OKEDI 75mg powder+solvent for suspension injection with prolonged release medication leaflet

OKEDI 75 mg powder and solvent for prolonged-release suspension for injection

OKEDI 100 mg powder and solvent for prolonged-release suspension for injection

OKEDI 75 mg powder and solvent for prolonged-release suspension for injection1 pre-filled syringe contains 75 mg of risperidone.

OKEDI 100 mg powder and solvent for prolonged-release suspension for injection1 pre-filled syringe contains 100 mg risperidone.

For the full list of excipients, see section 6.1.

Powder and solvent for prolonged-release suspension for injection.

Pre-filled syringe of powder

White to white-yellowish non-aggregated powder.

Pre-filled syringe of solvent for reconstitution

Clear solution.

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

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 oralantipsychotics (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 withoral risperidone before initiating treatment with OKEDI. The duration of the titration periodshould be sufficiently long (at least 6 days) to confirm the tolerability and responsiveness torisperidone.

Patients never treated before with oral Risperidone

Patients who are candidates to receive OKEDI and have NOT been previously treated withrisperidone, the tolerability and responsiveness to risperidone must be confirmed with a periodof oral risperidone treatment before initiating treatment with OKEDI. The duration of thetitration 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 activemoiety 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 28days

OKEDI must be initiated approximately 24 hours after the last oral risperidone dose. Doseadjustments of OKEDI may be made every 28 days. A maintenance dose of OKEDI 75 mgevery 28 days is generally recommended. However, some patients may benefit from OKEDI100 mg every 28 days, according to the patient’s clinical response and tolerability. Neither aloading 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 initiatedin 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 thenbe 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 asfollows:

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 prolongedrelease characteristics of the OKEDI formulation must be considered. In general, it isrecommended to start oral risperidone treatment 28 days after the last OKEDI administration.

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 byapproximately 50% during that week. The clinical relevance of this is unknown. If the dose isdelayed, the next 28-day interval injection should be scheduled according to the last injectiondate.

Efficacy and safety of OKEDI in elderly > 65 years have not been established for the OKEDIprolonged-release suspension for injection. OKEDI should be used with caution in elderly.

Tolerability to ≥ 3 mg daily oral risperidone should be reliably established prior toadministration of OKEDI.

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

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

OKEDI has not been systematically studied in patients with hepatic impairment.

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

OKEDI should be used with caution in these groups of patients. A careful titration with oralrisperidone (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 isconfirmed.

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

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

OKEDI should be administered by deep intramuscular deltoid or gluteal injection using theappropriate sterile needle. For deltoid administration, the 1-inch needle should be usedalternating injections between the two deltoid muscles. For gluteal administration, the 2-inchneedle 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 ofaccompanying solvent immediately prior to administration by injection.

The reconstitution process should be done accordingly to the Instructions for Use, see section6.6. An incorrect reconstitution could affect the correct dissolution of the powder and in case ofadministration a higher peak of risperidone could appear in the initial hours (overdose) and alower AUC of the entire dose treatment (underdose).

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

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

Increased mortality in elderly people with dementia

OKEDI has not been studied in elderly patients with dementia, hence it should not be used inthis group of patients. In a meta-analysis of 17 controlled trials of atypical antipsychotics,including risperidone, elderly patients with dementia treated with atypical antipsychotics havean increased mortality compared to placebo. In placebo-controlled trials with oral risperidone inthis population, the incidence of mortality was 4% for risperidone-treated patients compared to3.1% 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 twolarge observational studies showed that elderly people with dementia who are treated withconventional antipsychotics are also at a small increased risk of death compared with those whoare not treated. There are insufficient data to give a firm estimate of the precise magnitude of therisk and the cause of the increased risk is not known. The extent to which the findings ofincreased mortality in observational studies may be attributed to the antipsychotic activesubstance 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 incidenceof mortality was observed in patients treated with furosemide plus risperidone (7.3%; mean age89 years, range 75-97) when compared to patients treated with risperidone alone (3.1%; meanage 84 years, range 70-96) or furosemide alone (4.1%; mean age 80 years, range 67-90). Theincrease in mortality in patients treated with furosemide plus risperidone was observed in two ofthe four clinical trials. Concomitant use of risperidone with other diuretics (mainly thiazidediuretics used in low dose) was not associated with similar findings.

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

An approximately 3-fold increased risk of cerebrovascular adverse reactions (CVAEs) havebeen seen in randomised placebo-controlled clinical trials in the dementia population with someatypical antipsychotics. The pooled data from six placebo-controlled studies with risperidone inmainly 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) was2.96 (1.34; 7.50). The mechanism for this increased risk is not known. An increased risk cannotbe excluded for other antipsychotics or other patient populations.

