Version May 2024
Palovarotene is contraindicated in pregnancy. Palovarotene may cause fetal harm. Because of the risk of teratogenicity and to minimize fetal exposure, palovarotene is to be administered only if conditions for pregnancy prevention are met.
Premature epiphyseal closure occurs in growing pediatric patients treated with palovarotene, close monitoring is recommended.
Heterotopic ossification secondary to fibrodysplasia ossificans progressiva: Note: Minimum age for use dependent upon patient sex. Dose dependent on phase of disease (chronic or flare-up).
Chronic regimen: Oral:
Note: Discontinue chronic treatment at the initiation of flare-up treatment and reinitiate chronic treatment after completion of flare-up treatment.
|
Age |
Weight |
Dose |
|---|---|---|
|
Female Children ≥8 years or Male Children ≥10 years and Adolescents <14 years |
10 to <20 kg |
2.5 mg once daily |
|
20 to <40 kg |
3 mg once daily | |
|
40 to <60 kg |
4 mg once daily | |
|
≥60 kg |
5 mg once daily | |
|
Adolescents ≥14 years |
All weights |
5 mg once daily |
Flare-up regimen: Oral:
Note: Total flare-up treatment duration is 12 weeks; continue treatment even if symptoms resolve earlier. If the patient experiences another flare-up (new location or worsening) during a 12-week flare-up regimen, restart flare-up treatment schedule. If flare-up symptoms not resolved by the end of the 12-week regimen, week 5 to 12 dosing may be extended at 4-week intervals and continued until the flare-up symptoms resolve. If new flare-up symptoms occur after chronic dosing regimen is resumed, flare-up dosing may be restarted.
|
Age |
Weight |
Initial (Weeks 1 to 4) |
Subsequent (Weeks 5 to 12) |
|---|---|---|---|
|
Female Children ≥8 years or Male Children ≥10 years and Adolescents <14 years |
10 to <20 kg |
10 mg once daily |
5 mg once daily |
|
20 to <40 kg |
12.5 mg once daily |
6 mg once daily | |
|
40 to <60 kg |
15 mg once daily |
7.5 mg once daily | |
|
≥60 kg |
20 mg once daily |
10 mg once daily | |
|
Adolescents ≥14 years |
All weights |
20 mg once daily |
10 mg once daily |
Dosing adjustment for toxicity:
Female Children ≥8 years or Male Children ≥10 years and Adolescents: Oral:
Note: If intolerable adverse reactions occur during chronic or flare-up regimen, palovarotene doses should be reduced to the next lower dose. If patient is receiving the lowest possible tolerated dose, consider holding dose or discontinuing. Subsequent flare-up dosing should be initiated at last tolerated dose.
|
Dose Prescribed |
Reduced Dose |
|---|---|
|
2.5 mg |
1 mg |
|
3 mg |
1.5 mg |
|
4 mg |
2 mg |
|
5 mg |
2.5 mg |
|
6 mg |
4 mg |
|
7.5 mg |
5 mg |
|
10 mg |
7.5 mg |
|
12.5 mg |
10 mg |
|
15 mg |
12.5 mg |
|
20 mg |
15 mg |
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Female Children ≥8 years or Male Children ≥10 years and Adolescents: Oral:
Mild to moderate impairment: No dosage adjustment required. Note: No pharmacokinetic differences were observed in patients with mild or moderate renal impairment (Ref).
Severe impairment: Use is not recommended (has not been studied).
Female Children ≥8 years or Male Children ≥10 years and Adolescents: Oral:
Mild impairment: No dosage adjustment required.
Moderate to severe impairment: Use is not recommended (has not been studied).
(For additional information see "Palovarotene: Drug information")
Heterotopic ossification:
Chronic regimen: Oral: 5 mg once daily.
Note: Discontinue chronic treatment at the initiation of flare-up treatment and reinitiate treatment after completion of flare-up treatment.
