RISPIDE Oral solution Ref.[115328] Active ingredients: Risperidone

Source: Health Products Regulatory Authority (ZA)  Publisher: Abex Pharmaceutica (Pty) Ltd, Suite C, Rubenstein Ridge, 617 Rubenstein Drive, Moreleta Park, 0181

Contraindications

  • Hypersensitivity to risperidone or to any of the excipients of RISPIDE listed in section 6.1.
  • Conduct and other disruptive behaviour disorders in children: RISPIDE is contra-indicated in children under 5 years of age as efficacy and safety in these children have not been demonstrated.
  • Parkinson's disease and Lewy Body dementia (see section 4.4).

Special warnings and precautions for use

Elderly patients with dementia (see section 4.5)

Before prescribing, medical practitioners are advised to carefully assess the risks and benefits of the use of atypical antipsychotics in elderly patients with dementia, taking into account risk predictions for stroke in the individual patient (e.g. hypertension, diabetes, current smoking, atrial fibrillation, and age >80 years).

Where the use of antipsychotics in the elderly is considered essential, the lowest effective dose should be used. These patients should be carefully monitored to avoid or reduce hypotension, gait disturbances, oversedation and complications associated with hyperglycaemia.

Risperidone is not indicated in elderly patients with dementia exhibiting behavioural disturbances.

Increased mortality in elderly people with dementia

Elderly patients with dementia treated with atypical antipsychotic medicines have an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic medicines, including risperidone. In placebo-controlled trials with oral risperidone in this population, the incidence of mortality was 4,0% for risperidone-treated patients compared to 3,1% for placebo-treated patients. The mean age (range) of patients who died was 86 years (range 67 to 100).

Concomitant use with furosemide (see section 4.5)

In risperidone placebo-controlled trials in elderly patients with dementia, a higher incidence of mortality was observed in patients treated with furosemide and risperidone (7,3%; mean age 89 years, range 75 to 97) when compared to patients treated with risperidone alone (3,1%; mean age 84 years, range 70 to 96) or furosemide alone (4,1%; mean age 80 years, range 67 to 90). The increase in mortality in patients treated with furosemide plus risperidone was observed in two of the four clinical trials.

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 should be considered prior to the decision to use. There was no increased incidence of mortality among patients taking other diuretics as concomitant medicine with risperidone. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.

Cerebrovascular adverse events (CAE)

In placebo-controlled clinical trials in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischaemic attacks), including fatalities, in patients treated with risperidone compared to patients receiving placebo (mean age 85 years; range 73 to 97 years).

Orthostatic hypotension

Due to the alpha-blocking activity of risperidone, (orthostatic) hypotension can occur, especially during the initial dose titration period. Risperidone as in RISPIDE should be used with caution in patients with known cardiovascular disease, and the dosage should be gradually titrated as recommended. A dose reduction should be considered if hypotension occurs.

Leukopenia, neutropenia, and agranulocytosis

Events of leukopenia, neutropenia and agranulocytosis have been reported with risperidone as in RISPIDE. Agranulocytosis has been reported during post-marketing surveillance. Patients with a history of a clinically significant low white blood cell count (WBC) or a medicine-induced leukopenia/neutropenia should be monitored during therapy and discontinuation of RISPIDE should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

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

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with risperidone. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with risperidone as in RISPIDE and preventive measures undertaken.

Tardive dyskinesia/ extrapyramidal symptoms (TD/EPS)

Risperidone as in RISPIDE has been associated with the induction of tardive dyskinesia (TD) characterised by potentially irreversible rhythmical involuntary movements, predominantly of the tongue and/or face. It has been reported that the occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. TD appears to be most prominent in the elderly especially elderly females. If signs and symptoms of tardive dyskinesia appear, the discontinuation of RISPIDE should be considered.

Neuroleptic malignant syndrome (NMS)

Neuroleptic malignant syndrome, a potentially fatal symptom complex, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels has been reported to occur in association with risperidone as in RISPIDE. Additional signs may include elevated creatine phosphokinase levels, myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, RISPIDE should be discontinued.

Parkinson's disease/Lewy Body dementia and NMS

Patients with Parkinson's disease or dementia with Lewy Bodies (DLB) have an increased risk of neuroleptic malignant syndrome (NMS) as well as having an increased sensitivity to antipsychotic medicines (see section 4.3). Manifestation of this increased sensitivity can include confusion, obtundation and postural instability with frequent falls, in addition to extrapyramidal symptoms. In addition, in clinical trials, elderly patients have a higher mortality than placebo-treated elderly patients (see section 4.3).

