Rispolept^® Consta (Powder) Instructions for Use

Marketing Authorization Holder

Johnson & Johnson, LLC (Russia)

Manufactured By

Cilag, AG (Switzerland)

Contact Information

JANSSEN, pharmaceutical division of Johnson & Johnson LLC

ATC Code

N05AX08 (Risperidone)

Active Substance

Risperidone (Rec.INN registered by WHO)

Dosage Forms

	Rispolept® Consta®	Powder for preparation of prolonged-release suspension for intramuscular administration 25 mg: vial 1 pc. in a set with solvent (syringes)
		Powder for preparation of prolonged-release suspension for intramuscular administration 37.5 mg: vial 1 pc. in a set with solvent (syringes)
		Powder for preparation of prolonged-release suspension for intramuscular administration 50 mg: vial 1 pc. in a set with solvent (syringes)

Dosage Form, Packaging, and Composition

Powder for preparation of prolonged-release suspension for intramuscular administration white or almost white, free from visible foreign particles; the supplied solvent is clear colorless, free from visible mechanical particles; the drug should readily form a suspension in the solvent; the suspension should be free of lumps or visible particles; the suspension should pass through the needle smoothly, with little or no resistance.

Excipients: copolymer of lactic and glycolic acids – 619 mg (per 1 g of microgranules).

Solvent sodium carboxymethylcellulose 40 mPa.s – 22.5 mg, polysorbate 20 – 1 mg, sodium phosphate dibasic dihydrate – 1.27 mg, anhydrous citric acid – 1 mg, sodium chloride – 6 mg, sodium hydroxide – 0.54 mg, water for injections – up to 1 ml.

Vials with a pink cap (1) in a set with a syringe filled with solvent (2 ml), 1 Alaris^® Smart Site^® needle-free device for suspension preparation, 1 Needle-Pro^® safety needle (with protective device) for intramuscular injection (1 pc.) – blister packs (1) – cardboard boxes.

Powder for preparation of prolonged-release suspension for intramuscular administration white or almost white, free from visible foreign particles; the supplied solvent is clear colorless, free from visible mechanical particles; the drug should readily form a suspension in the solvent; the suspension should be free of lumps or visible particles; the suspension should pass through the needle smoothly, with little or no resistance.

Excipients: copolymer of lactic and glycolic acids – 619 mg (per 1 g of microgranules).

Solvent sodium carboxymethylcellulose 40 mPa.s – 22.5 mg, polysorbate 20 – 1 mg, sodium phosphate dibasic dihydrate – 1.27 mg, anhydrous citric acid – 1 mg, sodium chloride – 6 mg, sodium hydroxide – 0.54 mg, water for injections – up to 1 ml.

Vials with a green cap (1) in a set with a syringe filled with solvent (2 ml), 1 Alaris^® Smart Site^® needle-free device for suspension preparation, 1 Needle-Pro^® safety needle (with protective device) for intramuscular injection (1 pc.) – blister packs (1) – cardboard boxes.

Powder for preparation of prolonged-release suspension for intramuscular administration white or almost white, free from visible foreign particles; the supplied solvent is clear colorless, free from visible mechanical particles; the drug should readily form a suspension in the solvent; the suspension should be free of lumps or visible particles; the suspension should pass through the needle smoothly, with little or no resistance.

Excipients: copolymer of lactic and glycolic acids – 619 mg (per 1 g of microgranules).

Solvent sodium carboxymethylcellulose 40 mPa.s – 22.5 mg, polysorbate 20 – 1 mg, sodium phosphate dibasic dihydrate – 1.27 mg, anhydrous citric acid – 1 mg, sodium chloride – 6 mg, sodium hydroxide – 0.54 mg, water for injections – up to 1 ml.

Vials with a blue cap (1) in a set with a syringe filled with solvent (2 ml), 1 Alaris^® Smart Site^® needle-free device for suspension preparation, 1 Needle-Pro^® safety needle (with protective device) for intramuscular injection (1 pc.) – blister packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psycholeptics; antipsychotics; other antipsychotics

Pharmacological Action

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 alpha₁-adrenergic receptors and, to a lesser extent, to H₁-histaminergic and alpha₂-adrenergic receptors.

Risperidone does not bind to cholinergic receptors.

Although Risperidone is a potent D₂ receptor antagonist, which improves the positive symptoms of schizophrenia, this drug, compared to typical neuroleptics, suppresses motor activity to a lesser extent and causes catalepsy less frequently.

Due to the balanced central antagonism of serotonin and dopamine receptors, Risperidone causes fewer 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-hydroxyrisperidone constitute the active antipsychotic fraction.

