Risperidone 1mg/Ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Risperidone 1mg/ml Oral Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml contains 1 mg of risperidone.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Oral solution.
The solution is clear and colourless.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Risperidone is indicated for:
• the treatment of schizophrenia. Risperidone is also effective in maintaining the clinical improvement in patients who showed an initial treatment response;
• the treatment of moderate to severe manic episodes.
4.2 Posology and method of administration
For the treatment of schizophrenia and the treatment of manic episode Risperidone can be given once or twice daily.
Up till now there is limited experience with the treatment of elderly.
Schizophrenia
Switching to Risperidone from other antipsychotics
When starting Risperidone therapy gradual discontinuation of the previous treatment is recommended, if medically appropriate. When switching from depot antipsychotics
to Risperidone, initiation of Risperidone therapy is recommended at the time of the next scheduled injection, if medically appropriate.
The need for continuing existing treatment of extrapyramidal symptoms (antiparkinson medication) should be re-evaluated recurrently.
Adults
Risperidone can be administered once or twice daily.
All patients should be started on 2 mg per day. On the second day the dose should be increased to 4 mg per day. Thereafter, the dose maybe maintained unchanged, or further individualised, if needed from day 3 onwards to 6 mg per day. The usual optimal dose is between 4-6mg, although doses up to 8 mg are also accepted. However, some patients may benefit from a lower dose and/or a more gradual titration schedule. Doses above 10 mg/day were not found to be therapeutically superior to lower doses and carry an increased risk of extrapyramidal side effects.
The safety of doses above 16 mg per day has not been investigated and therefore these should not be used.
If sedation is required, a benzodiazepine can be administered concomitantly.
Elderly
A starting dose of 0.5 mg twice daily is recommended. This dose can be maintained unchanged or individually adjusted in increments of 0.5 mg twice daily until 1-2 mg twice daily is reached. Caution should be exercised as there is limited clinical experience in elderly patients.
Children and adolescents below 15 years of age
There is no experience with the treatment of schizophrenia in children aged less than 15 years.
Therefore it cannot be recommended to use the medicinal product for this patient group.
Hepatic and renal impairment
The recommended initial dose is 0.5 mg twice daily. This dosage can be individually adjusted with a dosing schedule of 0.5 mg twice daily till 1-2 mg twice daily. Since clinical experience in these patients is limited, caution should be exercised.
Manic Episode
Risperidone should be taken once daily. Starting dose is 2 mg. Adjustments of the dose, if necessary, should be carried out with intervals not less than 24 hours in steps of 1 mg per day. The recommended dosing range is 2-6 mg per day. Daily doses of more than 6 mg Risperidone have not been investigated in patients with manic episodes.
Children and adolescents
There is no experience with the treatment of manic episodes in children and adolescents aged less than 18 years.
Elderly
It is recommended to initiate the treatment with 0.5 mg twice daily. This dosage can be maintained unchanged or adapted individually by increasing in increments of 0.5 mg twice daily till 1-2 mg twice daily. Since clinical experience in elderly is limited, caution should be exercised.
Instructions for opening the bottle and using the pipette
Instructions for opening the bottle and using the dosing syringe
• Remove cap from the bottle
• Fit the adaptor into the neck of the bottle , it is not necessary to remove after use
• While the bottle is sitting on a firm, flat surface, hold it steady with one hand. With the other hand insert the tip of the syringe into the adaptor
• Invert the bottle (turn upside-down)
• Slowly pull back the plunger of the syringe until the mark that matches the number of mg or ml to be taken is just visible
• If large bubbles can be seen in the syringe, slowly push the plunger back into the syringe. This will force the medicine back into the bottle. Repeat the above step again
• Return the bottle to it original position, and remove the dosing syringe
• The contents of the syringe may be emptied directly into the mouth or into a, drink of mineral water, orange juice or black coffee by slowly pushing down the plunger of the syringe. Do not mix with tea.
• Close the bottle
• Rinse the dosing syringe with water.
4.3 Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients.
4.4. Special warnings and precautions for use
Tardive dyskinesia
With prolonged antipsychotic therapy (particularly at high doses) tardive dyskinesia, characterised by rhythmical involuntary movements, predominantly of the tongue and/or face may occur. These symptoms may worsen temporarily or even develop after treatment has been discontinued.
The risk of irreversibility is greater in elderly patients and patients with organic brain damage. Regular monitoring of the patient for these symptoms 3-6 months after the start of treatment is recommended, as well as informing the patient of this risk prior to initiating treatment. The incidence of extrapyramidal side effects with Risperidone at an optimal antipsychotic dose is lower than with haloperidol.
