Paliperidone (Page 2 of 10)

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. Paliperidone extended-release tablets were not marketed at the time these studies were performed. Paliperidone extended-release tablets are not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)].

5.3 Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure.

If NMS is suspected, immediately discontinue paliperidone and provide symptomatic treatment and monitoring.

5.4 QT Prolongation

Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.

In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n = 50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate-release was more than twice the exposure observed with the maximum recommended 12 mg dose of paliperidone extended-release tablets (Cmax ss = 113 ng/mL and 45 ng/mL, respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which Cmax ss = 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study.

For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the paliperidone extended-release tablets 12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving paliperidone extended-release tablets had a QTcLD exceeding 500 msec at any time in any of these three studies.

5.5 Tardive Dyskinesia

A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with duration of treatment and the cumulative dose The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, paliperidone extended-release tablets should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient treated with paliperidone extended-release tablets, drug discontinuation should be considered. However, some patients may require treatment with paliperidone extended-release tablets despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with all atypical antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or diabetes in trial subjects treated with paliperidone extended-release tablets. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because paliperidone extended-release tablets were not marketed at the time these studies were performed, it is not known if paliperidone extended-release tablets are associated with this increased risk.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 1a.

Table 1a. Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia
Paliperidone Extended-Release Tablets
Placebo 3 mg/day 6 mg/day 9 mg/day 12 mg/day
Mean change from baseline (mg/dL)
n = 322 n = 122 n = 212 n = 234 n = 218
Serum GlucoseChange from baseline 0.8 -0.7 0.4 2.3 4.3
Proportion of Patients with Shifts
Serum GlucoseNormal to High 5.1% 3.2% 4.5% 4.8% 3.8%
(< 100 mg/dL to≥ 126 mg/dL) (12/236) (3/93) (7/156) (9/187) (6/157)

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were associated with a mean change in glucose of +3.3 mg/dL at Week 24 (n = 570) and +4.6 mg/dL at Week 52 (n = 314).Data from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) with schizophrenia are presented in Table 1b.

Table 1b. Change in Fasting Glucose from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12 to 17 years of age) with Schizophrenia
Paliperidone Extended-Release Tablets
Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day
Mean change from baseline (mg/dL)
n = 41 n = 44 n = 11 n = 28 n = 32
Serum GlucoseChange from baseline 0.8 -1.4 -1.8 -0.1 5.2
Proportion of Patients with Shifts
Serum GlucoseNormal to High 3% 0% 0% 0% 11%
(< 100 mg/dL to≥ 126 mg/dL) (1/32) (0/34) (0/9) (0/20) (3/27)

DyslipidemiaUndesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia are presented in Table 2a.

Table 2a. Change in Fasting Lipids from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia
Paliperidone Extended-Release Tablets
Placebo 3 mg/day 6 mg/day 9 mg/day 12 mg/day
Mean change from baseline (mg/dL)
Cholesterol n = 331 n = 120 n = 216 n = 236 n = 231
Change from baseline -6.3 -4.4 -2.4 -5.3 -4.0
LDL n = 322 n = 116 n = 210 n = 231 n = 225
Change from baseline -3.2 0.5 -0.8 -3.9 -2.0
HDL n = 331 n = 119 n = 216 n = 234 n = 230
Change from baseline 0.3 -0.4 0.5 0.8 1.2
Triglycerides n = 331 n = 120 n = 216 n = 236 n = 231
Change from baseline -22.3 -18.3 -12.6 -10.6 -15.4
Proportion of Patients with Shifts
Cholesterol
Normal to High 2.6% 2.8% 5.6% 4.1% 3.1%
(< 200 mg/dL to ≥ 240 mg/dL (5/194) (2/71) (7/125) (6/147) (4/130)
LDL
Normal to High 1.9% 0.0% 5.0% 3.7% 0.0%
(< 100 mg/dL to ≥ 160 mg/dL) (2/105) (0/44) (3/60) (3/81) (0/69)
HDL
Normal to Low 22.0% 16.3% 29.1% 23.4% 20.0%
(≥ 40 mg/dL to < 40 mg/dL) (44/200) (13/80) (39/134) (32/137) (27/135)
Triglycerides
Normal to High 5.3% 11.0% 8.8% 8.7% 4.3%
(< 150 mg/dL to ≥ 200 mg/dL) (11/208) (9/82) (12/136) (13/150) (6/139)

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were associated with a mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n = 573) and -1.5 mg/dL at Week 52 (n = 317), (b) triglycerides of -6.4 mg/dL at Week 24 (n = 573) and -10.5 mg/dL at Week 52 (n = 317); (c) LDL of -1.9 mg/dL at Week 24 (n = 557) and -2.7 mg/dL at Week 52 (n = 297); and (d) HDL of +2.2 mg/dL at Week 24 (n = 568) and +3.6 mg/dL at Week 52 (n = 302).

