Side Effects of Invega (paliperidone)

Invega (paliperidone) is an oral, atypical antipsychotic used to treat schizophrenia. Atypical antipsychotics differ from typical antipsychotics because they cause a lesser degree of movement (extrapyramidal) side effects and constipation.

The exact mechanism of action of Invega is unknown, but, like other anti-psychotics, it is believed it affects the way the brain works by interfering with neurotransmitters nerves use to communicate with each other in the brain.

The neurotransmitters travel to other nearby nerves where they attach to receptors on the nerves, which either stimulates or inhibits the function of the nearby nerves. Invega blocks several of the receptors on nerves including dopamine type 2, serotonin type 2, and alpha 2 adrenergic receptors.

It is believed that many psychotic illnesses are caused by abnormal communication among nerves in the brain and that by altering communication through neurotransmitters, Invega can alter the psychotic state.

Common side effects of Invega include

• drowsiness,
• weight gain,
• headache,
• upper respiratory tract infection,
• increased heart rate,
• constipation,
• restlessness or difficulty sitting still,
• stiffness,
• shuffling walk,
• tremors, and
• slow movements.

Serious side effects of Invega include

• increased risk of stroke and death in elderly patients with dementia-related psychosis,
• neuroleptic malignant syndrome (high fever, sweating, severe muscle stiffness or rigidity, confusion, loss of consciousness, high blood pressure, rapid heartbeat, and changes in breathing),
• extrapyramidal side effects (painful spasms of the oral, throat, or neck muscles that may cause problems with speech, swallowing, and stiff neck; feelings of restlessness or difficulty sitting still; drug induced Parkinson's symptoms; movement problems affecting the tongue, lips, jaw, face, and extremities),
• metabolic changes (high blood sugar, diabetes mellitus, increased cholesterol, and weight gain),
• high blood levels of prolactin (menstrual abnormalities, leakage of milk from the breast, development of breast in males, and erection problems in men), and
• seizures.

Drug interactions of Invega include other drugs associated with low blood pressure especially when standing up from a sitting or lying position (orthostatic hypotension).

• Invega is metabolized by liver enzymes. Drugs that increase the action of these enzymes such as carbamazepine, phenytoin, rifampin, and St. John's wort will decrease blood levels of Invega thereby decreasing its effect. 
• Invega blocks the effect of dopamine in the brain while dopamine agonists such as levodopa increase the levels of dopamine in the brain.
• Combining these agents is not recommended since the effect of both drugs will be reduced.
• Divalproex sodium increases blood levels of Invega by 50%.

Unborn babies exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and withdrawal symptoms after birth. Invega should only be used during pregnancy if the potential benefit to the mother outweighs the potential for side effects in the fetus. A pregnancy exposure registry has been established to monitor the use of atypical antipsychotics, including Invega, during pregnancy.

Invega enters human milk but its effects on the breastfeeding infant or milk production is not known. Consult your doctor before breastfeeding.

The most common side effects include

• drowsiness,
• weight gain,
• headache,
• upper respiratory tract infection,
• increased heart rate,
• constipation,
• feeling restlessness or difficulty sitting still,
• stiffness, and shuffling walk,
• tremors, and
• slow movements.

Less common but serious side effects include:

• Increased risk of stroke and death in elderly patients with dementia-related psychosis.
• Neuroleptic malignant syndrome (NMS): NMS is a rare but serious side effects associated with the use of antipsychotics. NMS may result in death and must be treated in the hospital. Signs and symptoms of NMS may include
  • high fever,
  • sweating (diaphoresis),
  • severe muscle stiffness or rigidity,
  • confusion,
  • loss of consciousness,
  • high blood pressure,
  • rapid heartbeat, and
  • changes in breathing.
• Extrapyramidal side effects (EPS) including:
  • Dystonia: painful spasms of the oral, throat, or neck muscles that may cause problems with speech, swallowing, and stiff neck.
  • Akathisia: feelings of restlessness or difficulty sitting still.
  • Pseudoparkinsonism: drug induced Parkinson's symptoms.
• Tardive dyskinesia (TD): Tardive dyskinesia usually occurs after long-term use of antipsychotics and usually presents with movement problems affecting the tongue, lips, jaw, face, and extremities.
• Metabolic changes including high blood sugar (hyperglycemia), diabetes mellitus, increase in blood cholesterol, and weight gain.
• HHigh blood levels of prolactin. Prolactin is a hormone that allows the production of breast milk. High levels of prolactin may cause menstrual abnormalities, leakage of milk from the breast, development of breast in males (gynecomastia), and erection problems in men.
• Seizures

