OKEDI^®
(risperidone)

Very Common (≥1/10):

Insomnia, parkinsonism, headache.

Common (≥1/100 to <1/10):

Pneumonia, bronchitis, upper respiratory tract infection, sinusitis, urinary tract infection, ear infection, influenza, hyperprolactinaemia, weight increased, increased appetite, decreased appetite, sleep disorder, agitation, depression, anxiety, sedation/ somnolence, akathisia, dystonia, dizziness, dyskinesia, tremor, vision blurred, conjunctivitis, tachycardia, hypertension, dyspnoea, pharyngolaryngeal pain, cough, nasal congestion, abdominal pain, abdominal discomfort, vomiting, nausea, constipation, diarrhoea, dyspepsia, dry mouth, toothache, rash, erythema, muscle spasms, musculoskeletal pain, back pain, arthralgia, urinary incontinence, oedema, pyrexia, chest pain, asthenia, fatigue, pain, fall, injection site pain, injection site swelling.

Uncommon (≥1/1,000 to <1/100):

Respiratory tract infection, cystitis, eye infection, tonsillitis, onychomycosis, cellulitis localised infection, viral infection, acarodermatitis, neutropenia, white blood cell count decreased, thrombocytopenia, anaemia, haematocrit decreased, eosinophil count increased, hypersensitivity, diabetes mellitus, hyperglycaemia, polydipsia, weight decreased, anorexia, blood cholesterol increased, blood triglycerides increased, mania, confusional state, libido decreased, nervousness, nightmare, tardive dyskinesia, cerebral ischaemia, loss of consciousness, convulsion, syncope, psychomotor hyperactivity, balance disorder, coordination abnormal, dizziness postural, disturbance in attention, dysarthria, dysgeusia, hypoaesthesia, paraesthesia, photophobia, dry eye, lacrimation increased, ocular hyperaemia, vertigo, tinnitus, ear pain, atrial fibrillation, atrioventricular block, conduction disorder, electrocardiogram QT prolonged, bradycardia, electrocardiogram abnormal, palpitations, hypotension, orthostatic hypotension, flushing, respiratory tract congestion, wheezing, epistaxis, faecal incontinence, faecaloma, gastroenteritis, dysphagia, flatulence, transaminases increased, gamma-glutamyltransferase increased, hepatic enzyme increased, urticaria, pruritus, alopecia, hyperkeratosis, eczema, dry skin, skin discolouration, acne, seborrhoeic dermatitis, skin disorder, skin lesion, blood creatine phosphokinase increased, posture abnormal, joint stiffness, joint swelling muscular weakness, neck pain, pollakiuria, urinary retention, dysuria, erectile dysfunction, ejaculation disorder, amenorrhoea, menstrual disorder, gynaecomastia, galactorrhoea, sexual dysfunction, breast pain, breast discomfort, vaginal discharge, face oedema, chills, body temperature increased, gait abnormal, thirst, chest discomfort, malaise, feeling abnormal, discomfort, procedural pain, injection site discomfort, injection site erythema.

Rare (≥1/10,000 to <1/1,000):

Infection, agranulocytosis, anaphylactic reaction, inappropriate antidiuretic hormone secretion, glycosuria, water intoxication, hypoglycaemia, hyperinsulinaemia, catatonia, somnambulism, sleep-related eating disorder, blunted affect, anorgasmia, neuroleptic malignant syndrome, cerebrovascular disorder, diabetic coma, head titubation, unresponsive to stimuli, depressed level of consciousness, glaucoma, eye movement disorder, eye rolling, eyelid margin crusting, floppy iris syndrome (intraoperative), sinus arrhythmia, pulmonary embolism, venous thrombosis, sleep apnoea syndrome, hyperventilation, rales, pneumonia aspiration, pulmonary congestion, dysphonia, respiratory disorder, pancreatitis, intestinal obstruction, swollen tongue, cheilitis, jaundice, drug eruption, dandruff, rhabdomyolysis, drug withdrawal syndrome neonatal, priapism, menstruation delayed, breast engorgement, breast enlargement, breast discharge, hypothermia, body temperature decreased, peripheral coldness, drug withdrawal syndrome, induration.

Very Rare (<1/10,000):

Diabetic ketoacidosis, ileus, angioedema.

Not Known (cannot be estimated from the available clinical trial data):

Stevens-Johnson syndrome/toxic epidermal necrolysis.

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.

Hypersensitivity to the active substance or to any of the excipients listed:

• Pre-filled syringe of powder
  • poly(D,L-lactide-co-glycolide)
• Pre-filled syringe of solvent
  • Dimethyl sulfoxide

For risperidone-naive patients, it is recommended to establish tolerability with oral risperidone prior to initiating treatment with OKEDI. 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.

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.

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.

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.