Flare-up regimen: Oral: 20 mg once daily for 4 weeks followed by 10 mg once daily for 8 weeks for a total of 12 weeks; continue treatment even if symptoms resolve earlier. If flare-up symptoms have not resolved at the end of the 12-week period, treatment may be extended in 4-week intervals with 10 mg once daily until flare-up symptoms resolve. If new flare-up symptoms occur after the 5 mg daily dosing is resumed, flare-up dosing may be restarted.
Note: Initiate flare-up treatment at the onset of the first symptom or high-risk traumatic event likely to lead to a flare-up. If an additional flare-up (a new flare-up location or marked worsening of the original flare-up) occurs at any time during the flare-up treatment, the 12-week flare-up regimen should be restarted.
Missed dose: Take missed dose as soon as possible on the same day; skip dose if missed by >6 hours. Do not double doses to compensate for a missed dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild to moderate impairment (CrCl ≥30 mL/minute): No dosage adjustment necessary.
Severe impairment (CrCl 15 to 29 mL/minute): Use is not recommended (has not been studied).
Mild impairment (Child-Turcotte-Pugh class A): No dosage adjustment necessary.
Moderate to severe impairment (Child-Turcotte-Pugh class B or C): Use is not recommended (has not been studied).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for children, adolescents, and adults.
>10%:
Cardiovascular: Peripheral edema (9% to 19%)
Dermatologic: Alopecia (24% to 30%), cheilitis (38% to 47%), erythema of skin (19% to 32%), exfoliation of skin (15% to 29%), pruritus (34% to 48%), skin irritation (11%), skin rash (28% to 30%), xeroderma (57% to 61%)
Gastrointestinal: Nausea (13% to 15%)
Hypersensitivity: Hypersensitivity reaction (10% to 20%)
Nervous system: Fatigue (5% to 11%; including asthenia), headache (19%)
Neuromuscular & skeletal: Arthralgia (31% to 36%), back pain (11% to 17%), limb pain (28% to 29%), musculoskeletal pain (13% to 14%), myalgia (9% to 12%), premature epiphyseal closure (children and adolescents: 31%)
Ophthalmic: Dry eye syndrome (10% to 22%)
1% to 10%:
Endocrine & metabolic: Hypertriglyceridemia (2% to 4%)
Hepatic: Increased serum alanine aminotransferase (2% to 7%)
<1%: Ophthalmic: Night blindness
Frequency not defined:
Nervous system: Psychiatric disturbance (including anxiety, depression, mood changes, suicidal ideation, suicidal tendencies)
Neuromuscular & skeletal: Decreased bone mineral density
Hypersensitivity to palovarotene, retinoids, or to any component of the formulation; pregnancy.
Canadian labeling: Breastfeeding; patients who could become pregnant, unless all the conditions for pregnancy prevention are met, or they are not at risk of pregnancy due to physical limitations as assessed by the health care provider.
Concerns related to adverse effects:
• Bone disorders: Bone toxicity (eg, reductions in bone mass, spontaneous osteoporosis, spontaneous fracture) as well as hyperostotic changes (bone spurs) and ligament/tendon calcification have been reported with retinoid use; may be more common with long-term use or higher doses. Decreased vertebral bone mineral content and bone density and increased risk of radiologically observed vertebral (T4 to L4) fractures have been reported with palovarotene use.
• Mucocutaneous effects: Mucocutaneous reactions, including dry skin, dry lips, alopecia, pruritus, erythema, rash, skin exfoliation, and dry eye may occur; treatment may further contribute to an increased risk of skin and soft tissue infections (eg, paronychia, decubitus ulcer) due to a decrease in the skin barrier from dry and peeling skin. Dose reduction, more frequent during flare-up dosing, was required in some cases. Prophylactic measures (eg, skin emollients, sunscreen, lip moisturizers, artificial tears) to minimize risk and/or treat the mucocutaneous effects should be considered.
• Ophthalmic effects: Night blindness has been reported. Night blindness is typically reversible after discontinuation of treatment; use caution when operating vehicles at night. Inform patients to contact health care provider if vision impairment occurs.
