Palovarotene

Co-administration of moderate CYP3A4 inducers with palovarotene may decrease palovarotene exposure, which may reduce the effectiveness of palovarotene.

Avoid concomitant use of moderate CYP3A4 inducers with palovarotene.

Co-administration of palovarotene with strong CYP3A4 inhibitors increased the exposures of palovarotene, which may increase the risk of palovarotene adverse reactions.

Avoid concomitant use of a strong CYP3A4 inhibitor during palovarotene treatment.

Co-administration of palovarotene with moderate CYP3A4 inhibitors may increase the exposure of palovarotene, which may increase the risk of palovarotene adverse reactions.

Avoid concomitant use of a moderate CYP3A inhibitor, if possible. If concomitant use will occur, reduce the dose of palovarotene by half as shown in the following table when co-administered with moderate CYP3A inhibitors.

Dose reduction of palovarotene for use with moderate CYP3A inhibitors:

^* All pediatric patients ≥14 years of age and adults should receive the dose in the ≥60 kg weight category.

Co-administration of palovarotene with strong CYP3A4 inducers decreased the exposure of palovarotene, which may reduce the effectiveness of palovarotene.

Avoid concomitant use of strong CYP3A4 inducers with palovarotene.

Use of palovarotene in patients with severe (CL_cr 15 to 29 mL/min) renal impairment is not recommended.

The effect of moderate or severe hepatic impairment on the pharmacokinetics of palovarotene has not been evaluated. Palovarotene undergoes extensive hepatic metabolism. Use of palovarotene in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment is not recommended.

Systemic retinoid use has been associated with cases of benign intracranial hypertension (also called pseudotumor cerebri), some of which involved the concomitant use of tetracyclines. Avoid coadministration of palovarotene with tetracycline derivatives.

Palovarotene belongs to the same pharmacological class as vitamin A. Therefore, the use of both vitamin A and palovarotene at the same time may lead to additive effects. Concomitant administration of vitamin A in doses higher than the recommended daily allowance (RDA) and/or other oral retinoids with palovarotene must be avoided because of the risk of hypervitaminosis A.

New or worsening psychiatric events were reported with palovarotene use. Individuals with a history of psychiatric illness may be more susceptible to these adverse effects.

Risk Summary

Palovarotene is contraindicated during pregnancy. Based on the findings in animal studies and 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 resulted in multiple fetal malformations typical of retinoids (e.g., cleft palate, malformed skull bone, shortening of the long bones) at doses ≥0.25 mg/kg/day (less than the clinical exposure) (see Data). There are no available human data on palovarotene use in pregnant women. 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.

Data

Animal Data

Palovarotene oral administration to pregnant rats during the period of organogenesis (gestation day 6 to 17) at doses of 0.01, 0.25 and 1.25 mg/kg/day resulted in fetal malformations consistent with retinoid-mediated embryopathy. Palovarotene exposure resulted in fetal external, visceral and skeletal malformations typical of retinoids, including defects in the mouth (cleft palate, protruding tongue), eye (anophthalmia, microphthalmia), skull (dilated cerebral ventricle, misshapen brain), skeleton (shortening of the long bones), blood vessels, kidney, and ureters at doses ≥ 0.25 mg/kg/day (less than the clinical exposure). The fetal toxicity was observed at maternal rat exposures well below the range of clinically relevant exposures.

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 palovarotene, and for at least 1 month after the final dose of palovarotene.

Carcinogenesis and Mutagenesis

Long term studies to assess the carcinogenic potential of palovarotene have not been conducted.

Palovarotene and its metabolites were negative in the vitro bacterial reverse mutation (Ames) assay and an in vitro micronucleus assay in primary human lymphocyte. Palovarotene did not have any clastogenic effect in the in vivo mouse micronucleus study.

Impairment of Fertility

Palovarotene effects on fertility and reproductive function were assessed in male and female rats. In a female rat fertility study, palovarotene was orally administered to females for 14 days prior to mating with drug naïve males and up to GD 7 at the dose levels of 0.3, 1 and 3 mg/kg/day. Palovarotene caused prolonged periods of diestrous and reduced ovulation rate, resulting in lower numbers of implantation sites and live embryos at 3 mg/kg/day, a dose associated with maternal toxicity.

In a male rat fertility study, palovarotene was orally administered prior to mating, during mating, and up to scheduled euthanasia (approximately 11 weeks in total) at 0.3, 1 and 3 mg/kg/day. Palovarotene did not cause adverse effects on mating, fertility indices, conception rate, reproductive organ weights or sperm parameters up to 1 mg/kg/day (less than the clinical exposure). Males did not tolerate 3 mg/kg/day, as it produced severe systemic toxicity including deaths, adverse skin and hair coat clinical signs, and substantially reduced body weight.

