Date of approval.
Date of revision.
Paliperidone Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Increases mortality in elderly patients with dementia-related psychosis
The risk of death is increased when atypical antipsychotics are used to treat elderly patients with dementia-related psychosis compared to placebo. An analysis of 17 placebo-controlled clinical trials (mean plural treatment duration of 10 weeks) in elderly patients with dementia-related psychosis showed that the risk of death was 1.6 – 1.7 times greater in the drug-treated group than in the placebo-controlled group. In a typical 10-week controlled trial, the mortality rate was 4.5% in the drug-treated group and 2.6% in the placebo-controlled group. Although the causes of death varied, most deaths were due to cardiovascular disease (e.g., heart failure, sudden death) or infection (e.g., pneumonia). This product is not approved for the treatment of patients with dementia-related psychosis (see [Precautions]).
[Drug Name].
Generic Name: Paliperidone Extended Release Tablets
English Name: Paliperidone Extended-Release
Tablets
Hanyu Pinyin: Palipaitong Huanshi Pian
Ingredients
Active ingredient: Paliperidone
Chemical name: (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
Chemical structure formula.
Molecular formula: C23H27FN4O3
Molecular weight: 426.49
Excipients.
Drug-containing layer: polyoxyethylene, polyvinylpyrrolidone, dibutylhydroxytoluene, colloidal silicon dioxide, stearic acid, purified water
Push layer: polyoxyethylene, polyvinylpyrrolidone, sodium chloride, temptation red aluminum precipitate, dibutyl hydroxytoluene, colloidal silicon dioxide, stearic acid, purified water
Isolation layer: hydroxypropyl cellulose, polyvinylpyrrolidone, ethanol
Controlled release layer: cellulose acetate fully formulated coating premix, acetone, purified water
Coloring layer: film-coated premix (gastric soluble type), ethanol, purified water
Properties
This product is white or off-white film-coated tablets (3mg specification) or orange film-coated tablets (6mg specification), after removing the coating, the core of the tablets is double-layered, with one side showing white and the other side showing red.
Indications
Paliperidone extended-release tablets are indicated for the treatment of schizophrenia in adults and adolescents aged 12-17 years (weight ≥29Kg).
Specification
(1) 3 mg (2) 6 mg
Dosage
Recommended Dose
Adults
The recommended dose of this product is 6 mg once a day, taken in the morning. The starting dose does not need to be titrated. Although no other benefits have been systematically established for doses above 6 mg, there is a general trend toward greater efficacy at higher doses, but this must be weighed against the side effect factor, as adverse effects increase with dose. Thus, some patients may benefit from higher doses of up to 12 mg/day, while some patients may benefit from lower doses of 3 mg/day, which may be sufficient. Doses should be increased beyond 6 mg/day only after clinical evaluation and usually at intervals greater than 5 days. When an increase in dose is indicated, incremental increases of 3 mg/day are recommended, with a recommended maximum dose of 12 mg/day.
In a longer-term clinical study, this product was effective in delaying relapse in patients who reached 6 weeks of stability with this product (see [Clinical Trials]). The product should be prescribed at the lowest effective dose during the maintenance phase of treatment, and each patient’s long-term use should be periodically reassessed by the physician.
Adolescents aged 12-17 years (weight ≥ 29 Kg)
The recommended dose of this product for the treatment of schizophrenia in adolescents aged 12-17 years (weight ≥ 29 Kg) is 3 mg once a day, taken in the morning. The starting dose does not need to be titrated. Doses should be increased only after clinical evaluation and should be increased in increments of 3 mg/day at intervals of >5 days. Prescribers should note that in studies of adolescent schizophrenia, there are no clear results that higher doses (e.g., 6 mg in subjects weighing less than 51 kg and 12 mg in subjects weighing 51 kg or more) enhance efficacy, but adverse events increase with increasing dose.
Weight Starting Dose Recommended Dose Maximum Dose 51 Kg> Weight ≥ 29 Kg3 mg/day3-6 mg/day6 mg/dayWeight ≥ 51 Kg3 mg/day3-12 mg/day12 mg/day
Dosing instructions
This product can be taken with or without meals. Clinical trials to establish the safety and efficacy of this product have been conducted in subjects without regard to meal times.
This product must be swallowed whole with the aid of liquid. The tablet should not be chewed, broken or crushed. The drug is contained in a non-absorbable shell designed to release the drug at a controlled rate. The tablet shell as well as the insoluble core component are excreted from the body, and patients should not be concerned if they occasionally observe some tablet-like material in the stool.
Combined Use with Risperidone
The combination of this product and risperidone has not been studied. Since paliperidone is the primary active metabolite of risperidone, consideration should be given to the potential for accumulation of paliperidone exposure if risperidone is administered concomitantly with this product.
Dosage for Special Populations
Patients with renal impairment
Dose adjustments must be individualized according to the patient’s renal function. For patients with mild renal impairment (creatinine clearance: 50 mL/min to <80 mL/min), the recommended starting dose is 3 mg once a day, which may be subsequently increased to a maximum dose of 6 mg once a day based on clinical efficacy and tolerability. For patients with moderate to severe renal impairment (creatinine clearance: 10 mL/min to <50 mL/min), the recommended starting dose is 3 mg every other day, which may be increased to 3 mg once daily following clinical evaluation. Because this product has not been studied in patients with creatinine clearance <10 mL/min, it is not recommended for use in such patients.
Patients with hepatic impairment
Dose adjustment is not recommended in patients with mild to moderate hepatic impairment (Child-Pugh classifications A and B) (see [Pharmacokinetics]). This product has not been studied in patients with severe hepatic impairment.
Geriatric patients
Because elderly patients may experience decreased renal function, dose adjustments may sometimes be necessary based on their renal function. In general, the recommended dose for elderly patients with normal renal function is the same as for adults with normal renal function. For patients with moderate to severe renal impairment (creatinine clearance: 10 mL/min to <50 mL/min), the recommended starting dose is 3 mg every other day, which may be increased to 3 mg once daily after clinical evaluation. Because this product has not been studied in patients with a creatinine clearance <10 mL/min, it is not recommended for such patients.
(See above for patients with renal impairment).
Adolescents and Children
The safety and efficacy of this product in patients with schizophrenia aged <12 years is not known (see [Pediatric Dosage]).
[Adverse Reactions].
The following adverse reactions are discussed in more detail elsewhere in the insert (see [Precautions]).
Increased mortality in elderly patients with dementia-related psychosis
Cerebrovascular adverse reactions, including stroke (seen in elderly patients with dementia-related psychosis)
malignant syndromes
Prolonged QT interval
delayed movement disorders
hyperglycemia and diabetes mellitus
Hyperprolactinemia
Possibility of gastrointestinal obstruction
Orthostatic hypotension and syncope
Possible cognitive and motor dysfunction
Convulsive episodes
Dysphagia
Suicide
Abnormal penile erection
Thrombotic thrombocytopenic purpura (TTP)
Disruption of thermoregulatory function
Antiemetic effect
Increased sensitivity in patients with Parkinson’s disease or the presence of Lewy body dementia
Diseases or conditions that affect metabolic or hemodynamic responses
The most common adverse reactions in clinical trials (which need to be reported at a rate of 5% or higher in subjects treated with this product in any dose group and at least twice the rate reported in the placebo group) were inability to sit still and extrapyramidal disturbances.
The most common adverse reaction associated with subject withdrawal from clinical trials (resulting in 2% of subjects in the treatment arm) was central nervous system disorders.
Safety evaluation data for this product were obtained from 1205 subjects with schizophrenia in three placebo-controlled, 6-week, double-blind clinical trials in which 850 subjects received a fixed dose of this product ranging from 3 mg to 12 mg once a day. The information presented below is from the pooled data from these three trials. Also included is additional safety information from the placebo-controlled phase of the long-term maintenance treatment study in which subjects received this product at daily doses ranging from 3 mg to 15 mg (n=104).
Adverse events that occurred during study treatment exposure were obtained as general inquiries and were recorded by clinical investigators in their own terms. Therefore, to provide meaningful estimates of the proportion of individuals experiencing adverse events, events were grouped according to the standard classification in MedDRA terminology.
The reported adverse reactions are shown in this section. Among the adverse reactions (adverse drug reactions) are those that are considered reasonably relevant to the use of the product based on a comprehensive evaluation of the available adverse event information. In individual cases, it is usually not possible to determine with certainty the causal relationship between the event and the product. In addition, the incidence of adverse reactions observed in clinical trials of one drug is not directly comparable to the incidence in clinical trials of another drug and may not reflect the incidence observed in clinical practice because of the wide variability of conditions under which clinical studies are performed.
Frequently Observed Adverse Reactions in Clinical Trials
Adults
The most commonly reported adverse drug reactions (ADRs) in clinical trials in adults include headache, insomnia, sedation/drowsiness, Parkinson’s disease, inability to sit still, tachycardia, tremor, dystonia, upper respiratory tract infection, anxiety, dizziness, weight gain, nausea, agitation, constipation, vomiting, fatigue, depression, dyspepsia, diarrhea, dry mouth, toothache, musculoskeletal pain, hypertension, weakness, back pain, prolonged electrocardiogram QT, and cough.
Table 1 lists adverse reactions reported in ≥2% of adult subjects with schizophrenia treated with this product in three 6-week, double-blind, placebo-controlled, fixed-dose studies.
