Risperidone

As with other antipsychotics, caution is advised when prescribing risperidone with medicinal products known to prolong the QT interval such as antiarrhythmics (e.g. quinidine, dysopiramide, procainamide, propafenone, amiodarone, sotalol, tricyclic antidepressant (i.e. amitriptyline), tetracyclic antidepressants (i.e. maprotiline), some antihistaminics, other antipsychotics, some antimalarials (i.e. quinine and mefloquine), and with medicines causing electrolyte imbalance (hypokalaemia, hypomagnesiaemia), bradycardia, or those which inhibit the hepatic metabolism of risperidone. This list is indicative and not exhaustive.

Risperidone should be used with caution in combination with other centrally-acting substances notably including alcohol, opiates, antihistamines and benzodiazepines due to the increased risk of sedation.

Phenothiazines may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone.

Irrespective of the indication, starting and consecutive dosing should be halved, and dose titration should be slower for patients with hepatic impairment.

Risperidone should be used with caution in these groups of patients.

Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than in adults with normal renal function.

Irrespective of the indication, starting and consecutive dosing should be halved, and dose titration should be slower for patients with renal impairment.

Risperidone should be used with caution in these groups of patients.

Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

Co-administration of Risperidone with a strong CYP3A4 and/or P-gp inhibitor may substantially elevate plasma concentrations of the risperidone active antipsychotic fraction. When concomitant itraconazole or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physician should re-evaluate the dosing of risperidone.

Co-administration of Risperidone with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone. CYP3A4 inducers exert their effect in a time-dependent manner, and may take at least 2 weeks to reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline.

Co-administration of Risperidone with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction (e.g. paroxetine, see below). It is expected that other CYP2D6 inhibitors, such as quinidine, may affect the plasma concentrations of risperidone in a similar way. When concomitant paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at higher doses, is initiated or discontinued, the physician should re-elevate the dosing of risperidone.

Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment.

Some beta-blockers may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction.

No formal study data are available; however, since ritonavir is a strong CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and ritonavir-boosted protease inhibitors potentially raise concentrations of the risperidone active antipsychotic fraction.

As with other drugs that antagonize dopamine D₂ receptors, risperidone elevates prolactin level. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

There were no relevant effects observed in the non-clinical studies.

Carbamazepine, a strong CYP3A4 inducer and a P–gp inducer, has been shown to decrease the plasma concentrations of the active antipsychotic fraction of risperidone. Similar effects may be observed with e.g. phenytoin and phenobarbital which also induce CYP 3A4 hepatic enzyme, as well as P-glycoprotein.

Cimetidine and ranitidine, both weak inhibitors of CYP2D6 and CYP3A4, increased the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction.

Chronic administration of clozapine with risperidone may decrease the clearance of risperidone.

Fluoxetine, a strong CYP2D6 inhibitor, increases the plasma concentrations of risperidone, but less so of the active antipsychotic fraction.

Fluvoxamine, a weak inhibitor of CYP3A4, at dosages up to 100 mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, doses higher than 100 mg/day of fluvoxamine may elevate concentrations of the risperidone active antipsychotic fraction.

In the Risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age 89 years, range 75-97) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70-96) or furosemide alone (4.1%; mean age 80 years, range 67-90). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.

No pathophysiological mechanism has been identified to explain this finding, and no consistent pattern for cause of death observed. Nevertheless, caution should be exercised and the risks and benefits of this combination or co-treatment with other potent diuretics should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant medication with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Itraconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200mg/day increased the plasma concentrations of the active antipsychotic fraction by about 70%, at risperidone doses of 2 to 8 mg/day.

Ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200mg/day increased the plasma concentrations of risperidone and decreased the plasma concentrations of 9-hydroxyrisperidone.

Risperidone may antagonise the effect of levodopa and other dopamine agonists. If this combination is deemed necessary, particularly in end-stage Parkinson’s disease, the lowest effective dose of each treatment should be prescribed.

Concomitant use of oral Risperidone with paliperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive active antipsychotic fraction exposure.

