Rispolettes Consta, 25 mg

Risperidone is a selective monoaminergic antagonist. It has a high affinity for serotonergic 5-HT2 receptors and dopaminergic D2 receptors. In addition, risperidone binds to α1-adrenergic receptors and, to a lesser extent, to H1-histaminergic and α2-adrenergic receptors.

Risperidone does not bind to cholinergic receptors. Although risperidone is a potent D2-receptor antagonist, due to which it improves positive symptoms of schizophrenia, this drug, compared to typical neuroleptics, is less likely to inhibit motor activity and less likely to cause catalepsy. Because of its balanced central antagonism to serotonin and dopamine receptors, risperidone is less likely to cause extrapyramidal side effects and has a therapeutic effect on the negative and affective symptoms of schizophrenia.

Pharmacokinetics

Risperidone is metabolized by the CYP2D6 isoenzyme to 9-hydroxyrisperidone, which has the same pharmacological activity as risperidone itself. Risperidone and 9-hydroxysperidone form the active antipsychotic fraction. Another route of metabolism of risperidone is N-dealkylation.

In fast metabolizers, the clearance of the active antipsychotic fraction and risperidone is 5 and 13.7 L/h, respectively, and in weak metabolizers it is 3.2 and 3.3 L/h, respectively.

General characteristics of risperidone after injection in patients with Rispolette Consta®

In a single infusion of Rispolette Consta®, the release profile of risperidone consists of a small initial phase (®.

The combination of the risperidone release profile and the dosing regimen (i.m. injection once every 2 weeks) ensures that therapeutic plasma concentrations of risperidone are maintained. Therapeutic concentrations are maintained until the 4th to 6th week after the last injection of Rispolet Consta®. The elimination phase is completed approximately 7-8 weeks after the last injection.

Risperidone is completely absorbed from Risolept Consta® suspension. Risperidone is rapidly distributed in body tissues. Vd is 1-2 l/kg. In plasma, risperidone binds to albumin and α1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of 9-hydroxyrisperidone is 77%. After intravenous injections of Rispolept Consta® in doses of 25 or 50 mg once every 2 weeks, the mean Cmin and Cmax values in plasma of the active antipsychotic fraction are 9.9-19.2 and 17.9-45.5 ng/ml, respectively.

In this dosing regimen, the pharmacokinetics of risperidone are linear. In long-term use (12 months), no cumulation of risperidone was observed in patients who were administered Rispolet Consta® once every 2 weeks at doses of 25-50 mg.

A study of a single-dose oral form of risperidone showed higher plasma concentrations and decreased clearance of the active antipsychotic fraction by 30% in elderly patients and by 60% in patients with renal impairment. Plasma concentrations of risperidone in patients with hepatic impairment were normal, but the mean free plasma fraction was increased by 35%.

Indications

Treatment and prevention of exacerbations of schizophrenia and schizoaffective disorders.

Active ingredient

Composition

Active ingredient:

Risperidone (in the form of sustained release microgranules);

Associates:

Lactic and glycolic acid copolymer, 619 mg (in 1 g microgranules);

Solvent:

Sodium carmellose (40 mPa-s) – 22.5 mg;

polysorbate 20 – 1 mg;

sodium hydrophosphate dihydrate – 1.27 mg;

Citric acid anhydrous – 1 mg;

sodium chloride – 6 mg;

p> sodium hydroxide – 0.54 mg;

water for injection – up to 1 ml;

How to take, the dosage

I/m, once every 2 weeks, deep into the gluteal muscle, using the sterile needle supplied with the syringe. Injections should be given alternately in the right and left buttocks. The drug should not be injected intravenously.

In patients who have not previously received risperidone, it is recommended that the tolerability of oral dosage forms of risperidone be determined before initiating treatment with Risopalept Consta®.

Adults. The recommended dose is 25 mg once every 2 weeks. Some patients require higher doses of 37.5 or 50 mg. No increase in efficacy was observed in clinical studies when 75 mg was used. The maximum dose should not exceed 50 mg once every 2 weeks.

In a 3-week period after the first administration of Rispolettes Consta®, the patient should take an effective antipsychotic.

The dose of the drug may be increased no more frequently than once every 4 weeks. The effect of such dose increases should not be expected until 3 weeks after the first injection of the increased dose.

