4.1. Therapeutic indications

RISPERDAL CONSTA is indicated for the maintenance treatment of schizophrenia in patients currently stabilised with oral antipsychotics.

4.2. Posology and method of administration

Posology

Adults

Starting dose

For most patients the recommended dose is 25 mg intramuscular every two weeks. For those patients on a fixed dose of oral risperidone for two weeks or more, the following conversion scheme should be considered. Patients treated with a dosage of 4 mg or less oral risperidone should receive 25 mg RISPERDAL CONSTA, while patients treated with higher oral doses should be considered for the higher RISPERDAL CONSTA dose of 37.5 mg.

Where patients are not currently taking oral risperidone, the oral pre-treatment dosage should be considered when choosing the I.M. starting dose. The recommended starting dose is 25 mg RISPERDAL CONSTA every two weeks. Patients on higher dosages of the used oral antipsychotic should be considered for the higher RISPERDAL CONSTA dose of 37.5 mg.

Sufficient antipsychotic coverage with oral risperidone or the previous antipsychotic should be ensured during the three-week lag period following the first RISPERDAL CONSTA injection (see section 5.2).

RISPERDAL CONSTA should not be used in acute exacerbations of schizophrenia without ensuring sufficient antipsychotic coverage with oral risperidone or the previous antipsychotic during the three-week lag period following the first RISPERDAL CONSTA injection.

Maintenance dose

For most patients the recommended dose is 25 mg intramuscular every two weeks. Some patients may benefit from the higher doses of 37.5 mg or 50 mg. Upward dosage adjustment should not be made more frequently than every 4 weeks. The effect of this dose adjustment should not be anticipated earlier than 3 weeks after the first injection with the higher dose. No additional benefit was observed with 75 mg in clinical trials. Doses higher than 50 mg every 2 weeks are not recommended.

Elderly

No dose adjustment is required. The recommended dose is 25 mg intramuscularly every two weeks. Where patients are not currently taking oral risperidone, the recommended dose is 25 mg RISPERDAL CONSTA every two weeks. For those patients on a fixed dose of oral risperidone for two weeks or more, the following conversion scheme should be considered. Patients treated with a dosage of 4 mg or less oral risperidone should receive 25 mg RISPERDAL CONSTA, while patients treated with higher oral doses should be considered for the higher RISPERDAL CONSTA dose of 37.5 mg.

Sufficient antipsychotic coverage should be ensured during the three-week lag period following the first RISPERDAL CONSTA injection (see section 5.2). RISPERDAL CONSTA clinical data in elderly are limited. RISPERDAL CONSTA should be used with caution in elderly.

Hepatic and renal impairment

RISPERDAL CONSTA has not been studied in hepatically and renally impaired patients.

If hepatically or renally impaired patients require treatment with RISPERDAL CONSTA, a starting dose of 0.5 mg twice daily oral risperidone is recommended during the first week. The second week 1 mg twice daily or 2 mg once daily can be given. If an oral total daily dose of at least 2 mg is well tolerated, an injection of 25 mg RISPERDAL CONSTA can be administered every 2 weeks.

Sufficient antipsychotic coverage should be ensured during the three-week lag period following the first RISPERDAL CONSTA injection (see section 5.2).

Paediatric population

The safety and efficacy of RISPERDAL CONSTA in children below 18 years of age have not been established. No data are available.

Method of administration

RISPERDAL CONSTA should be administered every two weeks by deep intramuscular deltoid or gluteal injection using the appropriate safety needle. For deltoid administration, use the 1-inch needle alternating injections between the two arms. For gluteal administration, use the 2-inch needle alternating injections between the two buttocks. Do not administer intravenously (see sections 4.4 and 6.6).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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

For risperidone-naïve patients, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with RISPERDAL CONSTA (see section 4.2).

Elderly with dementia

RISPERDAL CONSTA has not been studied in elderly patients with dementia, hence it is not indicated for use in this group of patients. RISPERDAL CONSTA is not licensed for the treatment of dementia-related behavioural disturbances.

Increased mortality in elderly with dementia

In a meta-analysis of 17 controlled trials of atypical antipsychotics, including oral RISPERDAL, elderly patients with dementia treated with atypical antipsychotics have an increased mortality compared to placebo. In placebo-controlled trials with oral RISPERDAL in this population, the incidence of mortality was 4.0% for RISPERDAL-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 antipsychotic drug as opposed to some characteristic(s) of the patients is not clear.