Another pathway of risperidone metabolism is N-dealkylation.

In extensive metabolizers, the clearance of the active antipsychotic fraction and risperidone is 5.0 and 13.7 L/h, respectively, and in poor metabolizers it is 3.2 and 3.3 L/h, respectively.

General characteristics of risperidone after injection of Rispolept^® Consta^® to patients

After a single intramuscular injection of Rispolept^® Consta^®, the release profile of risperidone consists of a small initial phase (<1% of the dose), followed by an interval lasting 3 weeks.

After intramuscular injection, the main release of risperidone begins after 3 weeks, is maintained from the 4th to the 6th week, and decreases by the 7th week.

Therefore, the patient should take an additional antipsychotic drug during the first 3 weeks after starting treatment with Rispolept^® Consta^®.

The combination of the risperidone release profile and the dosing regimen (intramuscular injection once every two weeks) ensures the maintenance of therapeutic plasma concentrations of risperidone.

Therapeutic concentrations persist until the 4th-6th week after the last injection of Rispolept^® Consta^®.

The elimination phase is completed approximately 7-8 weeks after the last injection.

Risperidone is completely absorbed from the Rispolept^® Consta^® suspension.

Risperidone is rapidly distributed in body tissues.

The volume of distribution is 1-2 L/kg.

In plasma, Risperidone binds to albumin and alpha₁-acid glycoprotein.

Plasma protein binding of risperidone is 90%, and that of 9-hydroxyrisperidone is 77%.

After intramuscular injections of Rispolept^® Consta^® at doses of 25 or 50 mg once every two weeks, the mean minimum and maximum plasma concentrations of the active antipsychotic fraction are 9.9-19.2 ng/ml and 17.9-45.5 ng/ml, respectively.

With this dosing regimen, the pharmacokinetics of risperidone are linear.

In long-term use (12 months), no accumulation of risperidone was observed in patients who received Rispolept^® Consta^® at doses of 25-50 mg once every two weeks.

A study of the use of a single dose of the oral form of risperidone showed higher plasma concentrations and a reduced clearance of the active antipsychotic fraction by 30% in elderly patients and by 60% in patients with renal failure.

Plasma concentrations of risperidone in patients with hepatic insufficiency were within the normal range, but the mean free fraction in plasma increased by 35%.

Indications

• Treatment and prevention of exacerbations of schizophrenia and schizoaffective disorders.

ICD codes

Dosage Regimen

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

Rispolept^® Consta^® is administered once every 2 weeks by deep injection into the gluteal or deltoid muscle, using the sterile needle supplied with the syringe.

For injection into the deltoid muscle, use a 25 mm long needle; for injection into the gluteal muscle, use a 51 mm long needle.

Injections should be made alternately into the right and left gluteal or deltoid muscles.

The drug must not be administered intravenously.

Instructions for use are given below in the subsection “Instructions for Use”.

Adults (over 18 years)

The recommended dose is 25-50 mg intramuscularly once every 2 weeks.

Transfer of patients taking oral Risperidone at a fixed dose for two weeks or more to Rispolept^® Consta^® is recommended according to the following scheme.

Patients taking oral Risperidone at a dose of 4 mg or less should be transferred to Rispolept^® Consta^® at a dose of 25 mg.

Patients taking oral Risperidone at a dose of more than 4 mg should be transferred to Rispolept^® Consta^® at a dose of 37.5 mg.

Clinical studies did not show an increase in efficacy with the use of 75 mg.

The maximum dose should not exceed 50 mg once every 2 weeks.

During the 3-week period after the first administration of Rispolept^® Consta^® and during exacerbation of schizophrenia, the patient should take an effective antipsychotic agent. (Oral Risperidone or a previously used antipsychotic).

The dose of the drug can be increased no more than once every 4 weeks.

The effect of such a dose increase should not be expected earlier than 3 weeks after the first injection of the increased dose.

Children (18 years and under)

Rispolept^® Consta^® has not been studied in children under 18 years of age.

Elderly patients (65 years and over)

The recommended dose is 25 mg intramuscularly once every 2 weeks.

During the 3-week period after the first injection of Rispolept^® Consta^®, the patient should take an effective antipsychotic agent.

Clinical data on the use of Rispolept^® Consta^® in elderly patients are limited, so the drug should be used with caution in this category of patients.

Patients with impaired liver or kidney function

There are currently no data on the use of Rispolept^® Consta^® in patients with impaired liver or kidney function.