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with risperidone as in RISPIDE.

Patients with an established diagnosis of diabetes mellitus who are starting on risperidone as in RISPIDE should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with RISPIDE should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with RISPIDE should undergo fasting blood glucose testing.

In some cases, hyperglycaemia has resolved when risperidone was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone.

Weight gain

Significant weight gain has been reported. Monitoring weight gain is advisable when RISPIDE is being used. Patients may be advised to refrain from excessive eating in view of the possibility of weight gain.

Hyperprolactinaemia

Hyperprolactinaemia is a common side effect of treatment with risperidone as in RISPIDE. 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. RISPIDE should be used with caution in patients with pre-existing hyperprolactinaemia and in patients with possible prolactin-dependent tumours.

QT-interval

Caution should be exercised when RISPIDE is prescribed in patients with a history of cardiac dysrhythmias, in patients with congenital long QT syndrome, and in concomitant use with medicines known to prolong the QT-interval.

Priapism

Medicines with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with risperidone as in RISPIDE during post-marketing surveillance (see section 4.8).

Body temperature regulation

Disruption of the body's ability to reduce core body temperature may occur. Appropriate care is advised when prescribing RISPIDE 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 medicines with anticholinergic activity, or being subject to dehydration.

Antiemetic effect

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

Renal and hepatic impairment

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

Intraoperative floppy iris syndrome

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients treated with medicines with alpha1a-adrenergic antagonist effect, including risperidone as in RISPIDE.

IFIS may increase the risk of eye complications during and after the operation. Current or past use of RISPIDE should be made known to the ophthalmic surgeon in advance of surgery. The potential benefit of stopping RISPIDE prior to cataract surgery has not been established and should be weighed against the risk of stopping RISPIDE therapy.

Seizures

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

Paediatric population

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

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

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

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

Results from a small post-marketing observational study showed that risperidone-exposed subjects between the ages of 8 to 16 years were on average approximately 3,0 to 4,8 cm taller than those who received other atypical antipsychotic medicines. This study was not adequate to determine whether exposure to risperidone had any impact on final adult height, or whether the result was due to a direct effect of risperidone on bone growth, or the effect of the underlying disease itself on bone growth, or the result of better control of the underlying disease with resulting increase in linear growth.

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

RISPIDE contains 1,5 mg benzoic acid per 1 ml solution.

An increase in bilirubinaemia following its displacement from albumin may increase neonatal jaundice which may develop into kernicterus (non-conjugated bilirubin deposits in the brain tissue).

Interaction with other medicinal products and other forms of interaction

The risk of using risperidone as in RISPIDE in combination with other medicines has not been systematically evaluated.

Pharmacodynamic-related interactions

Medicines known to prolong the QT interval

Caution is advised when prescribing risperidone with medicines known to prolong the QT-interval, such as antidysrhythmics (e.g., quinidine, dysopiramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressant (i.e., amitriptyline), tetracyclic antidepressants (i.e., maprotiline), some antihistamines, other antipsychotics, some antimalarials (i.e., quinine and mefloquine), and with medicines causing electrolyte imbalance (hypokalaemia, hypomagnesaemia), bradycardia, or those which inhibit the hepatic metabolism of risperidone. This list is indicative and not exhaustive.

Centrally acting medicines and alcohol

Risperidone as in RISPIDE should be used with caution in combination with other centrally acting substances notably including alcohol, opiates, antihistamines, and benzodiazepines due to the increased risk of sedation.

Levodopa and dopamine agonists

Risperidone as in RISPIDE 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.

Psychostimulants

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

Medicines with hypotensive effect

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

Paliperidone

Concomitant use of oral risperidone as in RISPIDE with paliperidone is not recommended as paliperidone is the active metabolite of risperidone and the combination of the two may lead to additive active antipsychotic fraction exposure.

Pharmacokinetic-related interactions

Food does not affect the absorption of risperidone.

Risperidone is mainly metabolised through CYP2D6, and to a lesser extent through CYP3A4. Both risperidone and its active metabolite 9-hydroxyrisperidone are substrates of P-glycoprotein (P-gp). Substances that modify CYP2D6 activity, or substances strongly inhibiting or inducing CYP3A4 and/or P-gp activity, may influence the pharmacokinetics of the risperidone active antipsychotic fraction.