OKEDI should be used with caution in patients with risk factors for stroke.

Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur. Somecases of hypotension or orthostatic hypotension have been reported during the clinicaldevelopment program of OKEDI at doses that ranged from 50 mg to 100 mg. Clinicallysignificant hypotension has been observed post-marketing with concomitant use of risperidoneand antihypertensive treatment. OKEDI should be used with caution in patients with knowncardiovascular disease (e.g., heart failure, myocardial infarction, conduction abnormalities,dehydration, hypovolaemia, or cerebrovascular disease). The risk/benefit of further treatmentwith 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-marketingsurveillance.

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 anddiscontinuation of OKEDI should be considered at the first sign of a clinically significantdecline in WBC in the absence of other causative factors.

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

Tardive dyskinesia/extrapyramidal symptoms (TD/EPS)

Medicines with dopamine receptor antagonistic properties have been associated with theinduction of tardive dyskinesia (TD) characterised by rhythmical involuntary movements,predominantly of the tongue and/or face. The onset of extrapyramidal symptoms (EPS) is a riskfactor for TD. If signs and symptoms of TD appear, the discontinuation of all antipsychoticsshould be considered.

Caution is warranted in patients receiving both psychostimulants (e.g. methylphenidate) andrisperidone 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), characterised by hyperthermia, muscle rigidity,autonomic instability, altered consciousness and elevated serum creatine phosphokinase levelshas 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 worsenwith risperidone. Both groups may be at increased risk of Neuroleptic Malignant Syndrome aswell as having an increased sensitivity to antipsychotic medicinal products; these patients wereexcluded from clinical trials. Manifestation of this increased sensitivity can include confusion,obtundation, postural instability with frequent falls, in addition to extrapyramidal symptoms.

Hyperglycaemia, diabetes mellitus, and exacerbation of pre-existing diabetes have been reportedduring treatment with risperidone. In some cases, a prior increase in body weight has beenreported which may be a predisposing factor. Association with ketoacidosis has been reportedvery rarely and rarely with diabetic coma. Appropriate clinical monitoring is advisable inaccordance with utilised antipsychotic guidelines. Patients treated with OKEDI should bemonitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia andweakness) and patients with diabetes mellitus should be monitored regularly for worsening ofglucose control.

Significant weight gain has been reported with risperidone use. Weight should be monitoredregularly.

Hyperprolactinaemia is a common side effect of treatment with risperidone. Evaluation of theprolactin plasma level is recommended in patients with evidence of possible prolactin-relatedside effects (e.g., gynaecomastia, menstrual disorders, anovulation, fertility disorder, decreasedlibido, erectile dysfunction, and galactorrhoea).

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

QT prolongation has very rarely been reported. Caution should be exercised when risperidone isprescribed in patients with known cardiovascular disease, family history of QT prolongation,bradycardia, or electrolyte disturbances (hypokalaemia, hypomagnesaemia), as it may increasethe risk of arrhythmogenic effects, and in concomitant use with medicines known to prolong the

OKEDI should be used cautiously in patients with a history of seizures or other conditions thatpotentially lower the seizure threshold.

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

Disruption of the body's ability to reduce core body temperature has been attributed toantipsychotic medicines. Appropriate care is advised when prescribing OKEDI to patients whowill be experiencing conditions which may contribute to an elevation in core body temperature,e.g., exercising strenuously, exposure to extreme heat, receiving concomitant treatment withanticholinergic activity, or being subject to dehydration.

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

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinalproducts. 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 inpatients treated with risperidone (see section 4.8).

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

Although tolerability of oral risperidone should be established prior to initiating treatment inpatients who have not been previously treated with risperidone, rarely anaphylactic reactionshave been reported during post-marketing experience with parenteral risperidone in patientswho have previously tolerated oral risperidone. If hypersensitivity reactions occur, the use of

OKEDI should be discontinued and general supportive measures should be initiated as clinicallyappropriate 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 subcutaneoustissue. If administered intravenously, it is expected that a solid formation will be formedimmediately 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 issubcutaneous, the injection might be more painful, and a slower release of risperidone isexpected.

If a dose is incorrectly administered by intravenous or subcutaneous route, the dose should notbe repeated since it is difficult to estimate the resulting exposure to the medicine. The patientshould be closely monitored and managed as clinically appropriate until the next scheduled 28-day interval injection of OKEDI.