If therapy with Rispolept^® Consta^® is necessary for a patient with impaired liver or kidney function, it is recommended to take 0.5 mg of the oral dosage form of risperidone twice daily during the first week.

During the second week, the patient may take 1 mg of risperidone twice daily or 2 mg of risperidone once daily.

If the patient tolerates an oral dose of at least 2 mg well, then 25 mg of Rispolept^® Consta^® can be administered intramuscularly once every 2 weeks.

Instructions for Use

Important information

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

The package of Rispolept^® Consta^® should be taken out of the refrigerator and allowed to warm to room temperature for at least 30 minutes before preparing the suspension.

Do not heat by any other means.

The components of this kit are specifically designed for the use of Rispolept^® Consta^®.

Only the solvent supplied in the kit can be used to prepare the suspension from the Rispolept^® Consta^® prolonged-release microgranules in the vial.

Do not replace the components in the package with any other items.

Do not store the suspension after preparation.

The drug should be administered immediately after preparation of the suspension.

To ensure the administration of the full dose of risperidone, the entire contents of the vial must be administered.

Administration of part of the vial contents cannot provide the patient with the required dose of the drug.

Do not reuse: this device is for single use only.

Any attempt at subsequent reuse may adversely affect the integrity of the device itself or lead to deterioration in its performance.

1. Assemble the device components

Connect the needle-free device to the vial

Remove the cap from the vial:
– Remove the colored plastic cap from the vial.
– Wipe the unopened vial with an alcohol wipe and allow to dry.
– Do not remove the gray rubber stopper.

Prepare the needle-free device
– Holding the sterile blister with one hand, pull back and remove the paper backing with the other.
– Do not remove the needle-free device from the blister.
– To avoid contamination, do not touch the sharp tip of the device.

Connect the needle-free device to the vial
– Place the vial on a hard surface and hold the base of the vial.

Place the needle-free device vertically on the vial so that the sharp tip is in the center of the rubber stopper.

Pressing from top to bottom, push the sharp tip of the needle-free device through the center of the vial’s rubber stopper until the device is securely attached to the top of the vial.
– Do not connect the needle-free device at an angle, as the solvent may leak when transferred into the vial.

Connect the pre-filled syringe to the needle-free device

Remove the sterile blister. Important!The sterile blister of the needle-free device should only be removed when ready to remove the white cap from the syringe.
– Hold the vial vertically to avoid leakage.

Holding the base of the vial, pull the blister to remove it.
– Do not shake.
– To prevent contamination, do not touch the luer tip.
– Hold the syringe by the white collar.
– Do not hold the syringe by the glass barrel.

Remove the cap

• Holding the syringe by the white collar, break off the white cap.
  – Do not unscrew or cut off the white cap.
  – To prevent contamination, do not touch the syringe tip.
  – The broken-off cap can be discarded.

Connect the syringe and the needle-free device

• To prevent rotation during connection, firmly hold the “skirt” of the needle-free device.
  – Holding the syringe by the white collar, insert the syringe tip into the luer tip of the needle-free device.
  – Do not hold the syringe by the glass barrel. This may cause the white collar to detach.
  – Firmly screw the syringe onto the needle-free device clockwise.
  – Avoid over-tightening. This may cause the syringe to malfunction.

2. Dissolve the microgranules

Introduce the solvent

• Introduce the entire contents of the syringe with solvent into the vial. Important! The contents of the vial will now be under pressure. You need to hold the syringe plunger with your thumb.

Suspend the microgranules in the solvent

• While holding the syringe plunger with your thumb, vigorously shake the contents of the vial for at least 10 seconds until a uniform suspension is formed. After proper mixing, the suspension becomes uniform, thick, and milky in color. Microgranules may be visible in the liquid, but there should be no dry microgranules not wetted by the solvent.
  – Proceed immediately to the next step, as the suspension may settle.

Transfer the suspension into the syringe

• Turn the vial upside down and SLOWLY draw the entire contents of the vial into the syringe.

Remove the needle-free device

• Holding the syringe by the white collar, unscrew the syringe from the needle-free device.
  – Separate part of the label from the vial along the perforated line and stick it to the syringe (for identification).
  – Dispose of the vial and needle-free device in accordance with local regulations for the disposal of such waste.

3. Attach the needle

Select the appropriate needle
– Select the needle depending on the injection site (gluteal or deltoid).

Attach the needle

• Open the blister package and grasp the base of the needle.
  – Continuing to hold the syringe by the white collar, firmly secure the syringe into the luer cannula of the needle’s protective device by pressing and turning clockwise.
  – To prevent contamination, do not touch the luer tip of the protective device.