Strong CYP2D6 inhibitors

Co-administration of risperidone as in RISPIDE with a strong CYP2D6 inhibitor may increase the plasma concentrations of risperidone, but less so of the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may elevate concentrations of the risperidone active antipsychotic fraction (e.g., paroxetine, see below). It is expected that other CYP2D6 inhibitors, such as quinidine, may affect the plasma concentrations of risperidone in a similar way. When concomitant paroxetine, quinidine, or another strong CYP2D6 inhibitor, especially at higher doses, is initiated or discontinued, the medical practitioner should re-evaluate the dosing of RISPIDE.

CYP3A4 and/or P-gp inhibitors

Co-administration of risperidone as in RISPIDE with a strong CYP3A4 and/or P-gp inhibitor may substantially elevate plasma concentrations of the risperidone active antipsychotic fraction. When concomitant itraconazole or another strong CYP3A4 and/or P-gp inhibitor is initiated or discontinued, the medical practitioner should re-evaluate the dosing of RISPIDE.

CYP3A4 and/or P-gp inducers

Co-administration of risperidone with a strong CYP3A4 and/or P-gp inducer may decrease the plasma concentrations of the risperidone active antipsychotic fraction. When concomitant carbamazepine or another strong CYP3A4 and/or P-gp inducer is initiated or discontinued, the medical practitioner should re-evaluate the dosing of RISPIDE. 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 medicines

When risperidone as in RISPIDE is taken together with highly protein-bound medicines, there is no clinically relevant displacement of either medicine from the plasma proteins. When using concomitant medicines, the corresponding label should be consulted for information on the route of metabolism and the possible need to adjust dosage.

Paediatric population

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

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

Effect of other medicines on the pharmacokinetics of risperidone

Antibacterials

  • Erythromycin, a moderate CYP3A4 inhibitor and P-gp inhibitor, does not change the pharmacokinetics of risperidone as in RISPIDE and the active antipsychotic fraction.
  • Rifampicin, a strong CYP3A4 inducer and a P-gp inducer, decreased the plasma concentrations of the active antipsychotic fraction.

Anticholinesterases

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

Antiepileptics

  • Carbamazepine, a strong CYP3A4 inducer and a P-gp inducer, has been shown to decrease the plasma concentrations of the active antipsychotic fraction of risperidone. Similar effects may be observed with e.g. phenytoin and phenobarbital (phenobarbitone), which also induce CYP3A4 hepatic enzyme, as well as P-glycoprotein.
  • Topiramate modestly reduced the bioavailability of risperidone, but not that of the active antipsychotic fraction. Therefore, this interaction is unlikely to be of clinical significance.

Antifungals

  • Itraconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of the active antipsychotic fraction by about 70%, at risperidone doses of 2 to 8 mg/day.
  • Ketoconazole, a strong CYP3A4 inhibitor and a P-gp inhibitor, at a dosage of 200 mg/day increased the plasma concentrations of risperidone and decreased the plasma concentrations of 9-hydroxyrisperidone.

Antipsychotics

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

Antivirals

Protease inhibitors: No formal study data are available; however, since ritonavir is a strong CYP3A4 inhibitor and a weak CYP2D6 inhibitor, ritonavir and ritonavir-boosted protease inhibitors potentially raise concentrations of the risperidone active antipsychotic fraction.

Beta blockers

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

Calcium channel blockers

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

Gastrointestinal medicines

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

SSRIs and Tricyclic antidepressants

  • Fluoxetine, a strong CYP2D6 inhibitor, increases the plasma concentration of risperidone, but less so of the active antipsychotic fraction.
  • Paroxetine, a strong CYP2D6 inhibitor, increases the plasma concentrations of risperidone, but, at dosages up to 20 mg/day, less so of the active antipsychotic fraction. However, higher doses of paroxetine may elevate concentrations of the risperidone active antipsychotic fraction.
  • Venlafaxine administered under steady state conditions at 150 mg/day inhibited the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone AUC. However, venlafaxine co-administration did not significantly alter the pharmacokinetic profile of the total active antipsychotic fraction.
  • Tricyclic antidepressants may increase the plasma concentrations of risperidone but not those of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.
  • Sertraline, a weak inhibitor of CYP2D6, and fluvoxamine, a weak inhibitor of CYP3A4, at dosages up to 100 mg/day are not associated with clinically significant changes in concentrations of the risperidone active antipsychotic fraction. However, doses higher than 100 mg/day of sertraline or fluvoxamine may elevate concentrations of the risperidone active antipsychotic fraction.

