4.1. Therapeutic indications

OKEDI is indicated for the treatment of schizophrenia in adults for whom tolerability and effectiveness have been established with oral risperidone

4.2. Posology and method of administration

Posology

OKEDI should be administered every 28 days by intramuscular (IM) injection. OKEDI should be initiated according to the patient's clinical context:

Patients with history of previous response to Risperidone who are currently stabilised with oral antipsychotics (mild to moderate psychotic symptoms)

Patients stabilised with oral risperidone can be switched to OKEDI without previous titration.

Patients stabilised on other oral antipsychotics (different from risperidone) should be titrated with oral risperidone before initiating treatment with OKEDI. The duration of the titration period should be sufficiently long (at least 6 days) to confirm the tolerability and responsiveness to risperidone.

Patients never treated before with oral Risperidone

Patients who are candidates to receive OKEDI and have NOT been previously treated with risperidone, the tolerability and responsiveness to risperidone must be confirmed with a period of oral risperidone treatment before initiating treatment with OKEDI. The duration of the titration period is recommended to be at least 14 days.

Switching from oral risperidone to OKEDI

The recommended doses of oral risperidone and OKEDI needed to maintain a similar active moiety steady-state exposure are as follows:

Previous oral risperidone dose of 3 mg/day to OKEDI injection 75 mg every 28 days

Previous oral risperidone dose of 4 mg/day or higher to OKEDI injection 100 mg every 28 days

OKEDI must be initiated approximately 24 hours after the last oral risperidone dose.

Dose adjustments of OKEDI may be made every 28 days. A maintenance dose of OKEDI 75 mg every 28 days is generally recommended. However, some patients may benefit from OKEDI 100 mg every 28 days, according to the patient's clinical response and tolerability. Neither a loading dose nor any supplemental oral risperidone is recommended when using OKEDI.

Switching from Risperidone bi-weekly long-acting injection to OKEDI

When switching from Risperidone bi-weekly long-acting injection, OKEDI should be initiated in place of the next regularly scheduled injection of risperidone bi-weekly long-acting injection (i.e, two weeks after the last risperidone bi-weekly long-acting injection). OKEDI should then be continued at 28-day intervals. No oral concomitant risperidone is recommended.

When switching patients previously stabilised on risperidone bi-weekly long-acting injection to OKEDI, the recommended dose to maintain a similar active moiety steady-state exposure is as follows:

Risperidone bi-weekly long-acting 37.5 mg to OKEDI injection 75 mg every 28 days

Risperidone bi-weekly long-acting 50 mg to OKEDI injection 100 mg every 28 days

Switching from OKEDI to oral risperidone

When switching patients from OKEDI injection back to oral risperidone therapy, the prolonged release characteristics of the OKEDI formulation must be considered. In general, it is recommended to start oral risperidone treatment 28 days after the last OKEDI administration.

Missed doses

Avoiding missed doses

To avoid a missed 28-day dose, patients may be given the injection up to 3 days before the 28-day time point. If a dose is delayed by 1 week, the median trough concentration decreases by approximately 50% during that week. The clinical relevance of this is unknown. If the dose is delayed, the next 28-day interval injection should be scheduled according to the last injection date.

Special populations

Elderly

Efficacy and safety of OKEDI in elderly > 65 years have not been established for the OKEDI prolonged-release suspension for injection. OKEDI should be used with caution in elderly. Tolerability to ≥ 3 mg daily oral risperidone should be reliably established prior to administration of OKEDI.

In general, recommended dosing of risperidone for elderly patients with normal renal function is the same as for adult patients with normal renal function. However, if it is considered clinically appropriate, starting with 75 mg OKEDI should be considered (see Renal impairment below for dosing recommendations in patients with renal impairment).

Renal impairment

OKEDI has not been systematically studied in patients with renal impairment. For patients with mild renal impairment (creatinine clearance 60 to 89 mL/min) no dose adjustment is required for OKEDI.