Paroxetine, a strong CYP2D6 inhibitor, increases the plasma concentrations of risperidone, but, at dosages up to 20 mg/day, less so of the active antipsychotic fraction. However, higher doses of paroxetine may elevate concentrations of the risperidone active antipsychotic fraction.

Sertraline, a weak inhibitor of CYP2D6, at dosages up to 100 mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, doses higher than 100 mg/day of sertraline may elevate concentrations of the risperidone active antipsychotic fraction.

Terbinafine may reduce the metabolism and clearance of risperidone.

Topiramate modestly reduced the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance.

Co-administration of triprolidin and risperidone can cause additional anticholinergic effects and enhance their side effects and toxicity.

Co-administration of trospium and risperidone can cause additional anticholinergic effects and enhance their side effects and toxicity.

Verapamil, a moderate inhibitor of CYP3A4 and an inhibitor of P-gp, increases the plasma concentration of risperidone and the active antipsychotic fraction.

Medicines with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia, characterised by rhythmical involuntary movements, predominantly of the tongue and/or face.

The onset of extrapyramidal symptoms is a risk factor for tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics should be considered.

Risperidone should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels has been reported to occur with antipsychotics. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, all antipsychotics, including Risperidone, should be discontinued.

Hyperprolactinaemia is a common side-effect of treatment with Risperidone. Evaluation of the prolactin plasma level is recommended in patients with evidence of possible prolactin-related side-effects (e.g. gynaecomastia, menstrual disorders, anovulation, fertility disorder, decreased libido, erectile dysfunction, and galactorrhea).

Tissue culture studies suggest that cell growth in human breast tumours may be stimulated by prolactin. Although no clear association with the administration of antipsychotics has so far been demonstrated in clinical and epidemiological studies, caution is recommended in patients with relevant medical history. Risperidone should be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours.

Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur, especially during the initial dose-titration period. Clinically significant hypotension has been observed postmarketing with concomitant use of risperidone and antihypertensive treatment. Risperidone should be used with caution in patients with known cardiovascular disease (e.g. heart failure, myocardial infarction, conduction abnormalities, dehydration, hypovolemia, or cerebrovascular disease), and the dosage should be gradually titrated as recommended. A dose reduction should be considered if hypotension occurs.

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha-1a-adrenergic antagonist effect, including risperidone.

IFIS may increase the risk of eye complicationsduring and after the operation. Current or past use of medicines with alpha-1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha-1 blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with risperidone and preventive measures undertaken.

Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including risperidone, to patients with Parkinson’s disease or Dementia with Lewy Bodies (DLB). Parkinson’s disease may worsen with risperidone. Both groups may be at increased risk of Neuroleptic Malignant Syndrome as well as having an increased sensitivity to antipsychotic medicinal products; these patients were excluded from clinical trials. Manifestation of this increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Priapism may occur with risperidone treatment due to its alpha-adrenergic blocking effects.

Hyperglycaemia, diabetes mellitus and exacerbation of pre-existing diabetes have been reported during treatment with Risperidone. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Association with ketoacidosis has been reported very rarely, and rarely with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any atypical antipsychotic including Risperidone should be monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus should be monitored regularly for worsening of glucose control.

Events of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including risperidone. Agranulocytosis has been reported very rarely (<1/10,000 patients) during post-marketing surveillance.

Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should be monitored during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1 X 10⁹/L) should discontinue risperidone and have their WBC followed until recovery.

QT prolongation has very rarely been reported postmarketing. As with other antipsychotics, caution should be exercised when risperidone is prescribed in patients with known cardiovascular disease, family history of QT prolongation, bradycardia, or electrolyte disturbances (hypokalaemia, hypomagnesaemia), as it may increase the risk of arrhythmogenic effects, and in concomitant use with medicines known to prolong the QT interval.

There are no adequate data from the use of risperidone in pregnant women.

Risperidone was not teratogenic in animal studies but other types of reproductive toxicity were seen. The potential risk for humans is unknown.

Neonates exposed to antipsychotics (including risperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

Risperidone should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.

