4.1. Therapeutic indications

Risperidone Grindeks is indicated for the treatment of schizophrenia.

Risperidone Grindeks is indicated for the treatment of moderate to severe manic episodes associated with bipolar disorders.

Risperidone Grindeks is indicated for the short-term treatment (up to 6 weeks) of persistent aggression in patients with moderate to severe Alzheimer's dementia, unresponsive to non-pharmacological approaches and when there is a risk of harm to self or others.

Risperidone Grindeks is indicated for the short-term symptomatic treatment (up to 6 weeks) of persistent aggression in conduct disorder in children from the age of 5 years and adolescents with subaverage intellectual functioning or mental retardation, diagnosed according to DSM-IV criteria, in whom the severity of aggressive or other disruptive behaviours require pharmacological treatment. Pharmacological treatment should be an integral part of a more comprehensive treatment programme, including psychosocial and educational intervention. It is recommended that risperidone be prescribed by a specialist in child neurology and child and adolescent psychiatry or physicians well familiar with the treatment of conduct disorder of children and adolescents.

4.2. Posology and method of administration

Posology

Schizophrenia

Adults

Risperidone Grindeks may be given once or twice daily.

Patients should start with 2 mg/day risperidone. The dosage may be increased on the second day to 4 mg. Subsequently, the dosage can be maintained unchanged, or further individualised, if needed. Most patients will benefit from daily doses between 4 and 6 mg. In some patients, a slower titration phase and a lower starting and maintenance dose may be appropriate.

Doses above 10 mg/day have not demonstrated superior efficacy to lower doses and may cause increased incidence of extrapyramidal symptoms. The safety of doses above 16 mg/day has not been evaluated, and are therefore not recommended.

Elderly

A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 to 2 mg twice daily.

Paediatric population

Risperidone is not recommended for use in children below 18 years of age with schizophrenia due to a lack of data on efficacy.

Manic episodes in bipolar disorder

Adults

Risperidone Grindeks should be administered on a once daily schedule, starting with 2 mg risperidone. Dosage adjustments, if indicated, should occur at intervals of not less than 24 hours and in dosage increments of 1 mg per day. Risperidone can be administered in flexible doses a range of 1 to 6 mg per day to optimize the level of efficacy and tolerability for each patient. Daily doses above 6 mg risperidone have not been studied in patients with manic episodes.

As with all symptomatic treatment, the continued use of Risperidone Grindeks must be evaluated and justified on an ongoing basis.

Elderly

A starting dose of 0.5 mg twice daily is recommended. This dosage can be individually adjusted with 0.5 mg twice daily increments to 1 to 2 mg twice daily. As clinical experience in elderly is limited, caution should be exercised.

Paediatric population

Risperidone is not recommended for use in children below 18 years of age with bipolar mania due to a lack of data on efficacy.

Persistent aggression in patients with moderate to severe Alzheimer's dementia

A starting dose of 0.25 mg of the oral solution twice daily is recommended. The oral solution is the recommended pharmaceutical form to administer 0.25 mg. This dosage can be individually adjusted by increments of 0.25 mg twice daily, not more frequently than every other day, if needed. The optimum dose is 0.5 mg twice daily for most patients. Some patients, however, may benefit from doses up to 1 mg twice daily.

Risperidone Grindeks should not be used more than 6 weeks in patients with persistent aggression in Alzheimer's dementia. During treatment, patients should be evaluated frequently and regularly, and the need for continuing treatment reassessed.

Conduct disorder

Children and adolescents from 5 to 18 years of age

For subjects weighing ≥50 kg, a starting dose of 0.5 mg once daily is recommended. This dosage can be individually adjusted by increments of 0.5 mg once daily not more frequently than every other day, if needed. The optimum dose is 1 mg once daily for most patients. Some patients, however, may benefit from 0.5 mg once daily, while others may require 1.5 mg once daily.

For subjects weighing <50 kg, a starting dose of 0.25 mg of the oral solution once daily is recommended. The oral solution is the recommended pharmaceutical form to administer 0.25 mg. This dose can be individually adjusted by increments of 0.25 mg once daily not more frequently than every other day, if needed. The optimum dose is 0.5 mg once daily for most patients. Some patients, however, may benefit from 0.25 mg once daily, while others may require 0.75 mg of the oral solution once daily. The oral solution is the recommended pharmaceutical form to administer 0.75 mg.

