DRUG INTERACTIONS-(summary)

1 Effect of Other Drugs on SOHONOS

• Premature Epiphyseal Closure:                                                                              Premature epiphyseal closure occurred with SOHONOS. Assess baseline skeletal maturity before SOHONOS therapy and monitor linear growth in growing pediatric patients

 • Mucocutaneous Adverse Reactions:                                                                              Dry skin, lip dry, pruritis, rash, alopecia, erythema, skin exfoliation, and dry eye occurred with SOHONOS. Prevent or treat with skin emollients, sunscreen, artifical tears. Dosage reduction may be required in some patients

 • Metabolic Bone Disorders:                                                                                    Decreased vertebral bone mineral content and bone density may occur. Assess for spinal fracture periodically using radiologic method

 • Psychiatric Disorder                                                                                       Depression, anxiety, mood alterations and suicidal thoughts and behaviors occurred with SOHONOS. Contact healthcare provider if new or worsening symptoms develop in patients treated with SOHONOS

 • Night Blindness: May occur and make driving at night hazardous

BRIEF SUMMARY-

PALVAROTENE-(Aug 2023)

Indication-  To reduce volume of new heterotropic ossificstion in adults           Dose-  •  Recommended dosage is 5 mg once daily, with an increase in dose at the time of a flare-up to 20 mg once daily for 4 weeks

ADR-  dry skin, lip dry, arthralgia, pruritis, pain in extremity.  

 CI-  Pregnancy,Hypersensitivity to retinoids 

 P. inform-  SOHONOS can cause fetal harm and is contraindicated during pregnancy.

===================================================================

U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 34

Name-                      SOHONOS

Acive  Ingredient -  Palovarotene

Pharmacological clssificiation-        To reduce thr volume of new heterotropic                                                                       ossification in adults  and pediatric  patients                                                                  ( aged 8 years and older for Females and 10                                                                    years and for Males   with fibrodysplasia                                                                         ossificaaa progressive                                                                                                                                                                                                                                                                                              

 Date of Approval-         8/16/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION

WARNINGS AND PRECAUTIONS

- These highlights do not include all the information needed to use                SOHONOSTM safely and effectively.

See full prescribing information for SOHONOS. SOHONOS (palovarotene) capsules, for oral use

Initial U.S. Approval: 2023

WARNING:

EMBRYO-FETAL TOXICITY and PREMATURE EPIPHYSEAL CLOSURE IN GROWING PEDIATRIC PATIENTS

See full prescribing information for complete boxed warning.

• SOHONOS is contraindicated in pregnancy                                                                Because of the risk of teratogenicity and to minimize fetal exposure, SOHONOS is to be administered only if conditions for pregnancy prevention are met

 • SOHONOS causes premature epiphyseal closure in growing pediatric patients with FOP, close monitoring is recommended

INDICATIONS AND USAGE-

SOHONOS is a retinoid indicated for reduction in the volume of new heterotopic ossification in adults and children aged 8 years and older for females and 10 years and older for males with fibrodysplasia ossificans progressiva (FOP)

ADVERSE REACTIONS-

 Most common adverse reactions (incidence =10%) are dry skin, lip dry, arthralgia, pruritis, pain in extremity, rash, alopecia, erythema, headache, back pain, skin exfoliation, nausea, musculoskeletal pain, myalgia, dry eye, hypersensitivity, peripheral edema, and fatigue

CONTRAINDICATIONS-

 • Pregnancy

 • Hypersensitivity to retinoids or any component of SOHONOS

WARNINGS AND PRECAUTIONS-

 These highlights do not include all the information needed to use SOHONOSTM safely and effectively.

See full prescribing information for SOHONOS. SOHONOS (palovarotene) capsules, for oral use

DOSAGE AND ADMINISTRATION-

 • Obtain a negative pregnancy test in females of reproductive potential before initiation of SOHONOS

 • Recommended dosage includes a chronic daily dose, which can be increased for flare-up symptoms

 • For adults and pediatric patients 14 years and older: Recommended dosage is 5 mg once daily, with an increase in dose at the time of a flare-up to 20 mg once daily for 4 weeks, followed by 10 mg once daily for 8 weeks for a total of 12 weeks (20/10 mg flare-up treatment)

 • For pediatric patients under 14 years: Weight-adjusted for daily and flare-up dosing. Recommended daily dosage range from 2.5 to 5 mg. Refer to Table 1 in Full Prescribing Information for complete pediatric dosing

 • Take SOHONOS with food preferably at same time each day

 • Reduce the dose in the event of adverse reactions as appropriate

 • See Full Prescribing Information for complete dosing instructions

DOSAGE FORMS AND STRENGTHS-

 Capsules: 1, 1.5, 2.5, 5, 10 mg 

PATIENT COUNSELING INFORMATION-

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).