Overall Adverse Reaction Profile

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

• Increased mortality in elderly patients with dementia-related psychosis
• Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis
• Neuroleptic malignant syndrome
• QT prolongation
• Tardive dyskinesia
• Metabolic changes
• Hyperprolactinemia
• Potential for gastrointestinal obstruction
• Orthostatic hypotension and syncope
• Falls
• Leukopenia, neutropenia, and agranulocytosis
• Potential for cognitive and motor impairment
• Seizures
• Dysphagia
• Suicide
• Priapism
• Thrombotic thrombocytopenic purpura (TTP)
• Disruption of body temperature regulation
• Antiemetic effect
• Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies
• Diseases or conditions that could affect metabolism or hemodynamic responses

The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with Invega and at least twice the placebo rate in any of the dose groups) were

• extrapyramidal symptoms,
• tachycardia, and
• akathisia.

The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with Invega and at least twice the placebo rate) were

• extrapyramidal symptoms,
• somnolence,
• dyspepsia,
• constipation,
• weight increased, and
• nasopharyngitis.

The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of Invega-treated subjects) were nervous system disorders.

The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of Invega-treated subjects.

The safety of Invega was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received Invega at fixed doses ranging from 3 mg to 12 mg once daily.

The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received Invega at daily doses within the range of 3 mg to 15 mg (n=104), is also included.

The safety of Invega was evaluated in 150 adolescent subjects 12-17 years of age with schizophrenia who received Invega in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

The safety of Invega was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of Invega: 6 mg with the option to reduce to 3 mg (n=108) or 12 mg with the option to reduce to 9 mg (n=98) once daily.

In the other study, 214 subjects received flexible doses of Invega (3-12 mg once daily).

Both studies included subjects who received Invega either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. 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.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of Invega (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for Invega often 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.

Commonly-Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia In Adults And Adolescents

Adult Patients With Schizophrenia

Table 4 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred in 2% or more of subjects treated with Invega in any of the dose groups, and for which the incidence in Invega-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 4: Adverse Reactions Reported by ≥ 2% of Invega-Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials*

Adolescent Patients With Schizophrenia

Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12-17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with Invega in any of the dose groups, and for which the incidence in Invega-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 5: Adverse Reactions Reported by ≥ 2% of Invega-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial*

Commonly-Observed Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder In Adults

Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with Invega and for which the incidence in Invega-treated subjects was greater than the incidence in subjects treated with placebo.

Table 6: Adverse Drug Reactions Reported by ≥ 2% of Invega-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials *

Monotherapy Versus Adjunctive Therapy

The designs of the two placebo-controlled, 6-week, double-blind trials in adult subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine).

In the subject population evaluated for safety, 230 (55%) subjects received Invega as monotherapy and 190 (45%) subjects received Invega as an adjunct to mood stabilizers and/or antidepressants.

When comparing these 2 subpopulations, only nausea occurred at a greater frequency (≥ 3% difference) in subjects receiving Invega as monotherapy.

Discontinuations Due To Adverse Reactions

Schizophrenia Trials

The percentages of subjects who discontinued due to adverse reactions in the three schizophrenia placebo-controlled, 6-week, fixed-dose studies in adults were 3% and 1% in Invega-and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in Invega-and placebo-treated subjects, respectively).

Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, only dystonia led to discontinuation (<1% of Invega-treated subjects).

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo-controlled 6-week studies in adults were 1% and <1% in Invega-and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in Invega-and placebo-treated subjects, respectively).

Dose-Related Adverse Reactions

Schizophrenia Trials

Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with Invega, the incidences of the following adverse reactions increased with dose:

• somnolence,
• orthostatic hypotension,
• akathisia,
• dystonia,
• extrapyramidal disorder,
• hypertonia,
• parkinsonism, and
• salivary hypersecretion.

For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.