Concomitant use with furosemide

In the oral RISPERDAL 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 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 have been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics. The pooled data from six placebo-controlled studies with RISPERDAL 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. RISPERDAL CONSTA should be used with caution in patients with risk factors for stroke.

Orthostatic hypotension

Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur, especially during initiation of treatment. Clinically significant hypotension has been observed post-marketing 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, hypovolaemia, or cerebrovascular disease). The risk/benefit of further treatment with RISPERDAL CONSTA should be assessed if clinically relevant orthostatic hypotension persists.

Leucopenia, neutropenia, and agranulocytosis

Events of leucopenia, neutropenia and agranulocytosis have been reported with antipsychotic agents, including RISPERDAL CONSTA. 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 therapy and discontinuation of RISPERDAL CONSTA 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 × 109/L) should discontinue RISPERDAL CONSTA 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 medications. 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 RISPERDAL CONSTA, should be discontinued.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing antipsychotics, including RISPERDAL CONSTA, 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.

Hypersensitivity reactions

Although tolerability with oral risperidone should be established prior to initiating treatment with RISPERDAL CONSTA, rarely anaphylactic reactions have been reported during post-marketing experience in patients who have previously tolerated oral risperidone (see sections 4.2 and 4.8).

If hypersensitivity reactions occur, discontinue use of RISPERDAL CONSTA; initiate general supportive measures as clinically appropriate and monitor the patient until signs and symptoms resolve (see sections 4.3 and 4.8).

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reported during treatment with RISPERDAL CONSTA. 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 RISPERDAL CONSTA, 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 RISPERDAL CONSTA use. Weight should be monitored regularly.

Hyperprolactinaemia

Hyperprolactinaemia is a common side effect of treatment with RISPERDAL CONSTA. 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, 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. RISPERDAL CONSTA should be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible 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

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

Priapism

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

Body temperature regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic medicines. Appropriate care is advised when prescribing RISPERDAL CONSTA 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.

Venous thromboembolism

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 RISPERDAL CONSTA and preventative measures undertaken.

Intraoperative floppy iris syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including RISPERDAL CONSTA (see section 4.8).

IFIS may increase the risk of eye complications during and after the operation. Current or past use of medicines with alpha1a-adrenergic antagonist effect should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1-blocking therapy prior to cataract surgery has not been established and must be weighed against the risk of stopping the antipsychotic therapy.

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 or hepatic impairment

Although oral risperidone has been studied, RISPERDAL CONSTA has not been studied in patients with renal or liver insufficiency. RISPERDAL CONSTA should be administered with caution in this group of patients (see section 4.2).

Administration

Care must be taken to avoid inadvertent injection of RISPERDAL CONSTA into a blood vessel.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially 'sodium-free'.

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

The interactions of RISPERDAL CONSTA with co-administration of other drugs have not been systematically evaluated. The drug interaction data provided in this section are based on studies with oral RISPERDAL.

Pharmacodynamic-related interactions

Drugs 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, dysopiramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (i.e., amitriptyline), tetracyclic antidepressant (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 drugs 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

RISPERDAL CONSTA 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.

Drugs 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).

Pharmacokinetic-related interactions

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 RISPERDAL CONSTA 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-evaluate the dosing of RISPERDAL CONSTA.

CYP3A4 and/or P-gp inhibitors

Co-administration of RISPERDAL CONSTA 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 RISPERDAL CONSTA.

CYP3A4 and/or P-gp inducers

Co-administration of RISPERDAL CONSTA 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 RISPERDAL CONSTA. 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.

Highly protein-bound drugs

When RISPERDAL CONSTA is taken together with highly protein-bound drugs, there is no clinically relevant displacement of either drug from the plasma proteins.

When using concomitant medication, the corresponding label should be consulted for information on the 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 from these studies in paediatric patients is unknown.

Examples

Examples of drugs 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 concentrations of the active antipsychotic fraction.

Anticholinesterases:

● Donepezil and galantamine, both CYP2D6 and CYP3A4 substrates, do not show a 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 concentrations 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 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 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 concentrations of the risperidone active antipsychotic fraction.

Beta-blockers:

● Some beta-blockers may increase the plasma concentrations 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 drugs:

● 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.

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 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.

● Tricyclic antidepressants may increase the plasma concentrations 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 risperidone active antipsychotic fraction.

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 injections 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 RISPERDAL CONSTA) 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.

RISPERDAL CONSTA should not be used during pregnancy unless clearly necessary.