Table 1: Adverse reactions reported in ≥2% of subjects treated with this product in three 6-week, double-blind, placebo-controlled, fixed-dose studies in adults
Percentage of patients reporting events
This product placebo
3 mg
6 mg once daily
9 mg once daily
1 time daily 12 mg
1 time daily Body System/Organ Classification
Adverse reactions (N=127)
% (N=235)
% (N=246)
% (N=242)
% (N=355)
% All types of neurological disorders Headache 1112141412 Dizziness 65454 Extrapyramidal disorders 52772 Drowsiness 53753 Sedentary inability 438104 Tremor 33433 Hypertonia 21431 Dystonia 11441 Sedation 15364 Parkinson’s 0<1210 Ocular organ disorders Actinic nerve crisis 00200 Cardiac organ disorders Sinus Tachycardia94474 Tachycardia27773 Bundle branch block313<12 Sinus arrhythmia211<10 First degree atrioventricular block20211 Vascular and lymphatic vessel diseaseUpright hypotension21241 Gastrointestinal system diseaseVomiting23455 Dry mouth23131 Epigastric pain13221 Salivary hypersecretion0<114<1 Systemic disease Weakness2<1221Fatigue21221
Adolescents
In a short-term study and 2 longer-term studies of paliperidone extended-release tablets in adolescents 12 years of age and older with schizophrenia, the overall safety of paliperidone was similar to the results observed in adults. In the combined population of adolescents with schizophrenia exposed to this product (12 years and older, N = 545), the incidence and type of adverse reactions were similar to those in adults, except that the following ADRs were reported more frequently in adolescents treated with this product than in adults (and more frequently than in the placebo group): sedation/drowsiness, parkinsonism, weight gain, upper respiratory tract infection, inability to sit still and tremor were common in adolescents (≥1/10); abdominal pain, breast overflow, gynecomastia, acne, dysphonia, gastroenteritis, epistaxis, ear infections, elevated blood triglycerides, and vertigo were common in adolescents (≥1/100, <1/10).
Table 2 lists the adverse reactions reported in ≥2% of adolescent schizophrenic subjects aged 12-17 years treated with this product in a fixed-dose, placebo-controlled study.
Table 2: Adverse Reactions Reported in ≥2% of Subjects Treated With This Product in a Fixed-Dose, Placebo-Controlled Study in Adolescents
Percentage of patients reporting events
This product placebo
1.5 mg
3 mg once daily
6 mg once daily
12 mg once daily
1 time daily Body system/organ classification
Adverse reactions (N=54)
(N=16)
(N=45)
(N=35)
(N=51)
Infectious and Infectious Diseases Nasopharyngitis 40402 Psychiatric
Insomnia
9671422 Anxiety
00294 All types of neurological disorders drowsiness
61313262 Inability to sit still
4611170 Headache
964144 Tremor
267110 Dystonia
20490 Cogwheel ankylosis
000110 Dizziness
26230 Movement disorders
26230 Sedation
40202 Hypersomnia
00400 Extrapyramidal disorders 06000 Sleepiness
00030 Involuntary muscle contraction 00030 Tongue palsy
00030 Ocular organ disease actinic nerve crisis 00430 blurred vision 00030 Cardiac organ disease tachycardia 06760 sinus tachycardia 00200 Respiratory, thoracic and mediastinal disease epistaxis 00200 Gastrointestinal disease vomiting 0611310 nausea 002912 hypersalivation 26200 epigastric pain 20202 dry mouth 00032 swollen tongue 00030 various Musculoskeletal and Connective Tissue Disorders Muscle Tonicity
00230 Muscle contracture
00030 Oblique neck
00200 Reproductive and breast disorders overflowing breast
00400 Menorrhagia
06000 Breast swelling
00030 Systemic disorders
Fatigue
40230 Lethargy
00230 All types of examination weight gain
76230
Study Withdrawal Due to Adverse Reactions
In the three placebo-controlled, 6-week fixed-dose studies, the percentage of subjects who withdrew from the studies due to adverse reactions was 3% and 1% in the Benzedrine treatment group and the placebo group, respectively. The most common reason for withdrawal was neurological disorders (2% and 0% in the drug-treated and placebo groups, respectively).
In the 6-week fixed-dose, placebo-controlled study in adolescent schizophrenia patients, only dystonia adverse events resulted in study withdrawal (<1% of subjects treated with this product).
Dose-related Adverse Reactions
Based on pooled data from three placebo-controlled, 6-week fixed-dose studies, of the adverse reactions occurring in >2% of subjects treated with this product, the incidence of the following adverse reactions increased with increasing dose: drowsiness, upright hypotension, inability to sit still, dystonia, extrapyramidal symptoms, hypertonia, parkinsonism, and hypersalivation. Most of the increased incidence of adverse reactions was seen mainly in the 12 mg dose group and in some cases in the 9 mg dose group.
Based on data from a placebo-controlled, 6-week fixed-dose study in adolescent schizophrenia subjects, of the adverse reactions with an incidence greater than 2% in the treatment group, the incidence of the following increased with dose: tachycardia, inability to sit still, extrapyramidal symptoms, drowsiness, and headache.
Demographic differences
Examination of population subgroups in the three placebo-controlled, 6-week fixed-dose studies did not show any evidence of differences in safety by sex or race alone; nor were there differences between age groups (see [Geriatric Dosing]).
Extrapyramidal symptoms (EPS)
Dystonia-an adverse reaction common to antipsychotics: During the first few days of treatment initiation with this product, some more sensitive patients may experience dystonia with abnormal delayed contraction of muscle groups. Symptoms of dystonia include: neck muscle spasms, pharyngeal urgency, dysphagia, dyspnea, and/or tongue protrusion. For first-generation antipsychotics, these symptoms can occur at low doses of the medication, and they occur more frequently and with greater severity at high or higher doses. The risk of acute dystonia is increased in men and in younger patient populations.
Pooled data from three placebo-controlled, 6-week fixed-dose studies provide information about EPS during treatment. EPS was measured mostly using (1) the Simpson-Angus global score (mean change from baseline) for a broad evaluation of Parkinson’s disease, (2) the Barnes Sedentary Inability Scale, a comprehensive clinical rating scale (mean change from baseline) for evaluation of sedentary inability, (3) treatment with anticholinergic drugs for emergency EPS (Table 3), and (4) reporting rate of spontaneous EPS reports (Table 4). Dose-related increases were observed in the 9 mg and 12 mg dose groups with respect to Simpson-Angus scale, spontaneous EPS reporting and anticholinergic drug use. No differences were observed between the placebo group and the 3 mg and 6 mg dose groups of this product in any EPS measure.
Table 3: Treatment-induced extrapyramidal symptoms (EPS) evaluated according to different rating scales and rates of anticholinergic drug use
Percentage of patients in EPS group Placebo Benadryl 3 mg 6 mg 9 mg 12 mg Once a day Once a day Once a day Once a day (N=355) (N=127) (N=235) (N=246) (N=242) Parkinson’s diseasea
91131514 Sedentary inability b 66479 Anticholinergic drug use c101092222a: Percentage of patients with Parkinson’s disease as percentage of patients with Simpson-Angus global score>0.3 (global score defined as the sum of the scores divided by the number of items)
b: Percentage of patients with sedentary inability is the percentage of patients with an overall score of ≥2 on the Sedentary Inability Scale
c: Percentage of patients treated with anticholinergic drugs for EPS caused by medication use
Table 4: Treatment-triggered extrapyramidal symptoms (EPS)-related adverse events under different MedDRA preferred terms
Percentage of patients in EPS group Placebo Benadryl 3 mg6 mg9 mg12 mg once a day once a day once a day once a day (N=355) (N=127) (N=235) (N=246) (N=242) Total percentage of patients with EPS-related AEs 1113102526 Dyskinesia 35389 Dystonia 11155 Hyperkinesia 443810Parkinsonism23376Tremor33343Motor disorder group includes: dyskinesia, extrapyramidal symptoms, muscle twitching, delayed dyskinesia
Dystonia group includes: dystonia, muscle spasms, eye spinning, teeth clenching
Hyperkinetic group includes: sedentary inability, hyperkinetic
Parkinson’s group includes: bradykinesia, cogwheel tonicity, salivation, hyperkinesia, hypokinesia, muscular tonicity, musculoskeletal tonicity, Parkinson’s disease
Tremor group includes: tremor
The adolescent schizophrenia study showed a similar incidence of EPS-related adverse events to the dose-related pattern seen in the adult schizophrenia study. Of note, the incidence of dystonia, hyperkinesia, tremor, and parkinsonism was higher in the adolescent population compared to the adult population (Table 5).
Table 5: Treatment-triggered extrapyramidal symptoms (EPS)-related adverse events under different MedDRA preferred terms – Adolescent Schizophrenia Study (double-blind, placebo-controlled study)
EPS group Percentage of patients Placebo Benadryl 1.5 mg
3 mg once a day
6 mg once a day
12 mg once a day
Once a day (N=51) (N=54) (N=16) (N=45) (N=35) Total percentage of patients with EPS-related AE 06252240 Hyperkinesia 0461117 Dystonia 0201114 Tremor 026711 Parkinson’s disease 006214 Dyskinesia 02626 The hyperkinesia group included: inability to sit still
Dystonia group includes: dystonia, muscle spasms, motoneurosis, tongue palsy, slant neck
Tremor group includes: tremor
Parkinson’s disease group includes: cogwheel-like ankylosis, extrapyramidal disease, muscle ankylosis
Movement disorders group includes: dyskinesia, involuntary muscle contractions
Abnormal laboratory test results
Between-group comparisons of three placebo-controlled, 6-week fixed-dose studies in adult subjects with schizophrenia showed no medically significant differences between the product and placebo groups in the proportion of subjects with potentially clinically significant alterations in routine serum chemistry, hematology, or urinalysis parameters. Similarly, the incidence of events that were withdrawn from the study due to alterations in hematology, urinalysis or serum chemistry, including mean changes from baseline in fasting glucose, insulin, C-peptide, triglycerides, HDL, LDL and total cholesterol measurements, did not differ between the Benadryl and placebo groups. However, this product may be associated with an increase in blood prolactin (see [Precautions]).