As with all symptomatic treatments, the continued use of Risperidone Grindeks should be evaluated and justified on an ongoing basis.

Risperidone Grindeks is not recommended in children less than 5 years of age, as there is no experience in children less than 5 years of age with this disorder.

Renal and hepatic impairment

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

Risperidone Grindeks should be used with caution in these patient groups.

Method of administration

Risperidone Grindeks is for oral use. Food does not affect the absorption of Risperidone Grindeks.

Upon discontinuation, gradual withdrawal is advised. Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been very rarely been described after abrupt cessation of high doses of antipsychotic medicines (see section 4.8). Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) have been reported.

Switching from other antipsychotics

When medically appropriate, gradual discontinuation of the previous treatment while Risperidone Grindeks therapy is initiated, is recommended. Also, if medically appropriate, when switching patients from depot antipsychotics, initiate Risperidone Grindeks therapy in place of the next scheduled injection. The need for continuing existing anti-Parkinson medicines should be re-evaluated periodically.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Elderly patients with dementia

Increased mortality in elderly people with dementia

In a meta-analysis of 17 controlled trials of atypical antipsychotics, including risperidone, elderly patients with dementia treated with atypical antipsychotics have an increased mortality compared to placebo. In placebo-controlled trials with oral risperidone in this population, the incidence of mortality was 4.0% for risperidone-treated patients compared to 3.1% for placebo-treated patients. The odds ratio (95% exact confidence interval) was 1.21 (0.7; 2.1). The mean age (range) of patients who died was 86 years (range 67-100). Data from two large observational studies showed that elderly people with dementia who are treated with conventional antipsychotics are also at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotics as opposed to some characteristic(s) of the patients is not clear.

Concomitant use of furosemide

In the placebo-controlled trials of risperidone 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 years) when compared to patients treated with risperidone alone (3.1%; mean age 84 years, range 70–96 years) or furosemide alone (4.1%; mean age 80 years, range 67–90 years). The increased 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 treatment with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Cerebrovascular adverse events (CVAE)

An approximately 3-fold increased risk of cerebrovascular adverse events has been observed in randomized placebo-controlled clinical trials in the dementia population with some atypical antipsychotics. The pooled data from six placebo-controlled studies with risperidone in mainly elderly patients (>65 years of age) with dementia showed that CVAEs (serious and non-serious, combined) occurred in 3.3% (33/1,009) of patients treated with risperidone and 1.2% (8/712) of patients treated with placebo. The odds ratio (95% exact confidence interval) was 2.96 (1.34; 7.50). The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Risperidone Grindeks should be used with caution in patients with risk factors for stroke.

The risk of CVAEs was significantly higher in patients with mixed or vascular type of dementia when compared to Alzheimer's dementia. Therefore, patients with other types of dementias than Alzheimer's should not be treated with risperidone.

Physicians are advised to assess the risks and benefits of the use of Risperidone Grindeks in elderly patients with dementia, taking into account risk predictors for stroke in the individual patient. Patients/caregivers should be cautioned to immediately report signs and symptoms of a potential CVAEs such as sudden weakness or numbness in the face, arms or legs, and speech or vision problems. All treatment options should be considered without delay, including discontinuation of risperidone.

Risperidone Grindeks should only be used the short-term for persistent aggression in patients with moderate to severe Alzheimer's dementia to supplement non-pharmacological approaches which have had limited or no efficacy and when there is potential risk of harm to self or others.

Patients should be reassessed regularly, and the need for continuing treatment reassessed.

Orthostatic hypotension

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 post-marketing with concomitant use of risperidone and antihypertensive treatment. Risperidone Grindeks 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 (see section 4.2). A dose reduction should be considered if hypotension occurs.

Leucopenia, neutropenia and agranulocytosis

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 leucopenia/neutropenia should be monitored during the first few months of treatment and discontinuation of Risperidone Grindeks 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 Grindeks and have their WBC followed until recovery.

Tardive dyskinesia/extrapyramidal symptoms (TD/EPS)

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.

Caution is warranted in patients receiving both psychostimulants (e.g. methylphenidate) and risperidone concomitantly, as extrapyramidal symptoms could emerge when adjusting one or both medicinal products. Gradual withdrawal of stimulant treatment is recommended (see section 4.5).