Embryo-Fetal Toxicity:

Advise patients that SOHONOS can cause fetal harm and is contraindicated during pregnancy.

Advise patients to verify that they are not pregnant prior to initiating and periodically during SOHONOS treatment as well as one month after treatment discontinuation

 • Advise females of reproductive potential that they must avoid pregnancy while taking SOHONOS and for at least one month following discontinuation of therapy

 • Advise females of childbearing potential to use at least one highly effective method of contraception (i.e. IUD) or two effective methods (i.e. combined hormonal contraception in combination with another method of contraception such as a barrier method) during treatment with SOHONOS 

 • Instruct patients to immediately stop taking SOHONOS if she becomes pregnant while taking SOHONOS and to rapidly consult her healthcare provider if there is a risk of pregnancy or if she might be pregnant.

• Instruct patients to not donate blood during SOHONOS treatment and for 1 week following discontinuation to avoid blood donation to a pregnant patient and fetus.

Lactation-

Because of the potential for serious adverse reactions from SOHONOS in a breastfed child, advise females not to breastfeed during treatment with SOHONOS, and for at least 1 month after the last dose of SOHONOS.

Premature Epiphyseal Closure:

Inform patients that SOHONOS has been shown to cause premature epiphyseal closure in growing pediatric patients with FOP and discuss the proposed monitoring plan with the patient and caregiver.

Mucocutaneous Adverse Reactions:

Advise patients that they may experience dry skin, lip dry, pruritis, rash, alopecia, erythema, skin exfoliation, and dry eye.

Discuss the plan to assess their symptoms and adjust the dose if needed

Recommend prophylactic measures to minimize risk and/or treat the mucocutaneous adverse reactions are recommended (e.g. skin emollients, sunscreen, lip moisturizers, artificial tears) 

Photosensitivity:

Advise patients of potential increased skin sensitivity to sunlight while taking SOHONOS and to minimize exposure to sunlight and artificial ultraviolet light.

Radiological Vertebral Fractures:

Inform patients that SOHONOS resulted in decreased vertebral bone mineral content, bone density and bone strength as well as an increased risk of radiologically observed vertebral fractures and that periodic radiological assessment of the spine is recommended

Psychiatric Disorders:

Advise patients of the possibility of experiencing new or worsening psychiatric effects, including suicidal thoughts and behaviors, depression, depression aggravated, anxiety, and mood alterations.

Particular care should be taken in patients with history of psychiatric illness.

Patients should be monitored for signs of depression and referred for appropriate treatment if necessary

Night Blindness:

Advise patients of the risk of experiencing night blindness

Drug Interactions:

Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products

Dosing Instructions:

Advise the patient to take SOHONOS capsules with food. If the patient is unable to swallow the capsule, the capsule contents may be emptied onto soft food

Missed dose:

If a dose is missed, it should be taken as soon as the patient remembers.

If the dose has been 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 two doses at the same time or in the same day.

Distributed by: Ipsen Biopharmaceuticals, Inc. Cambridge, MA; 02142. SOHONOS is a trademark of Clementia Pharmaceuticals Inc. ©2023. Ipsen Biopharmaceuticals, Inc. All rights reserved.

CLINICAL PHARMACOLOGY

1. Mechanism of Action

In patients with FOP, abnormal bone formation, including heterotrophic ossification (HO), is driven by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ALK2 (ACVR1).

2. Pharmacodynamics

Cardiac Electrophysiology- At doses up to 2.5 times the maximum recommended dose, palovarotene does not prolong the QT interval to any clinically relevant extent.

3. Pharmacokinetics

Palovarotene exposure (AUC) increases proportionally from 0.02 to 50 mg (0.001 to 2.5 times the maximum recommended dosage).

Steady-state is achieved by Day 3 following once daily dosing.

Absorption-

 The median time to achieve peak concentration (Tmax) of palovarotene was 3.0 to 4.0 hours across the chronic dose of 5 mg to flare-up dose of 10 and 20 mg.

Effect of Food-

 Palovarotene mean AUC and mean Cmax increased by approximately 40% and 16%, respectively; Tmax was delayed by approximately 2 hours with a high-fat, high-calorie meal (800 to 1000 calories, 15% protein, 25% carbohydrate, and 50 to 60% fat).

No clinically significant differences in the AUC and Cmax of palovarotene were observed when palovarotene was administered whole compared to the contents sprinkled onto one teaspoon of applesauce following a high-fat, high-caloric breakfast.

Distribution-

 The mean (SD) apparent volume of distribution (Vd/F) is 237 (± 90.1) L following administration of a single 20 mg dose with food.

Protein binding of palovarotene is 97.9% to 99.6% in vitro. The mean blood-to-plasma ratio of palovarotene in humans is 0.62.