If symptoms of Tardive dyskinesia appear, a termination of risperidone therapy should be considered.
Lewy body dementia and Parkinson’s disease
Before prescription of Risperidone to patients who suffer also from Lewy body dementia or Parkinson’s disease the risk benefit ratio should be considered. An elevated risk is present on the so called neuroleptic malignant syndrome or Parkinson-like symptoms may worsen.
Hypotension
In hypotension a dose reduction should be considered.
Orthostatic hypotension
The a-blocking properties of risperidone may cause orthostatic hypotension, particularly during the dose titration period. Risperidone should be administered with caution to patients with cardiovascular disease or family history of QT prolongation (e.g., heart failure, cardiac infarction, cardiac conduction disturbances, dehydration, hypovolaemia or cerebrovascular disease), and the dose should be titrated carefully (see section 4.2).
Cardiovascular diseases
As with other antipsychotics, caution is advised when prescribing with medicinal products known to prolong QTc interval. Risperidone should be used with caution in patients with known cardiovascular disease (e.g. congenital long QTc syndrome, coronary heart disease, disturbances in conduction, arrhythmia, hereditary long QT syndrome) or concomitant treatment with medicinal products, which also induce QT interval prolongation or hypokalaemia. Simultaneous treatment with other neuroleptics should be avoided.
Elderly
In general it is recommended to be cautious with the prescription in elderly (see section 4.2).
In elderly patients, the frequency of dizziness, bradycardia and injury through falls appears to be higher than in young patients.
Children and adolescents
Since experience with schizophrenia in children and adolescents younger than 15 years of age is lacking, it can not be recommended to use the medicinal product for this patient group.
There is no experience in the treatment of manic episodes in children and adolescents younger than 18 years.
Baseline weight measurement prior to treatment and regular weight monitoring are recommended.
Liver and kidney dysfunction
In patients with liver or kidney dysfunction and in geriatric patients, halving both the starting dose and the subsequent dose increments is recommended (see section 4.2).
Neuroleptic malignant syndrome
As with other antipsychotics, it is important to be vigilant for neuroleptic malignant syndrome, in which hyperthermia, extreme muscle rigidity and autonomic instability are key symptoms. Other symptoms may include: increased serum creatine phosphokinase level and leucocytosis, tachypnea, altered consciousness and profuse perspiration. Life-threatening is usually the occurrence of rhabdomyolysis and the complementary renal insufficiency. All antipsychotic medicinal products should be withdrawn.
Avoid concomitant neuroleptics.
Except for the common supportive measures (external cooling and rehydration), anticholinergics and benzodiazepines are often given in the first instance. In severe cases these drugs may be insufficiently effective and dantrolene and/or dopamine agonists should be given. If this treatment does not take effect or in an extremely life-threatening situation, electroconvulsive therapy may be life-saving.
Organic mental disorders
In patients with organic mental disorders, an increased risk of undesirable effects should be taken into account.
Epilepsy
As with other antipsychotics, Risperidone may lower the seizure threshold. In patients with epilepsy, Risperidone should therefore be administered with the necessary caution.
Weight gain
In view of the potential for weight gain, patients should be given dietary advice.
Exacerbation of symptoms
Antipsychotics can, paradoxically, exacerbate symptoms such as excitation, agitation and aggressiveness. In the presence of these symptoms, a dose reduction of Risperidone or treatment discontinuation may be necessary, as with other antipsychotics.
Valproate or lithium
Data of Risperidone in combination with valproate or lithium in moderate or severe manic episodes are limited and not unambiguous. Furthermore there exist no data of the combination therapy from controlled studies concerning efficacy longer than 3 weeks (see Section 4.5).
Carbamazepine
Carbamazepine has been shown to lower plasma levels of the antipsychotic fraction of Risperidone (see Section 4.5). The dose should be adjusted.
Hyperglycaemia
Hyperglycaemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with Risperidone. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus (see also section 4.8 Undesirable effects).
Elderly patients with dementia
An increased risk on cerebrovascular events, including CVA’s, TIA’s, patients who suffer from dementia. Data from randomised clinical trials conducted in patients treated with risperidone indicate that there is an approximately 3-fold increased risk of cerebrovascular adverse events, compared with placebo (Respectively 3.4% versus 1.1%). It is therefore not recommended to prescribe Risperidone to patients with dementia with a CVA/TIA, hypertension or diabetes in the anamnesis.
Elderly patients with dementia treated with atypical antipsychotic drugs had an increased mortality compared to placebo in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including Risperidone. In placebo-controlled trials with 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 (67-100).