Neuroleptic malignant syndrome (NMS)

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 Grindeks, should be discontinued.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including Risperidone Grindeks, 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 the increased sensitivity can include confusion, obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Hyperglycaemia and diabetes mellitus

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 with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with any atypical antipsychotic, including Risperidone Grindeks, 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.

Weight gain

Significant weight gain has been reported with the use of risperidone. Weight should be monitored regularly.

Hyperprolactinaemia

Hyperprolactinaemia is a common side effect of treatment with Risperidone Grindeks. 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 galactorrhoea).

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 Grindeks should be used with caution in patients with pre-existing hyperprolactinaemia and in patients with probable prolactin-dependent tumours.

QT prolongation

QT prolongation has very rarely been reported post-marketing. 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.

Seizures

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

Priapism

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

Body temperature regulation

Disruption of the body's ability to reduce core body temperature has been attribute to antipsychotic medicines. Appropriate care is advised when prescribing Risperidone Grindeks to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant treatment with anticholinergic activity, or being subject to dehydration.

Antiemetic effect

An antiemetic effect was observed in preclinical studies with risperidone. This effect, if it occurs in humans, may mask the signs and symptoms of overdosage with certain medicines or of conditions such as intestinal obstruction, Reye's syndrome, and brain tumour.

Renal and hepatic impairment

Patients with renal impairment have less ability to eliminate the active antipsychotic fraction than adults with normal renal function. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone (see section 4.2).

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported for antipsychotic medicines.

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 Grindeks and preventive measures undertaken.

Intraoperative Floppy Iris Syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha 1a-adrenergic antagonist effect, including Risperidone Grindeks (see section 4.8).

IFIS may increase the risk of eye complications during 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 antipsychotic treatment.

Paediatric population

Before risperidone is prescribed to a child or adolescent with conduct disorder they should be fully assessed for physical and social causes of the aggressive behaviour such as pain or inappropriate environmental demands.

The sedative effect of risperidone should be closely monitored in this population because of possible consequences on learning ability. A change in the time of administration of risperidone could improve the impact of the sedation on attention faculties of children and adolescents.

Risperidone was associated with mean increases in body weight and body mass index (BMI). Baseline weight measurement prior to treatment and regular weight monitoring are recommended. Changes in height in the long-term open-label extension studies were within expected age-appropriate norms. The effect of long-term risperidone treatment on sexual maturation and height has not been adequately studied.

Because of the potential effects of prolonged hyperprolactinaemia on growth and sexual maturation in children and adolescents, regular clinical evaluation of endocrinological status should be considered, including measurements of height, weight, sexual maturation, monitoring of menstrual functioning and other potential prolactin-related effects.

Results from a small post-marketing observation study showed that risperidone-exposed subjects between the ages of 8 and 16 years were on average approximately 3.0 to 4.8 cm taller than those who received other atypical psychotropic medicines. This study was not adequate to determine whether the exposure to risperidone had any impact on final adult height, or whether the result was due to a direct effect of risperidone on bone growth, or the effect of the underlying disease itself on bone growth, or the result of better control of the underlying disease with resulting increase in linear growth.

During treatment with risperidone regular examination for extrapyramidal symptoms and other movement disorders should also be conducted.

For specific posology recommendations in children and adolescents see section 4.2.

Excipients

The film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Pharmacodynamic-related interactions

Medicinal products known to prolong the QT interval

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, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (i.e., amitriptyline) tetracyclic antidepressants (i.e., maprotiline), some antihistamines, other antipsychotics, some antimalarials (i.e., quinine and mefloquine) and with medicines causing electrolyte imbalance (hypokalaemia, hypomagnesaemia), bradycardia or those which inhibit the hepatic metabolism of risperidone. This list is indicative and not exhaustive.

Centrally-acting medicines and alcohol

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.

Levodopa and dopamine agonists

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

Medicines with hypotensive effect

Clinically significant hypotension has been observed post-marketing with concomitant use of risperidone and antihypertensive treatment.

Psychostimulants

The combined use of psychostimulants (e.g., methylphenidate) with risperidone can lead to extrapyramidal symptoms upon change of either or both treatments (see section 4.4).

Paliperidone

Concomitant use of oral Risperidone Grindeks and 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.

Pharmacokinetic-related interactions

Food does not affect the absorption of Risperidone Grindeks.