Elderly patients. The recommended dose is 25 mg once every 2 weeks. In a 3-week period after the first injection of Rispolettes Consta®, the patient should take an effective antipsychotic.

Patients with impaired hepatic or renal function. There are currently no data on the use of Rispolettes Consta® in patients with impaired hepatic or renal function.

If patients with hepatic or renal dysfunction require treatment with Rispolettes Consta®, oral dosage form of risperidone 0.5 mg 2 times daily is recommended for the first week. During the second week, the patient may take 1 mg twice daily or 2 mg once daily. If the patient tolerates the oral dose of at least 2 mg well, the patient may be given 25 mg of Rispolept Consta® once every 2 weeks by injection.

Instructions for use

The use of Rispolettes Consta® requires strict adherence to the instructions for suspension preparation to ensure accurate administration of the drug and avoid possible errors.

Only the solvent in the pre-filled syringe can be used to prepare the suspension from the Rispolettes Consta® Prolonged Action Microgranules in the vial. The ready suspension is administered intramuscularly to the gluteal area only. Components in the package must not be substituted with any other products. To ensure application of the full dose of risperidone the entire contents of the vial must be injected. Administration of part of the contents of the vial may not ensure that the patient receives the desired dose of the drug. The drug should be administered immediately after preparation of the suspension.

Please first remove the Rispolettes Consta® container from the refrigerator and allow it to warm to room temperature for 30 minutes before preparing the suspension.

Interaction

Rispolettes Consta® increases the severity of CNS depressant effects of opioid analgesics, hypnotics, anxiolytics, tricyclic antidepressants, drugs for general anesthesia, alcohol.

Rispolettes Consta® may attenuate the effects of levodopa and other dopamine receptor agonists.

Clinically significant arterial hypotension is observed with the co-administration of risperidone with antihypertensive agents.

Caution should be exercised when co-administering Rispolept Consta® with drugs that prolong the QT interval.

Carbamazepine has been found to decrease plasma levels of the active antipsychotic fraction of risperidone. Other inducers of microsomal liver enzymes may cause similar effects. When prescribing and after withdrawal of carbamazepine or other inducers of microsomal liver enzymes the dose of Rispolett Consta® should be adjusted.

Fluoxetine and paroxetine, hepatic microsomal enzyme inducers, increase the plasma concentration of risperidone, but to a lesser extent, the concentration of the active antipsychotic fraction. When prescribing and after withdrawal of fluoxetine or paroxetine, the dose of Rispolept Consta® should be adjusted.

Topiramate moderately reduces the bioavailability of risperidone, but not of the active antipsychotic fraction. This interaction is not considered clinically significant.

Phenothiazines, tricyclic antidepressants and some β-adrenoblockers may increase plasma concentrations of risperidone, but less so the concentration of the active antipsychotic fraction.

Cimetidine and ranitidine increase the bioavailability of risperidone, but have minimal effect on the concentration of the active antipsychotic fraction.

Eritromycin, an inhibitor of microsomal liver enzyme inducers has no effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.

The cholinesterase inhibitors (galantamine and donepezil) have no clinically significant effect on the pharmacokinetics of risperidone and the active antipsychotic fraction.

There is no clinically significant displacement of the drug from plasma proteins when co-administered with drugs with high plasma protein binding.

Risperidone has no clinically significant effect on the pharmacokinetics of lithium, valproic acid, digoxin or topiramate.

Special Instructions

In patients who have not previously received risperidone, it is recommended to determine the tolerability of oral dosage forms of risperidone before initiating treatment with Rispolettes Consta®.

The use in elderly patients with dementia

The use of Rispolettes Consta® has not been studied in elderly patients with dementia because it is not indicated for this group of patients. Rispolettes Consta® is not indicated for the treatment of behavioral disorders associated with dementia.

Elevated mortality in older patients with dementia

Elderly patients with dementia treated with atypical antipsychotics had increased mortality compared to the placebo group in a meta-analysis of 17 controlled trials of atypical antipsychotics, including oral risperidone. In placebo-controlled studies of oral risperidone for this population, the mortality rate was 4% for patients taking risperidone compared with 3.1% for the placebo group. The mean age of patients who died was 86 years (range, 67-100 years). Data collected from two extensive observational studies indicate that elderly patients with dementia treated with typical antipsychotics also have a slightly increased risk of death compared with untreated patients. At this time, insufficient data have been collected to estimate this risk accurately. Nor is the cause of the increased risk known. Also, the extent to which the increased mortality may be applicable to antipsychotic medications, rather than to the characteristics of this patient group, has not been determined.