Resuspend the microgranules

• Completely remove the blister.
  – Immediately before administration, the microgranules must be resuspended, as some microgranules may settle after the suspension is prepared in the vial. The syringe must be shaken vigorously.

4.Administer the drug

Remove the transparent needle cover

• Pull the needle protector in the direction away from the syringe. While holding the syringe by the white collar, remove the transparent needle cover. DO NOT BEND the cover, as this may damage the Luer lock connection.

Remove air bubbles

• Gently tap the syringe with a finger to allow any air bubbles inside to rise to the top. While holding the syringe with the needle pointing vertically upwards, gently push the plunger upwards to remove air bubbles from the syringe and needle.

Administer the drug

• Immediately administer the entire contents of the syringe intramuscularly into the patient’s gluteal or deltoid muscle.
  – The gluteal injection must be given into the upper outer quadrant of the gluteal region.
  – The suspension must not be administered intravenously.

Retract the needle into the safety device

• Place the safety device on a flat surface at a 45-degree angle with one hand. Press down firmly with a quick motion until the needle is fully engaged in the safety device.

Precaution:

• Do not use both hands.
  – Do not disassemble the needle safety device.
  – Do not attempt to straighten the needle and do not touch the needle safety device if the needle is bent or damaged.

Dispose of the needle properly

• Before discarding the needle, ensure that the needle is securely locked inside the needle safety device.
  – Dispose of in accordance with local regulations for such waste.
  – The unused needle provided in the kit should also be disposed of.

Adverse Reactions

The most frequent adverse reactions (≥1/10) are: insomnia, anxiety, headache, upper respiratory tract infections, parkinsonism, depression, and akathisia.

In the post-marketing surveillance period, serious injection site reactions have been observed, including necrosis, abscess, cellulitis, ulceration, hematoma, cyst, and induration. The frequency of these reactions is unknown (cannot be estimated from the available data). In some cases, surgical intervention was required.

Below are the adverse reactions of Rispolept^® Consta^® that have been observed in clinical trials and during post-marketing surveillance. The frequency of adverse effects is classified as follows: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000) and frequency not known (cannot be estimated from the available data).

Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

Adverse effects are listed by frequency and system organ class.

Investigations : common – ECG abnormalities, increased prolactin level¹, increased hepatic microsomal enzymes, increased transaminases, increased or decreased body weight; uncommon – prolonged QT interval on electrocardiogram.

Cardiac disorders : common – atrioventricular block, tachycardia; uncommon – bundle branch block, atrial fibrillation, bradycardia, sinus bradycardia, palpitations.

Blood and lymphatic system disorders : common – anemia; uncommon – thrombocytopenia, neutropenia; very rare – agranulocytosis.

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

Eye disorders : common – blurred vision, conjunctivitis; rare – intraoperative floppy iris syndrome⁴; frequency not known – retinal artery occlusion.

Ear and labyrinth disorders : common – vertigo; uncommon – ear pain.

Respiratory, thoracic and mediastinal disorders : common – dyspnea, cough, nasal congestion, pharyngolaryngeal pain; rare – sleep apnea syndrome.

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

Renal and urinary disorders : common – urinary incontinence; uncommon – urinary retention.

Skin and subcutaneous tissue disorders : common – rash, eczema; uncommon – angioedema, pruritus, acne, alopecia, dry skin.

Musculoskeletal and connective tissue disorders : common – arthralgia, back pain, limb pain, myalgia; uncommon – muscle weakness, neck pain, gluteal pain, musculoskeletal chest pain.

Endocrine disorders : rare – impaired antidiuretic hormone secretion.

Metabolism and nutrition disorders : common – hyperglycemia; uncommon – diabetes mellitus³, increased appetite, decreased appetite; rare – hypoglycemia; very rare – diabetic ketoacidosis; frequency not known – water intoxication.

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

Injury, poisoning and procedural complications : common – fall; uncommon – pain during drug administration procedure.

Vascular disorders common – hypertension, hypotension; uncommon – orthostatic hypotension.

General disorders and administration site conditions common – pyrexia, peripheral edema, chest pain, fatigue, pain, injection site pain, asthenia, influenza-like illness; uncommon – injection site induration, induration, injection site reactions, chest discomfort, slowness, malaise; rare – hypothermia.

Immune system disorders : uncommon – hypersensitivity; frequency not known – anaphylactic reactions.

Hepatobiliary disorders : rare – jaundice.

Reproductive system and breast disorders : common – amenorrhea, erectile dysfunction, galactorrhea; uncommon – sexual dysfunction, gynecomastia; frequency not known – priapism.