Effect of risperidone on the pharmacokinetics of other medicines

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.

Digoxin

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 RISPIDE with furosemide

There is increased mortality in elderly patients with dementia concomitantly receiving furosemide and risperidone as in RISPIDE (see section 4.4).

Fertility, pregnancy, and lactation

The safety of risperidone as in RISPIDE in pregnancy and breastfeeding women has not been established.

Pregnancy

Although, in experimental animals, risperidone did not show direct reproductive toxicity, some indirect, prolactin- and CNS-mediated effects were observed. No teratogenic effect of risperidone was noted in any study.

Neonates exposed to antipsychotic medicines (including risperidone) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms that may vary in severity following delivery. These symptoms in the neonates may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Therefore, RISPIDE should only be used during pregnancy if the benefits outweigh the risks.

Breastfeeding

In animal studies risperidone and 9-hydroxy-risperidone are excreted in the milk. It has been demonstrated that risperidone and 9-hydroxy-risperidone are also excreted in human breast milk. Therefore, women receiving RISPIDE should not breastfeed.

Fertility

Risperidone elevates prolactin levels. 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.

Effects on ability to drive and use machines

RISPIDE may impair mental alertness. Patients should therefore be advised not to drive or operate machinery until their individual susceptibility is known.

Undesirable effects

Summary of the safety profile

The most frequently reported adverse drug reactions (ADRs) are parkinsonism, sedation/somnolence, headache, and insomnia. The ADRs that appeared to be dose-related included parkinsonism and akathisia.

Tabulated summary of adverse reactions

System Organ
Class
FrequentLess frequent
Infections and
infestations
pneumonia, influenza, bronchitis,
upper respiratory tract infection,
urinary tract infection, sinusitis, ear
infection
viral infection, tonsillitis, cellulitis,
otitis media, eye infection, localised
infection, acarodermatitis,
respiratory tract infection, cystitis,
onychomycosis, chronic otitis
media
Blood and
lymphatic
system
disorders
 anaemia, neutropenia,
granulocytopenia, white blood cell
count decreased,
thrombocytopenia, haematocrit
decreased, eosinophil count
increased, agranulocytosis
Immune system
disorders
 hypersensitivity, anaphylactic
reaction, angioedema
Endocrine
disorders
Hyperprolactinaemia (which can in
some cases lead to gynaecomastia,
menstrual disturbances,
amenorrhoea, anovulation,
galactorrhoea, fertility disorder,
decreased libido, erectile
dysfunction)
inappropriate antidiuretic hormone
secretion, glucose urine present
Metabolism and
nutrition
disorders
weight increased, increased appetite,
decreased appetite
diabetes mellitus, hyperglycaemia,
polydipsia, weight decreased,
anorexia, blood cholesterol
increased, water intoxication,
hypoglycaemia, hyperinsulinemia,
blood triglycerides increased,
diabetic ketoacidosis
Psychiatric
disorders
insomnia1, sleep disorder, agitation,
depression, anxiety
mania, confusional state, libido
decreased, nervousness,
nightmare, catatonia,
somnambulism, sleep related
eating disorder, blunted affect,
anorgasmia
Nervous system
disorders
Sedation/somnolence,
parkinsonism1, headache,
akathisia1, dystonia1, dizziness,
dyskinesia1, tremor
tardive dyskinesia, cerebral
ischaemia, unresponsive to stimuli,
loss of consciousness, depressed
level of consciousness,
cerebrovascular accident, transient
ischaemic attack, convulsion1,
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
Eye disordersvision blurred, conjunctivitisphotophobia, dry eye, lacrimation
increased, ocular hyperaemia,
glaucoma, eye movement disorder,
eye rolling, eyelid margin crusting,
floppy iris syndrome
(intraoperative)
Ear and
labyrinth
disorders
 vertigo, tinnitus, ear pain
Cardiac
disorders
tachycardiaatrial fibrillation, atrioventricular
block, conduction disorder,
electrocardiogram QT prolonged,
bradycardia, electrocardiogram
abnormal, palpitations, sinus
dysrhythmia
Vascular
disorders
hypertensionhypotension, orthostatic
hypotension, flushing, pulmonary
embolism, venous thrombosis
Respiratory,
thoracic and
mediastinal
disorders
dyspnoea, pharyngolaryngeal pain,
cough, epistaxis, nasal congestion
pneumonia aspiration, pulmonary
congestion, respiratory tract
congestion, rales, wheezing,
dysphonia, respiratory disorder,
sleep apnoea syndrome,
hyperventilation
Gastrointestinal
disorders
abdominal pain, abdominal
discomfort, vomiting, nausea,
constipation, diarrhoea, dyspepsia,
dry mouth, toothache
faecal incontinence, faecaloma,
gastroenteritis, dysphagia,
flatulence, pancreatitis, intestinal
obstruction, swollen tongue, ileus,
cheilitis
Skin and
subcutaneous
tissue disorders
rash, erythemaurticaria, pruritus, alopecia,
hyperkeratosis, eczema, dry skin,
skin discolouration, acne,
seborrheic dermatitis, skin disorder,
skin lesion, drug eruption, dandruff
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 incontinencepollakiuria, urinary retention,
dysuria
Pregnancy,
puerperium,
and neonatal
conditions
 neonatal medicine withdrawal
syndrome
Reproductive
system and
breast
disorders
 erectile dysfunction, ejaculation
disorder, amenorrhoea, menstrual
disorder1, gynaecomastia,
galactorrhoea, sexual dysfunction,
breast pain, breast discomfort,
vaginal discharge, priapism,
menstruation delayed, breast
engorgement, breast enlargement,
breast discharge
General
disorders and
administration
site conditions
oedema1, 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, induration
Hepatobiliary
disorders
 transaminases increased, gamma-
glutamyltransferase increased,
hepatic enzyme increased,
jaundice
Injury,
poisoning and
procedural
complications
fallprocedural pain