The interactions of OKEDI with co-administration of other medicinal products have not beensystematically evaluated. The interaction data provided in this section are based on studies withoral 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 QTinterval, 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., quinineand 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 riskof sedation.

Levodopa and dopamine agonists

OKEDI may antagonise the effect of levodopa and other dopamine agonists. If this combinationis deemed necessary, particularly in end-stage Parkinson's disease, the lowest effective dose ofeach treatment should be prescribed.

Medicinal products with hypotensive effect

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

Psychostimulants

The combined use of psychostimulants (e.g. methylphenidate) with OKEDI can lead toextrapyramidal 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 activemetabolite of risperidone and the combination of the two may lead to additive active moietyexposure.

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 inhibitingor inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of therisperidone active moiety.

Strong CYP2D6 inhibitors

Co-administration of OKEDI with a strong CYP2D6 inhibitor may increase the plasmaconcentrations 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 theplasma concentrations of risperidone in a similar way. When concomitant paroxetine, quinidine,or another strong CYP2D6 inhibitor, especially at higher doses, is initiated or discontinued, thephysician 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 substantiallyelevate plasma concentrations of the risperidone active moiety. When concomitant itraconazoleor another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the physicianshould 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 theplasma concentrations of the risperidone active moiety. When concomitant carbamazepine oranother strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the physician shouldre-evaluate the dosing of OKEDI. CYP3A4 inducers exert their effect in a time-dependentmanner and may take at least 2 weeks to reach maximal effect after introduction. Conversely, ondiscontinuation, 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 noclinically relevant displacement of either medicine from the plasma proteins.

When using concomitant medicinal products, the corresponding label should be consulted forinformation 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 interactwith 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 thepharmacokinetics of risperidone and the active moiety.

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

Anticholinesterases:

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

- Carbamazepine, a strong CYP3A4 inducer and a P-gp inducer, has been shown todecrease the plasma concentrations of the active moiety. Similar effects may be observedwith e.g., phenytoin and phenobarbital which also induce CYP3A4 hepatic enzyme, aswell as P-glycoprotein.

- Topiramate modestly reduced the bioavailability of risperidone, but not that of the activemoiety. 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/dayincreased the plasma concentrations of the active moiety by about 70%, at risperidonedoses of 2 to 8 mg/day.

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

Antipsychotics:

- Phenothiazines may increase the plasma concentrations of risperidone but not those of theactive moiety.

Antivirals:

- Protease inhibitors: No formal study data are available; however, since ritonavir is astrong CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and ritonavir-boostedprotease inhibitors potentially raise concentrations of the risperidone active moiety.

Beta-blockers:

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

Calcium channel blockers:

- Verapamil, a moderate inhibitor of CYP3A4 and an inhibitor of P-gp, increases theplasma 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 theactive 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 ofrisperidone, 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 notthose of the active moiety. Amitriptyline does not affect the pharmacokinetics ofrisperidone 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 inconcentrations of the risperidone active moiety. However, doses higher than 100 mg/dayof sertraline or fluvoxamine may elevate concentrations of the risperidone active moiety.

Effect of risperidone on the pharmacokinetics of other medicinal products

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

Antipsychotics:

- Aripiprazole, a CYP2D6 and CYP3A4 substrate: Risperidone tablets or injections did notaffect 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 ofdigoxin.

- 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 concomitantlyreceiving furosemide.

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 ofpregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawalsymptoms that may vary in severity and duration following delivery. There have been reports ofagitation, 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.

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 oftherapy for the woman.

Risperidone elevates prolactin level. Hyperprolactinaemia may suppress hypothalamic GnRH,resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductivefunction by impairing gonadal steroidogenesis in both female and male patients.

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

OKEDI can have minor or moderate influence on the ability to drive and use machines due topotential nervous system and visual effects (see section 4.8). Therefore, patients should beadvised not to drive or operate machinery until their individual susceptibility is known.

The most frequently reported adverse drug reactions (ADRs) that were reported in a phase 3clinical 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%).

The following are all the ADRs that were reported in clinical trials and post-marketingexperience with risperidone by frequency category estimated from risperidone clinical trials.

The following terms and frequencies are applied: very common (≥ 1/10), common (≥ 1/100 to< 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare(< 1/10,000).