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

¹– hyperprolactinemia may in some cases lead to gynecomastia, menstrual cycle disturbances, amenorrhea and galactorrhea.

²– extrapyramidal disorders may manifest as: parkinsonism (hypersalivation, musculoskeletal stiffness, parkinsonism, drooling, cogwheel rigidity, bradykinesia, hypokinesia, masked facies, muscle tightness, akinesia, nuchal rigidity, muscle rigidity, parkinsonian gait, glabellar reflex abnormal), akathisia (akathisia, restlessness, hyperkinesia and restless legs syndrome), tremor, dyskinesia (dyskinesia, muscle twitching, choreoathetosis, athetosis and myoclonus), dystonia.

Dystonia includes dystonia, muscle spasms, hypertonia, torticollis, involuntary muscle contractions, muscle contracture, blepharospasm, oculogyration, tongue paralysis, facial spasm, laryngospasm, myotonia, opisthotonus, oropharyngeal spasm, pleurothotonus, tongue spasm and trismus. Tremor includes tremor and parkinsonian rest tremor. It should also be noted that there is a wider range of symptoms that are not always of extrapyramidal origin.

³– in placebo-controlled trials, diabetes mellitus was observed in 0.18% of patients taking Risperidone compared with 0.11% of patients in the placebo group. The overall incidence of diabetes mellitus across all clinical trials was 0.43% of all patients taking Risperidone.

⁴– observed only in the post-marketing period.

Below are additionally listed adverse reactions observed in clinical trials of oral dosage forms of risperidone, but not manifested with the use of the prolonged-release injectable form of risperidone – Rispolept^® Consta^®. Adverse effects are listed by system organ class.

Investigations: increased body temperature, increased eosinophil count, increased white blood cell count, decreased hemoglobin level, increased creatine phosphokinase level, decreased body temperature.

Infections and infestations : tonsillitis, cellulitis, otitis media, eye infections, acarodermatitis, respiratory tract infections, onychomycosis, chronic otitis media.

Blood and lymphatic system disorders: granulocytopenia.

Immune system disorders: drug hypersensitivity.

Metabolism and nutrition disorders: anorexia, polydipsia.

Psychiatric disorders: confusion, lethargy, anorgasmia, affective flattening.

Nervous system disorders: unresponsiveness to stimuli, loss of consciousness, neuroleptic malignant syndrome, diabetic coma, stroke, depressed level of consciousness, cerebral ischemia, cerebrovascular disorders, transient ischemic attack, dysarthria, attention disturbance, balance disorder, speech disorder, coordination abnormal, movement disorder.

Eye disorders : ocular hyperemia, eye discharge, periorbital edema, dry eye, increased lacrimation, photophobia, visual acuity reduced, nystagmus, glaucoma.

Ear and labyrinth disorders: tinnitus.

Vascular disorders : flushing.

Respiratory, thoracic and mediastinal disorders: wheezing, aspiration pneumonia, pulmonary congestion, respiratory disorder, rales, epistaxis, nasal congestion, hyperventilation, dysphonia.

Gastrointestinal disorders: dysphagia, fecal incontinence, fecaloma, lip edema, cheilitis.

Skin and subcutaneous tissue disorders: skin lesion, skin disorder, skin discoloration, seborrheic dermatitis, hyperkeratosis, dandruff, erythema.

Musculoskeletal and connective tissue disorders : rhabdomyolysis, joint swelling, posture abnormal, joint stiffness.

Renal and urinary disorders: enuresis, dysuria, pollakiuria.

Reproductive system and breast disorders : erectile dysfunction, vaginal discharge, menstruation irregular.

General disorders and administration site conditions: generalized edema, face edema, gait disturbance, thirst, chills, cold extremities, withdrawal syndrome.

Class effects

As with other antipsychotic drugs, very rare cases of QT interval prolongation have been reported during post-marketing surveillance. Other cardiovascular class effects observed with antipsychotic drugs that prolong the QT interval include: ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sudden death, cardiac arrest, and torsade de pointes.

Venous thromboembolism

Cases of venous thromboembolism, including pulmonary embolism and cases of deep vein thrombosis, have been observed with the use of antipsychotic drugs (frequency unknown).

Weight increased

In 12-week placebo-controlled trials, 9% of patients taking Rispolept^® Consta^® compared with 6% of patients taking placebo, experienced a weight gain of at least 7% of their body weight at the end of the trial. In another clinical trial lasting 1 year, the change in body weight for individual patients was ±7% of the mean; 25% of patients experienced a weight gain of at least 7%.