(1) Extrapyramidal disorder

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 is included, that do not necessarily have an extrapyramidal origin. Insomnia includes: initial insomnia, middle insomnia; Convulsion includes: Grand mal convulsion; Menstrual disorder includes: Menstruation irregular, oligomenorrhoea; Oedema includes: generalised oedema, oedema peripheral, pitting oedema.

Undesirable effects noted with paliperidone formulations

Paliperidone is the active metabolite of risperidone, therefore, the adverse reaction profiles of these compounds (including both the oral and injectable formulations) are relevant to one another. In addition to the above adverse reactions, the following adverse reaction has been noted with the use of paliperidone products and can be expected to occur with risperidone as in RISPIDE.

Cardiac disorders

Postural orthostatic tachycardia syndrome.

Class effects

Cases of QT-prolongation have been reported post-marketing with risperidone. Other class-related cardiac effects reported with antipsychotics which prolong QT-interval include ventricular dysrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and Torsades de Pointes.

Venous thromboembolism

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicines (frequency unknown).

Weight gain

The proportions of risperidone and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of ≥7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for risperidone (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week studies in adult patients with acute mania, the incidence of weight increase of ≥7% at endpoint was comparable in the risperidone (2,5%) and placebo (2,4%) groups and was slightly higher in the active-control group (3,5%).

In a population of children and adolescents with conduct and other disruptive behaviour disorders, in long-term studies, weight increased by a mean of 7,3 kg after 12 months of treatment. The expected weight gain for normal children between 5 to 12 years of age is 3 to 5 kg per year. From 12 to 16 years of age, this magnitude of gaining 3 to 5 kg per year is maintained for girls, while boys gain approximately 5 kg per year.

Additional information on special populations

ADRs that were reported with higher incidence in elderly patients with dementia or paediatric patients than in adult populations are described below.

Elderly patients with dementia

Transient ischaemic attack and cerebrovascular accident were ADRs reported in clinical trials with a frequency of 1,4% and 1,5%, respectively, in elderly patients with dementia. In addition, the following ADRs were reported with a frequency ≥5% in elderly patients with dementia and with at least twice the frequency seen in other adult populations: urinary tract infection, peripheral oedema, lethargy, and cough.

Paediatric population

In general, the type of adverse reactions in children is expected to be similar to those observed in adults.

The following ADRs were reported with a frequency ≥5% in paediatric patients (5 to 17 years) and with at least twice the frequency seen in clinical trials in adults: somnolence/sedation, fatigue, headache, increased appetite, vomiting, upper respiratory tract infection, nasal congestion, abdominal pain, dizziness, cough, pyrexia, tremor, diarrhoea, and enuresis.

The effect of long-term risperidone treatment on sexual maturation and height has not been adequately studied (see 4.4, subsection "Paediatric population")

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the "6.04 Adverse Drug Reactions Reporting Form", found online under SAHPRA's publications: https://www.sahpra.org.za/Publications/Index/8.

Incompatibilities

Incompatible with most types of tea, including black tea.

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