Elimination-

 The mean elimination half-life is 8.7 hours following administration of a 20 mg once daily dosage for 14 days with a standard breakfast (800 to 1000 calories, 15% protein, 25% carbohydrate, and 50 to 60% fat).

The apparent total body clearance (CL/F) of palovarotene is estimated at 19.9 L/h. 

Metabolism-

Palovarotene is extensively metabolized by CYP3A4 and to a minor extent by CYP2C8 and CYP2C19.

Following administration of [14-C]-radiolabeled palovarotene, the contribution of palovarotene and its four known major metabolites (M2, M3, M4a, and M4b) represented collectively 40% of the total exposure in plasma.

The pharmacological activity of M3 and M4b is approximately 1.7% and 4.2% of the activity of the parent drug.

Excretion-

Following administration of a 1 mg dose of [14C]-radiolabeled palovarotene in healthy subjects, 97.1% of the dose was recovered in the feces and 3.2% in the urine.

Specific Populations-

There were no clinically significant differences in the pharmacokinetics of palovarotene based on age (2 to 85 years old), sex, race (Asian, black, white and others), smoking status, mild to moderate renal impairment, or mild hepatic impairment.

The effect of severe renal impairment, or moderate to severe hepatic impairment on the pharmacokinetics of palovarotene is unknown.

Body Weight Body weight (13 to 130 kg) was found to have a significant effect on the pharmacokinetics of palovarotene resulting in increasing exposure with decreasing weight at the same dose.

Pediatric Patients-                                                                                                            

The estimated steady-state AUC0-t and Cmax,ss following weight-based dosing for 5, 10, and 20 mg (or dose equivalent) in pediatric patients <14 years old are comparable for the equivalent doses across the different weight groups.

Drug Interaction Studies-

Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitor: Co-administration of palovarotene with ketoconazole (strong CYP3A4 inhibitor) increased the Cmax and AUC of palovarotene by 2 and 3-fold, respectively.

Moderate CYP3A Inhibitor:

Co-administration of palovarotene with erythromycin (moderate CYP3A4 inhibitor) increased the Cmax and AUC of palovarotene by 1.6 and 2.5-fold, respectively.

Strong CYP3A Inducer:

Co-administration of palovarotene with rifampicin (strong CYP3A4 inducer) decrease the Cmax and AUC0-t of palovarotene by 19% and 11%, respectively.

Other Drugs:

No clinically significant differences in the pharmacokinetics of palovarotene were observed when co-administered with prednisone 40 mg. No clinically significant differences in the pharmacokinetics of midazolam (CYP3A4 substrate) were observed when co-administered with palovarotene. In Vitro Studies Cytochrome P450 (CYP)

Enzymes:

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.

USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary

SOHONOS is contraindicated during pregnancy. Based on the findings in animal studies and class effects of retinoids, SOHONOS can cause fetal harm when administered during pregnancy

There are no available human data on SOHONOS use in pregnant women. If pregnancy occurs during treatment with SOHONOS, discontinue treatment immediately and refer the patient to an obstetrician/gynecologist or other specialist experienced in reproductive toxicity for further evaluation and counseling.

2 Lactation Risk Summary-

There are no data available on the presence of palovarotene or its main metabolites in either animal or human milk, the effects on the breastfed infant, or on milk production.

Because of the potential for serious adverse reactions in breastfed infants exposed to palovarotene through breastmilk, advise females that breastfeeding is not recommended during treatment with SOHONOS, and for at least 1 month after the final dose of SOHONOS.

3 Females and Males of Reproductive Potential-

SOHONOS can cause fetal harm when administered during pregnancy

Pregnancy Testing-                                                                                                    Obtain a negative serum pregnancy test within one week prior to SOHONOS therapy. Verify that patient is not pregnant periodically, as needed, over the course of treatment with SOHONOS and one month after treatment discontinuation unless they are not at risk of pregnancy.

Contraception Females-                                                                                          SOHONOS can cause embryo-fetal harm when administered during pregnancy.

Advise females of reproductive potential to use effective contraception at least one month prior to treatment, during treatment with SOHONOS and for 1 month after the last dose, unless continuous abstinence is chosen.

 Males- Palovarotene is present in semen (0.7 ng/mL) in amounts 100-fold lower than the maternal plasma exposure at the no observed adverse effect level (NOAEL) for fetal toxicity observed in animal studies.

Administration of SOHONOS to a male patient is considered unlikely to affect development of an embryo or fetus carried by a pregnant female sexual partner exposed to SOHONOS via the patient’s semen.

4. Pediatric Use-                                       

The safety and effectiveness of SOHONOS for the treatment of FOP have been established in pediatric patients aged 8 years and older for females and 10 years and older for males.

Use of SOHONOS for this indication is supported by evidence from clinical studies in adults and pediatric subjects.

The safety and effectiveness of SOHONOS for the treatment of FOP have not been established in pediatric patients less than 8 years of age in females and less than 10 years