Weight gain
In pooled data from three placebo-controlled, 6-week fixed-dose studies comparing the proportion of subjects achieving a weight gain of ³ 7%, it was shown that the 3 mg and 6 mg (7% and 6%, respectively) groups of this product were similar to the placebo group (5%), while a higher incidence of weight gain occurred in the 9 mg and 12 mg (9% and 9%, respectively) groups of this product.
Other clinical trial data
Paliperidone is the active metabolite of risperidone, and therefore the adverse effect profiles of this class of compounds (both oral and injectable) are correlated with each other. This section includes reports of additional adverse reactions from clinical trials of paliperidone and/or risperidone.
Table 6a shows adverse reactions reported in patients treated with paliperidone and/or risperidone in 9 double-blind (8 adults, 1 adolescent), placebo-controlled clinical studies in schizophrenia, bipolar disorder, and schizoaffective disorder with a reporting rate of ≥2% of the treated population of this product.
Table 6a: Shown are adverse reactions reported by patients treated with paliperidone and/or risperidone in 9 double-blind (8 adults, 1 adolescent), placebo-controlled clinical studies of schizophrenia, bipolar disorder, and schizoaffective disorder with a reporting rate of ≥2% of the treated population
System/Organ Classification
Adverse Reactions Infectious and Infectious Diseases
Upper respiratory tract infections
Psychiatric
Insomnia*
All types of neurological disorders
Sedentary inability*, dystonia*, Parkinson’s disease*
Gastrointestinal system disorders
Abdominal discomfort, diarrhea
Various musculoskeletal and connective tissue disorders
Musculoskeletal pain* insomnia including: difficulty in falling asleep, intermediate waking insomnia; sedentary inability including: hyperkinesia, restless leg syndrome, restlessness; dystonia including: blepharospasm, cervical spasm, anterior arch recoil, facial spasm, hypertonia, laryngospasm, involuntary muscle contraction, myotonia, eye rotation, corneal arch recoil, oropharyngeal spasm, lateral arch recoil, spasmodic laughter, twitching, tongue paralysis, tongue spasms, slanting neck, and dental inhibition; Parkinson’s disease included: motor inability, motor bradykinesia, cogwheel-like tonicity, salivation, extrapyramidal symptoms, abnormal interbrow reflexes, muscle tonicity, myotonia, and musculoskeletal tonicity.
Shown in Table 6b are adverse reactions reported by patients treated with paliperidone and/or risperidone in 9 (8 adults, 1 adolescent) double-blind, placebo-controlled clinical studies of schizophrenia, bipolar disorder, and schizoaffective disorder with a reported rate of <2% of the population treated with this product.
Table 6b: Shown are adverse reactions reported by patients treated with paliperidone and/or risperidone in 9 (8 adults, 1 adolescent) double-blind, placebo-controlled clinical studies of schizophrenia, bipolar disorder, and schizoaffective disorder in a reported rate of <2% of the treated population
System/Organ Classification
Adverse Reactions Infectious and Infectious Diseases
Mite dermatitis, bronchitis, cellulitis, cystitis, ear infections, influenza, metritis, pneumonia, respiratory tract infections, sinusitis, tonsillitis, urinary tract infections
Blood and lymphatic system diseases
Anemia, decreased erythrocyte volume, neutropenia, decreased white blood cell count
Immune system disorders
Rapid-onset allergic reactions, hypersensitivity reactions
Endocrine system disorders
Hyperprolactinemia
Metabolic and nutritional disorders
Anorexia, elevated blood cholesterol, elevated blood triglycerides, decreased appetite, hyperglycemia, weight loss
Psychiatric disorders
Sexual pleasure deficiency, depression, loss of libido, nightmares, sleep disorders
All kinds of neurological diseases
Cerebrovascular accidents, convulsions*, attention disorders, postural dizziness, movement disorders*, hypoesthesia, loss of consciousness, sensory abnormalities, psychomotor excitement, syncope, delayed movement disorders
Diseases of eye organs
Conjunctivitis, dry eyes, increased lacrimation, photophobia
Ear and vagus disorders
Ear pain, tinnitus, vertigo
Heart diseases
Atrioventricular block, bradycardia, conduction disorders, ECG abnormalities, prolonged QT interval, palpitations
Vascular and lymphatic disorders
Facial flushing, hypertension, hypotension, ischemia
Respiratory, thoracic and mediastinal disorders
Cough, dyspnea, hyperventilation, nasal congestion, sore throat, croup
Diseases of the gastrointestinal system
Labyrinthitis, dysphagia, fecal incontinence, flatulence, gastroenteritis, intestinal obstruction, swollen tongue, toothache
Hepatobiliary system diseases
Elevated gamma-glutamyl transferase, elevated liver enzymes, elevated transaminases
Skin and subcutaneous tissue disorders
Acne, dry skin, eczema, erythema, pruritus, rash, seborrheic dermatitis, skin discoloration
Various musculoskeletal and connective tissue disorders
Arthralgia, back pain, elevated blood creatine phosphokinase, joint ankylosis, joint swelling, muscle spasm, muscle weakness, neck pain
Kidney and urinary system disorders
Difficulty in urination, urinary frequency, urinary incontinence
Reproductive system and breast diseases
Breast overflow, breast discomfort, breast engorgement, ejaculation disorder, erectile dysfunction, gynecomastia, menstrual irregularities*, sexual dysfunction, vaginal discharge
Systemic diseases
Increased body temperature, chest discomfort, chills, facial edema, abnormal gait, edema*, fever, thirst
All types of injuries, poisoning and surgical complications
Falls* convulsions include: grand mal seizure convulsions; movement disorders include: tardive dyskinesia, chorea, choreoathetosis, dyskinesia, muscle twitches, myoclonus; menstrual irregularities include: irregular menstruation, scanty menstruation; edema includes: generalized edema, peripheral edema, sunken edema.
Shown in Table 6c are adverse reactions reported by patients using paliperidone and/or risperidone in other clinical trials but not reported in a pooled analysis of nine double-blind, placebo-controlled clinical studies of schizophrenia, bipolar disorder, and schizoaffective disorder (eight adults and one adolescent).
Table 6c: Shown are adverse reactions reported by patients using paliperidone and/or risperidone in other clinical trials but not reported in a pooled analysis of 9 double-blind, placebo-controlled clinical studies of schizophrenia, bipolar disorder, and schizoaffective disorder (8 adults and 1 adolescent)
System/Organ Classification
Adverse Reactions Infections and Infectious Diseases
Eye infections
Blood and lymphatic system disorders
Elevated eosinophil count
Endocrine system disorders
Diabetes detection
Metabolic and nutritional disorders
Hyperinsulinemia, thirst
Psychiatric disorders
Emotional retardation, blurred state of consciousness
Various neurological disorders
Balance disorders, cerebrovascular disorders, ataxia, decreased level of consciousness, diabetic coma, head tremor, malignant syndrome, loss of stimulus response
Diseases of the eye organs
Eye movement disorders, eye rotation, glaucoma, eye congestion
Cardiac disorders
Postural tachycardia syndrome
Respiratory system, chest and mediastinal diseases
Dysphonia, aspiration pneumonia, pulmonary congestion, rales, airway congestion
Gastrointestinal system disorders
Bulbous stool
Skin and subcutaneous tissue disorders
Drug rash, keratosis pilaris, urticaria
Various musculoskeletal and connective tissue disorders
Postural abnormalities, rhabdomyolysis
Reproductive system and breast disorders
Breast enlargement, delayed menstruation
Systemic diseases
Decreased body temperature, drug withdrawal syndrome, sclerosis, discomfort
Clinical trials: adverse reactions in long-term placebo-controlled studies
The safety of this product was also evaluated in a long-term clinical trial conducted in adults with schizophrenia to evaluate its maintenance efficacy (see [Clinical Trials]). Overall, the type, frequency and severity of adverse reactions during the initial 14-week open phase of the study were generally comparable to those observed in the 6-week, placebo-controlled, fixed-dose study. The type and severity of adverse reactions reported in the long-term, double-blind phase of the study were similar to those observed in the initial 14-week open phase.
Postmarketing Data
The frequency of adverse reactions during post-marketing use of this product, as defined by the following criteria, is shown in Table 7.
Very common ≥10%
Common 1% to 10%
Occasional 0.1% to 1%
Rare 0.01%～0.1%
Very rare <0.01%, including single case reports
Unknown Unable to estimate based on available data
The rates of adverse reactions in Tables 7 and 8 are spontaneous reporting frequencies.