• Photosensitivity: Photosensitivity reactions (eg, exaggerated sunburn reactions [burning, erythema, blistering]) have been associated with the use of retinoids. Avoid excessive exposure to sun or artificial ultraviolet light by wearing protective clothing, sunglasses, and sunscreen.
• Psychiatric effects: New onset or worsening of existing depression, mood changes, anxiety, and suicidal ideation have been reported with retinoids; risk may be increased in patients with a history of psychiatric illness. Inform patients and caregivers to contact health care provider if psychiatric symptoms occur.
Special populations:
• Pediatrics: Skeletal effects: Premature epiphyseal closure and potential adverse effects on growth have been reported in growing children and may be irreversible. In patients that exhibit premature epiphyseal closure or adverse effects on growth based on clinical and radiologic evaluations, assess risks versus benefits of continued treatment versus temporary or permanent discontinuation of palovarotene until the patient reaches epiphyseal closure or skeletal maturity.
Dosage form specific issues:
• Lactose: May contain lactose.
Other warnings/precautions:
• Blood donation: Patients should not donate blood during therapy and for 1 week after discontinuing therapy due to the potential risk to the fetus of a pregnant transfusion recipient.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Sohonos: 1 mg
No
Capsules (Sohonos Oral)
1 mg (per each): $410.40
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral:
Sohonos: 1 mg
Oral: Administer at the same time every day with food. Capsules may be swallowed whole or entire contents emptied onto 1 teaspoonful (5 mL) of soft food (eg, applesauce, yogurt, pudding, milk, oatmeal, rice cereal, nutritional supplement) to be administered immediately; administer up to a maximum of 1 hour after sprinkling (provided it was maintained at room temperature and not exposed to direct sunlight). Do not administer with grapefruit, grapefruit juice, pomelo, or pomelo juice.
Note: Canadian labeling recommends that individuals handling capsules should wear disposable gloves, use disposable paper towels and a container to collect waste (eg, a resealable bag), and states that caregivers who are pregnant or who plan to become pregnant should not handle capsules.
Missed dose: If <6 hours since scheduled dose, administer missed dose as soon as possible. If ≥6 hours since scheduled dose, skip dose and continue with next scheduled dose. Do not double doses to compensate for a missed dose.
Oral: Administer preferably at the same time every day with food. Capsules may be swallowed whole or entire contents emptied onto 1 teaspoonful (5 mL) of soft food (ie, applesauce, low-fat yogurt, or warm oatmeal) to be used immediately. If opened capsule is not used immediately, it can be taken after a maximum of 1 hour after opening (provided it was maintained at room temperature and not exposed to direct sunlight). Do not administer with grapefruit, grapefruit juice, pomelo, or pomelo juice.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Palovarotene may cause teratogenicity and has a structural/toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in original carton to protect from light.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Sohonos: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/215559s000lbl.pdf#page=20
Reduction of the formation of heterotopic ossification in patients with fibrodysplasia (myositis) ossificans progressiva (FDA approved in females ≥8 years of age and males ≥10 years of age and adults).
Substrate of CYP2C19 (minor), CYP2C8 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination
Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Palovarotene. Risk X: Avoid combination
CYP3A4 Inducers (Strong): May decrease the serum concentration of Palovarotene. Risk X: Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Palovarotene. Management: Avoid concomitant use of palovarotene and moderate CYP3A4 inhibitors when possible. If combined, decrease palovarotene dose by 50% as described in the full interaction monograph. Monitor for palovarotene toxicities when combined. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Palovarotene. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Grapefruit Juice: May increase the serum concentration of Palovarotene. Risk X: Avoid combination
Methotrexate: Retinoic Acid Derivatives may enhance the hepatotoxic effect of Methotrexate. Risk C: Monitor therapy
Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy
Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Multivitamins/Minerals (with AE, No Iron): May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Progestins (Contraceptive): Retinoic Acid Derivatives may diminish the therapeutic effect of Progestins (Contraceptive). Retinoic Acid Derivatives may decrease the serum concentration of Progestins (Contraceptive). Management: Two forms of effective contraception should be used in patients receiving retinoic acid derivatives. Microdosed progesterone-only preparations (ie, minipills that do not contain estrogen) are considered an inadequate method of contraception. Risk D: Consider therapy modification
Tetracyclines: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. The development of pseudotumor cerebri is of particular concern. Risk X: Avoid combination
Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy
Vitamin A: May enhance the adverse/toxic effect of Retinoic Acid Derivatives. Risk X: Avoid combination
Food increases absorption. Grapefruit, grapefruit juice, pomelo, or pomelo juice may interfere with metabolism. Management: Administer with meals; grapefruit, grapefruit juice, pomelo, or pomelo juice should be avoided during therapy.
