Side Effects of Invega Trinza (paliperidone palmitate)

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

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 Trinza 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 Trinza 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 Trinza can alter the psychotic state.

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

• Invega Trinza 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 Trinza thereby decreasing its effect. 
• Invega Trinza 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 Trinza 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 Trinza, during pregnancy.

Invega Trinza 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

• 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 are increased risk of stroke in elderly patients with dementia-related psychosis.

Neuroleptic malignant syndrome or NMS is a rare but serious side effect associated with the use of antipsychotics. Neuroleptic malignant syndrome may result in death and must be treated in the hospital. Signs and symptoms of heuroleptic malignant syndrome may include

• high fever,
• sweating (diaphoresis),
• severe muscle stiffness or rigidity,
• confusion,
• loss of consciousness,
• high blood pressure,
• rapid heartbeat, and
• changes in breathing breathing.

Extrapyramidal side effects include:

• Dystonia are painful spasms of the oral, throat, or neck muscles that may cause problems with speech, swallowing, and stiff neck.
• Akathisia are feelings of restlessness or difficulty sitting still.
• Pseudoparkinsonism is drug induced Parkinson's symptoms.
• 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.
• 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.
• 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

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.

Patient Exposure

The data described in this section include data from two clinical trials. One is a long-term maintenance trial, in which

• 506 subjects with schizophrenia received several doses of the 1-month paliperidone palmitate extended-release injectable suspension during the open-label phase, of which
• 379 subjects continued to receive a single injection of Invega Trinza during the open-label phase, and
• 160 subjects were subsequently randomized to receive at least one dose of Invega Trinza and 145 subjects received placebo during the double-blind placebo-controlled phase.

The mean (SD) duration of exposure during the double-blind phase was 150 (79) days in the placebo group and 175 (90) days in the Invega Trinza group. The other is a Phase 1 study (N=308), which included patients with schizophrenia who received a single injection of Invega Trinza concomitantly with other oral antipsychotics.

Adverse Reactions In A Double-Blind, Placebo-Controlled (Long-Term Maintenance) Clinical Trial

Commonly Observed Adverse Reactions:

The most common adverse reactions (incidence at least 5% in the open-label phase, or in the Invega Trinza group and at least twice the incidence in the placebo group during the double-blind phase) were

• injection site reaction,
• weight increased,
• headache,
• upper respiratory tract infection,
• akathisia, and
• parkinsonism.

Discontinuation of Treatment Due to Adverse Events:

The percentages of subjects who discontinued due to adverse events in the long-term maintenance trial were 5.1% during the open-label phase. During the double-blind phase, no Invega Trinza-treated subject and one placebo-treated subject discontinued due to adverse events.

Adverse Reactions Occurring at an Incidence of 2% or More in Invega Trinza-Treated Patients:

The safety profile of Invega Trinza was similar to that seen with the 1-month paliperidone extended-release injectable suspension. Table 8 lists the adverse reactions reported in a long-term maintenance trial in subjects with schizophrenia.

Table 8. Incidences of Adverse Reactions 2% or More of Invega Trinza-Treated Patients (and Greater than Placebo) for the Open-Label and Double-Blind Phases of a Long-Term Maintenance Trial in Patients with Schizophrenia

Demographic Differences

An examination of population subgroups in the long-term maintenance trial 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 and older.

Extrapyramidal Symptoms (EPS)

Data from the long-term maintenance trial provided information regarding EPS. Several methods were used to measure EPS:

• (1) the Simpson-Angus global score which broadly evaluates parkinsonism,
• (2) the Barnes Akathisia Rating Scale global clinical rating score which evaluates akathisia,
• (3) the Abnormal Involuntary Movement Scale scores which evaluates dyskinesia, and
• (4) use of anticholinergic medications to treat EPS (Table 9), and (5) incidence of spontaneous reports of EPS (Table 10).

Table 9. Extrapyramidal Symptoms (EPS) Assessed by Incidence of Rating Scales and Use of Anticholinergic Medication

Table 10. Extrapyramidal Symptoms (EPS)-Related Events by MedDRA Preferred Term

After injection of Invega Trinza in the open-label phase, 12 (3.2%) subjects had EPS that were new or worsened in severity, with events under the groupings of hyperkinesia (1.6%) and parkinsonism (1.3%) being the most common. After injection of Invega Trinza in the open-label or double-blind phases, one subject discontinued from the open-label phase due to restlessness.

An examination of the time to EPS during the double-blind phase showed no clustering of these events at visits that would be expected to correspond to median peak plasma concentrations of paliperidone for subjects randomized to Invega Trinza.

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.

Pain Assessment And Local Injection Site Reactions

Investigator ratings of injection site. Redness and swelling were observed in 2% or less of subjects in the Invega Trinza and placebo groups during the double-blind phase of the long-term maintenance study, and were rated mild based on investigator ratings using a 4-point scale (0=absent; 1=mild; 2=moderate; 3=severe).

There were no reports of induration in either group during the double-blind phase, and no subjects discontinued due to Invega Trinza injection.

Subject ratings of injection site pain

Subject evaluations of injection pain during the double-blind phase also were similar for placebo and Invega Trinza.

Subject ratings of injection site pain in the single-dose Phase 1 study allowed for assessment of the temporal course of injection site pain. Residual injection pain peaked 1 or 6 hours after injection, and trended downward 3 days after the injection. Deltoid injections were numerically more painful than gluteal injections, although most pain ratings were below 10 mm on a 100-mm scale.

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

The following additional adverse reactions were identified in the long-term maintenance trial. 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,
• 4) which were not considered to have significant clinical implications, or
• 5) occurred at an incidence lower than that of placebo-treated patients.

Cardiac disorders: tachycardia

Gastrointestinal disorders: nausea, vomiting

Metabolism and nutrition disorders: hyperinsulinemia

Psychiatric disorders: anxiety

Additional Adverse Reactions Reported In Clinical Trials With The 1-Month Paliperidone Palmitate Extended-Release Injectable Suspension

The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month paliperidone palmitate extended-release injectable suspension:

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

Ear and labyrinth disorders: vertigo

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

Gastrointestinal disorders: abdominal discomfort/abdominal pain upper, diarrhea, dry mouth, toothache

General disorders and administration site conditions: asthenia, fatigue

Immune system disorders: hypersensitivity

Investigations: electrocardiogram abnormal

Metabolism and nutrition disorders: decreased appetite, increased appetite

Musculoskeletal and connective tissue disorders: back pain, myalgia, pain in extremity, joint stiffness, muscle spasms, muscle twitching, nuchal rigidity

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

Psychiatric disorders: agitation, nightmare

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

Respiratory, thoracic and mediastinal disorders: cough

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

Vascular disorders: hypertension

Additional 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

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

Nervous system disorders: 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.

Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate extended-release suspension have been reported during postmarketing experience in patients who have previously tolerated oral risperidone or oral paliperidone.

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.

Drugs Having Clinically Important Interactions With Invega Trinza

Because paliperidone palmitate is hydrolyzed to paliperidone, results from studies with oral paliperidone should be taken into consideration when assessing drug-drug interaction potential. In addition, consider the 3-month dosing interval and long half-life of Invega Trinza.

Table 11. Clinically Important Drug Interactions with Invega Trinza

Drugs Having No Clinically Important Interactions With Invega Trinza

Based on pharmacokinetic studies with oral paliperidone, no dosage adjustment of Invega Trinza is required when administered concomitantly with valproate. Additionally, no dosage adjustment is necessary for valproate when coadministered with Invega Trinza.

Pharmacokinetic Interaction Between Lithium And Invega Trinza Is unlikely.

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