Side Effects of Invega Sustenna (paliperidone palmitate)

Invega Sustenna (paliperidone palmitate) is an atypical antipsychotic used to treat schizophrenia. It is a long acting form of Invega (paliperidone).

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 Sustenna is unknown, but, like other antipsychotics, 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 Sustenna 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 Sustenna can alter the psychotic state.

Common side effects of Invega Sustenna include

• injection site reaction,
• weight gain,
• headache,
• upper respiratory tract infection,
• restlessness or difficulty sitting still,
• stiffness and shuffling walk,
• tremors, and
• slow movements.

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

• Invega Sustenna 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 Sustenna thereby decreasing its effect. 
• Invega Sustenna 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.

Unborn babies exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and withdrawal symptoms after birth. Invega Sustenna should only be used during pregnancy if the potential benefit to the mother outweighs the potential for side effects in the fetus.

Invega Sustenna is known to enter human milk but its effects on the breastfeeding infants or milk production is unknown.

The most common side effects include

• injection site reaction,
• weight gain,
• headache,
• upper respiratory tract infection,
• 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 in elderly patients with dementia-related psychosis.
• Neuroleptic malignant syndrome (NMS). NMS is a rare but serious side effect 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 your breathing.
• Extrapyramidal side effects (EPS) include:
  • 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). TD usually occurs after long term use of antipsychotics and usually causes 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.
• High 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 breasts in (males gynecomastia), and erection problems in men (erectile dysfunction).
• Seizures

The following 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
• Orthostatic hypotension and syncope
• Falls
• Leukopenia, neutropenia, and agranulocytosis
• Hyperprolactinemia
• Potential for cognitive and motor impairment
• Seizures
• Dysphagia
• Priapism
• Disruption of body temperature regulation

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 in subjects with schizophrenia were

• injection site reactions,
• somnolence/sedation,
• dizziness,
• akathisia, and
• extrapyramidal disorder.

No occurrences of adverse events reached this threshold in the long-term double-blind, placebo-controlled study in subjects with schizoaffective disorder.

The data described in this section are derived from a clinical trial database consisting of a total of 3817 subjects (approximately 1705 patient-years exposure) 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 (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 234 mg Invega Sustenna initiation dose followed by treatment with either 39 mg, 156 mg, or 234 mg every 4 weeks.

The safety of Invega Sustenna was also evaluated in a long-term study in adult subjects with schizoaffective disorder. 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).

Adverse reactions that occurred more frequently in the Invega Sustenna than the placebo group (a 2% difference or more between groups) were

• weight increased,
• nasopharyngitis,
• headache,
• hyperprolactinemia, and
• pyrexia.

Clinical Trials Experience

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 Reported Adverse Reactions In Double-Blind, Placebo-Controlled Clinical Trials

Table 10 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 10: Incidence of Adverse Reactions in ≥ 2% of Invega Sustenna-Treated Subjects (and greater than Placebo) with Schizophrenia in Four Fixed-Dose, Double-Blind, Placebo-Controlled Trials

Other Adverse Reactions Observed During The Clinical Trial Evaluation Of Invega Sustenna

The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, or 4) which were not considered to have significant clinical implications.

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: constipation, dyspepsia, flatulence, salivary hypersecretion

Immune system disorders: hypersensitivity

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, electrocardiogram abnormal

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

Musculoskeletal and connective tissue disorders: arthralgia, 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: insomnia, restlessness

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

Respiratory, thoracic and mediastinal disorders: nasal congestion

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

Discontinuations Due To Adverse Events

The percentage of subjects who discontinued due to adverse events in the four fixed-dose, double-blind, placebo-controlled schizophrenia trials were similar for Invega Sustennaand placebo-treated subjects.

The percentage of subjects who discontinued due to adverse events in the open-label period of the long-term study in subjects with schizoaffective disorder was 7.5%. During the double-blind, placebo-controlled period of that study, the percentages of subjects who discontinued due to adverse events were 5.5% and 1.8% 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 in subjects with schizophrenia, 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 in adult subjects with schizophrenia provided information regarding 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 EPS,
• (4) the Abnormal Involuntary Movement Scale scores (mean change from baseline or scores at the end of trial) (Table 11), and
• (5) incidence of spontaneous reports of EPS (Table 12).

Table 11: Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication - Schizophrenia Studies in Adults

Table 12: Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term - Schizophrenia Studies in Adults

The results across all phases of the maintenance trial in subjects with schizophrenia 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 in subjects with schizophrenia involving 234 mg initiation dosing, the incidence of any EPS 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%).

In the long-term study in subjects with schizoaffective disorder, the EPS during the 25-week open-label Invega Sustenna treatment were

• hyperkinesia (12.3%),
• parkinsonism (8.7%),
• tremor (3.4%),
• dyskinesia (2.5%), and
• dystonia (2.1%).

During the 15-month double-blind treatment, the incidence of any EPS was similar to that of the placebo group (8.5% and 7.1% respectively). The most commonly reported treatment-emergent EPS-related adverse events ( > 2%) in any treatment group in the double-blind phase of the study (Invega Sustenna versus placebo) were

• hyperkinesia (3.7% vs. 2.9%),
• parkinsonism (3.0% vs. 1.8%), and
• tremor (1.2% vs. 2.4%).

Dystonia

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 in subjects with schizophrenia, 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, triglycerides, HDL, LDL, and total cholesterol measurements.

However, Invega Sustenna was associated with increases in serum prolactin. 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 in subjects with schizophrenia 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 in subjects with schizophrenia, 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 in subjects with schizophrenia, 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, 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: 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: 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.

Blood disorders: thrombotic thrombocytopenic purpura

Gastrointestinal disorders: ileus

Genitourinary disorders: urinary incontinence, urinary retention

Immune system disorders: angioedema, swollen tongue

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.

Because paliperidone palmitate is hydrolyzed to paliperidone, 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

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.

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.

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

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.

No dose adjustment is necessary for Invega Sustenna when valproate is added to treatment.

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 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.