Table 7: Adverse reactions occurring during post-marketing use of paliperidone extended-release tablets or risperidone prodrugs, assessed by spontaneous reporting rate
Blood and lymphatic system disorders
Very rare Granulocyte deficiency, thrombocytopenia
Endocrine system disorders
Unknown Disorders of antidiuretic hormone secretion
Metabolic and nutritional disorders
Very rare Diabetes mellitus, diabetic ketoacidosis, hypoglycemia
Unknown Water intoxication
Psychiatric disorders
Very rare Catatonia, mania, sleepwalking disorder
Unknown Sleep-related eating disorders
Various neurological disorders
Very rare Taste disorders
Eye organ disorders
Unknown Iris relaxation syndrome (intraoperative)
Heart organ disorders
Very rare Atrial fibrillation
Vascular and lymphatic vessel disorders
Very rare Deep vein thrombosis, pulmonary embolism
Respiratory, thoracic and mediastinal disorders
Very rare Sleep apnea syndrome
Gastrointestinal disorders
Very rare Pancreatitis
Very rare Intestinal obstruction
Hepatobiliary system disorders
Unknown Jaundice
Skin and subcutaneous tissue disorders
Rare Angioedema
Very rare Alopecia
Kidney and urinary system disorders
Very rare Urinary retention
Pregnancy, puerperium and perinatal conditions
Very rare Neonatal drug withdrawal syndrome
Reproductive and breast disorders
Very rare Abnormal penile erection
Systemic disease
Very rare Hypothermia
Table 8: Adverse reactions to paliperidone and/or risperidone occurring during post-marketing double-blind placebo-controlled clinical trials, assessed by incidence
Blood and lymphatic system disorders
Unknown Granulocyte deficiency
Rare Thrombocytopenia
Endocrine system disorders
Unknown Disorders of antidiuretic hormone secretion
Metabolic and nutritional disorders
Unknown Diabetic ketoacidosis
Rare Diabetes mellitus*, hypoglycemia, water intoxication
Psychiatric disorders
Common Mania
Unknown Catatonia, sleep-related eating disorders, sleepwalking disorder
All types of neurological disorders
Occasional Taste disorders
Eye organ disorders
Unknown Iris relaxation syndrome (intraoperative)
Cardiac organ disorders
Rare Atrial fibrillation
Vascular and lymphatic vessel disorders
Unknown Deep vein thrombosis, pulmonary embolism
Respiratory, thoracic and mediastinal disorders
Rare Sleep apnea syndrome
Gastrointestinal system disorders
Unknown Pancreatitis
Unknown Intestinal obstruction
Diseases of the hepatobiliary system
Unknown Jaundice
Skin and subcutaneous tissue disorders
Rare Hair loss, angioedema
Kidney and urinary system disorders
Occasionally urinary retention
Pregnancy, puerperium and perinatal conditions
Unknown Neonatal drug withdrawal syndrome
Reproductive system and breast disease
Unknown Abnormal penile erection
Systemic diseases
Unknown Hypothermia* Reported diabetes in the placebo-controlled pivotal clinical trial treated with this product was 0.05% and 0% in the placebo group. The incidence of reported diabetes in patients treated with this product in all clinical trials was 0.14%. [Contraindication].
Hypersensitivity reactions, including tachyphylaxis and angioedema, have been observed in patients treated with risperidone and paliperidone. This product (paliperidone) is a metabolite of risperidone and is therefore contraindicated in patients with known hypersensitivity to paliperidone, risperidone, or any of the components of this product.
[Precautions].
Increased mortality in patients with Alzheimer’s-related psychiatric disorders
Elderly patients with dementia-related psychosis treated with atypical antipsychotics have an increased risk of death compared to placebo. This product is not approved for the treatment of dementia-related psychosis.
Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis
In placebo-controlled trials using risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) than in subjects treated with placebo, including death. This product was not available at the time the study was conducted. It was not approved for the treatment of patients with dementia-associated psychosis.
Malignant Syndromes
A syndrome with a potential for death, known as malignant syndrome (NMS), has been reported in patients using antipsychotics, including paliperidone. clinical signs of NMS are hyperthermia, muscle tonicity, altered state of consciousness, and autonomic disturbances (irregular pulse or blood pressure, tachycardia, sweating, and arrhythmias). Other signs may include elevated blood creatine phosphokinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure.
The diagnostic evaluation of patients presenting with this syndrome is more complex. An important point in the diagnosis is to identify cases in which the clinical presentation involves both a serious medical condition (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other things to focus on in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and major CNS histopathology.
Management of NMS should include (1) immediate discontinuation of antipsychotics and other medications that are not essential to current treatment, (2) administration of intensive symptomatic treatment and medical monitoring, and (3) treatment of any comorbid serious medical problems under conditions where specific treatment can be administered. For uncomplicated NMS, there is no consistent specific pharmacologic treatment plan.
If a patient shows a need for antipsychotic medication after recovery from NMS, medication may be reintroduced, but close monitoring is required, as relapse of NMS has been reported.
Prolonged QT interval
Paliperidone causes some degree of prolongation of the corrected QT (QTc) interval. Paliperidone use should be avoided in combination with other drugs known to prolong the QTc, including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmics, antipsychotics (e.g., chlorpromazine, methiodiazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or other types of drugs known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital QT interval prolongation syndrome and in patients with a history of cardiac arrhythmias.
Specific settings may increase the risk of torsional ventricular tachycardia and/or sudden death associated with QTc interval prolongation medication use, including: (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) combination with other medications that prolong the QTc interval; and (4) the presence of congenital QT interval prolongation.
The effect of paliperidone on the QT interval was evaluated in a double-blind, active drug-control (single dose moxifloxacin 400 mg), multicenter QT study in adult patients with schizophrenia and schizoaffective disorder, and in three placebo and active drug-control studies conducted in adult patients with schizophrenia. A 6-week, fixed-dose efficacy trial was conducted in adult schizophrenic patients.
In the QT study (n = 141), the difference in QTcLD from baseline was 12.3 msec higher in the 8 mg dose of immediate-release oral paliperidone tablets (n = 50) group 1.5 hours after day 8 dosing than in the placebo group (90% CI: 8.9;15.6). the mean steady-state peak plasma concentration of 8 mg immediate-release paliperidone was more than twice as high as that observed with the recommended maximum 12 mg dose of the drug (more than twice the exposure). exposure was more than twofold higher (Cmax ss of 113 ng/mL and 45 ng/mL, respectively, when administered under the condition of eating a standard breakfast). In the same study, the QTcLD difference from baseline was 6.8 msec (90% CI: 3.6; 10.1) higher in the 4 mg dose of immediate-release oral paliperidone tablets (Cmax ss = 35 ng/mL) group 1.5 hours after day 2 dosing than in the placebo group. No subject in the study had a change of more than 60 ms or a QTcLD of more than 500 ms at any time.
In the three fixed-dose efficacy studies, electrocardiogram (ECG) examinations at various time points showed that only one subject in the 12 mg treatment group of this product had an alteration of more than 60 ms at one time point on day 6 (an increase of 62 ms). No subject receiving this product had a QTcLD of more than 500 ms at any time in any of the three studies.
Late-onset movement disorders and extrapyramidal symptoms
Patients receiving antipsychotic medication may develop a syndrome that manifests as potentially irreversible, involuntary movement disorders. Although the incidence of the syndrome is highest in the elderly, especially in older women, it is still not possible to predict specifically which patients will develop the syndrome. It remains unclear whether the likelihood of triggering delayed dyskinesia varies between antipsychotics.
The risk of tardive dyskinesia and the likelihood of an irreversible response have been shown to increase with duration of treatment and the cumulative dose of antipsychotic medication given to the patient, but the syndrome may also occur at lower doses and after relatively short treatment periods, although it is uncommon.
Although the syndrome is partially or completely alleviated after discontinuation of antipsychotic medication, there is no definitive treatment for the identified delayed-onset movement disorder. Antipsychotic treatment itself suppresses (or partially suppresses) the signs and symptoms of the syndrome and therefore may mask the underlying process. The impact of symptom suppression on the long-term course of the syndrome is unclear.
Based on these considerations, this product should be prescribed in a manner that is most likely to minimize the incidence of tardive dyskinesia. Long-term antipsychotic treatment is usually indicated for chronic patients who are known to be effective on antipsychotic therapy. For patients who do require long-term treatment, the smallest dose and shortest duration of treatment that will produce a satisfactory clinical response should be sought. The need for continued treatment should be re-evaluated periodically.
If patients treated with this drug develop signs and symptoms of delayed dyskinesia, discontinuation of the drug should be considered. However, some patients may need to continue treatment with this drug despite the development of the syndrome.
Extrapyramidal symptoms and psychostimulants
Caution should be exercised in patients receiving concomitant treatment with psychostimulants (e.g., methylphenidate) and paliperidone, as extrapyramidal symptoms may occur during adjustment to either or both drugs. Gradual discontinuation of one or both drugs should be considered (see [Drug Interactions]).
Hyperglycemia and diabetes mellitus
Hyperglycemia and diabetes mellitus have been reported in certain specific cases in patients treated with all atypical antipsychotics and in cases associated with ketoacidosis or hyperosmolar coma or death. In most cases, these cases have been seen in post-marketing clinical use as well as in epidemiological studies and, less frequently, in clinical trials. Hyperglycemia, diabetes mellitus, and worsening diabetes have been reported in the therapeutic use of this product. Furthermore, evaluating the relationship between atypical antipsychotic use and dysglycemia based on the likelihood of an increased risk of diabetes in patients with schizophrenia and the increased incidence of diabetes in the general population is complex. Based on these factors, a comprehensive understanding of the relationship between atypical antipsychotic use and hyperglycemia-associated adverse events has not been achieved. However, epidemiological studies suggest that patients treated with atypical antipsychotics are at increased risk for hyperglycemia-associated adverse events during treatment. Because the product was not available at the time these studies were conducted, it is unclear whether the product was associated with an increased risk.