Data from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) with schizophrenia are presented in Table 2b.

Table 2b. Change in Fasting Lipids from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12 to 17 years of age) with Schizophrenia
Paliperidone Extended-Release Tablets
Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day
Mean change from baseline (mg/dL)
Cholesterol n = 39 n = 45 n = 11 n = 28 n = 32
Change from baseline -7.8 -3.3 12.7 3.0 -1.5
LDL n = 37 n = 40 n = 9 n = 27 n = 31
Change from baseline -4.1 -3.1 7.2 2.4 0.6
HDL n = 37 n = 41 n = 9 n = 27 n = 31
Change from baseline -1.9 0.0 1.3 1.4 0.0
Triglycerides n = 39 n = 44 n = 11 n = 28 n = 32
Change from baseline -8.9 3.2 17.6 -5.4 3.9
Proportion of Patients with Shifts
Cholesterol
Normal to High 7% 4% 0% 6% 11%
(< 170 mg/dL to ≥ 200 mg/dL) (2/27) (1/26) (0/6) (1/18) (2/19)
LDL
Normal to High 3% 4% 14% 0% 9%
(< 110 mg/dL to ≥ 130 mg/dL) (1/32) (1/25) (1/7) (0/22) (2/22)
HDL
Normal to Low 14% 7% 29% 13% 23%
(≥ 40 mg/dL to < 40 mg/dL) (4/28) (2/30) (2/7) (3/23) (5/22)
Triglycerides
Normal to High 3% 5% 13% 8% 7%
(< 150 mg/dL to ≥ 200 mg/dL) (1/34) (2/38) (1/8) (2/26) (2/28)

Weight Gain
Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Schizophrenia TrialsData on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects are presented in Table 3a.

Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia
Paliperidone Extended-Release Tablets
Placebo 3 mg/day 6 mg/day 9 mg/day 12 mg/day
n = 323 n = 112 n = 215 n = 235 n = 218
Weight (kg) Change from baseline -0.4 0.6 0.6 1.0 1.1
Weight Gain ≥ 7% increase from baseline 5% 7% 6% 9% 9%

In the uncontrolled, longer-term open-label extension studies, paliperidone extended-release tablets were associated with a mean change in weight of +1.4 kg at Week 24 (n = 63) and +2.6 kg at Week 52 (n = 302).

Weight gain in adolescent subjects with schizophrenia was assessed in a 6-week, double-blind, placebo-controlled study and an open-label extension with a median duration of exposure to paliperidone extended-release tablets of 182 days. Data on mean changes in body weight and the proportion of subjects meeting a weight gain criterion of ≥ 7% of body weight [see Clinical Studies (14.1)] from the placebo-controlled 6-week study in adolescent subjects (12 to 17 years of age) are presented in Table 3b.

Table 3b. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight from a Placebo-Controlled 6-Week Study in Adolescent Subjects (12 to 17 years of age) with Schizophrenia
Paliperidone Extended-Release Tablets
Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day
n =51 n =54 n = 16 n = 45 n =34
Weight (kg) Change from baseline 0.0 0.3 0.8 1.2 1.5
Weight Gain ≥ 7% increase from baseline 2% 6% 19% 7% 18%

In the open-label long-term study the proportion of total subjects treated with paliperidone extended-release tablets with an increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with paliperidone extended-release tablets, weight gain should be assessed against that expected with normal growth. When taking into consideration the median duration of exposure to paliperidone extended-release tablets in the open-label study (182 days) along with expected normal growth in this population based on age and gender, an assessment of standardized scores relative to normative data provides a more clinically relevant measure of changes in weight. The mean change from open-label baseline to endpoint in standardized score for weight was 0.1 (4% above the median for normative data). Based on comparison to the normative data, these changes are not considered to be clinically significant.

Schizoaffective Disorder Trials
In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, a higher percentage of paliperidone extended-release tablets-treated subjects (5%) had an increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥ 7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group.

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2021. All Rights Reserved.