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

Adverse Drug Reaction

System Frequency

Organ Class Very Very Not

Common Uncommon Rare

Common Rare known

Infections pneumonia, respiratory tract infectionand bronchitis, upper infection, cystitis,infestations respiratory tract eye infection,infection, tonsillitis,

Adverse Drug Reaction

System Frequency

Organ Class Very Very Not

Common Uncommon Rare

Common Rare knownsinusitis, urinary onychomycosis,tract infection, ear cellulitis localisedinfection, infection, viralinfluenza infection,acarodermatitis

Blood and neutropenia, white agranulocytosislymphatic blood cell count csystem decreased,disorders thrombocytopenia, anaemia,haematocritdecreased,eosinophil countincreased

Immune hypersensitivity anaphylacticsystem reactioncdisorders

Endocrine hyperprolactinae inappropriatedisorders miaa antidiuretichormonesecretion,glycosuria

Metabolism weight increased, diabetes mellitusb, water diabeticand increased appetite, hyperglycaemia, intoxicationc, ketoacidonutrition decreased appetite polydipsia, weight hypoglycaemia, sisdisorders decreased, hyperinsulinaeanorexia, blood miaccholesterolincreased, bloodtriglyceridesincreased

Psychiatric insomniad sleep disorder, mania, catatonia,disorders agitation, confusional state, somnambulism,depression, libido decreased, sleep-relatedanxiety nervousness, eating disorder,nightmare blunted affect,anorgasmia

Nervous sedation/ tardive dyskinesia, neurolepticsystem parkinsonismd, somnolence, cerebral malignantdisorders headache akathisiad, ischaemia, loss of syndrome,dystoniad, consciousness, cerebrovasculardizziness, convulsiond, disorder,dyskinesiad, syncope, diabetic coma,tremor psychomotor head titubation,hyperactivity, unresponsive tobalance disorder, stimuli,coordination depressed levelabnormal, ofdizziness postural, consciousnessdisturbance in

Adverse Drug Reaction

System Frequency

Organ Class Very Very Not

Common Uncommon Rare

Common Rare knownattention,dysarthria,dysgeusia,hypoaesthesia,paraesthesia

Eye vision blurred, photophobia, dry glaucoma, eyedisorders conjunctivitis eye, lacrimation movementincreased, ocular disorder, eyehyperaemia rolling, eyelidmargincrusting, floppyiris syndrome(intraoperative)c

Ear and vertigo, tinnitus,labyrinth ear paindisorders

Cardiac tachycardia atrial fibrillation, sinusdisorders atrioventricular arrhythmiablock, conductiondisorder,electrocardiogram

QT prolonged,bradycardia,electrocardiogramabnormal,palpitations

Vascular hypertension hypotension, pulmonarydisorders orthostatic embolism,hypotension, venousflushing thrombosis

Respiratory, dyspnoea, respiratory tract sleep apnoeathoracic and pharyngolaryngea congestion, syndrome,mediastinal l pain, cough, wheezing, hyperventilatiodisorders nasal congestion epistaxis n, rales,pneumoniaaspiration,pulmonarycongestion,dysphonia,respiratorydisorder

Gastrointesti abdominal pain, faecal pancreatitis, ileusnal disorders abdominal incontinence, intestinaldiscomfort, faecaloma, obstruction,vomiting, nausea, gastroenteritis, swollen tongue,constipation, dysphagia, cheilitisdiarrhoea, flatulencedyspepsia, drymouth, toothache

Adverse Drug Reaction

System Frequency

Organ Class Very Very Not

Common Uncommon Rare

Common Rare known

Hepatobiliar transaminases jaundicey disorders increased,gamma-glutamyltransferase increased,hepatic enzymeincreased

Skin and rash, erythema urticaria, pruritus, drug eruption, angioede Stevens-subcutaneou alopecia, dandruff ma Johnsons tissue hyperkeratosis, syndromedisorders eczema, dry skin, /toxicskin epidermaldiscolouration, necrolysisacne, seborrhoeicc cdermatitis, skindisorder, skinlesion

Musculoskel muscle spasms, blood creatine rhabdomyolysisetal and musculoskeletal phosphokinaseconnective pain, back pain, increased, posturetissue arthralgia abnormal, jointdisorders stiffness, jointswelling muscularweakness, neckpain

Renal and urinary pollakiuria,urinary incontinence urinary retention,disorders dysuria

Pregnancy, drugpuerperium, withdrawaland syndromeperinatal neonatalcconditions

Reproductiv erectile priapismc,e system and dysfunction, menstruationbreast ejaculation delayed, breastdisorders disorder, engorgement,amenorrhoea, breastmenstrual enlargement,disorderd, breast dischargegynaecomastia,galactorrhoea,sexualdysfunction,breast pain, breastdiscomfort,vaginal discharge