Contraindications

• Hypersensitivity to risperidone or to any other ingredient of this drug;
• Lactation period (breastfeeding);
• Children and adolescents under 18 years of age.

With caution

Use with caution in the following conditions

• Cardiovascular diseases (chronic heart failure, history of myocardial infarction, cardiac conduction disorders);
• Dehydration and hypovolemia;
• Cerebrovascular disorders;
• Parkinson’s disease;
• Convulsions and epilepsy (including history);
• Severe renal failure;
• Hepatic failure;
• Drug abuse or drug dependence;
• Conditions predisposing to torsade de pointes tachycardia (bradycardia, electrolyte imbalance, concomitant use of drugs that prolong the QT interval);
• Brain tumor, intestinal obstruction, cases of acute drug overdose, Reye’s syndrome (the antiemetic effect of risperidone may mask the symptoms of these conditions);
• Pregnancy.

Use in Pregnancy and Lactation

Pregnancy

There are no data on the safety of risperidone use in pregnant women. In animal experiments, Risperidone did not have a direct toxic effect on the reproductive system, but caused some indirect effects mediated through prolactin and the CNS. In none of the studies did Risperidone have a teratogenic effect. If a woman has taken antipsychotic drugs (including Rispolept) in the third trimester of pregnancy, there is a risk of extrapyramidal disorders and/or withdrawal syndrome of varying severity in the newborn. These symptoms may include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder.

Rispolept^® Consta^® can be used during pregnancy only in cases where the potential benefit to the woman outweighs the possible risk to the fetus.

Lactation

In animal experiments, Risperidone and 9-hydroxyrisperidone are excreted in milk. Risperidone and 9-hydroxyrisperidone have also been found to be excreted in human milk. Therefore, women taking Rispolept^® Consta^®**, should not breastfeed.

Use in Hepatic Impairment

There are currently no data on the use of Rispolept^® Consta^® in patients with hepatic impairment.

Use in Renal Impairment

There are currently no data on the use of Rispolept^® Consta^® in patients with renal impairment.

Pediatric Use

Contraindication: children and adolescents under 18 years of age.

Geriatric Use

For elderly patients the recommended dose is 25 mg IM every 2 weeks. For the first 3 weeks after the first administration of Rispolept^® Consta^® (i.e., before the onset of action of the drug), the patient should take an effective antipsychotic agent.

Special Precautions

In patients who have not previously received Risperidone, it is recommended to determine tolerance to oral dosage forms of risperidone before initiating treatment with Rispolept^® Consta ^®.

Use in elderly patients with dementia

The use of Rispolept^® Consta^® has not been studied in elderly patients with dementia, as it is not indicated for this patient group. Rispolept^® Consta^® is not intended for the treatment of behavioral disorders associated with dementia.

Increased mortality in elderly patients with dementia

Elderly patients with dementia treated with atypical antipsychotic drugs had an increased mortality compared to the placebo group in a meta-analysis of 17 controlled trials of atypical antipsychotic drugs, including oral Risperidone. In placebo-controlled trials of oral risperidone for this population, the mortality rate was 4.0% for patients taking Risperidone compared with 3.1% for the placebo group. The average age of deceased patients was 86 years (range 67-100 years). Data from two large observational studies suggest that elderly patients with dementia treated with typical antipsychotic drugs also have a slightly increased risk of death compared to untreated patients. Currently, there is insufficient data to accurately assess this risk. The cause of this increased risk is also unknown. The extent to which the increased mortality may be applicable to antipsychotic drugs rather than the characteristics of this patient group has not been determined.

Concomitant use with furosemide

In elderly patients with dementia, increased mortality was observed with the concomitant use of furosemide and oral risperidone (7.3%, average age 89 years, range 75-97 years) compared with the group taking Risperidone alone (3.1%, average age 84 years, range 70-96 years) and the group taking furosemide alone (4.1%, average age 80 years, range 67-90 years). Increased mortality in patients taking Risperidone concomitantly with furosemide was observed in 2 out of 4 clinical trials. Concomitant use of risperidone with other diuretics (mainly low-dose thiazide diuretics) was not associated with increased mortality.

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

Cerebrovascular adverse events

In placebo-controlled clinical trials in patients with dementia taking some atypical antipsychotic drugs, an approximately 3-fold increased risk of cerebrovascular adverse events was observed. Pooled data from 6 placebo-controlled trials, which mainly included elderly patients with dementia (age over 65 years), show that cerebrovascular adverse events (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, 7.50) with a 95% confidence interval. The mechanism of the increased risk is unknown. An increased risk cannot be excluded for other antipsychotic drugs or for other patient populations. Rispolept^® Consta^® should be used with caution in patients with risk factors for stroke.