OKEDI is not recommended in patients with moderate to severe renal impairment (creatinine clearance < 60 mL/min).

Hepatic impairment

OKEDI has not been systematically studied in patients with hepatic impairment. Patients with impaired hepatic function have increases in plasma concentration of the free fraction of risperidone.

OKEDI should be used with caution in these groups of patients. A careful titration with oral risperidone (halving starting doses and slowing titration) before initiating treatment with OKEDI at a dose of 75 mg is recommended, if tolerability of an oral dose of at least 3 mg is confirmed.

Paediatric population

The safety and efficacy of OKEDI in children and adolescents less than 18 years have not been established. No data are available.

Method of administration

OKEDI is only intended for intramuscular use and should not be administered intravenously or subcutaneously (see sections 4.4 and 6.6) or by any other route. It should be administered by a healthcare professional.

OKEDI should be administered by deep intramuscular deltoid or gluteal injection using the appropriate sterile needle. For deltoid administration, the 1-inch needle should be used alternating injections between the two deltoid muscles. For gluteal administration, the 2-inch needle should be used alternating injections between the two gluteal muscles.

The pre-filled syringe of OKEDI powder should be reconstituted with the pre-filled syringe of accompanying solvent immediately prior to administration by injection.

The reconstitution process should be done accordingly to the Instructions for Use, see section 6.6. An incorrect reconstitution could affect the correct dissolution of the powder and in case of administration a higher peak of risperidone could appear in the initial hours (overdose) and a lower AUC of the entire dose treatment (underdose).

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-naive patients, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with OKEDI (see section 4.2). Consideration should be given to the prolonged release nature of the medicinal product and the long elimination half-life of risperidone when assessing treatment needs and the potential need to be able to discontinue treatment.

Elderly patients with dementia

Increased mortality in elderly people with dementia

OKEDI has not been studied in elderly patients with dementia, hence it should not be used in this group of patients. 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% 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 antipsychotic active substance as opposed to some characteristic(s) of the patients is not clear.

Concomitant use with furosemide

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 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 reactions

An approximately 3-fold increased risk of cerebrovascular adverse reactions (CVAEs) 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 risperidone in mainly elderly patients (> 65 years of age) with dementia showed that CVAEs (serious and non-serious, combined) occurred in 3.3% (33/1009) 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.

OKEDI 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. Some cases of hypotension or orthostatic hypotension have been reported during the clinical development program of OKEDI at doses that ranged from 50 mg to 100 mg. Clinically significant hypotension has been observed post-marketing with concomitant use of risperidone and antihypertensive treatment. OKEDI 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 OKEDI should be assessed if clinically relevant orthostatic hypotension persists.

Leukopenia, neutropenia, and agranulocytosis

Events of leukopenia, neutropenia and agranulocytosis have been reported with 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 OKEDI 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 OKEDI 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 (TD) characterised by rhythmical involuntary movements, predominantly of the tongue and/or face. The onset of extrapyramidal symptoms (EPS) is a risk factor for TD. If signs and symptoms of TD appear, the discontinuation of all antipsychotics should be considered.

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

Neuroleptic malignant syndrome (NMS)

Neuroleptic Malignant Syndrome (NMS) 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, OKEDI should be discontinued.

Parkinson's disease and dementia with Lewy bodies

Physicians should weigh the risks versus the benefits when prescribing OKEDI 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.

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 and rarely with diabetic coma. Appropriate clinical monitoring is advisable in accordance with utilised antipsychotic guidelines. Patients treated with OKEDI 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 risperidone use. Weight should be monitored regularly.

Hyperprolactinaemia

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 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. OKEDI 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. 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

OKEDI 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 OKEDI 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 OKEDI 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.

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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 OKEDI and preventative measures undertaken.

Intraoperative floppy iris syndrome

Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in patients treated with risperidone (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 the antipsychotic therapy.

