Invega Sustenna Adverse Reactions

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of paliperidone palmitate based on the comprehensive assessment of the available adverse event information. A causal relationship with paliperidone palmitate cannot be reliably established in individual cases. Further, 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 clinical practice.
Clinical trial data: The data described in this section are derived from clinical trial database consisting of a total of 3817 adult subjects (approximately 1705 patient-years exposure) with schizophrenia who received at least one dose of INVEGA SUSTENNA in the recommended dose range of 25 to 150 mg and a total of 510 subjects with schizophrenia who received placebo. Among the 3817 INVEGA SUSTENNA-treated subjects, 1293 received INVEGA SUSTENNA in four fixed-dose, double-blind, placebo-controlled trials (one 9-week and three 13-week studies), 849 received INVEGA SUSTENNA in the long-term recurrence prevention trial (median exposure 229 days during the initial 33-week open-label phase of this study, of whom 205 continued to receive INVEGA SUSTENNA during the double-blind placebo-controlled phase of this study [median exposure 171 days]), and 1675 received INVEGA SUSTENNA in five non-placebo controlled trials (three noninferiority active-comparator trials, one long-term open-label pharmacokinetic and safety study and an injection site [deltoid-gluteal] cross-over trial). One of the 13-week studies included a 150 mg INVEGA SUSTENNA initiation dose followed by treatment with either 25 mg, 100 mg, or 150 mg every 4 weeks.
The safety of INVEGA SUSTENNA was also evaluated in a 15-month, long-term study comparing INVEGA SUSTENNA to selected oral antipsychotic therapies in adult subjects with schizophrenia. A total of 226 subjects received INVEGA SUSTENNA during the 15-month, open-label period of this study; 218 subjects received selected oral antipsychotic therapies. The safety of INVEGA SUSTENNA was similar to that seen in previous double-blind, placebo-controlled clinical trials in adult subjects with schizophrenia.
The safety of INVEGA SUSTENNA was also evaluated in adult subjects with schizoaffective disorder who participated in a long-term relapse prevention trial. A total of 667 subjects received INVEGA SUSTENNA during the initial 25-week open-label period of this study (median exposure 147 days); 164 subjects continued to receive INVEGA SUSTENNA during the 15-month double-blind placebo-controlled period of this study (median exposure 446 days).
The majority of adverse reactions were mild to moderate in severity.
Double-blind placebo-controlled data: Adverse reactions reported by >2% of INVEGA SUSTENNA-treated subjects with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials are shown in Table 5. (See Table 5.)

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In the long-term recurrence prevention trial, adverse reaction types, frequencies, and severities during the open-label phases of this study were generally comparable to those observed in the four 13-week and the 9-week placebo-controlled fixed-dose studies shown in Table 5. Adverse reactions reported during the double-blind phase of this study were generally similar in type and severity to those observed in the open-label phases.
Other clinical trial data: Paliperidone palmitate is hydrolyzed to paliperidone. Paliperidone is the active metabolite of risperidone, therefore the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. This subsection includes additional adverse reactions reported with paliperidone and/or risperidone in clinical trials.
Adverse reactions reported with paliperidone and/or risperidone by ≥ 2% of INVEGA SUSTENNA-treated subjects in a pooled dataset of the 4 double-blind, placebo-controlled schizophrenia trials are shown in Table 6. (See Table 6.)

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Adverse reactions reported with paliperidone and/or risperidone by <2% of INVEGA SUSTENNA-treated subjects in a pooled dataset of the 4 double-blind, placebo-controlled schizophrenia trials are shown in Table 7. (See Table 7.)

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Adverse reactions reported with paliperidone and/or risperidone in other clinical trials but not reported by INVEGA SUSTENNA-treated subjects in a pooled dataset of the 4 double-blind, placebo-controlled schizophrenia trials are shown in Table 8. (See Table 8.)