General oedemad, pyrexia, face oedema, hypothermia,disorders chest pain, chills, body bodyand temperature temperature

Adverse Drug Reaction

System Frequency

Organ Class Very Very Not

Common Uncommon Rare

Common Rare knownadministrati asthenia, fatigue, increased, gait decreased,on site pain abnormal, thirst, peripheralconditions chest discomfort, coldness, drugmalaise, feeling withdrawalabnormal, syndrome,discomfort indurationc

Injury, Fall, injection site procedural pain,poisoning pain, injection site injection siteand swelling discomfort,procedural injection sitecomplication erythemasa 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 arate of 0.11% in placebo group. Overall incidence from all clinical trials was 0.43% in all risperidone-treatedsubjects.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, musclecontractions involuntary, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm,laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm, and trismus. It shouldbe noted that a broader spectrum of symptoms is included, that do not necessarily have an extrapyramidal origin.

Insomnia includes initial insomnia, middle insomnia. Convulsion includes grand mal convulsion. Menstrualdisorder includes menstruation irregular, oligomenorrhoea. Oedema includes generalised oedema, oedemaperipheral, pitting oedema.

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

Postural orthostatic tachycardia syndrome

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

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deepvein 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 amean 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

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

Limited information exists on efficacy and safety of OKEDI in older patients withschizophrenia 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, inolder patients with dementia compared to other adults. In addition, the following ADRs werereported with a frequency ≥ 5% in older patients with dementia and with at least twice thefrequency seen in other adult populations: urinary tract infection, peripheral oedema, lethargy,and cough.

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. Healthcareprofessionals are asked to report any suspected adverse reactions the national reporting systemlisted in Appendix V.

In general, reported signs and symptoms have been those resulting from an exaggeration of theknown pharmacological effects of risperidone. These include drowsiness and sedation,tachycardia and hypotension, and extrapyramidal symptoms. In overdose, QT prolongation andconvulsions have been reported. Torsade de Pointes has been reported in association withcombined overdose of risperidone and paroxetine.

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

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

There is no specific antidote to OKEDI. Therefore, appropriate supportive measures should beinstituted. Hypotension and circulatory collapse should be treated with appropriate measuressuch as intravenous fluids and/or sympathomimetic agents. In case of severe extrapyramidalsymptoms, an anticholinergic medicinal product should be administered. Close medicalsupervision and monitoring should continue until the patient recovers.

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX08.

Risperidone is a selective monoaminergic antagonist with unique properties. It has a highaffinity for serotoninergic 5-HT2 and dopaminergic D2 receptors. Risperidone binds also toalpha 1-adrenergic receptors, and, with lower affinity, to H1-histaminergic and alpha 2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidoneis a potent D2 antagonist, which is considered to improve the positive symptoms ofschizophrenia, it causes less depression of motor activity and induction of catalepsy thanclassical antipsychotics. Balanced central serotonin and dopamine antagonism may reduceextrapyramidal side effect liability and extend the therapeutic activity to the negative andaffective symptoms of schizophrenia.

The efficacy of OKEDI (75 mg and 100 mg) in the treatment of schizophrenia in adults wasestablished in one Phase 3, multicentre, randomised, DB, placebo-controlled, parallel groupsstudy. The study admitted patients with an acute exacerbation or relapse of schizophrenia(DSM-5 criteria), who had a baseline Positive and Negative Syndrome Scale (PANSS) score of80-120. At the screening visit, all risperidone naïve patients received 2 mg/day oral risperidonefor 3 days to ensure a lack of hypersensitivity reactions before the trial. Patients with previoushistory of being treated with risperidone did not receive oral risperidone at the screening andstarted directly with OKEDI (75 mg or 100 mg) or placebo after randomization. Four hundredand thirty-eight (438) patients were randomised to receive 3 intramuscular doses of OKEDI (75mg or 100 mg) or placebo every 28 days. The mean age of patients was 42.0 (SD: 11.02) years.

No patients < 18 years or > 65 years were included. Demographic and other baselinecharacteristics were similar in each treatment group. No supplemental oral risperidone waspermitted during the study.

The primary endpoint was the change in PANSS total score from baseline to end of study (Day85). Both OKEDI 75 and 100 mg doses demonstrated a statistically significant improvementcompared with placebo based on the primary endpoint (Table 1 and Figure 1). These resultssupport efficacy across the entire duration of treatment and improvement in PANSS and wasobserved as early as day 4 with significant separation from placebo in the 100 mg and 75 mggroups by day 8 and 15, respectively. Similar to the PANSS Total Score, the three PANSSpositive, negative and general psychopathological subscale scores also showed an improvement(decrease) from baseline over time.