Patients with confirmed diabetes should be given regular monitoring to prevent deterioration in glycemic control when starting atypical antipsychotic therapy. For patients with risk factors for diabetes (e.g., obesity, family history of diabetes), fasting blood glucose should be tested at the start of treatment and periodically during treatment when atypical antipsychotic therapy is initiated. Any patient receiving atypical antipsychotics should be monitored for symptoms of hyperglycemia, including irritable thirst, excessive drinking, polyuria, polyphagia, and weakness. For patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, fasting blood glucose should be tested. In some cases, discontinuation of atypical antipsychotics will relieve hyperglycemia; however, some patients may still require continued antidiabetic therapy after discontinuation of the suspected medication.
Data obtained from a placebo-controlled, 6-week study in adolescent (12-17 years of age) subjects with schizophrenia are presented in Table 9a.
Table 9a: Fasting glucose changes in a placebo-controlled, 6-week study in adolescent (12-17 years old) subjects with schizophrenia
This product placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day Mean change from baseline (mg/dL)
Blood glucose n=41n=44n=11n=28n=32 Change from baseline value 0.8-1.4-1.8-0.15.2 Percentage of patients who showed change Blood glucose
Normal to high
3%
0%
0%
0% 0%
11% (<100 mg/dL to ≥126 mg/dL) (1/32) (0/34) (0/9) (0/20) (3/27)
Dyslipidemia
Some adverse changes in lipids have been observed in patients receiving atypical antipsychotic medications.
Data obtained from a placebo-controlled, 6-week study in adolescent (12-17 years) subjects with schizophrenia are presented in Table 9b.
Table 9b: Fasting lipid changes in a placebo-controlled, 6-week study in adolescent (12-17 years old) subjects with schizophrenia
This product Placebo 1.5 mg/day 3 mg/day 6 mg/day 12 mg/day Mean change from baseline (mg/dL) Cholesterol n=39n=45n=11n=28n=32 Change from baseline -7.8-3.312.73.0-1.5LDLn=37n=40n=9n=27n=31 Change from baseline – 4.1-3.17.22.40.6HDLn=37n=41n=9n=27n=31 Change from baseline-1.90.01.31.40.0Triglyceridesn=39n=44n=11n=28n=32 Change from baseline-8.93.217.6-5.43.9 Percentage of patients showing change Cholesterol Normal to High7%4%0%6%11% (<170 mg/dL to ≥200 mg/dL)(2/27)(1/26)(0/6)(1/18)(2/19)LDL
Normal to high
3%
4%
14%
0%
9% (<110 mg/dL to ≥130 mg/dL) (1/32) (1/25) (1/7) (0/22) (2/22) HDL Normal to low 14% 7% 29% 13% 23% (≥40 mg/dL to <40 mg/dL) (4/28) (2/30) (2/7) (3/23) (5/22) Triglycerides
Normal to high
3%
5%
13%
8%
7% (<150 mg/dL to ≥200 mg/dL) (1/34) (2/38) (1/8) (2/26) (2/28) Weight gain
Weight gain has been observed with atypical antipsychotic use. Weight monitoring at the time of clinical use is recommended.
Weight gain in adolescent subjects with schizophrenia was evaluated in a 6-week, double-blind, placebo-controlled study and in an open extension study with a median duration of exposure to this product of 182 days. Data on the mean change in body weight and the percentage of subjects with weight gain ≥7% (see [Clinical Trials]) in the placebo-controlled, 6-week study in adolescent subjects (12-17 years of age) are shown in Table 10.
Table 10: Percentage of subjects with placebo-controlled, 6-week study of mean weight change and weight gain ≥7% in adolescent subjects with schizophrenia (12-17 years of age)
Placebo
n=511.5 mg/day
n=543 mg/day
n=166 mg/day
n=4512 mg/day
n=34 weight (kg)
Change from baseline value
0.0
0.3
0.8
1.2
1.5 Weight gain
Increase ≥7% from baseline
2%
6%
19%
7% 18%
18%
In this open, long-term study, the percentage of all subjects treated with this product who gained ≥7% of their body weight from baseline was 33%. When evaluating weight gain in adolescent patients treated with this product, the weight gain expected from normal body growth should be considered. Standardized score assessment relative to normative data provides more clinically meaningful values for weight change when considering the median duration of exposure (182 days) to this product in open studies and the expected normal weight gain based on age and sex. The mean change in weight standardized score from open baseline to study endpoint was 0.1 (4% above the median of normative data). Based on comparisons with normative data, these changes were not considered clinically meaningful.
Hyperprolactinemia
Similar to other dopamine D2 receptor antagonists, paliperidone increases prolactin levels, and the increase persists over the course of long-term administration. Paliperidone has prolactin-increasing effects similar to those of risperidone (which has a higher prolactin-increasing effect than other antipsychotics).
Regardless of the etiology, hyperprolactinemia may suppress hypothalamic GnRH, which leads to a decrease in pituitary gonadotropin secretion. Thus, it may inhibit reproductive function by reducing gonadal steroid production in both female and male patients. Breast discharge, amenorrhea, gynecomastia, and impotence have been reported in patients treated with prolactin-increasing compounds. Prolonged hyperprolactinemia associated with gonadal dysgenesis may lead to decreased bone mineral density in both women and men.
Tissue culture tests have shown that approximately one-third of human breast cancers are prolactin-dependent in vitro, making this a potentially meaningful consideration when prescribing this class of drugs to patients with previously detected breast cancer. An increased incidence of pituitary, mammary and islet cellular tumors (breast, pituitary and pancreatic adenomas) has been observed in carcinogenicity studies with risperidone in mice and rats. Neither clinical studies nor epidemiological studies conducted to date have shown an association between long-term use of this class of drugs and human tumorigenesis, but the data are still too limited to draw firm conclusions.
Potential for gastrointestinal obstruction
Because the tablets are not deformed and do not change shape significantly in the gastrointestinal tract, they should not usually be used in patients with severe prior gastrointestinal strictures (pathologic or medical, such as esophageal dysfunction, inflammatory disease of the small intestine, adhesions or “short bowel” syndrome due to shortened transport time, previous history of peritonitis, cystic fibrosis, chronic pseudo-intestinal obstruction, or Meckel’s diverticulum). There are rare reports of obstructive symptoms in patients with GI strictures taking non-deformable extended-release formulations. Because of the extended-release design dosage form, this product should only be used in patients who are able to swallow the entire drug (see [DOSAGE]).
Shorter delivery times, as observed with diarrhea, are expected to decrease bioavailability, while longer delivery times, as observed with gastrointestinal neuropathy, diabetic gastroparesis, or other causes, are expected to increase bioavailability. And altered bioavailability is more likely to occur when the altered transport time occurs in the upper GI tract.
Orthostatic hypotension and syncope
In some patients, paliperidone induces upright hypotension and syncope through its alpha-blocking effect. In a pooling of results from three placebo-controlled, 6-week fixed-dose trials, the incidence of syncope was reported to be 0.8% (7/850) in patients treated with this product (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) in patients receiving placebo. Use with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities) or cerebrovascular disease and in those susceptible to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive agents). Monitoring of postural vital signs should be considered in patients prone to hypotension.
Leukopenia, neutropenia and granulocyte deficiency
Events of leukopenia, neutropenia, and granulocyte deficiency have been reported with antipsychotics, including this product. Postmarketing reports of granulocyte deficiency are rare (<1/10,000).
Patients with a history of clinically significant leukopenia or drug-induced leukopenia/neutropenia need to be monitored during the first few months of treatment, and discontinuation of this product should be considered at the first sign of clinically significant leukopenia if no other factors are contributing.
Patients with clinically significant neutropenia should be carefully monitored for fever or other signs or symptoms of infection and should be treated promptly if these signs or symptoms occur. Patients with severe neutropenia (absolute white blood cell count <1×109/L) should discontinue this product and continue monitoring white blood cell counts until they return to normal.
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Because acquired risk factors for VTE are often present in patients treated with antipsychotic medications, all possible risk factors for VTE should be identified and precautions taken prior to or during treatment with this product.
Possible cognitive and motor dysfunction
Drowsiness and sedative reactions have been reported in subjects treated with this product (see [ADVERSE REACTIONS]). Antipsychotic medications, including this product, have the potential to impair patient judgment, thinking, or motor skills. Patients should exercise caution when performing activities that require altered mental status, such as operating dangerous machinery or riding an electric bicycle, unless it is reasonably certain that paliperidone treatment will not produce adverse effects.
Convulsive seizures
In premarketing clinical trials (three placebo-controlled, 6-week fixed-dose studies and one study in elderly subjects with schizophrenia), convulsive seizures occurred in 0.22% of subjects treated with this product (3 mg, 6 mg, 9 mg, 12 mg) compared to 0.25% of subjects treated with placebo. Similar to other antipsychotics, this product should be used with caution in patients with a history of convulsive seizures or other conditions that may lower the threshold for convulsive seizures. Conditions that lower the threshold for convulsive seizures may be more common in patients aged 65 years or older.
Dysphagia
Esophageal motor dysfunction and aspiration may be associated with the use of antipsychotic medications. Among these is aspiration pneumonia, a common cause of morbidity and mortality in patients with advanced Alzheimer-type dementia. This and other antipsychotic drugs should be used with caution in patients at risk of aspiration pneumonia.
Suicide
The potential for suicide attempts is inherent in patients with psychiatric disorders and should be monitored closely during drug therapy in patients at risk. The dosage of this product should be prescribed in the smallest number of tablets that will achieve good patient management and reduce the risk of overdose.
Abnormal penile erection
Drugs with alpha-adrenoceptor blocking effects have been reported to have the potential to induce abnormal penile erections. Abnormal penile erections have been reported in post-marketing surveillance of this product (see [Adverse Reactions]).