In these trials treatment with furosemide plus risperidone was associated with a higher incidence of mortality compared to treatment with risperidone or furosemide alone, however, the mechanism for an interaction is unclear. Concomitant use of risperidone with other diuretics (mainly thiazide diuretics used in low dose) was not associated with similar findings.
No consistent pattern for cause of death observed. Nevertheless caution should be exercised and the risks and benefits of the combination of risperidone and furosemide or co-medication with other potent diuretics considered prior to the decision to use. Irrespective of treatment, dehydration was an overall risk factor for mortality and should therefore be carefully avoided in elderly patients with dementia.
Caution in patients with cardiovascular disease or family history of QT prolongation. Avoid concomitant neuroleptics.
Symptoms when stopping therapy
Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have very rarely been described after abrupt cessation of high doses of antipsychotic drugs.
Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.
Special caution should be exercised in patients with prolactin-dependent tumours (e.g. hypophysal prolactinoma) and possibly prolactin dependent tumors (e.g. breast cancer)”.
Esophageal dysmotility and aspiration have been associated with the use of antipsyhotic agents, including risperidone. Because aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced dementia of the Alzheimer’s type, risperidone and other antipsychotic drugs should be used with caution in patients at risk for aspiration pneumonia.
Because both hypothermia and hyperthermia have been associated with risperidone therapy, the medicinal products should be administered with caution in patients who will be exposed to temperature extremes.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Risperidone and preventive measures undertaken.
4.5 Interaction with other medicinal products and other forms of interaction
The risks associated with the use of Risperidone in combination with other drugs have not been systematically evaluated. Caution should be exercised when combining risperidone with other compounds that act on the central nervous system. Antipsychotics amplify the effect of alcohol, opioids, antihistamines and benzodiazepines, amongst others. Therefore, the use of alcohol is advised against.
Concomitant use of other antipsychotics, lithium, antidepressants, antiparkinson drugs and compounds with a central anticholinergic effect increases the risk of tardive dyskinesia.
Risperidone may antagonise the effect of levodopa and other dopaminergic agonists.
Carbamazepine decreases the plasma levels of risperidone. Similar effects may be observed with other drugs which induce hepatic enzymes, such as barbiturates, rifampicin, phenytoin and St. John’s Wart (Hypericum perforatum). On discontinuation of carbamazepine or other hepatic enzyme-inducing drugs, the Risperidone dose should be re-evaluated and decreased if necessary.
Phenothiazines, tricyclic antidepressants and some beta-blockers may increase the plasma concentrations of risperidone, but do not affect the antipsychotic fraction (see section 5.2 Pharmacokinetic properties). Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction. Cimetidine and ranitidine may increase the bioavailability of risperidone, but the antipsychotic effect is not necessarily increased, because the fraction of the active metabolite is increased. Quinidine, Fluoxetine, paroxetine and terbinafine, CYP2D6 inhibitors, may increase the plasma concentration of risperidone by inhibiting cytochrome P450 IID6. However, this inhibition reduces the formation of the active metabolite, as a result of which the increase in the total antipsychotic fraction (unchanged risperidone and active metabolite) is less marked. . When concomitant therapy with such drugs is initiated or discontinued, the physician should re-evaluate the dosing of Risperidone. Erythromycin, a CYP 3A4 inhibitor, does not change the pharmacokinetics of risperidone and the active antipsychotic fraction. The cholinesterase inhibitor galantamine and donepezil does not show a clinically relevant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.
Risperidone does not show a clinically relevant effect on the pharmacokinetics of lithium, valproate or digoxin.
The anti ai-adrenergic effect (particularly with phenothiazines) may amplify the blood pressure-lowering effect of phenoxybenzamine, labetalol and other a-blocking sympathicolytics, as well as methyldopa, reserpine and other central-acting antihypertensives.
By contrast, the antihypertensive effect of guanethidine is blocked.
The combination of some antipsychotics with diuretics such as furosemide and chlorothiazide may markedly increase the excretion of water, sodium and, in some cases, chloride. See section 4.4. regarding increased mortality in elderly patients with dementia, who are concomitantly receiving furosemide.
Antacids decrease the oral absorption of antipsychotics. Drugs that cause an increase in hepatic enzyme activity (barbiturates, phenytoin and carbamazepine), increase the rate at which antipsychotics are metabolised. During co-administration with other highly protein-bound active substances, there is no clinically relevant displacement from the plasma-proteins.