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Schizoaffective disorder: The safety profile of INVEGA SUSTENNA in patients with schizoaffective disorder is similar to that observed in patients with schizophrenia.
Events of particular interest to the class: Extrapyramidal symptoms (EPS). Pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled schizophrenia trials (see Pharmacology: Pharmacodynamics: Clinical efficacy under Actions) showed no differences in treatment-emergent EPS between placebo and INVEGA SUSTENNA. Evaluation of EPS included a pooled analysis of the following EPS groups: dyskinesia, dystonia, hyperkinesia, parkinsonism, and tremor. The results from the 13-week schizophrenia study involving the 150 mg initiation dosing, the 9-week, fixed-dose, double-blind, placebo-controlled schizophrenia trial, and across all phases of the long-term recurrence prevention trials in subjects with schizophrenia and schizoaffective disorder exhibited comparable findings.
Weight gain. The proportions of subjects meeting a weight gain criterion of ≥7% of body weight in the 13-week schizophrenia study involving 150 mg initiation dosing, weight increases from baseline of ≥7% were more common among subjects in the INVEGA SUSTENNA groups than in the placebo group. The proportion of subjects with an abnormal weight increase ≥7% showed a dose-related trend, with a 5% incidence rate in the placebo group compared with rates of 6%, 8%, and 13% in the INVEGA SUSTENNA 25 mg, 100 mg, and 150 mg groups, respectively.
In the two 13-week, fixed-dose, double-blind, placebo-controlled schizophrenia trials (pooled data), the proportions of subjects meeting a weight gain criterion of ≥7% of body weight were 6%, 9%, and 10% in the INVEGA SUSTENNA 25, 50, and 100 mg groups, respectively, compared with 2% in the placebo group. In the 9-week, fixed-dose, double-blind, placebo-controlled schizophrenia trial, 8% and 6% in the INVEGA SUSTENNA 50 and 100 mg groups, respectively, met this criterion compared with 4% in the placebo group.
During the 33-week open-label transition/maintenance period of the long-term recurrence prevention schizophrenia trial, 12% of INVEGA SUSTENNA-treated subjects met this criterion (weight gain of ≥ 7% from double-blind phase to endpoint); the mean (SD) weight change from open-label baseline was +0.7 (4.79) kg. In the variable length double-blind phase, this criterion was met by 6% of INVEGA SUSTENNA-treated subjects (median duration 171 days [range 1-407 days]) compared with 3% of placebo-treated subjects (median duration 105 days [range 8-441 days]); the mean (SD) weight change from double-blind baseline was +0.5 (3.83) kg for INVEGA SUSTENNA compared with -1.0 kg (3.08) for placebo. Similar results were observed in the open-label extension phase of this study.
During the initial 25-week open-label period of the long-term study in subjects with schizoaffective disorder, INVEGA SUSTENNA was associated with a mean change in weight of +2.2 kg and 18.4% of subjects had an increase in body weight of ≥ 7% (n=653). At the endpoint of the subsequent 15-month double-blind period of the study, INVEGA SUSTENNA was associated with a mean change in weight of -0.2 kg and 13.05 of subjects had an increase in body weight of ≥ 7% (n=161); the placebo group had a mean change in weight of -0.8 kg and 6.0% of subjects had an increase in body weight of ≥ 7% (n=168).
Laboratory tests: serum prolactin. Based on pooled data from the two 13-week, fixed-dose double-blind, placebo-controlled trials (see Pharmacology: Pharmacodynamics: Clinical efficacy under Actions), median increases in serum prolactin were observed in subjects of both genders who received INVEGA SUSTENNA. The results from the 13-week study involving 150 mg initiation dosing, the 9-week, fixed-dose, double-blind, placebo-controlled trial, and the double-blind phase of the recurrence prevention trial exhibited comparable findings.
Postmarketing data: In addition to the adverse reactions reported during clinical studies and listed above, the following adverse reactions have been reported during postmarketing experience with paliperidone and/or risperidone (Table 9). In the table, the frequencies are provided according to the following convention: Very common: ≥1/10, Common: ≥1/100 to <1/10, Uncommon: ≥1/1,000 to <1/100, Rare: ≥1/10,000 to <1/1,000, Very rare: <1/10,000, including isolated reports, Not known: Cannot be estimated from the available data.
In Table 9, adverse reactions are presented by frequency category based on spontaneous reporting rates. (See Table 9.)

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Very rarely, cases of anaphylactic reaction after injection with INVEGA SUSTENNA have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.