Thrombotic thrombocytopenic purpura (TTP)
No cases of TTP have been observed during clinical studies with paliperidone. Although cases of TTP associated with risperidone administration have been reported, the relationship to risperidone treatment remains unclear.
Thermoregulation
Antipsychotics can disrupt the body’s ability to lower central body temperature. Appropriate caution is recommended when prescribing this product if the patient is in a situation that may result in elevated central body temperature, such as intense exercise, exposure to extreme hyperthermic conditions, combined use of anticholinergics, or dehydration.
Antiemetic effect
Paliperidone was observed to have an antiemetic effect in preclinical studies. This effect, if present in humans, should be noted as it may mask some signs and symptoms of drug overdose or, for example, intestinal obstruction, Lehigh syndrome, or brain tumors.
Intraoperative iris relaxation syndrome
Intraoperative iris relaxation syndrome can be caused by the adrenergic α1a receptor antagonism of certain drugs found in cataract surgery, such as this product.
Intraoperative iris relaxation syndrome may increase intraoperative and postoperative ocular complications. The ophthalmic surgeon should be informed prior to surgery if medications with adrenergic alpha1a receptor antagonism are being or have been used. The potential benefits of discontinuing alpha1 blockade therapy prior to cataract surgery have not been determined and must be weighed against the risks of discontinuing antipsychotic medications.
Use in patients with concomitant disease
Clinical experience with the use of this product in patients with certain concomitant diseases remains limited (see [Pharmacology and Toxicology]).
Increased sensitivity to antipsychotic medications has been reported in patients with Parkinson’s disease or the presence of Lewy body dementia. Specific manifestations of increased sensitivity include confusion, slowness, postural instability accompanied by frequent falls, and extrapyramidal symptoms, with clinical features consistent with a malignant syndrome.
The product has not been evaluated and used to an extensive extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with confirmed presence of such disease were excluded from premarket clinical trials. Because of the risk of upright hypotension with this product, caution should be exercised in patients with known cardiovascular disease (see [Precautions]).
Laboratory Tests
There are no recommended specific laboratory tests.
Controlled Substances
This product is not a controlled substance.
Drug Abuse
No systematic studies have been conducted in animals or humans on the potential for abuse of paliperidone. Nor is it possible to predict with certainty the extent to which CNS-acting drugs will be misused, converted, and/or abused once marketed. Therefore, patients with a history of drug abuse should be carefully evaluated and those with signs of misuse or abuse of this product (e.g., development of drug resistance, dose escalation, drug-seeking behavior) should be closely monitored.
Drug dependence
The potential for tolerance or physical dependence of paliperidone has not been systematically studied in animals or humans.
Patients with renal impairment
Dose adjustment must be individualized according to the patient’s renal function (see [DOSAGE AND ADMINISTRATION]).
Patients with hepatic impairment
No dose adjustment is required in patients with mild to moderate hepatic impairment. This product has not been studied in patients with severe hepatic impairment.
Keep out of the reach of children.
Pregnant women and nursing mothers
Pregnancy
This product has not been adequately and well-controlled studied in pregnant women. It should be used during pregnancy only if the potential benefits outweigh the possible risks to the fetus.
A retrospective observational cohort study based on the US Claims database compared the risk of congenital malformations in live-born infants of women who used and did not use antipsychotics during early pregnancy. In that study, paliperidone (the active metabolite of risperidone) was not specifically evaluated. After adjusting for confounding variables available in the database, the risk of congenital malformations was elevated in the risperidone group compared to the unexposed antipsychotic group (relative risk = 1.26, 95% CI: 1.02-1.56). No biological mechanism has been identified to explain this finding, and no teratogenic effects were observed in nonclinical studies. Based on the results of this observational study alone, a causal relationship between intrauterine exposure to risperidone and congenital malformations has not been established.
Experimental animals receiving high doses of paliperidone administration showed a slight increase in stillbirths. This high dose of paliperidone is toxic to maternal animals. The offspring of the animals were not affected when the exposure was 20-34 times the maximum human exposure.
Extrapyramidal symptoms have been reported to occur in neonates with the use of first-generation antipsychotics in the last trimester of pregnancy. These symptoms are usually self-limiting. However, it is not clear whether paliperidone administered near the end of pregnancy results in similar neonatal signs and symptoms.
The severity of extrapyramidal symptoms and/or withdrawal symptoms in the newborn after delivery may vary when antipsychotic medications (including this product) are used in the last trimester of pregnancy. These symptoms may include: agitation, hypertonia, hypotonia, tremor, lethargy, respiratory distress, or feeding disorders.
Childbirth
The effect of this product on human labor is not known.
Nursing mothers
Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone. In animal studies, risperidone and 9-hydroxyrisperidone were secreted via breast milk. Risperidone and 9-hydroxyrisperidone can also be secreted via human milk. Therefore, caution should be exercised when administering this product to nursing women. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone when administering the drug.
[Pediatric Use].
The safety and efficacy of this product in patients aged <12 years is not known.
When used in pediatric and adolescent populations, the sedative effects of this product should be closely monitored. Changing the timing of administration of this product may improve the effect of sedation on patients.
Because of the potential effects of prolonged hyperprolactinemia on adolescent development and sexual maturation, periodic clinical evaluation of the patient’s endocrine status, including measurement of height, weight, sexual maturation, monitoring of menstrual function, and other potentially relevant effects of prolactin, should be considered.
Screening for extrapyramidal symptoms and other movement disorders should be performed periodically during treatment with this product.
[Geriatric Use].
The safety, tolerability and efficacy of this product were evaluated in a 6-week placebo-controlled study in 114 elderly subjects with schizophrenia (age ≥ 65 years, 21 of whom were ≥ 75 years old). Subjects in the study received flexible doses of this product (3 mg to 12 mg once a day). In addition, adult subjects with schizophrenia received a fixed dose of this product (3 mg to 15 mg once a day) in a 6-week placebo-controlled study in a small number of subjects ≥65 years of age.
Overall, of all subjects enrolled in clinical studies of this product (n = 1796), including those who received either this product or placebo, 125 (7.0%) were ≥65 years of age and 22 (1.2%) were ≥75 years of age. No differences in safety or efficacy were observed between these subjects and younger subjects from an overall perspective, and other reported clinical experience in older and younger patients did not show definite differences in drug response, although a higher drug sensitivity in some older patients cannot be excluded.
The drug is known to be excreted primarily through the kidneys; therefore, patients with moderate to severe renal impairment will experience decreased clearance (see [Pharmacokinetics]), and the drug dose should be reduced in this group of patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection and monitoring of renal function may sometimes be required (see [Dosage]).
Drug Interactions]
Effects of this product on other drugs
Considering the major central nervous system effects of paliperidone (see [Adverse Reactions]), this product should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone antagonizes the effects of levodopa and other dopamine agonists.
Because these potential effects can induce upright hypotension, cumulative effects may occur when this product is used with other therapeutic agents that have this effect (see [Precautions]).
Clinically significant pharmacokinetic interactions are not expected to occur when paliperidone is combined with other drugs metabolized by CYP450 isozymes. In vitro studies in human liver microsomes have shown that paliperidone does not significantly inhibit the metabolism of drugs that undergo metabolism by cytochrome CYP450 isozymes including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5 isoforms. Therefore paliperidone is not expected to inhibit the clearance of drugs metabolized via these pathways in a clinically meaningful manner. Paliperidone is also not expected to produce enzyme-inducing effects.
At therapeutic concentrations, paliperidone does not inhibit P-glycoprotein, and therefore is not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically meaningful manner.
The potential for interaction between this product and lithium is low.
Coadministration of this product (12 mg once daily) and sodium bivalate extended-release tablets (500 mg to 2000 mg once daily) under steady-state conditions does not affect the pharmacokinetic homeostasis of valproate.
Drug interaction studies have been conducted in adults only.
Effects of other drugs on this product
Paliperidone is not a substrate for CYP1A2, CYP2A6, CYP2C9, and CYP2C19, suggesting that interactions with inducers or inhibitors of these enzymes are unlikely. In vitro studies have shown that CYP2D6 and CYP3A4 are minimally involved in the metabolism of paliperidone, and in vivo studies have not shown that metabolic levels are reduced in the presence of these enzymes, accounting for only a small fraction of total organismal clearance. In vitro studies have shown that paliperidone is a P-gp substrate.
Paliperidone undergoes only limited metabolism in the presence of CYP2D6 (see [Pharmacokinetics]). In interaction studies in healthy subjects, administration of 20 mg/day of paroxetine (a potent CYP2D6 inhibitor) along with a single dose of 3 mg of this product showed a mean 16% increase in paliperidone exposure in those with strong CYP2D6 metabolism (90% CI: 4, 30). Higher doses of paroxetine have not been studied. Clinical relevance is unclear.
The combination of this product (once daily) with carbamazepine 200 mg (twice daily) reduced the mean steady-state Cmax and AUC of paliperidone by approximately 37%. The decrease may be due in large part to the induction of renal P-gp expression by carbamazepine, resulting in a 35% increase in renal clearance of paliperidone. There was minimal reduction in urinary prototype drug, suggesting minimal effect on CYP metabolism or bioavailability of paliperidone during co-administration with carbamazepine. When starting carbamazepine, the dose of this product should be reassessed and increased if needed. Conversely, when discontinuing carbamazepine, the dose of this product should be re-evaluated and, if needed, reduced.