Concomitant treatment with medicinal products, which also induce QT interval prolongation (e.g. antiarrhythmics class IA or III, macrolide antibiotics, antimalarial medicinal products, antihistaminic, antidepressants), cause hypokalaemia (e.g. certain diuretics), or inhibit the hepatic metabolism of risperidone should be avoided.
4.6. Fertility, pregnancy and lactation
Pregnancy
The safety of Risperidone for use during human pregnancy has not been established. In experimental animals, risperidone did not show direct or indirect harmful effects for pregnancy and embryo-foetal development. On the delivery and the post-natal development pharmacological effects have been found (see section 5.3) of which the potential risk for humans is unknown.
Of antipsychotics it is known that long term use until the partus can cause extrapyramidal disorders and withdrawal symptoms. Risperidone should not be used during pregnancy, unless absolutely necessary. Neonates exposed to antipsychotics (including risperidone) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Lactation
Data from a small number of women show that risperidone and its active metabolite are eliminated in small portions in the mother’s milk. Until now no negative effects for the newborn are known. Risperidone can increase the amount of milk by increasing the prolactin levels.
Risperidone should not be used during breast-feeding unless absolutely necessary.
4.7 Effects on ability to drive and use machines
No studies on the effect on the ability to drive and use machines have been performed.
Antipsychotic medicinal products like risperidone can influence the ability to react. Patients should be advised not to drive vehicles or operate machines until the individual reaction to risperidone has been evaluated.
4.8. Undesirable effects
Within each frequency group, undesirable effects are categorised in decreasing order of severity.
Very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1.000, < 1/100); rare > 1/10.000, < 1/1.000); very rare (< 1/10.000), not known (cannot be estimated from the available data).
Infections and infestations Uncommon: rhinitis
Blood and the lymphatic system disorders
Very rare: neutropenia and thrombocytopenia
Endocrine disorders
Uncommon: dose dependent increase in prolactin levels
Metabolism and nutrition disorders
Very rare: hyperglycaemia, aggravation of existing diabetes (see section 4.4)
Psychiatric disorders
Common: insomnia, agitation, anxiety
Uncommon: decreased concentration
Nervous system disorders
Common: headache, sedation
Uncommon: tremor, bradykinesia, acathisia, dizziness
Very Rare: tardive dyskinesia (see section 4.4), seizures, malignant
neuroleptic syndrome (see section 4.4).
Eye disorders
Uncommon: blurred vision
Cardiac disorders
Uncommon: reflex tachycardia. This undesirable effect has been reported with
higher initial doses.
Very rare: Risperidone can prolong the QT interval in the ECG, torsades de
pointes can not be ruled out. If so, therapy should be terminated (see section 4.4), hypertension
Vascular disorders
Uncommon: orthostatic hypotension
Rare: cerebrovascular undesirable effects including CVA’s and TIA’s (see section 4.4).
Respiratory, thoracic and mediastinal disorders
Gastrointestinal disorders
Uncommon: constipation, dyspepsia, nausea, abdominal pain
Very rare: vomiting
Skin and subcutaneous tissue disorders
Uncommon: rash and other hypersensitivity reactions
Very rare: angio-oedema, pruritus, photosensitivity
Musculoskeletal and connective tissue disorders Uncommon: rigidity, acute dystonia
Very rare: muscle weakness
Pregnancy, puerperium and perinatal conditions.
Not known: Drug withdrawal syndrome neonatal (see 4.6)
Renal and urinary disorders Very rare: enuresis
Reproductive system and breast disorders
Uncommon: erectile disturbances, ejaculatory disturbances, impotence in men
who previously did not have any sexual disturbances, orgasmic dysfunction.
Rare: galactorrhoea, gynaecomastia, cycles disturbances in women and amenorrhea.
Very rare: priapism
General disorders and administration site conditions Uncommon: somnolence, fatigue
Rare: Weight gain (see section 4.4)
Very rare: oedema
Investigations
Very rare: increased hepatic enzyme levels.
Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs-Frequency unknown
After long term use of antipsychotic medicinal products (months to years) dyskinesia may occur (especially tardive dyskinesia), during, as well as after treatment (see sections 4.4 and 4.5).
Like for traditional antipsychotic medicinal products some cases of water intoxication are observed. These were due to polydipsia or to the syndrome caused by inadequate secretion of antidiuretic hormone (SIADH). Furthermore rarely have been observed: convulsions, worsening of depression and dysphoria, disturbance of body temperature and malign neuroleptic syndrome (see section 4.4).
4.9 Overdose Symptoms
The reported symptoms represent an amplification of the known pharmacological effects of risperidone. In other words: drowsiness and sedation, tachycardia, hypotension and extrapyramidal effects. Overdoses of up to 360 mg have been reported. The available data appear to reflect a broad safety margin. Rare cases of QT prolongation have been reported with overdoses.