Hypersensitivity

Although tolerability of oral risperidone should be established prior to initiating treatment in patients who have not been previously treated with risperidone, rarely anaphylactic reactions have been reported during post-marketing experience with parenteral risperidone in patients who have previously tolerated oral risperidone. If hypersensitivity reactions occur, the use of OKEDI should be discontinued and general supportive measures should be initiated as clinically appropriate and the patient should be monitored until signs and symptoms resolve.

Reconstitution and administration

A lack of efficacy can occur in case of incorrect reconstitution (see sections 4.2 and 6.6).

Care must be taken to avoid inadvertent injection of OKEDI into a blood vessel or subcutaneous tissue. If administered intravenously, it is expected that a solid formation will be formed immediately due to the characteristics of OKEDI, producing a blockage of the needle. Consequently, a bleeding could occur at the injection site. In case the administration is subcutaneous, the injection might be more painful, and a slower release of risperidone is expected.

If a dose is incorrectly administered by intravenous or subcutaneous route, the dose should not be repeated since it is difficult to estimate the resulting exposure to the medicine. The patient should be closely monitored and managed as clinically appropriate until the next scheduled 28-day interval injection of OKEDI.

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

The interactions of OKEDI with co-administration of other medicinal products have not been systematically evaluated. The interaction data provided in this section are based on studies with oral risperidone.

Pharmacodynamic-related interactions

Medicinal products known to prolong the QT interval

Caution is advised when prescribing OKEDI 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 medicinal products and alcohol

OKEDI 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

OKEDI 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.

Medicinal products 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 OKEDI can lead to extrapyramidal symptoms upon change of either or both treatments (see section 4.4).

Paliperidone

Concomitant use of OKEDI with paliperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive active moiety exposure.

Pharmacokinetic-related interactions

OKEDI is mainly metabolised through Cytochrome P (CYP) 2D6, 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 moiety.

Strong CYP2D6 inhibitors

Co-administration of OKEDI with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active moiety. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active moiety (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 OKEDI.

CYP3A4 and/or P-gp inhibitors

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

CYP3A4 and/or P-gp inducers

Co-administration of OKEDI with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active moiety. When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the physician should re-evaluate the dosing of OKEDI. 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 medicinal products

When risperidone 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 medicinal products, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dosage.

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 moiety.

• Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the plasma concentrations of the active moiety.

Anticholinesterases:

• Donepezil and galantamine, both CYP2D6 and CYP3A4 substrates, do not show a clinically relevant effect on the pharmacokinetics of risperidone and the active moiety.

Antiepileptics:

• Carbamazepine, a strong CYP3A4 inducer and a P-gp inducer, has been shown to decrease the plasma concentrations of the active moiety. 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 moiety. 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 moiety 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 moiety.

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 moiety.

Beta-blockers:

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

Calcium channel blockers:

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

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 moiety.

SSRIs and tricyclic antidepressants:

• Fluoxetine, a strong CYP2D6 inhibitor, increases the plasma concentration of risperidone, but less so of the active moiety.

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

• Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of the active moiety. 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 moiety. However, doses higher than 100 mg/day of sertraline or fluvoxamine may elevate concentrations of the risperidone active moiety.

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 or limited amount of data from the use of risperidone in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

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.

OKEDI should not be used during pregnancy unless clearly necessary.

Breast-feeding

Physico-chemical data suggest excretion of risperidone/metabolites in breast milk. A risk to the breastfed child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from OKEDI therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Risperidone 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

OKEDI can 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

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) that were reported in a phase 3 clinical trial are: blood prolactin increased (11.7%), hyperprolactinaemia (7.2%), akathisia (5.5%), headache (4.8%), somnolence (4.1%), weight increased (3.8%), injection site pain (3.1%) and dizziness (3.1%).