In animal studies, risperidone and 9-hydroxy-risperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxy-risperidone are also excreted in human breast milk in small quantities. There are no data available on adverse reactions in breast-feeding infants. Therefore, the advantage of breast-feeding should be weighed against the potential risks for the child.

Fertility

As with other drugs that antagonize dopamine D₂ receptors, risperidone elevates prolactin level. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients.

There were no relevant effects observed in the non-clinical studies.

Risperidone can have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

Oral administration

The most frequently reported adverse drug reactions (ADRs) (incidence ≥10%) are: Parkinsonism, sedation/somnolence, headache, and insomnia.

The ADRs that appeared to be dose-related included parkinsonism and akathisia.

The following are all the ADRs that were reported in clinical trials and postmarketing experience with risperidone by frequency category estimated from risperidone clinical trials. The following terms and frequencies are applied: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

Common: pneumonia, bronchitis, upper respiratory tract infection, sinusitis, urinary tract infection, ear infection, influenza

Uncommon: respiratory tract infection, cystitis, eye infection, tonsillitis, onychomycosis, cellulitis localised infection, viral infection, acarodermatitis

Rare: infection

Blood and lymphatic system disorders

Uncommon: neutropenia, white blood cell count decreased, thrombocytopenia, anaemia, haematocrit decreased, eosinophil count increased

Rare: agranulocytosis^c

Immune system disorders

Uncommon: hypersensitivity

Rare: anaphylactic reaction^c

Endocrine disorders

Common: hyperprolactinaemia^a

Rare: inappropriate antidiuretic hormone secretion, glucose urine present

Metabolism and nutrition disorders

Common: weight increased, increased appetite, decreased appetite

Uncommon: diabetes mellitus^b, hyperglycaemia, polydipsia, weight decreased, anorexia, blood cholesterol increased

Rare: water intoxication^c, hypoglycemia, hyperinsulinaemia^c, blood triglycerides increased

Very Rare: diabetic ketoacidosis

Psychiatric disorders

Very Common: insomnia^d

Common: sleep disorder, agitation, depression, anxiety

Uncommon: mania, confusional state, libido decreased, nervousness, nightmare

Rare: somnambulism, sleep-related eating disorder, blunted affect, anorgasmia

Nervous system disorders

Very Common: sedation/somnolence, parkinsonism^d, headache

Common: akathisia^d, dystoniad, dizziness, dyskinesiad, tremor

Uncommon: tardive dyskinesia, cerebral ischaemia, unresponsive to stimuli, loss of consciousness, depressed level of consciousness, convulsiond, syncope, psychomotor hyperactivity, balance disorder, coordination abnormal, dizziness postural, disturbance in attention, dysarthria, dysgeusia, hypoaesthesia, paraesthesia

Rare: neuroleptic malignant syndrome, cerebrovascular disorder, diabetic coma, head titubation

Eye disorders

Common: vision blurred, conjunctivitis

Uncommon: photophobia, dry eye, lacrimation increased, ocular hyperaemia

Rare: glaucoma, eye movement disorder, eye rolling, eyelid margin crusting, floppy iris syndrome (intraoperative)^c

Ear and labyrinth disorders

Uncommon: vertigo, tinnitus, ear pain

Cardiac disorders

Common: tachycardia

Uncommon: atrial fibrillation, atrioventricular block, conduction disorder, electrocardiogram QT prolonged, bradycardia, electrocardiogram abnormal, palpitations

Rare: sinus arrhythmia

Vascular disorders

Common: hypertension

Uncommon: hypotension, orthostatic hypotension, flushing

Rare: pulmonary embolism, venous thrombosis

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion

Uncommon: pneumonia aspiration, pulmonary congestion, respiratory tract congestion, rales, wheezing, dysphonia, respiratory disorder

Rare: sleep apnoea syndrome, hyperventilation

Gastrointestinal disorders

Common: abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhoea, dyspepsia, dry mouth, toothache