Risperidone is mainly metabolised through CYP2D6 and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9-hydroxy-risperidone are substrates of P-glycoprotein (P-gp).

Substances that modify CYP2D6 activity or substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of the risperidone active antipsychotic fraction.

Strong CYP2D6 inhibitors

Co-administration of Risperidone Grindeks with a strong CYP2D6 inhibitor may increase the plasma concentration of risperidone, but less so for the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may increase the concentration of the risperidone active antipsychotic fraction (e.g. paroxetine, see below). It is expected that other CYP2D6 inhibitors, such as quinidine, may effect 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-evaluate the dosing of Risperidone Grindeks.

CYP3A4 and/or P-gp inhibitors

Co-administration of Risperidone Grindeks 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 Grindeks.

CYP3A4 and/or P-gp inducers

Co-administration of Risperidone Grindeks 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 Grindeks. CYP3A4 inducers exert their effect in a time-dependent manner, and it may take at least two weeks to reach maximum effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline.

Highly protein-bound medicinal products

When Risperidone Grindeks is taken together with highly protein-bound medicinal products, there is no clinically relevant displacement of either medicine from the plasma proteins.

When using concomitant medicines, the corresponding label should be consulted for information on route of metabolism and the possible need to adjust dosage.

Paediatric population

Interaction studies have only been performed in adults. The relevance of the results of these studies in paediatric patients is unknown.

The combined use of psychostimulants (e.g., methylphenidate) with risperidone in children and adolescents did not alter the pharmacokinetics and efficacy of risperidone.

Examples

Examples of medicinal products that may potentially interact or that were shown not to interact with risperidone are listed below:

Effect of other medicinal products on the pharmacokinetics of risperidone

Antibacterials:

- Erythromycin, a moderate CYP3A4 inhibitor and P-gp inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction.

- Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the plasma concentration of the active antipsychotic fraction.

Anticholinesterases:

- Donepezil and galantamine, both CYP2D6 and CYP3A4 substrates, do not show clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.

Antiepileptics:

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

- 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.

Antifungals:

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

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

Antipsychotics:

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

Antivirals:

- Protease inhibitors: 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 the concentration of the active antipsychotic fraction of risperidone.

Beta-blockers:

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

Calcium channel blockers:

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

Gastrointestinal medicinal products:

- H2-receptor antagonists: Cimetidine and ranitidine, both weak inhibitors of CYP2D6 and CYP3A4, increased the bioavailability of risperidone, but only marginally that of the active antipsychotic fraction.

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants:

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

- Paroxetine, a strong CYP2D6 inhibitor, increases the plasma concentration 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 active antipsychotic fraction of risperidone.

- Tricyclic antidepressants may increase the plasma concentration of risperidone but not those of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.

- Sertraline, a weak inhibitor of CYP2D6, and 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 sertraline or fluvoxamine may elevate concentrations of the active antipsychotic fraction of risperidone.

Effect of risperidone on the pharmacokinetics of other medicinal products

Antiepileptics:

- Risperidone does not show a clinically relevant effect on the pharmacokinetics of valproate or topiramate.

Antipsychotics:

- Aripiprazole, a CYP2D6 and CYP3A4 substrate: Risperidone tablets or injection did not affect the pharmacokinetics of the sum of aripiprazole and its active metabolite dehydroaripiprazole.

Digitalis glycosides:

- Risperidone does not show a clinically relevant effect on the pharmacokinetics of digoxin.

Lithium:

- Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium.

Concomitant use of risperidone with furosemide:

- See section 4.4 regarding increased mortality in elderly patients with dementia concomitantly receiving furosemide.

4.6. Fertility, pregnancy and lactation

Pregnancy

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 (see section 5.3). 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 Grindeks should not be used during pregnancy unless clearly necessary. If discontinuation during pregnancy is necessary, it should not be done abruptly.

Breast-feeding

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 medicinal products that antagonise dopamine D2-receptors, Risperidone Grindeks elevates prolactin level. Hyperprolactinaemia 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.

4.7. Effects on ability to drive and use machines

Risperidone Grindeks may have minor or moderate influence on the ability to drive and use machines due to potential nervous system and visual effects (see section 4.8). Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility is known.

