Palovarotene

7 DRUG INTERACTIONS CYP3A4 Inhibitors: May increase SOHONOS exposure. Avoid concomitant use of strong/moderate CYP3A4 inhibitors. If concomitant use of moderate CYP3A4 inhibitors is unavoidable, reduce the dose of SOHONOS by half ( 2.5 , 7.1 ) CYP3A4 Inducers: May decrease SOHONOS exposure. Avoid concomitant use of strong/moderate CYP3A4 inducers ( 7.1 ) Vitamin A: May cause additive effects ( 7.2 ) Tetracyclines: Avoid concomitant use with SOHONOS ( 7.3 ) Systemic Corticosteroids: No clinically significant drug interaction is expected with concomitant use of SOHONOS ( 7.4 )

7.1 Effect of Other Drugs on SOHONOS Clinically significant drug interactions affecting the exposure of SOHONOS are listed in Table 6. Table 6. Drugs that affect exposure of SOHONOS. Strong CYP3A Inhibitors Clinical Impact Co-administration of SOHONOS with strong CYP3A4 inhibitors increased the exposures of palovarotene [see Clinical Pharmacology (12.3) ] , which may increase the risk of SOHONOS adverse reactions. Prevention or Management Avoid concomitant use of a strong CYP3A4 inhibitor during SOHONOS treatment [see Dosage and Administration (2.5) ] .

Moderate CYP3A Inhibitors Clinical Impact Co-administration of SOHONOS with moderate CYP3A4 inhibitors may increase the exposure of palovarotene [see Clinical Pharmacology (12.3) ] , which may increase the risk of SOHONOS adverse reactions. Prevention or Management Avoid concomitant use of a moderate CYP3A4 inhibitor with SOHONOS, if possible. If co-administration will occur, reduce the SOHONOS dose by half when co-administered with moderate CYP3A inhibitors [see Dosage and Administration (2.5) ] .

Strong CYP3A Inducers Clinical Impact Co-administration of SOHONOS with strong CYP3A4 inducers decreased the exposure of palovarotene [see Clinical Pharmacology (12.3) ] , which may reduce the effectiveness of SOHONOS. Prevention or Management Avoid concomitant use of strong CYP3A4 inducers with SOHONOS. [see Dosage and Administration (2.5) ] . Moderate CYP3A Inducers Clinical Impact Co-administration of moderate CYP3A4 inducers with palovarotene may decrease palovarotene exposure [see Clinical Pharmacology (12.3) ], which may reduce the effectiveness of SOHONOS. Prevention or Management Avoid concomitant use of moderate CYP3A4 inducers with SOHONOS.

7.2 Vitamin A Palovarotene belongs to the same pharmacological class as vitamin A. Therefore, the use of both vitamin A and SOHONOS 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 SOHONOS must be avoided because of the risk of hypervitaminosis A.

7.3 Tetracyclines 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 SOHONOS with tetracycline derivatives [see Adverse Reactions (6.1) ] .

7.4 Systemic Corticosteroids No clinically significant drug-drug interaction is expected when SOHONOS is co-administered with prednisone [see Clinical Pharmacology (12.3) ] .

8.1 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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ] . 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 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. 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.