Uncommon: faecal incontinence, faecaloma, gastroenteritis, dysphagia, flatulence

Rare: pancreatitis, intestinal obstruction, swollen tongue, cheilitis

Very Rare: ileus

Skin and subcutaneous tissue disorders

Common: rash, erythema

Uncommon: urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin discolouration, acne, seborrhoeic dermatitis, skin disorder, skin lesion

Rare: drug eruption, dandruff

Very Rare: angioedema

Musculoskeletal and connective tissue disorders

Common: muscle spasms, musculoskeletal pain, back pain, arthralgia

Uncommon: blood creatine phosphokinase increased, posture abnormal, joint stiffness, joint swelling muscular weakness, neck pain

rhabdomyolysis

Renal and urinary disorders

Common: urinary incontinence

Uncommon: pollakiuria, urinary retention, dysuria

Pregnancy, puerperium, and neonatal conditions

Rare: drug withdrawal syndrome neonatal^c

Reproductive system and breast disorders

Uncommon: erectile dysfunction, ejaculation disorder, amenorrhoea, menstrual disorderd, gynaecomastia, galactorrhoea, sexual dysfunction, breast pain, breast discomfort, vaginal discharge

Rare: priapism^c, menstruation delayed, breast engorgement, breast enlargement, breast discharge

General disorders and administration site conditions

Common: oedema^d, pyrexia, chest pain, asthenia, fatigue, pain

Uncommon: face oedema, chills, body temperature increased, gait abnormal, thirst, chest discomfort, malaise, feeling abnormal, discomfort

Rare: hypothermia, body temperature decreased, peripheral coldness, drug withdrawal syndrome, indurationc

Hepatobiliary disorders

Uncommon: transaminases increased, gamma-glutamyltransferase increased, hepatic enzyme increased

Rare: jaundice

Injury, poisoning and procedural complications

Common: fall

Uncommon: procedural pain

^a Hyperprolactinemia can in some cases lead to gynaecomastia, menstrual disturbances, amenorrhoea, anovulation, galactorrhea, fertility disorder, decreased libido, erectile dysfunction.
^b In placebo-controlled trials, diabetes mellitus was reported in 0.18% in risperidone-treated subjects compared to a rate of 0.11% in placebo group. Overall incidence from all clinical trials was 0.43% in all risperidone-treated subjects.
^c Not observed in risperidone clinical studies but observed in post-marketing environment with risperidone.
^d Extrapyramidal disorder may occur: Parkinsonism (salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal, parkinsonian rest tremor), akathisia (akathisia, restlessness, hyperkinesia, and restless leg syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia.
Dystonia includes dystonia, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus. It should be noted that a broader spectrum of symptoms are included, that do not necessarily have an extrapyramidal origin. Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: Grand mal convulsion; Menstrual disorder includes: Menstruation irregular, oligomenorrhoea; Oedema includes: generalised oedema, oedema peripheral, pitting oedema.

IM administration

The most frequently reported adverse drug reactions (ADRs) (incidence ≥1/10) are: insomnia, anxiety, headache, upper respiratory tract infection, parkinsonism, and depression.

The ADRs that appeared to be dose-related included parkinsonism and akathisia.

Serious injection site reactions including injection site necrosis, abscess, cellulitis, ulcer, haematoma, cyst, and nodule were reported post-marketing. The frequency is considered not known (cannot be estimated from the available data). Isolated cases required surgical intervention.

The following are all the ADRs that were reported in clinical trials and post-marketing experience with risperidone by frequency category estimated from risperidone clinical trials. The following terms and frequencies are applied: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

Very Common: upper respiratory tract infection

Common: pneumonia, bronchitis, sinusitis, urinary tract infection, influenza

Uncommon: respiratory tract infection, cystitis, ear infection, eye infection, tonsillitis, onychomycosis, cellulitis, infection, localised infection, viral infection, acarodermatitis, subcutaneous abscess

Blood and lymphatic system disorders

Common: anaemia

Uncommon: white blood cell count decreased, thrombocytopenia, haematocrit decreased