There is no specific antidote to risperidone. Therefore, supportive measures should be taken. It is important to bear in mind that other drugs may be involved as well.
Treatment
In case of acute overdose, a clear airway should be established and maintained, and the patient should be given adequate oxygen and ventilation. Treatment should consist of gastric lavage (following intubation, if the patient has lost consciousness) and administration of activated charcoal and an osmotic laxative (sodium sulphate).
Cardiovascular parameters should also be monitored immediately. ECG monitoring will permit any arrhythmias to be detected. Hypotension and circulatory collapse should be treated with appropriate measures, such as administration of intravenous fluids and/or sympathicomimetics.
Severe extrapyramidal symptoms require administration of anticholinergic medication. The patient should be closely supervised and monitored until fully recovered.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other Antipsychotics, ATC code: N 05A X 08
Risperidone is, in chemical terms, a benzisoxazole derivative and therefore does not belong in the current class of antipsychotics.
Risperidone is a monoaminergic antagonist. It has a high affinity for serotonin 5-HT2 and dopamine D2 receptors. Risperidone also binds to a1-adrenergic receptors and, with a lower affinity, to histamine H1- and a2-adrenergic receptors. Risperidone has no affinity for cholinergic receptors.
Risperidone acts on positive symptoms, and appears to be associated with a potential effect on negative symptoms.
5.2 Pharmacokinetic properties Pharmacokinetics
Absorption
Risperidone is completely absorbed following oral administration.
Since the absorption is not influenced by food, risperidone can be administered independently of meals.
Distribution
Peak plasma concentrations are reached within 1-2 hours.
With most of the patients the steady-state concentration of risperidone is reached in one day and for 9- hydroxyrisperidone in 4-5 days. With therapeutic dosage the plasma concentrations of risperidone increases in straight proportion to dose amount. Risperidone distributes quickly, volume of distribution is 1-2 l/kg. Risperidone bounds to albumin and acid alfa1-glycoprotein in plasma. The plasma protein binding of risperidone is 88% and 77% for 9-hydroxyrisperidone.
Metabolism
Risperidone is metabolised by cytochrome P450 2D6 to 9-hydroxy-risperidone, which has a similar pharmacological activity to risperidone. Together they form the active antipsychotic fraction. Risperidone is also metabolised by N-dealkylation.
Elimination
Following oral administration to psychotic patients, the half-life of risperidone is about 3 hours. The half-life of 9-hydroxy-risperidone and the antipsychotic fraction is 24 hours in all patients.
One week after administration, 70% of the ingested risperidone is excreted in the urine and 14% is excreted in the faeces. In the urine, risperidone plus 9-hydroxy-risperidone represent 35-45% of the administered dose. The rest is made up of inactive metabolites.
The apparent plasma clearance following oral administration of the active fraction is 100 ml/minute.
Elderly patients/patient with hepatic and renal impairment
In pharmacokinetic studies the plasma concentrations of risperidone were higher than normally and the elimination was slower with elderly patients and patients with renal impairment.
In patients with hepatic impairment the plasma concentrations were normal.
5.3 Preclinical safety data
Conventional animal studies on pharmacodynamics, repeated dose toxicity, genotoxicity and carcinogenicity reveal no other risks for the patient than those which could be expected based on the pharmacological mechanism of action.
In vitro and in vivo animal models show that at high doses risperidone may cause QT interval prolongation, which has been associated with a theoretically increased risk of torsades de pointes in patients. In animal reproduction studies pharmacologically active doses revealed maternal toxicity, prolongation of the partus and increased postnatal deaths related to the pharmacodynamic action. The effects on postnatal development were shown to be predominantly due to the pharmacodynamic action on the dams (e.g. sedation and reduced care for the pups). These effects are not relevant for the assessment of a potential risk in humans.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tartaric acid (E334)
Benzoic acid (E210)
Purified Water
6.2 Incompatibilities
Risperidone solution is incompatible with tea.
6.3 Shelf life
2 years
After first opening: 2 months.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Risperidone solution is supplied in Type III amber glass bottle with a plastic child-resistant and tamper-evident cap. Bottle sizes of 30ml and 100 ml with a dosing pipette.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Morningside Healthcare Ltd 115 Narborough Road Leicester. LE3 0PA UK.
8 MARKETING AUTHORISATION NUMBER(S)
PL 20117/0066
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
20/08/2008
10 DATE OF REVISION OF THE TEXT
13/09/2013