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Invega Sustenna

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Invega Sustenna

Side Effects
Interactions

SIDE EFFECTS

The following are discussed in more detail in other sections of the labeling:

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.

The most common (at least 5% in any INVEGA® SUSTENNA® group) and likely drug-related (adverse events for which the drug rate is at least twice the placebo rate) adverse reactions from the double-blind, placebo-controlled trials were injection site reactions, somnolence/sedation, dizziness, akathisia, and extrapyramidal disorder.

The data described in this section are derived from a clinical trial database consisting of a total of 3817 subjects with schizophrenia who received at least one dose of INVEGA® SUSTENNA® in the recommended dose range of 39 mg to 234 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 maintenance trial (of whom 205 continued to receive INVEGA® SUSTENNA® during the double-blind placebo-controlled phase of this study), 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 [deltoidgluteal] cross-over trial). One of the 13-week studies included a 234 mg INVEGA® SUSTENNA® initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every 4 weeks.

Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

The majority of all adverse reactions were mild to moderate in severity.

Clinical Trials Experience

Commonly Reported Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials

Table 5 lists the adverse reactions reported in 2% or more of INVEGA® SUSTENNA® -treated subjects and at a greater proportion than in the placebo group with schizophrenia in the four fixed-dose, double-blind, placebo-controlled trials.

Table 5: Incidence of Treatment Emergent Adverse Reactions in ≥ 2% of INVEGA® SUSTENNA® -Treated Subjects (and greater than Placebo) with Schizophrenia in Four Fixed-Dose, Double-Blind, Placebo- Controlled Trials

System Organ Class Adverse Event Placeboa
(N=510)
INVEGA®SUSTENNA®
39 mg
(N=130)
78 mg
(N=302)
156 mg
(N=312)
234/39 mgb
(N=160)
234/156 mgb
(N=165)
234/234 mgb
(N=163)
Total percentage of subjects with adverse event 70 75 68 69 63 60 63
Gastrointestinal disorders
  Abdominal discomfort/abdominal pain upper 2 2 4 4 1 2 4
  Diarrhea 2 0 3 2 1 2 2
  Dry mouth 1 3 1 0 1 1 1
  Nausea 3 4 4 3 2 2 2
  Toothache 1 1 1 3 1 2 3
  Vomiting 4 5 4 2 3 2 2
General disorders and administration site conditions
  Asthenia 0 2 1 < 1 0 1 1
  Fatigue 1 1 2 2 1 2 1
  Injection site reactions 2 0 4 6 9 7 10
Infections and infestations
  Nasopharyngitis 2 0 2 2 4 2 2
  Upper respiratory tract infection 2 2 2 2 1 2 4
  Urinary tract infection 1 0 1 < 1 1 1 2
Investigations
  Weight increased 1 4 4 1 1 1 2
Musculoskeletal and connective tissue disorders
  Back pain 2 2 1 3 1 1 1
  Musculoskeletal stiffness 1 1 < 1 < 1 1 1 2
  Myalgia 1 2 1 < 1 1 0 2
  Pain in extremity 1 0 2 2 2 3 0
Nervous system disorders
  Akathisia 3 2 2 3 1 5 6
  Dizziness 1 6 2 4 1 4 2
  Extrapyramidal disorder 1 5 2 3 1 0 0
  Headache 12 11 11 15 11 7 6
  Somnolence/sedation 3 5 7 4 1 5 5
Psychiatric disorders
  Agitation 7 10 5 9 8 5 4
  Anxiety 7 8 5 3 5 6 6
  Nightmare < 1 2 0 0 0 0 0
Respiratory, thoracic and mediastinal disorders
  Cough 1 2 3 1 0 1 1
Vascular disorders
  Hypertension 1 2 1 1 1 1 0
Percentages are rounded to whole numbers. Table includes adverse events that were reported in 2% or more of subjects in any of the INVEGA® SUSTENNA® dose groups and which occurred at greater incidence than in the placebo group.
a Placebo group is pooled from all studies and included either deltoid or gluteal injection depending on study design.
b Initial deltoid injection of 234 mg followed by either 39 mg, 156 mg, or 234 mg every 4 weeks by deltoid or gluteal injection. Other dose groups (39 mg, 78 mg, and 156 mg) are from studies involving only gluteal injection. [See Clinical Studies]
Adverse events for which the INVEGA® SUSTENNA® incidence was equal to or less than placebo are not listed in the table, but included the following: dyspepsia, psychotic disorder, schizophrenia, and tremor. The following terms were combined: somnolence/sedation, breast tenderness/breast pain, abdominal discomfort/abdominal pain upper/stomach discomfort, and tachycardia/sinus tachycardia/heart rate increased. All injection site reaction-related adverse events were collapsed and are grouped under “Injection site reactions”.

Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA® SUSTENNA®

The following additional adverse reactions occurred in INVEGA® SUSTENNA® -treated subjects in the above four fixed-dose, double-blind, placebo-controlled trials, in the double-blind phase of the maintenance trial, or in INVEGA® SUSTENNA® -treated subjects with schizophrenia who participated in other clinical trials, and were not reported in Table 5 or in other sections of labeling above. They were determined to be adverse reactions based upon reasons to suspect causality such as timing of onset or termination with respect to drug use, plausibility in light of the drug's known pharmacology, occurrence at a frequency above that expected in the treated population or occurrence of an event typical of drug-induced adverse reactions.

Cardiac disorders: atrioventricular block first degree, bradycardia, bundle branch block, palpitations, postural orthostatic tachycardia syndrome, tachycardia

Ear and labyrinth disorders: vertigo

Eye disorders: eye movement disorder, eye rolling, oculogyric crisis, vision blurred

Gastrointestinal disorders: salivary hypersecretion

Immune system disorders: hypersensitivity

Investigations: electrocardiogram abnormal

Metabolism and nutrition disorders: decreased appetite, hyperinsulinemia, increased appetite

Musculoskeletal and connective tissue disorders: joint stiffness, muscle rigidity, muscle spasms, muscle tightness, muscle twitching, nuchal rigidity

Nervous system disorders: bradykinesia, cerebrovascular accident, convulsion, dizziness postural, drooling, dysarthria, dyskinesia, dystonia, hypertonia, lethargy, oromandibular dystonia, parkinsonism, psychomotor hyperactivity, syncope

Psychiatric disorders: restlessness

Reproductive system and breast disorders: amenorrhea, breast discharge, erectile dysfunction, galactorrhea, gynecomastia, menstrual disorder, menstruation delayed, menstruation irregular, sexual dysfunction

Skin and subcutaneous tissue disorders: drug eruption, pruritus, pruritus generalized, rash, urticaria

Discontinuations Due to Adverse Events

The percentages of subjects who discontinued due to adverse events in the four fixed-dose, double-blind, placebo-controlled trials were 5.0% and 7.8% in INVEGA® SUSTENNA® - and placebo-treated subjects, respectively.

Dose-Related Adverse Reactions

Based on the pooled data from the four fixed-dose, double-blind, placebo-controlled trials, among the adverse reactions that occurred at ≥ 2% incidence in the subjects treated with INVEGA® SUSTENNA® , only akathisia increased with dose. Hyperprolactinemia also exhibited a dose relationship, but did not occur at ≥ 2% incidence in INVEGA® SUSTENNA® -treated subjects from the four fixed-dose studies.

Demographic Differences

An examination of population subgroups in the double-blind placebo-controlled trials did not reveal any evidence of differences in safety on the basis of age, gender, or race alone; however, there were few subjects ≥ 65 years of age.

Extrapyramidal Symptoms (EPS)

Pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline or score at the end of trial) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline or score at the end of trial) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS, (4) the Abnormal Involuntary Movement Scale scores (mean change from baseline or scores at the end of trial) (Table 6), and (5) incidence of spontaneous reports of EPS (Table 7).