Rare: agranulocytosis^c, neutropenia, eosinophil count increased

Immune system disorders

Uncommon: hypersensitivity

Rare: anaphylactic reaction^c

Endocrine disorders

Common: hyperprolactinaemia^a

Uncommon: glucose urine present

Rare: inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

Common: hyperglycaemia, weight increased, increased appetite, weight decreased, decreased appetite

Uncommon: diabetes mellitus^b, anorexia, blood triglycerides increased, blood cholesterol increased

Rare: water intoxication^c, hypoglycaemia, hyperinsulinaemia^c, polydipsia

Very Rare: diabetic ketoacidosis

Psychiatric disorders

Very Common: insomnia^d, depression, anxiety

Common: sleep disorder, agitation, libido decreased

Uncommon: mania, confusional state, anorgasmia, nervousness, nightmare

Rare: catatonia, somnambulism, sleep-related eating disorder, blunted affect

Nervous system disorders

Very Common: parkinsonism^d, headache

Common: sedation/somnolence, akathisia^d, dystonia^d, dizziness, dyskinesia^d, tremor

Uncommon: tardive dyskinesia, cerebral ischaemia, loss of consciousness, convulsion^d, syncope, psychomotor hyperactivity, balance disorder, coordination abnormal, dizziness postural, disturbance in attention, dysarthria, dysgeusia, hypoaesthesia, paraesthesia

Rare: neuroleptic malignant syndrome, cerebrovascular disorder, unresponsive to stimuli, depressed level of consciousness, diabetic coma, head titubation

Eye disorders

Common: vision blurred

Uncommon: conjunctivitis, dry eye, lacrimation increased, ocular hyperaemia

Rare: retinal artery occlusion, glaucoma, eye movement disorder, eye rolling, photophobia, eyelid margin crusting, floppy iris syndrome (intraoperative)^c

Ear and labyrinth disorders

Uncommon: vertigo, tinnitus, ear pain

Cardiac disorders

Common: tachycardia

Uncommon: atrial fibrillation, atrioventricular block, conduction disorder, electrocardiogram QT prolonged, bradycardia, electrocardiogram abnormal, palpitations

Rare: sinus arrhythmia

Vascular disorders

Common: hypotension, hypertension

Uncommon: orthostatic hypotension

Rare: pulmonary embolism, venous thrombosis, flushing

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea, pharyngolaryngeal pain, cough, nasal congestion

Uncommon: hyperventilation, respiratory tract congestion, wheezing, epistaxis

Rare: sleep apnoea syndrome, pneumonia aspiration, pulmonary congestion, rales, dysphonia, respiratory disorder

Gastrointestinal disorders

Common: abdominal pain, abdominal discomfort, vomiting, nausea, constipation, gastroenteritis, diarrhoea, dyspepsia, dry mouth, toothache

Uncommon: faecal incontinence, dysphagia, flatulence

Rare: pancreatitis, intestinal obstruction, swollen tongue, faecaloma, cheilitis

Very Rare: ileus

Skin and subcutaneous tissue disorders

Common: rash

Uncommon: pruritus, alopecia, eczema, dry skin, erythema, skin discolouration, acne, seborrhoeic dermatitis

Rare: drug eruption, urticaria, hyperkeratosis, dandruff, skin disorder, skin lesion

Very Rare: angioedema

Musculoskeletal and connective tissue disorders

Common: muscle spasms, musculoskeletal pain, back pain, arthralgia

Uncommon: blood creatine phosphokinase increased, joint stiffness, joint swelling, muscular weakness, neck pain

rhabdomyolysis, posture abnormal

Renal and urinary disorders

Common: urinary incontinence

Uncommon: pollakiuria, urinary retention, dysuria

Pregnancy, puerperium, and neonatal conditions

Rare: drug withdrawal syndrome neonatal^c

Reproductive system and breast disorders

Common: erectile dysfunction, amenorrhoea, galactorrhoea

Uncommon: ejaculation disorder, menstruation delayed, menstrual disorder^d, gynaecomastia, sexual dysfunction, breast pain, breast discomfort, vaginal discharge

