate Cyp3a4 Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate CYP3A4 inhibitors may inhibit the metabolism of palovarotene.(1)

CLINICAL EFFECTS: Concurrent use of moderate CYP3A4 inhibitors may result in elevated levels of and toxicity from palovarotene, including rash, alopecia, skin exfoliation, photosensitivity, reduction in bone mass, hyperostosis, and night blindness.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of moderate CYP3A4 inhibitors with palovarotene should be avoided. If concurrent use cannot be avoided, reduce the dose of palovarotene by half, according to the US prescribing information.(1)

DISCUSSION: In a clinical trial, erythromycin, a moderate CYP3A4 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of palovarotene by 1.6- and 2.5-fold, respectively.(1) Moderate inhibitors of CYP3A4 include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, lefamulin, lenacapavir, letermovir, netupitant, nilotinib, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(3,4)

*Pregnancy.

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

• Lactation
• Pregnancy

There are no severe contraindications for this drug.

There are no moderate contraindications for this drug.

The most common adverse reactions of palovarotene (>=10% of patients) reported in clinical studies include dry skin, dry lips, arthralgia, pruritus, extremity pain, rash, alopecia, erythema, headache, back pain, skin exfoliation, nausea, musculoskeletal pain, myalgia, dry eyes, hypersensitivity, peripheral edema, and fatigue.

Less Frequent

• Cellulitis
• Conjunctival hyperemia
• Decubital ulcer
• Premature epiphyseal closure
• Skin and skin structure infection
• Suicidal ideation

Rare or Very Rare

• Anemia
• Seizure disorder

More Frequent

• Alopecia
• Arthralgia
• Cheilitis
• Cheilosis
• Dry eye
• Dry skin
• Eczema
• Epistaxis
• Erythema
• Headache disorder
• Nausea
• Paronychia
• Pruritus of skin
• Skin irritation
• Skin rash
• Xerostomia

Less Frequent

• Anorexia
• Back pain
• Blistering skin
• Conjunctivitis
• Depression
• Diarrhea
• Fatigue
• Flushing
• Gastroesophageal reflux disease
• Ingrown fingernail or toenail
• Madarosis of eyelid
• Mood changes
• Night blindness
• Onychoclasis
• Proteinuria
• Pyogenic granuloma
• Skin fissure
• Skin photosensitivity
• Symptoms of anxiety
• Urticaria
• Vomiting

No enhanced messaging available.

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

In clinical studies with palovarotene, assessments of growth and bone safety in growing children included linear and knee height, femur and tibia length measured by Whole-Body Computed Tomography, and hand/wrist and knee radiographs. Premature epiphyseal closure has been identified as an irreversible serious risk associated with palovarotene therapy. Premature epiphyseal closure was observed as early as 6 months after initiating therapy, with the majority of cases occurring at or after 12 months. In palovarotene-treated patients, there was a trend of declining height Z-scores in adolescents, potentially due to a loss of linear height and/or increasing spinal deformity. The long-term effects on final height in patients with FOP treated with palovarotene have not been established.

Prior to starting treatment with palovarotene, all growing children should undergo baseline clinical and radiological assessments including, but not limited to, an assessment of skeletal maturity via hand/wrist and knee x-rays, standard growth curves, and pubertal staging. Continued monitoring is recommended every 6-12 months until patients reach skeletal maturity (e.g., epiphyseal closure) or final adult height.

Palovarotene is contraindicated during pregnancy. There are no available human data on palovarotene use in pregnant women. Based on the findings in animal studies and the class effects of retinoids, palovarotene can cause fetal harm when administered during pregnancy. In animal reproduction studies, oral administration of palovarotene to pregnant rats during the period of organogenesis (gestation days 6 to 17) resulted in fetal external, visceral, and skeletal malformations typical of retinoids, including defects of the mouth (e.g., cleft palate), eye, skull (e.g., malformed skull bone), skeleton (e.g., shortening of long bones), blood vessels, kidney, and ureters at doses >=0.25 mg/kg/day (less than the clinical exposure).

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

There are no data available on the presence of palovarotene or its main metabolites in either animal or human milk, the effects on the breast-fed infant, or on milk production. Because of the potential for serious adverse reactions in breast-fed infants exposed to palovarotene through breast milk, advise females that breastfeeding is not recommended during treatment with palovarotene, and for at least 1 month after the final dose of the drug.

The manufacturer makes no specific dosage recommendations for geriatric patients but recommends cautious dosage selection, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Clinical studies of palovarotene did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between geriatric and younger patients. In general, dosage selection in geriatric patients should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.