In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the adverse reactions that occurred with >2% incidence in the subjects treated with Invega, the incidences of the following adverse reactions increased with dose:

• tachycardia,
• akathisia,
• extrapyramidal symptoms,
• somnolence, and
• headache.

Schizoaffective Disorder Trials

In a placebo-controlled, 6-week, high-and low-dose study in adult subjects with

• schizoaffective disorder,
• akathisia,
• dystonia,
• dysarthria,
• myalgia,
• nasopharyngitis,
• rhinitis,
• cough, and
• pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who received higher doses of Invega compared with subjects who received lower doses.

Demographic Differences

An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and in the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder did not reveal any evidence of clinically relevant differences in safety on the basis of gender or race alone; there was also no difference on the basis of age.

Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia provided information regarding treatment-emergent EPS. Several methods were used to measure EPS:

• (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates Parkinsonism,
• (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia,
• (3) use of anticholinergic medications to treat emergent EPS (Table 7), and
• (4) incidence of spontaneous reports of EPS (Table 8).

For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and Invega 3 mg and 6 mg doses for any of these EPS measures.

Table 7: Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults

Table 8: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adults

Compared to data from the studies in adults subjects with schizophrenia, pooled data from the two placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar types and frequencies of EPS as measured by rating scales, anticholinergic medication use, and spontaneous reports of EPS-related adverse events.

For subjects with schizoaffective disorder, there was no dose-related increase in EPS observed for parkinsonism with the Simpson-Angus scale or akathisia with the Barnes Akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS reports of hyperkinesia and dystonia and in the use of anticholinergic medications.

Table 9 shows the EPS data from the pooled schizoaffective disorder trials.

Table 9: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizoaffective Disorder Studies in  Adults

The incidences of EPS-related adverse events in the adolescent schizophrenia studies showed a similar dose-related pattern to those in the adult studies. There were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies (Table 10).

Table 10: Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adolescent Subjects

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 three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between Invega 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 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 was associated with increases in serum prolactin.

Other Adverse Reactions Observed During Premarketing Evaluation Of Invega

The following additional adverse reactions occurred in < 2% of Invega-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by Invega-treated subjects who participated in other clinical studies.

Cardiac disorders: bradycardia, palpitations

Eye disorders: eye movement disorder

Gastrointestinal disorders: flatulence

General disorders: edema

Immune system disorders: anaphylactic reaction

Infections and infestations: urinary tract infection

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased

Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity

Nervous system disorders: opisthotonus

Psychiatric disorders: agitation, insomnia, nightmare

Reproductive system and breast disorders: breast discomfort, menstruation irregular, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders: nasal congestion

Skin and subcutaneous tissue disorders: pruritus, rash

Vascular disorders: hypertension

The safety of Invega was also evaluated in a long-term trial designed to assess the maintenance of effect with Invega in adults with schizophrenia. In general, adverse reaction types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Invega; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, ileus, priapism, swollen tongue, tardive dyskinesia, urinary incontinence, urinary retention.

Adverse Reactions Reported With Risperidone

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the Adverse Reactions section of the risperidone package insert.

Potential For Invega To Affect Other Drugs

Given the primary CNS effects of paliperidone, Invega should be used with caution in combination 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 be observed when Invega is administered with other therapeutic agents that have this potential.

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including

• CYP1A2,
• CYP2A6,
• CYP2C8/9/10,
• CYP2D6,
• CYP2E1,
• CYP3A4, and
• CYP3A5.

Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown.

Pharmacokinetic interaction between lithium and Invega is unlikely.

In a drug interaction study, co-administration of Invega (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate.

In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when Invega 3-15 mg/day was added to their existing valproate treatment.

Potential For Other Drugs To Affect Invega

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism, in vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate.

Co-administration of Invega 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax and AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone.

A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of Invega should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of Invega should be re-evaluated and decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6. In an interaction study in healthy subjects in which a single 3 mg dose of Invega was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.

Co-administration of a single dose of Invega 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for Invega should be considered when Invega is co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and Invega is unlikely.

Drug Abuse And Dependence

Controlled Substance

Invega (paliperidone) is not a controlled substance.

Abuse

Paliperidone has not been systematically studied in animals or humans for its potential for abuse. It is not possible to predict the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of Invega misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Dependence

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