Simultaneous use with furosemide

. Elderly patients with dementia had an increased mortality when concomitant use of oral furosemide and risperidone was observed (7.3%, mean age 89 years, range 75-97 years) compared with the group taking risperidone alone (3.1%, mean age 84 years, range 70-96 years) and the group taking furosemide alone (4.1%, mean age 80 years, range 67-90 years). Increased mortality in patients taking risperidone together with furosemide was observed in 2 of 4 clinical trials. Co-administration of risperidone with other diuretics (mainly low-dose thiazide diuretics) was not associated with increased mortality.

There are no established pathophysiological mechanisms to explain this observation. Nevertheless, special caution should be exercised when prescribing the drug in such cases. The risk/benefit ratio should be carefully evaluated before prescribing. No increase in mortality has been found in patients taking other diuretics concomitantly with risperidone. Regardless of treatment, dehydration is a common risk factor for mortality and should be closely monitored in elderly patients with dementia.

Cerebrovascular side effects

In placebo-controlled clinical trials, patients with dementia taking certain atypical antipsychotics had an approximately 3-fold increased risk of cerebrovascular side effects. Combined data from 6 placebo-controlled studies including mostly elderly patients with dementia (age over 65 years) demonstrate that cerebrovascular side effects (serious and non-serious) occurred in 3.3% (33/1009) of patients taking risperidone and in 1.2% (8/712) of patients taking placebo. The risk ratio was 2.96 (1.34; 7.5 at 95% confidence interval). The mechanism of increased risk is unknown. Increased risk has not been ruled out for other antipsychotic drugs or for other patient populations. Rispolettes Consta® should be used with caution in patients with risk factors for stroke.

Orthostatic hypotension

Risperidone has α-adrenoblocking activity, and therefore may cause orthostatic hypotension in some patients, especially at the beginning of therapy. Clinically significant hypotension has been observed in the post-marketing period when concomitant use with antihypertensive drugs. Risperidone should be used with caution in patients with known cardiovascular diseases (e.g., heart failure, myocardial infarction, cardiac conduction disorders, dehydration, hypovolemia or cerebrovascular disease). It is recommended that the benefit/risk ratio be carefully evaluated when evaluating the feasibility of continuing therapy with Rispolettes Consta®.

Late dyskinesia and extrapyramidal disorders

Drugs with dopamine receptor antagonist properties may cause late dyskinesia, which is characterized by rhythmic involuntary movements, primarily of the tongue and/or facial muscles. The occurrence of extrapyramidal symptoms is a risk factor for the development of tardive dyskinesia. If a patient presents with objective or subjective symptoms suggestive of tardive dyskinesia, all antipsychotic medications should be considered for withdrawal.

Malignant neuroleptic syndrome (MNS)

Antipsychotic medications, including risperidone, may cause MNS, which is characterized by hyperthermia, muscle rigidity, instability of autonomic nervous system function, depressed consciousness, and elevated serum concentrations of CPK. Myoglobinuria (rhabdomyolysis) and acute renal failure may also occur in patients with MNS. If a patient develops symptoms of MNS it is necessary to immediately cancel all antipsychotic drugs, including Rispolettes Consta®.

Parkinson’s disease and dementia with Levi’s corpuscles

Prescribing antipsychotic drugs, including Rispolettes Consta®, to patients with Parkinson’s disease or dementia with Levi’s corpuscles should be done with caution because both groups of patients have an increased risk of MNS and increased sensitivity to antipsychotic medications (including blunting of pain sensitivity, confusion, postural instability with frequent falls and extrapyramidal symptoms). Risperidone may worsen the course of Parkinson’s disease.

Hyperglycemia and diabetes mellitus

Hyperglycemia, diabetes mellitus, and exacerbation of preexisting diabetes mellitus have been observed during treatment with Rispolept Consta®. It is likely that prior treatment weight gain is also a predisposing factor. Ketoacidosis may occur very rarely and diabetic coma is rare. All patients should be clinically monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). In patients with diabetes mellitus, regular monitoring for worsening glucose control should be performed.