Night blindness has been associated with systemic retinoids, including palovarotene. 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 also 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of palovarotene was evaluated in clinical studies that enrolled a total of 164 subjects with FOP, including 139 subjects in the indicated population of ages 8 years and above for females and 10 years and above for males (8/10 years and older). Most of these subjects received open label treatment with the chronic daily/flare-up regimen, consisting of 5 mg daily dosage of oral palovarotene with a 20/10 mg dosage as needed for 12 weeks at the time of flare-up (4 weeks of 20 mg once daily followed by 10 mg once daily for 8 weeks), with all doses reduced by weight in subjects who were less than 90% skeletally mature. The mean duration of exposure was 79 weeks for chronic dosing (N=131 subjects) and 35 weeks for flare-up dosing (N=105 subjects). The mean age of these subjects was 19 years (range 8 to 61 years); 51% were male.

Serious adverse reactions occurred in 21 (15%) palovarotene treated subjects in the 8/10 years or older population with the most common serious adverse reaction being premature epiphyseal closure. Adverse reactions leading to permanent discontinuation occurred in 11 (8%) palovarotene treated subjects with dry skin being the most common in 2 (1%) subjects. Mucocutaneous adverse reactions leading to dose reductions were more common during palovarotene 20/10 mg flare-up treatment (37%) than during chronic treatment (4%).

Table 5 below presents adverse reactions which occurred in at least 10% of FOP subjects 8/10 years and older during treatment with chronic or flare-up dosing.

Table 5. Summary of Adverse Reactions Reported at greater than 10% Frequency in FOP Subjects 8/10 years and older in Clinical Trials:

Doses were reduced according to body weight in subjects who were less than 90% skeletally mature.
^* includes lip dry, chapped lips, cheilitis
^† includes pruritus, pruritus generalized, and rash pruritic
^‡ includes rash, rash generalized, rash maculo-papular
^§ includes erythema, generalized erythema, flushing, rash erythematous
^¶ includes headache and migraine
^# includes back pain, flank pain, sciatica
^Þ includes myalgia, musculoskeletal discomfort
^ß includes drug eruption, hypersensitivity, pruritus allergic, drug hypersensitivity
^à includes peripheral swelling, edema peripheral
^è includes fatigue, lethargy, asthenia, malaise

Doses were reduced according to body weight in subjects who were less than 90% skeletally mature

Premature epiphyseal closure

Subjects under 18 years with open epiphyses were assessed for growth during the clinical studies. Premature epiphyseal closure was identified by scheduled imaging in 27% of subjects who were less than 18 years of age at enrollment and was more common in younger compared with older subjects (31% in subjects between 8/10 years to 14 years and no subjects 14 years or older). Many of the affected subjects exhibited slowing of growth in height.

Mucocutaneous Adverse Reactions

Mucocutaneous adverse reactions observed in over 10% of subjects (N=134) were dry skin (78%), lip dry (66%), pruritus (55%), alopecia (44%), rash (42%), erythema (37%), skin exfoliation [skin peeling] (31%), and skin irritation (11%). In addition, dry eye occurred in 25% of subjects.

Bone Mineral Density and Fractures

Loss of bone mineral density and radiological vertebral fractures (PT: Spinal fracture) were identified as a risk associated with palovarotene based on novel analyses performed on whole body CT data in FOP subjects in the Phase 3 study.

Hepatotoxicity

Retinoids have been associated with dose dependent elevations of liver enzymes and isolated cases of severe hepatitis. In palovarotene studies of FOP, elevated ALT was observed in 7.0% of subjects during 20/10 mg flare-up dosing and 1.5% of subjects during 5 mg chronic dosing. There were no subjects who required dose reduction or treatment discontinuation due to liver enzyme elevations.

Hypertriglyceridemia

Systemic retinoids may cause marked elevations of serum triglycerides. In FOP studies, hypertriglyceridemia was reported in 2 subjects during chronic palovarotene treatment (2%) and in 4 subjects during flare-up dosing (4%).

Pancreatitis

Pancreatitis has been reported with other systemic retinoids, both with and without elevated triglycerides, including fatal cases. In palovarotene studies, one healthy subject developed acute pancreatitis, possibly related to concomitant use of ketoconazole in a drug-drug interaction study. There were no reports of pancreatitis in the FOP clinical studies.

Night Blindness

One reaction of night blindness was observed in palovarotene treated subjects.

Intracranial Hypertension (Pseudotumor Cerebri)

Systemic retinoid use has been associated with cases of benign intracranial hypertension (also called pseudotumor cerebri), some of which involved the concomitant use of tetracyclines. There were no reports of benign intracranial hypertension in the FOP clinical studies.