Orthostatic Hypotension

Risperidone has alpha-adrenergic blocking 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 used concomitantly with antihypertensive drugs. Risperidone should be used with caution in patients with known cardiovascular diseases (e.g., heart failure, myocardial infarction, conduction disorders, dehydration, hypovolemia, or cerebrovascular disease). A thorough benefit/risk assessment is recommended when evaluating the possibility of continuing therapy with Rispolept^® Consta^®.

Blood Disorders (Leukopenia, Neutropenia, and Agranulocytosis)

Cases of leukopenia, neutropenia, and agranulocytosis have been reported with the use of antipsychotic agents, including Rispolept^® Consta^®. Post-registration surveillance reports very rare cases of agranulocytosis (<1/10,000 patients).

Patients with a clinically significant decrease in white blood cell count or a history of drug-induced leukopenia or neutropenia should be monitored during the first few months of therapy. Discontinuation of Rispolept^® Consta^® should be considered at the first sign of a clinically significant decrease in white blood cell count in the absence of other causative factors.

Patients with clinically significant neutropenia should be closely monitored for the occurrence of fever or other signs or symptoms of infection, and such conditions should be treated promptly. Rispolept^® Consta^® should be discontinued in patients with severe neutropenia (neutrophil count <1×10⁹/L) and white blood cell count should be monitored until recovery.

Tardive Dyskinesia and Extrapyramidal Disorders

Drugs with dopamine receptor antagonist properties can cause tardive dyskinesia, characterized by rhythmic involuntary movements, predominantly 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 develops objective or subjective symptoms suggestive of tardive dyskinesia, the advisability of discontinuing all antipsychotic drugs should be considered.

Neuroleptic Malignant Syndrome (NMS)

Antipsychotic drugs, including Risperidone, can cause neuroleptic malignant syndrome (NMS), which is characterized by hyperthermia, muscle rigidity, instability of autonomic nervous system function, impaired consciousness, and elevated serum creatine phosphokinase concentrations. Patients with NMS may also develop myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops symptoms of NMS, all antipsychotic drugs, including Rispolept^® Consta^®, must be discontinued immediately.

Parkinson’s Disease and Dementia with Lewy Bodies

Antipsychotic drugs, including Rispolept^® Consta^®, should be prescribed with caution to patients with Parkinson’s disease or dementia with Lewy bodies, as both groups of patients have an increased risk of developing neuroleptic malignant syndrome and increased sensitivity to antipsychotic drugs (including blunted pain sensitivity, confusion, postural instability with frequent falls, and extrapyramidal symptoms). Risperidone may worsen the course of Parkinson’s disease.

Hypersensitivity Reactions

Although tolerance to oral forms of risperidone should be checked prior to initiating therapy with Rispolept^® Consta^®, very rare cases of anaphylactic reactions have been reported during post-marketing use in patients who previously tolerated oral risperidone.

In case of hypersensitivity reactions, administration of Rispolept^® Consta^® should be discontinued, necessary supportive clinical measures should be taken, and the patient should be monitored until symptoms resolve.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes mellitus have been observed during treatment with Rispolept^® Consta^®. Pre-treatment weight gain is also likely a predisposing factor. Ketoacidosis may occur very rarely and diabetic coma rarely. All patients should be clinically monitored for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus should be regularly monitored for worsening glucose control.

Weight Gain

Significant weight gain has been observed during treatment with Rispolept^® Consta^®. Patient body weight should be monitored.

Hyperprolactinemia

Hyperprolactinemia is a common adverse reaction during treatment with risperidone. Blood prolactin concentration should be determined in patients with signs of hyperprolactinemia (e.g., gynecomastia, menstrual cycle disorders, anovulation, impaired fertility, decreased libido, erectile dysfunction, galactorrhea).

Based on tissue culture study results, it has been suggested that prolactin may stimulate cell growth in breast tumors. Although clinical and epidemiological studies have not established a clear association between hyperprolactinemia and antipsychotic drug use, caution should be exercised when prescribing risperidone to patients with a relevant history. Rispolept^® Consta^® should be used with caution in patients with existing hyperprolactinemia and in patients with possible prolactin-dependent tumors.

QT Interval Prolongation

QT interval prolongation has been very rarely observed in post-marketing surveillance. As with other antipsychotic agents, caution should be exercised when prescribing Rispolept^® Consta^® to patients with known cardiovascular disease, family history of QT prolongation, bradycardia, electrolyte imbalances (hypokalemia, hypomagnesemia), as this may increase the risk of arrhythmogenic effect; and when used concomitantly with drugs that prolong the QT interval.