Table 1: Mean change in PANSS and CGI-S total score from baseline to the end of study(day 85) (mITT Population)

Placebo OKEDI 75 mg OKEDI 100 mg

N=132 N=129 N=129

PANSS total score(a)

Mean baseline score (SD) 96.4 (7.21) 96.3 (8.47) 96.1 (8.42)

LS Mean Change, 95% CI (a) -11.0, -24.6, -24.7,

- 14.1 to -8.0 -27.5 to -21.6 -27.7 to -21.6

Treatment Difference, 95% CI (b) -13.0, -13.3,

- 17.3 to -8.8 -17.6 to -8.9

P-value < 0.0001 < 0.0001

CGI-S total score(c)

Mean baseline score (SD) 4.9 (0.52) 5.0 (0.65) 4.9 (0.48)

LS Mean Change, 95% CI (a) -0.6, -1.3, -1.3,

- 0.8 to -0.4 -1.5 to -1.2 -1.5 to -1.2

Treatment Difference, 95% CI (b) -0.7, -1.0 to -0.5 -0.7, -1.0 to -0.5

P-value < 0.0001 < 0.0001a Data were analyzed using a mixed model repeated measures (MMRM) approach.b Difference (OKEDI minus placebo) in least squares mean change from baseline adjusted by Lawrenceand Hung method.c The Clinical Global Impression - Severity (CGI-S) score asks the clinician one question: “Consideringyour total clinical experience with this particular population, how mentally ill is the patient at this time?”which is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline mentally ill;3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients.

0 4 8 15 29 DB Study Day 57 85

Placebo OKEDI 75 mg OKEDI 100 mgvs Placebo

OKEDI 75 mg *** **** **** ****

OKEDI 100 mg ** **** **** **** ****

** p < 0.01, *** p < 0.001, **** p < 0.0001.

Figure 1: PANSS Total Score Change from Baseline at Each Time Point in DB Phase(mITT Population)

LS Mean (SE) PANSS Change Total Score From

Baseline

The key secondary efficacy endpoint was defined as the mean change from baseline at Day 85on the Clinical Global Impression - Severity (CGI-S) score. Both OKEDI treatment groupsdemonstrated statistically significantly better CGI-S scores versus placebo from day 8 onwards(-0.4 (0.05) and -0.6 (0.05) score reduction from baseline for 75 mg and 100 mg, respectively).

Overall Response (PANSS total score reduction > 30% and/or CGI-I of 2 “much improved“ or 1“very much improved“) rate at endpoint for OKEDI was 56% and statistically significant from

Day 8 and 15 onwards for both doses in comparison to placebo.

The long-term (12 months) efficacy of OKEDI was evaluated in an open-label extension of themain study in 215 patients with schizophrenia. The extension study was open to enrolment forpatients from the DB phase (rollover patients) and stable patients not previously enrolled in thestudy (de novo patients). The de novo patients were switched from oral risperidone to OKEDI75 mg or 100 mg. Efficacy was maintained over time with a relapse rate of 10.7% (95% CI,6.9% to 15.6%) and a remittance rate of 61.0% (95% CI, 53.7% to 68.4%).

Risperidone is metabolised to 9-hydroxy-risperidone, which has a similar pharmacologicalactivity to risperidone (see Biotransformation and Elimination).

OKEDI contains risperidone in a suspension delivery system that shows a combined absorptionprocess. Following intramuscular injection, a small amount of the drug is immediately releasedat the moment of the injection that provides immediate plasma levels. After a first peakconcentration, mean plasma concentrations decrease sustainedly through Day 14 and thenincreased again to reach a second peak between approximately Day 21 and Day 24. Followingthe second peak, plasma concentrations decreased gradually over time. The suspension forms adepot that provides sustained therapeutic plasma concentrations that are maintained over the 28-day interval.

After single IM injection of OKEDI 75 and 100 mg, mean active moiety concentrations of 13 ±9 and 29 ± 13 ng/mL respectively are achieved at 2 hours after administration. Active moietyplasma concentrations of 17 ± 8 and 21 ± 17 ng/mL respectively one month after administration,and in most of the patients the drug is completely eliminated 75 days after administration, withactive moiety values lower than 1 ng/ml.