Body weight gain

A significant increase in body weight has been observed during treatment with Rispolettes Consta®. Patients’ body weight should be monitored.

Hyperprolactinemia

Based on the results of studies on tissue cultures, it is suggested that growth of breast tumor cells may be stimulated by prolactin. Although clinical and epidemiologic studies have not demonstrated a clear association of hyperprolactinemia with antipsychotic medication administration, caution should be exercised when prescribing risperidone to patients with a history of severe antipsychosis. Rispolept Consta® should be used with caution in patients with existing hyperprolactinemia and in patients with possible prolactin-dependent tumors.

Longening of the QT interval

Longening of the QT interval has very rarely been observed in the post-marketing follow-up period. As with other antipsychotics, caution should be exercised when prescribing Rispolettes Consta® in patients with known cardiovascular disease, a family history of QT interval prolongation, bradycardia, electrolyte disturbances (hypokalemia, hypomagnesemia) as this may increase the risk of arrhythmogenic effects; and when used in combination with QT interval prolonging agents.

Convulsions

Rispolettes Consta® should be used with caution in patients with a history of seizures or with other medical conditions in which the seizure threshold may decrease.

Priapism

Priapism may occur with risperidone because of its alpha-adrenoblocking effects.

The regulation of body temperature

Antipsychotic medications have been credited with the undesirable effect of impairing the body’s ability to regulate temperature. Caution should be exercised when prescribing Rispolettes Consta® to patients with conditions that may contribute to an increase in internal body temperature, which include intense physical exertion, dehydration of the body, exposure to high external temperatures or concomitant use of drugs with anticholinergic activity.

Venous thromboembolism

Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Because patients taking antipsychotic medications often have a risk of developing venous thromboembolism, all possible risk factors should be identified before and during treatment with Rispolettes Consta® and preventive measures should be taken.

Intraoperative Iris Flabby Syndrome (IISDR)

IISDR has been observed during cataract surgery in patients receiving therapy with drugs with α1-adrenoreceptor antagonist activity, including Risolettes Consta®.

IsDD increases the risk of vision-related complications during and after surgical intervention. The physician performing such surgery should be informed in advance that the patient has taken or is currently taking medications with α1-adrenoreceptor antagonist activity. The potential benefit of withdrawal of therapy with α1-adrenoreceptor antagonists prior to surgery has not been established, and should be evaluated in light of the risks associated with withdrawal of antipsychotic therapy.

Renal and hepatic impairment

While Rispolettes Consta® has not been studied in patients with renal or hepatic impairment, caution should be exercised when using the drug in these patient groups.

Caution must be taken to avoid accidental insertion of Rispolettes Consta® into a blood vessel.

The drug should not be exposed to temperatures above 25 °C.

In the absence of a refrigerator, Rispolette Consta® may be stored at 25 °C or less for up to 7 days before use.

After suspension preparation: the suspension is physically and chemically stable for 24 h at 25 °C. From the microbiological point of view, the suspension should preferably be used immediately after preparation. If the suspension is not used immediately after preparation, it can be stored for no more than 6 h at 25 °C.

Incompatible combinations

Risolepte Consta® must not be mixed or diluted with any other drugs or liquids other than the specific solvent contained in the package.

The effect on the ability to drive and operate machinery. Risperidone may decrease the speed of mental and physical reactions, and therefore pats

Contraindications

With caution: cardiovascular diseases (chronic heart failure, myocardial infarction, cardiac conduction disorders); dehydration and hypovolemia; cerebral circulatory disorders; Parkinson’s disease; seizures and epilepsy (including anamnesis).

Parkinson’s disease; seizures and epilepsy (including in anamnesis); severe renal or hepatic insufficiency; drug abuse or drug addiction; conditions predisposing to development of “pirouette” tachycardia (bradycardia, electrolyte imbalance, concomitant use of QT interval prolonging drugs); brain tumor, intestinal obstruction, cases of acute drug overdose, Reye’s syndrome (antiemetic effect of risperidone may mask symptoms of these conditions); pregnancy.

Side effects

Changes of laboratory and instrumental parameters: frequently – ECG abnormalities, increased prolactin1 levels, increased activity of microsomal liver enzymes, increased transaminase activity, increased or decreased body weight; infrequently – QT interval prolongation on ECG.

