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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 is derived from the randomized double-blind active controlled non-inferiority study of INVEGA HAFYERA and 3-month paliperidone palmitate prolonged-release suspension for injection. During the double-blind phase, 478 patients were randomized to receive 2 injection cycles of INVEGA HAFYERA over a 12-month duration. The mean (SD) duration of exposure was 329.8 (86.97) days in the INVEGA HAFYERA group and 336.4 (80.89) days in the PP3M group during the double-blind phase.
Adverse Reactions in the Double-Blind, Active-Controlled Clinical Trial: Commonly Observed Adverse Reactions: The most common adverse reactions (incidence at least 5% in the double-blind Phase) of the INVEGA HAFYERA clinical trial were, upper respiratory tract infection, injection site reaction, weight increased, headache and parkinsonism.
Discontinuation of Treatment Due to Adverse Reactions: In the double-blind phase of the INVEGA HAFYERA clinical trial 1.3% of subjects in the INVEGA HAFYERA group and 0.4% of subjects in the 3-month paliperidone palmitate prolonged-release suspension for injection group discontinued due to adverse reactions.
Adverse Reactions Occurring at an Incidence of 2% or More in INVEGA HAFYERA-Treated Patients: Table 7 lists the adverse reactions reported in the INVEGA HAFYERA clinical trial. (See Table 7.)
Click on icon to see table/diagram/imageDemographic Differences: An examination of population subgroups in the INVEGA HAFYERA trial did not reveal any evidence of differences in safety on the basis of age, gender, or race alone.
Extrapyramidal Symptoms (EPS): Data from the randomized double-blind active controlled study provided information regarding EPS. Several methods were used to measure EPS: (1) the Simpson-Angus Rating Scale 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 8) and (5) incidence of spontaneous reports of EPS (Table 9). (See Tables 8 and 9.)
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Click on icon to see table/diagram/imageDystonia: 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: Induration, redness and swelling were observed in 13% in the INVEGA HAFYERA group and 9% in the PP3M group during the double-blind Phase. Investigator evaluation of tenderness was higher for subjects in the INVEGA HAFYERA group versus the 3-month paliperidone palmitate prolonged-release suspension for injection group (31% vs. 19%) during the double-blind Phase. Active INVEGA HAFYERA medication was given at double-blind baseline and Month 6, while placebo medication was given at the other injection times.
Subject ratings of injection site pain: The average score for the subject's evaluation of injection pain on a scale of 0 to 100 was approximately 16 at the open-label Phase end point and approximately 5 in both groups at the double-blind Phase end point.
Other Adverse Reactions Observed During the Clinical Trial Evaluation of INVEGA HAFYERA: The following additional adverse reactions were identified in the randomized double-blind active controlled study. The following list does not include reactions: 1) already listed in previous tables or elsewhere in the monograph, 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.
Blood and lymphatic system disorders: anemia.
Cardiac disorders: bradycardia, tachycardia.
Ear and labyrinth disorders: vertigo.
Gastrointestinal disorders: constipation, nausea, vomiting.
General disorders and administration site conditions: fatigue.
Hepatobiliary disorders: transaminases increased.
Infections and infestations: cystitis, respiratory tract infection, tonsillitis.
Metabolism and nutritional disorders: decreased appetite, increased appetite, weight decreased.
Psychiatric disorders: depression.
Reproductive system and breast disorders: breast pain, menstrual disorder.
Skin and subcutaneous tissue disorders: rash.
Vascular disorders: hypertension.
Additional Adverse Reactions Reported in Clinical Trials with the 1-Month and 3-Month Paliperidone Palmitate Prolonged-Release Suspension for Injection: The following is a list of additional adverse reactions that have been reported in clinical trials with the 1-month and 3-month paliperidone palmitate prolonged-release suspensions for injection that are not listed elsewhere: Cardiac disorders: atrioventricular block first degree, bundle branch block, palpitations, postural orthostatic tachycardia syndrome.
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, chest discomfort.
Immune system disorders: hypersensitivity.
Investigations: electrocardiogram abnormal.
Metabolism and nutrition disorders: hyperinsulinemia.
Musculoskeletal and connective tissue disorders: 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, sexual dysfunction.
Respiratory, thoracic and mediastinal disorders: cough.
Skin and subcutaneous tissue disorders: drug eruption, eczema, pruritus, pruritus generalized, urticaria.
Vascular disorders: hypotension, orthostatic hypotension.
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, 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, retrograde ejaculation.
Respiratory, thoracic and mediastinal disorders: nasal congestion, pharyngolaryngeal pain, pneumonia aspiration.
Skin and subcutaneous tissue disorders: rash papular.
Vascular disorders: ischemia.
Postmarketing Experience: The following adverse reactions have been identified during post-approval 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, catatonia, ileus, somnambulism, swollen tongue, thrombotic thrombocytopenic purpura, urinary incontinence, and urinary retention.
Cases of anaphylactic reaction after injection with the 1-month paliperidone palmitate prolonged-release suspension for injection 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 section of the Prescribing Information for those products.
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