Summary

• No specific drug interaction studies have been performed with INVEGA SUSTENNA.
• Avoid using a strong inducer of CYP3A4 and/or P-glycoprotein (P-gp) (e.g., carbamazepine, rifampin, St John’s Wort) during a dosing interval for INVEGA SUSTENNA. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended-release (ER) tablets.¹
• 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. In vitro studies demonstrated that paliperidone is a substrate of P-gp and weakly inhibits it at high concentrations.²
• After oral administration, a decrease in mean C_max and AUC values at steady state is expected when patients are treated with carbamazepine, a strong inducer of both CYP3A4 and P-gp. This decrease may be caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone resulting from an induction of P-gp in the kidney.^2-4 Concomitant use of paliperidone and carbamazepine may alter the medication exposure and doses may need to be adjusted.⁵
• Outcomes described from 3 studies and one case report showed that plasma concentrations of paliperidone were significantly lower during coadministration of carbamazepine.^4,6-8

DOSAGE STRENGTH INFORMATION

Doses of INVEGA SUSTENNA extended-release injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to mg of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq. to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.

PUBLISHED LITERATURE

Helland et al (2017)⁸ retrospectively evaluated the relationship between dose and serum concentrations of paliperidone in 310 patients (110 male, 75 female; median age: 40 years; age range: 19 to 78 years) receiving paliperidone palmitate long-acting injections. Injection doses ranged from 78 mg to 312 mg, except for one patient who received 19.5 mg. (Note, 19.5 mg and 312 mg doses of paliperidone palmitate are not commercially available.) In three samples analyzed from patients receiving concomitant carbamazepine, all had low concentration/dose ratios and dose-adjusted serum concentrations >50% lower than patients not taking concomitant carbamazepine.

Akamine et al (2015)⁷ reported the case of a 53-year-old female patient with schizophrenia and hypertension who was receiving oral paliperidone 12 mg/day and amlodipine 5 mg/day. When carbamazepine 200-600 mg/day was added, the plasma concentrations of paliperidone and amlodipine greatly decreased in a dose-dependent fashion (paliperidone by 35%-48% and amlodipine by 36%-68%). The concentration of carbamazepine also decreased after administration of 600 mg/day vs 200 mg/day or 400 mg/day. There was no change in the patient’s psychotic symptoms following the addition of carbamazepine. However, the patient’s mean blood pressure increased from 138.4 mmHg to 160.1 mmHg after administration of carbamazepine 600 mg/day and returned to normal upon discontinuation.

Kerbusch-Herben et al (2014)⁴ conducted an open-label, multiple-dose, 2-treatment, 2-period sequential study which investigated the effect of repeated administration of carbamazepine on the steady-state pharmacokinetics of oral paliperidone ER in patients with schizophrenia or bipolar I disorder.

A total of 64 patients (43 men and 21 women, median age: 42 years, schizophrenia diagnosis: n=62) received the following treatments in a fixed sequential manner, without washout between treatments: (1) paliperidone ER 6 mg once daily for 7 days, and (2) paliperidone ER 6 mg once daily with carbamazepine controlled release 200 mg twice daily for 21 days (days 8-28).

After coadministration with carbamazepine, paliperidone AUC_24h and C_max at steady-state decreased by approximately 37% each vs treatment with paliperidone ER alone. In addition, there was a 35.5% increase in renal clearance of paliperidone and a 14% decrease in the amount of paliperidone excreted unchanged in the urine over a 24-hour period following coadministration with carbamazepine.

After receiving paliperidone ER monotherapy (30%) and in combination with carbamazepine (24%) the overall incidence of adverse events (AEs) was similar. The most common (≥5%) AEs after administration of paliperidone ER monotherapy were headache (11%) and extrapyramidal disorder (5%); following administration of paliperidone ER with carbamazepine weight increase (5%) was the most common AE reported.

Yasui-Furukori et al (2013)⁶ evaluated the interaction between paliperidone and carbamazepine in 6 patients (5 female, 1 male; mean age 47.7 years) with schizophrenia. Subjects received oral paliperidone 6-12 mg once daily for 8-24 weeks (mean dose 8.0 mg/day). Carbamazepine 100 mg twice per day was then added for 2-4 weeks, increased to 200 mg, then to 300 mg twice per day for 2-4 weeks. Paliperidone was administered at 8:00 AM, carbamazepine was administered at 8:00 AM and 8:00 PM, and blood samples were taken between 9:00 AM and 11:00 AM. The mean (standard deviation [SD]) plasma concentration of paliperidone before carbamazepine administration was 45.8±11.7 ng/mL, and the mean (SD) plasma concentrations of paliperidone with 200, 400, and 600 mg/day of carbamazepine were 26.9±13.7 ng/mL, 17.1±8.2 ng/mL, and 15.9±7.6 ng/mL, respectively (all P<0.001). The plasma concentrations of paliperidone with 200, 400, and 600 mg/day of carbamazepine were 55.7%±20.7%, 36.1%±12.2%, and 33.6%±10.4% of baseline concentration, respectively. A deterioration in condition (exacerbated psychotic symptoms) occurred in 5 of the 6 subjects approximately 2-3 months after initiation of carbamazepine.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 24 April 2024.