Administer with food. Avoid grapefruit, grapefruit juice, pomelo, or pomelo juice.
Evaluate pregnancy status and potential for pregnancy prior to use. A negative pregnancy test is required within 1 week prior to the first dose. Pregnancy testing is also required periodically during treatment and 1 month after the last dose of palovarotene in patients who could become pregnant.
Palovarotene is contraindicated in patients who could become pregnant unless they meet all conditions for pregnancy prevention. This includes use of at least 1 highly effective method of contraception (eg, IUD) or 2 effective methods (eg, combined hormonal contraceptive in combination with a barrier method or other method of contraception) during treatment with palovarotene. Effective contraception should be initiated 1 month prior to starting treatment, continued during therapy, and for 1 month after the last palovarotene dose. Patients using the palovarotene flare-up regimen should continue to follow contraception recommendations even during periods when palovarotene is not taken. Patients should understand the teratogenic risk if pregnancy should occur.
Palovarotene is present in semen; concentrations are considered unlikely to effect fetal development.
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to palovarotene may cause severe fetal harm.
Birth defects associated with exposure to retinoids include facial dysmorphia, cleft palate, eye abnormalities, and abnormalities of the CNS, cardiovascular system, musculoskeletal system, and parathyroid hormone deficiencies. All exposed fetuses have the potential to be affected.
Use of palovarotene is contraindicated during pregnancy. If pregnancy occurs during treatment, palovarotene should be discontinued immediately.
Pregnancy testing (blood or urine) for patients who could become pregnant: Before the first palovarotene dose (within 1 week) and periodically as needed throughout treatment, then 1 month after the last dose of palovarotene.
Pediatric patients: Growth assessments (baseline clinical and radiological assessment of skeletal maturity via hand/wrist and knee x-rays, standard growth curves, and pubertal staging); continued assessment of linear growth and skeletal maturity every 3 to 12 months until patient reaches skeletal maturity or final adult height (frequency of monitoring may vary depending on patient age, pubertal status, and skeletal maturity).
In all patients, monitor for new or worsening psychiatric symptoms.
Palovarotene is a retinoic acid receptor gamma (RARγ) selective agonist. RARγ is expressed in chondrogenic cells and chondrocytes operating as an unliganded transcriptional repressor. Through binding to RARγ, palovarotene decreases bone morphogenetic protein signaling and inhibits SMAD1/5/8 signaling. By interfering with these pathways, palovarotene prevents chondrogenesis and heterotopic ossification by enabling normal muscle tissue repair or regeneration to take place, thereby reducing damage to muscle tissue.
Absorption: AUC and Cmax increased ~40% and 16% respectively and Tmax was delayed ~2 hours after a high-fat (50% to 60% of total caloric content of the meal), high-calorie (800 to 1,000 calories, 15% protein, 25% carbohydrate) meal.
Distribution: Vd/F: 237 ±90.1 L following administration of 20 mg dose with food.
Protein binding: 97.9% to 99.6%.
Metabolism: Extensively by CYP3A4 and to a minor extent by CYP2C8 and CYP2C19.
Half-life elimination: Mean: 8.7 hours following administration of 20 mg dose for 14 days with standard breakfast (800 to 1,000 calories, 15% protein, 25% carbohydrate, 50% to 60% fat).
Time to peak: Median: 3 to 4 hours.
Excretion: Urine (3.2%); feces (97.1%).
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