Table 6: Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication

Scale Percentage of Subjects
Placebo
(N=262)
INVEGA® SUSTENNA®
39 mg
(N=130)
78 mg
(N=223)
156 mg
(N=228)
Parkinsonisma 9 12 10 6
Akathisiab 5 5 6 5
Dyskinesiac 3 4 6 4
Use of Anticholinergic Medicationsd 12 10 12 11
a For Parkinsonism, percent of subjects with Simpson-Angus Total score > 0.3 at endpoint (Total score defined as total sum of items score divided by the number of items)
b For Akathisia, percent of subjects with Barnes Akathisia Rating Scale global score ≥ 2 at endpoint
c For Dyskinesia, percent of subjects with a score ≥ 3 on any of the first 7 items or a score ≥ 2 on two or more of any of the first 7 items of the Abnormal Involuntary Movement Scale at endpoint
d Percent of subjects who received anticholinergic medications to treat emergent EPS

Table 7: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term

EPS Group Percentage of Subjects
Placebo
(N=262)
INVEGA® SUSTENNA®
39 mg
(N=130)
78 mg
(N=223)
156 mg
(N=228)
Overall percentage of subjects with EPS-related adverse events 10 12 11 11
Parkinsonism 5 6 6 4
Hyperkinesia 2 2 2 4
Tremor 3 2 2 3
Dyskinesia 1 2 3 1
Dystonia 0 1 1 2
Parkinsonism group includes: Extrapyramidal disorder, hypertonia, musculoskeletal stiffness, parkinsonism, drooling, masked facies, muscle tightness, hypokinesia
Hyperkinesia group includes: Akathisia, restless legs syndrome, restlessness
Dyskinesia group includes: Dyskinesia, choreoathetosis, muscle twitching, myoclonus, tardive dyskinesia
Dystonia group includes: Dystonia, muscle spasms

The results across all phases of the maintenance trial exhibited comparable findings. In the 9-week, fixed-dose, double-blind, placebo-controlled trial, the proportions of Parkinsonism and akathisia assessed by incidence of rating scales were higher in the INVEGA® SUSTENNA® 156 mg group (18% and 11%, respectively) than in the INVEGA® SUSTENNA® 78 mg group (9% and 5%, respectively) and placebo group (7% and 4%, respectively).

In the 13-week study involving 234 mg initiation dosing, the incidence of any treatmentemergent EPS-related adverse events was similar to that of the placebo group (8%), but exhibited a dose-related pattern with 6%, 10%, and 11% in the INVEGA® SUSTENNA® 234/39 mg, 234/156 mg, and 234/234 mg groups, respectively. Hyperkinesia was the most frequent category of EPS-related adverse events in this study, and was reported at a similar rate between the placebo (4.9%) and INVEGA® SUSTENNA® 234/156 mg (4.8%) and 234/234 mg (5.5%) groups, but at a lower rate in the 234/39 mg group (1.3%).

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Laboratory Test Abnormalities

In the pooled data from the two double-blind, placebo-controlled, 13-week, fixed-dose trials, a between-group comparison revealed no medically important differences between INVEGA® SUSTENNA® and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between INVEGA® SUSTENNA® and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, INVEGA® SUSTENNA® was associated with increases in serum prolactin [see WARNINGS AND PRECAUTIONS]. The results from the 13-week study involving 234 mg initiation dosing, the 9-week, fixed-dose, double-blind, placebo-controlled trial, and the double-blind phase of the maintenance trial exhibited comparable findings.

Pain Assessment and Local Injection Site Reactions

In the pooled data from the two 13-week, fixed-dose, double-blind, placebo-controlled trials, the mean intensity of injection pain reported by subjects using a visual analog scale (0 = no pain to 100 = unbearably painful) decreased in all treatment groups from the first to the last injection (placebo: 10.9 to 9.8; 39 mg: 10.3 to 7.7; 78 mg: 10.0 to 9.2; 156 mg: 11.1 to 8.8). The results from both the 9-week, fixed-dose, double-blind, placebo-controlled trial and the double-blind phase of the maintenance trial exhibited comparable findings.