Rare: priapism^c, breast engorgement, breast enlargement, breast discharge

General disorders and administration site conditions

Common: oedema^d, pyrexia, chest pain, asthenia, fatigue, pain, injection site reaction

Uncommon: face oedema, chills, body temperature increased, gait abnormal, thirst, chest discomfort, malaise, feeling abnormal, indurationc

Rare: hypothermia, body temperature decreased, peripheral coldness, drug withdrawal syndrome, discomfort

Hepatobiliary disorders

Common: transaminases increased, gamma-glutamyltransferas increased

Uncommon: hepatic enzyme increased

Rare: jaundice

Injury, poisoning and procedural complications

Common: fall

Uncommon: procedural pain

^a Hyperprolactinaemia can in some cases lead to gynaecomastia, menstrual disturbances, amenorrhoea, anovulation, galactorrhoea, fertility disorder, decreased libido, erectile dysfunction.
^b In placebo-controlled trials diabetes mellitus was reported in 0.18% in risperidone-treated subjects compared to a rate of 0.11% in placebo group. Overall incidence from all clinical trials was 0.43% in all risperidone-treated subjects.
^c Not observed in risperidone clinical studies but observed in post-marketing environment with risperidone.
^d Extrapyramidal disorder may occur: Parkinsonism (salivary hypersecretion, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, and glabellar reflex abnormal, parkinsonian rest tremor), akathisia (akathisia, restlessness, hyperkinesia, and restless leg syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis, and myoclonus), dystonia. Dystonia includes dystonia, hypertonia, torticollis, muscle contractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus. It should be noted that a broader spectrum of symptoms are included, that do not necessarily have an extrapyramidal origin. Insomnia includes initial insomnia, middle insomnia. Convulsion includes grand mal convulsion. Menstrual disorder includes menstruation irregular, oligomenorrhoea. Oedema includes generalised oedema, oedema peripheral, pitting oedema.

Undesirable effects noted with paliperidone formulations

Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. In addition to the above adverse reactions, the following adverse reaction has been noted with the use of paliperidone products and can be expected to occur with risperidone.

Cardiac disorders

Postural orthostatic tachycardia syndrome.

Anaphylactic reaction

Rarely, cases of anaphylactic reaction after injection with risperidone have been reported during post-marketing experience in patients who have previously tolerated oral risperidone.

Class effects

As with other antipsychotics, very rare cases of QT prolongation have been reported post-marketing with risperidone. Other class-related cardiac effects reported with antipsychotics which prolong QT interval include ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest and Torsades de Pointes.

Venous thromboembolism

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic drugs (frequency unknown).

Weight gain

The proportions of risperidone and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of ≥7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for risperidone (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week studies in adult patients with acute mania, the incidence of weight increase of ≥7% at endpoint was comparable in the risperidone (2.5%) and placebo (2.4%) groups, and was slightly higher in the active-control group (3.5%).

In a population of children and adolescents with conduct and other disruptive behaviour disorders, in long-term studies, weight increased by a mean of 7.3 kg after 12 months of treatment. The expected weight gain for normal children between 5-12 years of age is 3 to 5 kg per year. From 12-16 years of age, this magnitude of gaining 3 to 5 kg per year is maintained for girls, while boys gain approximately 5 kg per year.

Additional information on special populations

Adverse drug reactions that were reported with higher incidence in elderly patients with dementia or paediatric patients than in adult populations are described below:

Elderly patients with dementia

Transient ischaemic attack and cerebrovascular accident were ADRs reported in clinical trials with a frequency of 1.4% and 1.5%, respectively, in elderly patients with dementia. In addition, the following ADRs were reported with a frequency ≥5% in elderly patients with dementia and with at least twice the frequency seen in other adult populations: urinary tract infection, peripheral oedema, lethargy, and cough.

Paediatric population

In general, type of adverse reactions in children is expected to be similar to those observed in adults.The following ADRs were reported with a frequency ≥5% in paediatric patients (5 to 17 years) and with at least twice the frequency seen in clinical trials in adults: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infection, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhoea, and enuresis.

The effect of long-term risperidone treatment on sexual maturation and height has not been adequately studied.