A single dose of 12 mg of this product in combination with sodium bispropionate extended-release tablets (2 tablets of 500 mg/tablet once daily) resulted in an approximately 50% increase in paliperidone Cmax and AUC. When used in combination with valproate, a lower dose of this product should be considered after clinical evaluation.
Combined use with psychostimulants
The combination of psychostimulants (e.g., methylphenidate) with paliperidone may result in extrapyramidal symptoms if one or both drugs are changed (see [Precautions]).
[Drug overdose].
Clinical experience
Experience with paliperidone overdose is relatively limited, with the highest estimated intake being 405 mg in the few overdose cases reported in premarketing trials. signs and symptoms observed include extrapyramidal symptoms and gait instability. Other possible signs and symptoms include signs and symptoms due to the known pharmacological amplification of paliperidone, i.e., sleepiness and sedation, tachycardia and hypotension, and prolonged QT interval. Tip-twisting ventricular tachycardia and ventricular fibrillation have been reported as a result of oral paliperidone overdose.
Paliperidone is the major active metabolite of risperidone. See the overdose section of the Risperidone instruction manual for reported overdose experiences with Risperidone.
Overdose management
There is no specific antidote for paliperidone; therefore, in the event of an overdose, appropriate supportive therapy and close medical monitoring should be given until the patient recovers. When evaluating the need for treatment and the patient’s recovery, the slow-release properties of the drug should be considered, along with whether multiple drug use is involved.
In the event of an acute drug overdose, airway patency should be established and maintained to ensure adequate oxygenation and ventilation. Gastric lavage (if the patient is unconscious, this should be done after intubation) and administration of activated charcoal adsorbent along with a slow-release drug should be considered.
Overdose resulting in sluggishness, convulsive seizures, or dystonic head and neck responses may increase the patient’s risk of aspiration due to emetics.
Cardiovascular monitoring, including continuous ECG monitoring, should be initiated immediately to prevent possible arrhythmias. If antiarrhythmic drug therapy is given, there is a theoretical risk of cumulative QT interval prolongation in patients with acute paliperidone overdose taking pyridipyridamole, procainamide, and quinidine. Similarly, the alpha-blocking properties of bromelain may cause a cumulative effect of paliperidone, leading to hypotension.
Hypotension and circulatory collapse should be treated by appropriate measures such as intravenous fluids and/or sympathomimetics (epinephrine and dopamine should not be used, otherwise the beta-excitation effect of this class of drugs may exacerbate the hypotension produced by the alpha-blocking effect induced by paliperidone). If severe extrapyramidal symptoms are present, anticholinergics should be given.
Clinical trials]
Adults
The short-term efficacy of this product (3 mg-15 mg once a day) was established in three placebo-controlled and active-controlled (olanzapine), 6-week fixed-dose trials in non-elderly schizophrenic patients (adults, mean age 37 years) who met DSM-IV criteria. The studies were conducted in North America, Eastern Europe, Western Europe and Asia. The doses studied in the three studies included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day and 15 mg/day. Doses were taken in the morning, regardless of whether or not food was consumed.
The efficacy was evaluated using the Positive and Negative Symptom Scale (PANSS), a five-factor confirmatory multiple scale that can be used to evaluate positive symptoms, negative symptoms, disorganized thinking, uncontrolled hostility/agitation, and anxiety/depression. Efficacy can also be evaluated using the Personal and Social Behavior (PSP) scale, a validated clinically measured scale that measures personal and social functioning, primarily for socially useful activities, including work and school, personal and social relationships, self-care abilities, disruptive and aggressive behaviors.
In all 3 studies (n = 1665), the product was superior to placebo in all dose groups in terms of PANSS scores. The mean effects were nearly similar in all dose groups, but the higher dose was numerically superior in all studies. It was also superior to placebo in PSP in these trials.
Population subgroup studies did not show any evidence that gender, age (a few patients were over 65 years of age), or geography would lead to differences in responsiveness. There were also insufficient data to explore differences in efficacy between races.
In the long-term trial, adult outpatients with schizophrenia who met DSM-IV criteria for clinical response (defined as a PANSS score of £ 70 or a scheduled PANSS subscale score of £ 4 and received a stable dose of this product in the second two weeks of the 8-week trial period) were selected to enter this 6-week, open-label maintenance phase of treatment with this product (dose range 3-15 mg once daily). After the stabilization period, patients were randomly assigned in a double-blind fashion to either continue treatment with this product at the achieved stabilization dose or to receive placebo until a relapse of schizophrenic symptoms occurred. Relapse was predefined as a significant increase in PANSS scores (or predefined PANSS subscale scores), patient admission, clinically significant suicidal or homicidal ideation, or intentional self-harm or harm to others. An interim analysis of the data showed that the time to relapse was significantly longer in patients treated with this product compared to patients in the placebo group, and the trial was terminated early for reasons that had demonstrated the efficacy of maintenance treatment.
Adolescents
In a randomized, double-blind, placebo-controlled, 6-week study using a weight-based fixed-dose treatment group design, the efficacy of Benadryl was evaluated in adolescent subjects with schizophrenia in the 1.5-12 mg/day dose range (N = 149 in the Benadryl group and N = 51 in the placebo group). Subjects were aged 12-17 years and met DSM-IV criteria for schizophrenia. Efficacy was assessed using PANSS. This study demonstrated the efficacy of moderate doses of this product in adolescent subjects with schizophrenia. Secondary analyses by dose showed the efficacy of once-daily doses of 3 mg, 6 mg, and 12 mg.
Table 11: Adolescent Schizophrenia Study: R076477-PSZ-3001: 6-week, fixed-dose, placebo-controlled intention-to-treat analysis set. change from baseline in LOCF endpoints
Placebo group
N=51 Low dose group of this product
1.5 mg
N=54 Benzedrine medium dose group
3 or 6 mg*
N=48 high dose group
6 or 12 mg**
N=47PANSS score change
Baseline mean (SD)
Mean change (SD)
P-value (vs placebo)
Difference of least squares means (SE)
90.6 (12.13)
-7.9 (20.15)
91.6 (12.54)
-9.8 (16.31)
0.508
-2.1 (3.17)
90.6 (14.01)
-17.3 (14.33)
0.006
-10.1 (3.27)
91.5 (13.86)
-13.8 (15.74)
0.086
-6.6 (3.29) Response analysis
Responders, n (%)
Non-responders, n (%)
P value (vs placebo)
17 (33.3)
34 (66.7)
21 (38.9)
33 (61.1)
0.479
31 (64.6)
17 (35.4)
0.001
24 (51.1)
23 (48.9)
0.043 Response defined as ≥20% reduction in PANSS total score from baseline
Note: Negative score change indicates improvement. LOCF = end observation forward carryover method
* Moderate dose group: 3 mg for subjects weighing < 51 kg, 6 mg for subjects weighing ≥ 51 kg
** High dose group: 6 mg for subjects weighing < 51 kg, 12 mg for subjects weighing ≥ 51 kg
A randomized, double-blind, active-controlled study consisting of an 8-week double-blind acute phase and an 18-week double-blind maintenance phase also evaluated the efficacy of this product over a variable dose range of 3 mg/day to 9 mg/day in adolescent subjects (≥12 years of age) with schizophrenia (N = 112 in the drug group and N = 114 in the aripiprazole group). The change from baseline in the PANSS total score was numerically comparable between the drug-treated and aripiprazole-treated groups at weeks 8 and 26. In addition, the difference in the percentage of patients with ≥20% improvement in PANSS total score at week 26 was numerically close between the two treatment groups.
Table 12: Adolescent Schizophrenia Study: R076477-PSZ-3003: 26-week, variable-dose, active-controlled intention-to-treat analysis set. change from baseline in LOCF endpoints
This product
3-9 mg N=112 Aripiprazole 5-15 mg N=114 Change in PANSS score
8 weeks, acute endpoint Baseline mean (SD) Mean change (SD)
P-value (vs aripiprazole)
Difference of least squares means (SE)
89.6 (12.22)
-19.3 (13.80)
0.935
0.1 (1.83)
92.0 (12.09)
-19.8 (14.56) Change in PANSS score
26-week endpoint
Baseline mean (SD) Mean change (SD)
P-value (vs aripiprazole)
Difference of least squares means (SE)
89.6 (12.22)
-25.6 (16.88)
0.877
-0.3 (2.20)
92.0 (12.09)
-26.8 (18.82) Response analysis
26-week endpoint
Responders, n (%) Non-responders, n (%)
P-value (vs aripiprazole)
86 (76.8)
26 (23.2)
0.444
93 (81.6)
21 (18.4) Response defined as ≥ 20% reduction in PANSS total score from baseline
Note: Negative score change indicates improvement.
Pharmacology and Toxicology
Pharmacological effects
Paliperidone is the main metabolite of risperidone. As with other anti-schizophrenic drugs, the mechanism of action of paliperidone is unknown, but is currently thought to be mediated by a combined effect on central dopamine 2 (D2) receptor and 5-hydroxytryptamine 2 (5HT2A) receptor antagonism. Paliperidone is also an antagonist of α1 and α2 adrenergic receptors as well as H1 histamine receptors, which may account for some of the drug’s other effects. Paliperidone has no affinity for cholinergic muscarinic-type receptors or β1 and β2 adrenergic receptors. In vitro, the pharmacological activities of the (+)- and (-)-paliperidone enantiomers are similar.
Toxicological studies
Genotoxicity: Paliperidone Ames test, mouse lymphoma test, and rat micronucleus test results were negative.