In the 13-week study involving 234 mg initiation dosing, occurrences of induration, redness, or swelling, as assessed by blinded study personnel, were infrequent, generally mild, decreased over time, and similar in incidence between the INVEGA® SUSTENNA® and placebo groups. Investigator ratings of injection pain were similar for the placebo and INVEGA® SUSTENNA® groups. Investigator evaluations of the injection site after the first injection for redness, swelling, induration, and pain were rated as absent for 69-100% of subjects in both the INVEGA® SUSTENNA® and placebo groups. At Day 92, investigators rated absence of redness, swelling, induration, and pain in 95-100% of subjects in both the INVEGA® SUSTENNA® and placebo groups.

Adverse Reactions Reported In Clinical Trials With Oral Paliperidone

The following is a list of additional adverse reactions that have been reported in clinical trials with oral paliperidone:

Cardiac disorders: bundle branch block left, sinus arrhythmia

Gastrointestinal disorders: abdominal pain, constipation, flatulence, small intestinal obstruction

General disorders and administration site conditions: edema, edema peripheral immune system disorders: anaphylactic reaction Infections and infestations: rhinitis

Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, torticollis, trismus

Nervous system disorders: cogwheel rigidity, grand mal convulsion, parkinsonian gait, transient ischemic attack

Psychiatric disorders: sleep disorder

Reproductive system and breast disorders: breast engorgement, breast tenderness/breast pain, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration

Skin and subcutaneous tissue disorders: rash papular

Vascular disorders: hypotension, ischemia

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of paliperidone; because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: angioedema, ileus, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.

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.

Adverse Reactions Reported With Risperidone

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with oral risperidone and risperidone long-acting injection can be found in the ADVERSE REACTIONS sections of the package inserts for those products.

Read the Invega Sustenna (paliperidone palmitate extended-release injectable suspension) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Because paliperidone palmitate is hydrolyzed to paliperidone [see CLINICAL PHARMACOLOGY], results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential.

Potential For INVEGA® SUSTENNA® To Affect Other Drugs

Given the primary CNS effects of paliperidone [see ADVERSE REACTIONS], INVEGA® SUSTENNA® should be used with caution when administered concomitantly with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.

Because of its potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA® SUSTENNA® is administered with other therapeutic agents that have this potential [see WARNINGS AND PRECAUTIONS].

No dose adjustment is necessary for lithium when it is coadministered with INVEGA® SUSTENNA® . Pharmacokinetic interaction between INVEGA® SUSTENNA® and lithium is unlikely.

No dose adjustment is necessary for valproate when INVEGA® SUSTENNA® is added to the therapy. Steady-state pharmacokinetics of valproate was not affected when patients were coadministered oral paliperidone extended-release tablets [see CLINICAL PHARMACOLOGY].

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes [see CLINICAL PHARMACOLOGY].

Potential For Other Drugs To Affect INVEGA® SUSTENNA®

On initiation of strong inducers of both CYP3A4 and P-gp, (e.g., carbamazepine, rifampin, or St John's wort), it may be necessary to increase the dose of INVEGA® SUSTENNA® . Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of INVEGA® SUSTENNA® [see CLINICAL PHARMACOLOGY].

No dose adjustment is necessary for INVEGA® SUSTENNA® when valproate is added to treatment [see CLINICAL PHARMACOLOGY].

No dose adjustment is necessary for INVEGA® SUSTENNA® when it is coadministered with lithium. Pharmacokinetic interaction between INVEGA® SUSTENNA® and lithium is unlikely.

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 Reference ID: 3495576 29 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.

Drug Abuse And Dependence

Controlled Substance

INVEGA® SUSTENNA® (paliperidone) is not a controlled substance.

Abuse

Paliperidone has not been systematically studied in animals or humans for its potential for abuse.

Dependence

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

Read the Invega Sustenna Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 5/19/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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