The mean trough plasma concentrations (Ctrough). and mean maximum peak plasmaconcentrations (Cmax) of active moiety following repeated intramuscular injections with OKEDIare shown in Table 2.

Table 2: Ctrough) and Cmax of active moiety following repeated intramuscular injectionswith OKEDI

C

Dose trough (SD) Cmax (SD)ng/mL ng/mL75 mg(a) 17.6 35.9100 mg(b) 28.9 (13.7) 69.7 (27.8)a Summary simulated estimates pharmacokinetic (PK) variables following the 3rd dose of OKEDI 75 mgusing population (pop) PK modelb Summary statistics PK variables following the 4th dose of OKEDI 100 mg from multiple dose clinicaltrial

SD: standard deviation

Steady state concentrations for the typical subject were attained following the first dose.

The average exposure at steady state was similar for both deltoid and gluteal injection sites.

Risperidone is rapidly distributed. The volume of distribution is 1-2 l/kg. In plasma, risperidoneis bound to albumin and alpha 1-acid glycoprotein. The plasma protein binding of risperidone is90% that of 9-hydroxy-risperidone is 77%.

Risperidone is metabolised by CYP2D6 to 9-hydroxy-risperidone, which has a similarpharmacological activity as risperidone. Risperidone plus 9-hydroxy-risperidone form the activemoiety. CYP2D6 is subject to genetic polymorphism. Extensive CYP2D6 metabolisers convertrisperidone rapidly into 9-hydroxy-risperidone, whereas poor CYP2D6 metabolisers convert itmuch more slowly. Although extensive metabolisers have lower risperidone and higher 9-hydroxy-risperidone concentrations than poor metabolisers, the pharmacokinetics of risperidoneand 9-hydroxy-risperidone combined (i.e., the active moiety), after single and multiple doses,are similar in extensive and poor metabolisers of CYP2D6.

Another metabolic pathway of risperidone is N-dealkylation. In vitro studies in human livermicrosomes showed that risperidone at clinically relevant concentration does not substantiallyinhibit the metabolism of medicines metabolised by cytochrome P450 isozymes, including

CYP1A2, CYP2A6, CYP2C8/9/19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. One weekafter administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine,risperidone plus 9-hydroxy-risperidone represent 35-45% of the dose. The remainder is inactivemetabolites. After oral administration to psychotic patients, risperidone is eliminated with ahalf-life of about 3 hours. The elimination half-life of 9-hydroxy-risperidone and of the activemoiety is 24 hours.

The active moiety is eliminated within 75 days after OKEDI administration, with active moietyvalues lower than 1 ng/mL in most of the patients.

OKEDI injection versus oral risperidone

Initial plasma levels with OKEDI were within the exposure range observed with 3-4 mg of oralrisperidone. Steady state exposure after OKEDI 100 mg compared to 4 mg oral risperidone was39% higher for AUC and 32% for Cmax and was similar for Cmin. Simulations based onpopulation pharmacokinetic modelling show that OKEDI 75 mg exposure is similar to 3 mgoral risperidone at steady state.

When switching from oral risperidone to OKEDI, the predicted exposure of the active moiety isin a similar range, including peak concentrations.

OKEDI has been found to exhibit linear and dose-proportional pharmacokinetics at doses of 75and 100 mg.

OKEDI has not been systematically studied in elderly patients (see section 4.2).

OKEDI has not been systematically studied in patients with renal impairment. Patients withmild renal impairment (creatinine clearance 60 to 89 mL/min) that received OKEDIadministration showed similar active moiety exposure than patients with normal renal function.

No data is available in moderate renal disease or severe renal disease.

OKEDI has not been systematically studied in patients with hepatic impairment.

Body mass index (BMI)

Population pharmacokinetic simulations have shown potential increases in plasmaconcentrations of OKEDI in obese or morbid obese females in comparison with normal weightpatients with insignificant clinical impact.

Gender, race and smoking habits

A pop PK analysis revealed no apparent effect of gender, race or smoking habits on thepharmacokinetics of risperidone or the active moiety.

In vitro and in vivo, animal models show that at high doses risperidone may cause QT intervalprolongation, which has been associated with a theoretically increased risk of Torsade de

Pointes in patients.

In (sub)chronic oral toxicity studies, in which dosing was started in sexually immature rats anddogs, dose-dependent effects were present in male and female genital tract and mammary gland.

These effects were related to the increased serum prolactin levels, resulting from the dopamine

D2 receptor blocking activity of risperidone. In addition, tissue culture studies suggest that cellgrowth in human breast tumours may be stimulated by prolactin.