4.8. Undesirable effects

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 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, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

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

System Organ Class

Adverse drug reactions

Frequency

Very common

Common

Uncommon

Rare

Very rare

Not known

Infections and infestations

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

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

infection

Blood and lymphatic system disorders

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

agranulocytosis c

Immune system disorders

hypersensitivity

anaphylactic reaction c

Endocrine disorders

hyperprolactinaemia a

inappropriate excretion of antidiuretic hormone, glucose is presented in the urine

Metabolism and nutrition disorders

weight increased, increased appetite, decreased appetite

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

water intoxication c, hypoglycaemia, hyperinsulinemia c, blood triglycerides increased

diabetic ketoacidosis

Psychiatric disorders

insomnia d

sleep disorder, agitation, depression, anxiety

mania, confusional state, libido decreased, nervousness, nightmare

catatonia, somnambulism, sleep-related eating disorder, blunted affect, anorgasmia

Nervous system disorders

sedation/ somnolence, parkinsonismd, headache

akathisia d, dystonia d, dizziness, dyskinesia d, tremor

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

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

Eye disorders

blurred vision, conjunctivitis

photophobia, dry eye, lacrimation increased, ocular hyperaemia

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

Ear and labyrinth disorders

vertigo, tinnitus, ear pain

Cardiac disorders

tachycardia

atrial fibrillation, atrioventricular block, conduction disorder, prolonged QT interval on electrocardiogram (ECG), bradycardia, abnormal ECG, palpitations

sinus arrhythmia

Vascular disorders

hypertension

hypotension, orthostatic hypotension, flushing

pulmonary embolism, venous thrombosis

Respiratory, thoracic and mediastinal disorders

dyspnoea, pharyngolaryngeal pain, cough, epistaxis, nasal congestion

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

sleep apnoea syndrome, hyperventilation

Gastrointestinal disorders

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

faecal incontinence, faecaloma, gastroenteritis, dysphagia, flatulence

pancreatitis, intestinal obstruction, swollen tongue, cheilitis

ileus

Skin and subcutaneous tissue disorders

rash, erythema

urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin discoloration, acne, seborrhoeic dermatitis, skin disorder, skin lesion

drug eruption, dandruff

angioedema

Stevens-Johnson syndrome/ toxic epidermal necrolysis c

Musculoskeletal system and connective tissue disorders

muscle spasms, musculoskeletal pain, back pain, arthralgia

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

rhabdomyolysis

Renal and urinary disorders

urinary incontinence

pollakiuria, urinary retention, dysuria

Pregnancy, puerperium and perinatal period

neonatal drug withdrawal syndromec

Reproductive system and breast disorders

erectile dysfunction, ejaculation disorder, amenorrhoea, menstrual disorderd, gynecomastia, galactorrhoea, sexual dysfunction, breast pain, breast discomfort, vaginal discharge

priapismc, menstruation delayed, breast engorgement, breast enlargement, breast discharge

General disorders and administration site conditions

oedemad, pyrexia, chest pain, asthenia, fatigue, pain

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

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

Hepatobiliary disorders

transaminases increased, gamma-glutamyltransferase increased, hepatic enzyme increased

jaundice

Injury, poisoning and procedural complications

fall

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, involuntary muscle contractions, 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 irregular menstruation, oligomenorrhoea. Oedema includes generalised oedema, peripheral oedema, pitting oedema.

Undesirable effects noted in 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.

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 Torsade de Pointes.

Venous thromboembolic disease

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicines (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 groups (2.4%), 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 of ≥ 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 of ≥ 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. (see section 4.4, subsection “Paediatric population”).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

In general, reported signs and symptoms have been those resulted from an exaggeration of the known pharmacological effects of risperidone. These include drowsiness and sedation, tachycardia and hypotension, and extrapyramidal symptoms. In overdose, QT prolongation and convulsions have been reported. Torsade de Pointes has been reported in association with combined overdose of risperidone and paroxetine.

In case of acute overdose, the possibility of multiple medicinal products involvement should be considered.

Treatment

Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered only when medicinal product intake was less than one hour before. Cardiovascular monitoring should commence immediately and should include continuous electrocardiopraphic monitoring to detect possible arrhythmias.

There is no specific antidote to Risperidone Grindeks. Therefore, appropriate supportive measures should be instituted. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidal symptoms, an anticholinergic medicinal product should be administered. Close medical supervision and monitoring should continue until the patient recovers.