Particularly: often – AV blockade, tachycardia; infrequent – Gis bundle block, atrial fibrillation, bradycardia, sinus bradycardia, palpitations.

Hematological disorders and disorders of the lymphatic system: frequently – anemia; infrequently – thrombocytopenia, neutropenia; very rarely – agranulocytosis.

Nervous system disorders: very common – parkinsonism2, akathisia2, headache; common – dizziness, sedation, somnolence, tremor, dystonia2, tardive dyskinesia, dyskinesia2; infrequent – convulsions, syncope, postural dizziness, hypoesthesia, paresthesia, lethargy, hypersomnia.

An organ of vision: often – blurred vision, conjunctivitis; rarely – flabby iris syndrome (intraoperative)4; with unknown frequency – retinal artery occlusion.

Hearing and labyrinth organ: frequently – vertigo; infrequently – ear pain.

Respiratory, thoracic and mediastinal disorders: often – shortness of breath, cough, sinus congestion, pharyngolaryngeal pain; rarely – sleep apnea syndrome.

Gastrointestinal disorders: common – vomiting, diarrhea, constipation, nausea, abdominal pain, dyspepsia, toothache, dry mouth, discomfort in the stomach, gastritis; rarely – mechanical bowel obstruction, pancreatitis; very rare – bowel obstruction.

With the kidneys and urinary tract: often – urinary incontinence; infrequently – urinary retention.

Skin and subcutaneous tissue: often – rash, eczema; infrequent – Quincke’s edema, itching, acne, alopecia, dry skin.

Muscular system and connective tissue: often – arthralgia, back pain, pain in the extremities, myalgia; infrequently – muscle weakness, pain in the neck, pain in the buttocks, musculoskeletal pain in the chest.

Endocrine system disorders: rarely – disorders of antidiuretic hormone secretion.

Metabolic and nutritional disorders: frequent – hyperglycemia; infrequent – diabetes mellitus3, increased appetite, decreased appetite; rare – hypoglycemia; very rare – diabetic ketoacidosis; with unknown frequency – water intoxication.

Infections: very common – upper respiratory tract infections; common – pneumonia, influenza, lower respiratory tract infections, bronchitis, urinary tract infections, ear infections, sinusitis, viral infections; infrequent – cystitis, gastroenteritis, infections, localized infections, subcutaneous abscess.

Injuries, poisoning and complications associated with the procedure of administering the drug: often – fall; infrequently – pain during the procedure of administering the drug.

Vascular disorders: often – hypertension, hypotension; infrequently – orthostatic hypotension.

General disorders and disorders in the area of administration: often – pyrexia, peripheral edema, chest pain, fatigue, pain, pain in the area of administration, asthenia, flu-like condition; infrequently – thickening in the area of administration, thickening, reactions in the area of administration, chest discomfort, slowness, feeling unwell; rarely – hypothermia.

The immune system: infrequent hypersensitivity; with unknown frequency – anaphylactic reactions.

Hepatobiliary disorders: rarely – jaundice.

Reproductive system and mammary glands: frequently – amenorrhea, erectile dysfunction, galactorrhea; infrequently – sexual dysfunction, gynecomastia; with unknown frequency – priapism.

Mental disorders: very common – depression, insomnia, anxiety; common – agitation, sleep disorders; infrequent – mania, decreased libido, nervousness.

Overdose

Symptoms: Symptoms observed in overdose are amplified known pharmacological effects. They include sedation, somnolence, tachycardia, decreased BP and extrapyramidal disorders. QT interval prolongation and seizures have been observed. Bidirectional ventricular tachycardia has been observed when an increased dose of oral risperidone and paroxetine is taken concomitantly. In cases of overdose, multiple drugs should be considered.

Treatment: ensure and maintain airway patency, adequate oxygenation and ventilation. Monitoring of cardiac function is necessary and should include continuous EKG monitoring to detect possible arrhythmias. Risolept® has no specific antidote, and therefore treatment should be aimed at maintaining CNS and CPS function, and detoxification therapy should be performed. In severe extrapyramidal symptoms, anticholinergic drugs should be prescribed. Medical observation and monitoring should be continued until the signs of overdose disappear.

Similarities