Reproductive toxicity: In a fertility assay, paliperidone was given orally to rats at doses up to 2.5 mg/kg/day in which no effect was seen on pregnancy rates in females, however, at this dose there was an increased rate of pre- versus post-implantation loss and a slight decrease in the number of live fetuses, and a slight maternal toxicity was also seen. These indicators were not affected at a dose of 0.63 mg/kg, which is half of the maximum recommended human dose at mg/m2.
Fertility was not affected in male rats given paliperidone orally at doses up to 2.5 mg/kg/day, but sperm count and sperm viability studies were not performed. Risperidone is extensively converted to paliperidone in dogs and humans. In a repeat dosing toxicity test with risperidone in Beagle dogs, all doses (0.31-5.0 mg/kg) resulted in reduced serum testosterone and decreased sperm viability and concentration; serum testosterone and sperm parameters partially recovered after two months of discontinuation but remained at reduced levels.
Paliperidone was given orally to pregnant rats and rabbits during the organogenesis period, and no increase in the incidence of fetal malformations was observed at the highest dose (10 mg/kg/day in rats and 5 mg/kg/day in rabbits, equivalent to 8 times the maximum recommended human dose on a mg/m2 basis).
Risperidone is extensively converted to paliperidone in rats and humans. In a rat reproductive toxicity test with risperidone, an increase in pup mortality was seen at doses below the maximum recommended human dose at mg/m2 (see Risperidone insert).
Carcinogenicity: Paliperidone has not been tested for carcinogenicity.
Risperidone is extensively converted to paliperidone in rats, mice and humans. Risperidone carcinogenicity tests were conducted in Swiss albino mice and Wistar rats, where risperidone was administered by adulteration at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months in mice and 25 months in rats. The results showed a significant increase in the incidence of pituitary adenoma, pancreatic endocrine adenoma and mammary carcinoma in the animals. The no-effect dose for these tumors on a mg/m2 basis was less than or equal to the maximum recommended human dose of risperidone (see risperidone instructions). An increased incidence of mammary, pituitary, and pancreatic tumors has also been observed in rodent long-term dosing trials with other antipsychotics, thought to be due to long-term antagonism of dopamine D2 receptors and elevated prolactin levels. The relevance of these findings observed in rodents to humans has not been clarified.
Toxicity in young animals: reversible impairment of learning and memory was observed in young rats given paliperidone orally from 24 to 73 days of age only in females at a no-effect dose of 0.63 mg/kg/day, and blood concentrations (AUC) of paliperidone at this dose were similar to those in adolescents. No other consistent effects on neurobehavioral or reproductive development were observed in rats at the highest dose of 2.5 mg/kg/day, and the blood levels of paliperidone at this dose were 2 to 3 times higher than those in adolescents.
Risperidone is extensively converted to paliperidone in animals and humans. In young dogs given risperidone orally for 40 weeks at doses of 0.31, 1.25 or 5 mg/kg/day, a reduction in bone length and density was observed at a no-effect dose of 0.31 mg/kg/day, and blood concentrations (AUC) of risperidone + paliperidone at this dose were equivalent to those in children and adolescents receiving the maximum recommended human dose of risperidone. In addition, delayed sexual maturation was observed in both males and females in all dose groups. These effects were largely or completely irreversible in females after a 12-week recovery period of drug discontinuation.
Pharmacokinetics]
Pharmacokinetics
After a single dose, the plasma concentration of paliperidone increases steadily, reaching a peak concentration (Cmax) approximately 24 hours after dosing. Within the recommended clinical dose range (3 mg-12 mg), the pharmacokinetics of paliperidone after administration is proportional to the dose. The terminal half-life of paliperidone is approximately 23 hours.
Following administration, steady-state concentrations are reached in most subjects within approximately 4-5 days. At a paliperidone dose of 9 mg, the mean steady-state peak-to-valley ratio is 1.7 and ranges from 1.2-3.1.
The release characteristics of this product allow for minimal fluctuations compared to risperidone immediate-release agents. A study comparing the steady-state pharmacokinetics of paliperidone 12 mg once daily (administered as an extended-release tablet) and risperidone immediate-release tablets 4 mg in patients with schizophrenia resulted in a fluctuation index of 38% for the extended-release formulation of paliperidone compared to 125% for the immediate-release formulation of risperidone (see Figure 1).
Figure 1: Steady-state concentration characteristics (expressed as paliperidone concentration) of 12 mg of paliperidone taken as 2 mg extended-release tablets 6 tablets/dose once daily for 6 days compared with the steady-state concentrations (expressed as paliperidone + risperidone concentration) of the immediate-release formulation of risperidone 2 mg on day 1 and 4 mg/day on days 2-6
After administration of this product, the (+) and (-) enantiomeric isomers of paliperidone are interconverted and the (+) to (-) ratio of their AUCs at steady state is approximately 1.6.
Absorption and distribution
The absolute oral bioavailability of paliperidone after administration of this product is 28%.
In healthy ambulatory subjects given 12 mg of paliperidone extended-release tablets with a high-fat/heating diet, the mean Cmax and AUC of paliperidone were increased by 60% and 54%, respectively, compared to the fasted state. Additional clinical trials were conducted to establish the safety and efficacy of this product in subjects without regard to meal timing. Although this product is taken without regard to food intake, paliperidone exposure may be increased when taken with food (see [DOSAGE]).
Based on population analysis, the apparent volume of distribution of paliperidone is 487 L. The plasma protein binding rate of racemic paliperidone is 74%.
Metabolism and clearance
Although in vitro studies suggest that CYP2D6 and CYP3A4 are involved in the metabolism of paliperidone, in vivo results suggest that these isoenzymes play only a limited role in the overall clearance of paliperidone (see [Drug Interactions]).
After one week of oral administration of a single 1 mg 14C-labeled immediate-release formulation of paliperidone to five healthy volunteers, 59% (range: 51%-67%) of the administered dose was excreted in the urine as a prototype, 32% (26%-41%) of the dose was recovered as a metabolite, and 6%-12% of the dose was not recovered. Approximately 80% of the radioactive material is present in urine and approximately 11% in feces. Four metabolic pathways have been demonstrated in in vivo studies, none of which exceeds 10% of the administered dose: dehydroxylation, hydroxylation, dehydrogenation, and benzoisoxazole cleavage.
Population pharmacokinetic analysis found no differences in exposure or clearance of paliperidone between those with strong and weak metabolism of CYP2D6 substrates.
Special Populations
Patients with renal impairment
The dose of this product should be reduced in patients with moderate and severe renal impairment (see [DOSAGE AND ADMINISTRATION]). The distribution of paliperidone 3 mg extended-release tablets was studied in subjects with varying degrees of renal impairment. The results showed that a decrease in creatinine clearance was accompanied by a decrease in paliperidone clearance. Total paliperidone clearance decreased by 32% in subjects with mild renal impairment (CrCl = 50 mL/min to < 80 mL/min), 64% in subjects with moderate renal impairment (CrCl = 30 mL/min to < 50 mL/min), and 71% in subjects with severe renal impairment (CrCl = 10 mL/min to < 30 mL/min). The corresponding mean exposure (AUCinf) was 1.5-fold, 2.6-fold and 4.8-fold higher, respectively, in healthy subjects. The mean terminal clearance half-lives were 24 h, 40 h and 51 h for patients with mild, moderate and severe renal impairment, respectively, compared to 23 h for normal renal function subjects (CrCl ≥ 80 mL/min).
Patients with hepatic impairment
A study in subjects with moderate liver impairment (Child-Pugh Classification B) showed that plasma concentrations of free paliperidone approximated those of healthy subjects, but total paliperidone exposure was reduced because of decreased protein binding. Therefore, no dose adjustment is required in patients with mild to moderate liver impairment. This product has not been studied in patients with severe hepatic impairment.
Adolescents aged 12-17 years (weight ≥ 29 Kg)
The systemic exposure levels of paliperidone in adolescent subjects are comparable to those in adults. In adolescents weighing <51 kg (<112 lbs), exposure levels were observed to be 23% higher than those weighing ≥51 kg (≥112 lbs); it was not considered clinically significant. Age alone did not affect the level of paliperidone exposure.
Older adults
Dose adjustment based on age alone is not recommended. However, because creatinine clearance decreases with age, dose adjustment may be necessary in all older adults (see Patients with Renal Impairment above and [DOSAGE]).
Race
Dose adjustment based on race is not recommended. No pharmacokinetic differences were observed in pharmacokinetic studies conducted in Japanese and Caucasian populations.
Gender
Dose adjustment based on gender is not recommended. No pharmacokinetic differences were observed in pharmacokinetic studies conducted in males and females.
Smoking
Dose adjustment based on smoking status is not recommended. Based on data from in vitro studies using human liver enzymes, paliperidone is not a substrate of CYP1A2 and therefore smoking should not affect the pharmacokinetics of paliperidone.
[Storage].
Seal and store below 30℃.
Package】
Aluminum-plastic blister package, heat-sealed with polyester/aluminum/polyethylene pharmaceutical compound bag. 7 tablets/plate, 1 plate/bag, 1 bag/box. 7 tablets/plate, 1 plate/bag, 2 bags/box.
【Expiration date】.
12 months
【Execution standard
【Approval number】
【Drug marketing license holder
Name: Jiangsu Haosen Pharmaceutical Group Co.
Registered Address: Lianyungang Economic and Technological Development Zone, Jiangsu Province
Manufacturer
Company Name: Jiangsu Haosen Pharmaceutical Group Co.
Production Address: No. 5 Dongjin Road, Lianyungang Economic and Technological Development Zone
Postal Code: 222069
Customer Service Tel: 4008285227 Monday to Friday 9:00-17:00 (except holidays)
Web address: http://www.hansoh.cn