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 effects 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 antagonise dopamine D2 receptors, RISPERDAL CONSTA 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

RISPERDAL CONSTA has 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 ≥ 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 RISPERDAL CONSTA 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), 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 Reaction

Frequency

Very Common

Common

Uncommon

Rare

Very Rare

Not known

Infections and infestations

upper respiratory tract infection

pneumonia, bronchitis, sinusitis, urinary tract infection, influenza

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

Blood and lymphatic system disorders

anaemia

white blood cell count decreased, thrombocytopenia, haematocrit decreased

agranulocytosisc, neutropenia, eosinophil count increased

Immune system disorders

hypersensitivity

anaphylactic reactionc

Endocrine disorders

hyperprolactinaemiaa

glucose urine present

inappropriate antidiuretic hormone secretion

Metabolism and nutrition disorders

hyperglycaemia, weight increased, increased appetite, weight decreased, decreased appetite

diabetes mellitusb, anorexia, blood triglycerides increased, blood cholesterol increased

water intoxicationc, hypoglycaemia, hyperinsulinaemiac, polydipsia

diabetic ketoacidosis

Psychiatric disorders

insomniad, depression, anxiety

sleep disorder, agitation, libido decreased

mania, confusional state, anorgasmia, nervousness, nightmare

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

Nervous system disorders

parkinsonismd, headache

sedation/somnolence, akathisiad, dystoniad, dizziness, dyskinesiad, tremor

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

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

Eye disorders

vision blurred

conjunctivitis, dry eye, lacrimation increased, ocular hyperaemia

retinal artery occlusion, glaucoma, eye movement disorder, eye rolling, photophobia, 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, electrocardiogram QT prolonged, bradycardia, electrocardiogram abnormal, palpitations

sinus arrhythmia

Vascular disorders

hypotension, hypertension

orthostatic hypotension

pulmonary embolism, venous thrombosis, flushing

Respiratory, thoracic and mediastinal disorders

dyspnoea, pharyngolaryngeal pain, cough, nasal congestion

hyperventilation, respiratory tract congestion, wheezing, epistaxis

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

Gastrointestinal disorders

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

faecal incontinence, dysphagia, flatulence

pancreatitis, intestinal obstruction, swollen tongue, faecaloma, cheilitis

ileus

Skin and subcutaneous tissue disorders

rash

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

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

angioedema

Stevens-Johnson syndrome/toxic epidermal necrolysisc

Musculoskeletal and connective tissue disorders

muscle spasms, musculoskeletal pain, back pain, arthralgia

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

rhabdomyolysis, posture abnormal

Renal and urinary disorders

urinary incontinence

pollakiuria, urinary retention, dysuria

Pregnancy, puerperium, and neonatal conditions

drug withdrawal syndrome neonatalc

Reproductive system and breast disorders

erectile dysfunction, amenorrhoea, galactorrhoea

ejaculation disorder, menstruation delayed, menstrual disorderd, gynaecomastia, sexual dysfunction, breast pain, breast discomfort, vaginal discharge

priapismc, breast engorgement, breast enlargement, breast discharge

General disorders and administration site conditions

oedemad, pyrexia, chest pain, asthenia, fatigue, pain, injection site reaction

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

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

Hepatobiliary disorders

transaminases increased, gamma- glutamyltransferas 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 RISPERDAL CONSTA 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 RISPERDAL CONSTA.

Cardiac disorders

Postural orthostatic tachycardia syndrome

Anaphylactic reaction

Rarely, cases of anaphylactic reaction after injection with RISPERDAL CONSTA have been reported during post-marketing experience in patients who have previously tolerated oral risperidone (see section 4.4).

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

In the 12-week double-blind, placebo-controlled trial, 9% of patients treated with RISPERDAL CONSTA, compared with 6% of patients treated with placebo, experienced a weight gain of ≥ 7% of body weight at endpoint. In the 1-year, open-label study of RISPERDAL CONSTA, changes in body weight in individual patients were generally within ± 7% from baseline; 25% of patients had an increase in body weight of ≥ 7%.

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 the 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

While overdose is less likely to occur with parenteral than with oral medicinal products, information pertaining to oral is presented.

Symptoms

In general, reported signs and symptoms have been those resulting 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 oral RISPERDAL and paroxetine.

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

Treatment

Establish and maintain a clear airway and ensure adequate oxygenation and ventilation. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to RISPERDAL. 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, anticholinergic medicinal product should be administered. Close medical supervision and monitoring should continue until the patient recovers.