The major effects of treatment with OKEDI observed following chronic (12 months ofintramuscular administration) toxicity studies in dogs and rabbits were in accordance with thefindings following oral distribution of risperidone in rats and dogs, and related to thepharmacological effects of risperidone.

Local alterations, nodules, at the injection site in 12-cycle toxicity studies in dogs and rabbitswere observed after intramuscularly administration of OKEDI. They consisted of muscularforeign body granulomatous inflammation attributed to natural body response to the presence ofa foreign substance. Other local alterations observed in rabbits at 15 mg/kg (risperidone) wererelated to dimethyl sulfoxide (DMSO) content. These all alterations were strictly local and therewas evidence of reversibility. In dogs, transient pain associated to DMSO content was observedimmediately after administration.

There was no evidence of genotoxic potential for either risperidone or for OKEDI.

In oral carcinogenicity studies of risperidone in rats and mice, increases in pituitary glandadenomas (mouse), endocrine pancreas adenomas (rat), and mammary gland adenomas (bothspecies) were seen. These tumours can be related to prolonged dopamine D2 antagonism andhyperprolactinaemia. The relevance of these tumour findings in rodents in terms of human riskis unknown.

Risperidone was not teratogenic in rat and rabbit. In rat reproduction studies with risperidone,adverse effects were seen on mating behaviour of the parents, and on the birth weight andsurvival of the offspring. In rats, intrauterine exposure to risperidone was associated withcognitive deficits in adulthood. Other dopamine antagonists, when administered to pregnantanimals, have caused negative effects on learning and motor development in the offspring.

In a toxicity study in juvenile rats, increased pup mortality and a delay in physical developmentwas observed. In a 40-week study with juvenile dogs, sexual maturation was delayed. Based onarea under the curve (AUC), long bone growth was not affected in dogs at 3.6-times themaximum human exposure in adolescents (1.5 mg/day); while effects on long bones and sexualmaturation were observed at 15 times the maximum human exposure in adolescents.

Pre-filled syringe of powderpoly(D,L-lactide-co-glycolide)

Pre-filled syringe of solvent

Dimethyl sulfoxide

This medicinal product must not be mixed with other medicinal products except thosementioned in section 6.6.

3 years

OKEDI should be used immediately after reconstitution.

Store below 30ºC.

Store in the original package in order to protect from moisture.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Powder pre-filled syringe

Cyclic Olefin Polymer syringe with a nozzle cap and plunger stopper composed of chlorobutylrubber covered with polytetrafluoroethylene.

Solvent pre-filled syringe

Cyclic Olefin Polymer syringe with a tip cap composed of chlorobutyl rubber, and a plungerstopper composed of bromobutyl rubber covered with ethylene-tetrafluoroethylene copolymer.

The doses are differentiated by the colour used in the finger flange of the solvent pre-filledsyringe, 100mg (blue) and 75 mg (red).

The solvent for reconstitution is presented in the following dosage strengths:

- Pre-filled syringe of solvent containing 0.383 mL of dimethyl sulfoxide (solvent for

OKEDI 75 mg).

- Pre-filled syringe of solvent containing 0.490 mL of dimethyl sulfoxide (solvent for

OKEDI 100 mg).

Each kit box of OKEDI contains:

- An aluminium foil pouch with one pre-filled syringe containing powder and a silica geldesiccant sachet.

- An aluminium foil pouch with one pre-filled syringe containing the solvent and a silicagel desiccant sachet.

- One sterile needle for injection 2 inch (0.90 x 51mm [20G]) with safety shield used forgluteus administration.

- One sterile needle for injection 1 inch (0.80 x 25mm [21G]) with safety shield used fordeltoid administration.

IMPORTANT INFORMATION

- For intramuscular use only.

- Patient should be given the injection immediately after reconstitution.

- Two administration sterile needles with safety shield are included for a deltoid or gluteusinjection site. You will choose one prior to administration.

- Read the complete instructions before use. Full instructions for use and handling of

OKEDI are provided in the package leaflet (See Instructions for healthcareprofessionals).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Laboratorios Farmacéuticos Rovi, S.A.

Julián Camarillo, 3528037 Madrid.

Spain

OKEDI 75 mg powder and solvent for prolonged-release suspension for injection

EU/1/21/1621/001

OKEDI 100 mg powder and solvent for prolonged-release suspension for injection

EU/1/21/1621/002

Date of first authorisation: 14 February 2022

Detailed information on this medicinal product is available on the website of the European

Medicines Agency http://www.ema.europa.eu.