Paliperidone palmitate

Drugs that may cause orthostatic hypotension: An additive effect may occur when co-administered with ERZOFRI. ( 7.1 ) Strong CYP3A4 and P-glycoprotein (P-gp) inducers : Avoid using a strong inducer of CYP3A4 and/or P-gp during a dosing interval for ERZOFRI. If concomitant use is necessary, consider using paliperidone extended-release tablets. ( 2.5 , 7.1 , 12.3 )

7.1 Drugs Having Clinically Important Interactions with ERZOFRI Because paliperidone palmitate is hydrolyzed to paliperidone [see Clinical Pharmacology (12.3) ] , results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. Table 12 presents clinically significant drug interactions with ERZOFRI. Table 12: Clinically Important Drug Interactions with ERZOFRI Centrally Acting Drugs and Alcohol Clinical Rationale: Given the primary CNS effects of paliperidone, concomitant use of centrally acting drugs and alcohol may modulate the CNS effects of ERZOFRI.

Clinical Recommendation: ERZOFRI should be used with caution in combination with other centrally acting drugs and alcohol [see Adverse Reactions (6.1 , 6.2) ] . Drugs with Potential for Inducing Orthostatic Hypotension Clinical Rationale: Because ERZOFRI has the potential for inducing orthostatic hypotension, an additive effect may occur when ERZOFRI is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.7) ] . Clinical Recommendation: Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions (5.7) ] .

Strong Inducers of CYP3A4 and P-gp Clinical Rationale: The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3) ] . Clinical Recommendation: Avoid using CYP3A4 and/or P-gp inducers with ERZOFRI during the 1-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release tablets [see Dosage and Administration (2.5) ] . Levodopa and Other Dopamine Agonists Clinical Rationale: Paliperidone may antagonize the effect of levodopa and other dopamine agonists.

Clinical Recommendation: Monitor and manage patient as clinically appropriate.

7.2 Drugs Having No Clinically Important Interactions with ERZOFRI Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of ERZOFRI is required when administered with valproate [see Clinical Pharmacology (12.3) ]. Additionally, no dosage adjustment is necessary for valproate when co-administered with ERZOFRI [See Clinical Pharmacology (12.3) ]. Pharmacokinetic interaction between lithium and ERZOFRI is also unlikely. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes.

In vitro studies indicate that CYP2D6 and CYP3A4 may be involved in paliperidone metabolism; however, there is no evidence in vivo that inhibitors of these enzymes significantly affect the metabolism of paliperidone. Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19; an interaction with inhibitors or inducers of these isozymes is unlikely. [see Clinical Pharmacology (12.3) ]

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including ERZOFRI, during pregnancy. Healthcare providers are encouraged to advise patients to register by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at http://womensmentalhealth.org/clinical- and-research-programs/pregnancyregistry/ . Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations ) .

Overall, available data from published epidemiologic studies of pregnant women exposed to paliperidone have not established a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother associated with untreated schizophrenia and with exposure to antipsychotics, including ERZOFRI, during pregnancy (see Clinical Considerations ). Paliperidone has been detected in plasma in adult subjects up to 176 days after a single-dose administration of ERZOFRI [see Clinical Pharmacology (12.3) ] , and the clinical significance of ERZOFRI administered before pregnancy or anytime during pregnancy is not known.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal reproduction studies, there were no treatment related effects on the offspring when pregnant rats were injected intramuscularly with paliperidone palmitate during the period of organogenesis at doses up to 10 times the maximum recommended human dose (MRHD) of 234 mg paliperidone palmitate based on mg/m 2 body surface area (BSA). There were no increases in fetal abnormalities when pregnant rats and rabbits were treated orally with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg of paliperidone based on mg/m 2 BSA.

Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone ( see Animal data ). Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including…