Tabulated list of adverse reactions

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), very rare (< 1/10,000) and not known (cannot be estimated from the available clinical trial 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

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

agranulocytosisc

Immune system disorders

hypersensitivity

anaphylactic reactionc

Endocrine disorders

hyperprolactinaemiaa

inappropriate antidiuretic hormone secretion, glycosuria

Metabolism and nutrition disorders

weight increased, increased appetite, decreased appetite

diabetes mellitusb, hyperglycaemia, polydipsia, weight decreased, anorexia, blood cholesterol increased, blood triglycerides increased

water intoxicationc, hypoglycaemia, hyperinsulinaemiac

diabetic ketoacidosis

Psychiatric disorders

insomniad

sleep disorder, agitation, depression, anxiety

mania, confusional state, libido decreased, nervousness, nightmare

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

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, diabetic coma, head titubation, unresponsive to stimuli, depressed level of consciousness

Eye disorders

vision blurred, 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, electrocardiogram QT prolonged, bradycardia, electrocardiogram abnormal, palpitations

sinus arrhythmia

Vascular disorders

hypertension

hypotension, orthostatic hypotension, flushing

pulmonary embolism, venous thrombosis

Respiratory, thoracic and mediastinal disorders

dyspnoea, pharyngolaryngeal pain, cough, nasal congestion

respiratory tract congestion, wheezing, epistaxis

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

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

Hepatobiliary disorders

transaminases increased, gamma-glutamyltransferase increased, hepatic enzyme increased

jaundice

Skin and subcutaneous tissue disorders

rash, erythema

urticaria, pruritus, alopecia,

hyperkeratosis, eczema, dry skin, skin discolouration, acne, seborrhoeicc dermatitis, skin disorder, skin lesion

drug eruption, dandruff

angioedema

Stevens-Johnson syndrome/toxic epidermal necrolysisc

Musculoskeletal and connective tissue disorders

muscle spasms, musculoskeletal pain, back pain, arthralgia

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

rhabdomyolysis

Renal and urinary disorders

urinary incontinence

pollakiuria, urinary retention, dysuria

Pregnancy, puerperium, and perinatal conditions

drug withdrawal syndrome neonatalc

Reproductive system and breast disorders

erectile dysfunction, ejaculation disorder, amenorrhoea, menstrual

disorderd, gynaecomastia, 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, gait abnormal, thirst, chest discomfort, malaise, feeling abnormal, discomfort

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

Injury, poisoning and procedural complications

Fall, injection site pain, injection site swelling

procedural pain, injection site discomfort, injection site erythema

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.

Description of selected adverse reactions

Injection site reactions

The most commonly reported injection site related adverse reaction was pain. In the phase 3 study 14 out of 386 patients (3.6%) reported 18 events of injection pain reactions after 2827 injections (0.6%) of OKEDI. The majority of these reactions were reported to be of mild to moderate severity. Subject evaluations of injection site pain based on a visual analogue scale tended to lessen in frequency and intensity over time.

Cardiac disorders

Postural orthostatic tachycardia syndrome

Class effects

Very rare cases of QT prolongation ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden death, cardiac arrest and Torsades de Pointes have been reported post marketing with risperidone.

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).

Changes in body weight

Data from a 12-week double-blind (DB), placebo-controlled trial indicated that there was a mean increase in weight from baseline of 1.4 (-8 to 18) kg, 0.8 (-8 to 47) kg, and 0.2 (-12 to 18) kg after treatment with the OKEDI 75 mg, OKEDI 100 mg and placebo, respectively.

Additional information on special populations

Paediatric patients

No information exists on efficacy and safety of OKEDI in children.

Elderly patients

Limited information exists on efficacy and safety of OKEDI in older patients with schizophrenia or dementia. In clinical trials with oral risperidone transient ischaemic attack and Cerebrovascular accident were reported with a frequency of 1.4% and 1.5%, respectively, in older patients with dementia compared to other adults. In addition, the following ADRs were reported with a frequency ≥ 5% in older patients with dementia and with at least twice the frequency seen in other adult populations: urinary tract infection, peripheral oedema, lethargy, and cough.

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:

Website: 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 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 risperidone and paroxetine.

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

Treatment

A clear airway should be established and maintained, and adequate oxygenation and ventilation should be ensured. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to OKEDI. 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.