Seizures

Rispolept^® Consta^® should be used with caution in patients with a history of seizures or with other medical conditions that may lower the seizure threshold.

Priapism

Priapism may occur with risperidone use due to its alpha-adrenergic blocking effects.

Body Temperature Regulation

Antipsychotic drugs are associated with an adverse effect of impairing the body’s ability to regulate temperature. Caution is advised when prescribing Rispolept^® Consta^® to patients with conditions that may contribute to an increase in core body temperature, which include strenuous physical exercise, dehydration, 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. Since patients taking antipsychotic drugs often have risk factors for venous thromboembolism, all possible risk factors should be identified before and during treatment with Rispolept^® Consta^®, and preventive measures should be taken.

Intraoperative Floppy Iris Syndrome (IFIS)

IFIS has been observed during cataract surgery in patients receiving therapy with drugs possessing α₁-adrenergic antagonist activity, including Rispolept^® Consta^®.

IFIS increases the risk of eye-related complications during and after surgery. The operating surgeon should be informed in advance that the patient is or has been taking drugs with α₁-adrenergic antagonist activity. The potential benefit of discontinuing α₁-adrenergic antagonist therapy prior to surgery has not been established and should be weighed against the risks associated with discontinuing antipsychotic therapy.

Antiemetic Effect

An antiemetic effect was observed in preclinical studies of risperidone. The appearance of this effect in a patient may mask signs and symptoms of overdose of certain drugs or conditions such as intestinal obstruction, Reye’s syndrome, or brain tumor.

Renal and Hepatic Impairment

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

Care must be taken to avoid accidental intravascular injection of Rispolept^® Consta^®.

Effect on Ability to Drive and Use Machines

Risperidone may reduce the speed of mental and physical reactions, and therefore patients should be advised to refrain from driving vehicles and operating machinery.

Incompatible Combinations

Rispolept^® Consta^® must not be mixed or diluted with any other medicines or liquids other than the specific solvent supplied in the package.

Overdose

Overdose is less likely with parenteral forms of risperidone than with oral forms (film-coated tablets and oral solution), and therefore information concerning oral forms is provided here.

Symptoms symptoms observed in overdose are an exaggeration of known pharmacological effects. They include sedation, drowsiness, tachycardia, decreased blood pressure, and extrapyramidal disorders. QT interval prolongation and seizures have been observed. Bidirectional ventricular tachycardia has been reported with concomitant high-dose oral risperidone and paroxetine.

The possibility of multiple drug involvement should be considered in case of overdose.

Treatment ensure and maintain a patent airway, adequate oxygenation, and ventilation. Monitoring of cardiovascular function is necessary and should include continuous ECG monitoring to detect possible arrhythmias. Rispolept^® has no specific antidote, so treatment should be aimed at supporting central nervous system and cardiovascular function, and detoxification therapy should be administered. Anticholinergic drugs should be administered for severe extrapyramidal symptoms. Medical supervision and monitoring should continue until signs of overdose have resolved.

Drug Interactions

Drug interactions of Rispolept^® Consta^® with other medicinal products have not been systematically evaluated. The interaction data presented in this section are based on studies of the oral form of Rispolept^®.

Pharmacodynamic Interactions

Centrally Acting Drugs and Alcohol

Rispolept^® Consta^® enhances the CNS depressant effects of opioid analgesics, hypnotics, anxiolytics, tricyclic antidepressants, general anesthetics, and alcohol.

Levodopa and Dopamine Receptor Agonists

Rispolept^® Consta^® may antagonize the effects of levodopa and other dopamine receptor agonists. If concomitant use is necessary, particularly in patients with end-stage Parkinson’s disease, the minimum effective doses of each drug should be used.

Drugs with Hypotensive Action

Clinically significant arterial hypotension is observed when risperidone is used concomitantly with antihypertensive agents.

Drugs that Prolong the QT Interval

Caution should be exercised when Rispolept^® Consta^® is used concomitantly with drugs that prolong the QT interval, such as antiarrhythmic agents (quinidine, disopyramide, procainamide, propafenone, amiodarone, sotalol), tricyclic antidepressants (amitriptyline), tetracyclic antidepressants (maprotiline), some antihistamines, other antipsychotic agents, some antimalarial agents (quinine, mefloquine), drugs causing electrolyte imbalance (hypokalemia, hypomagnesemia), bradycardia, and drugs that inhibit the hepatic metabolism of risperidone.

Paliperidone

Since paliperidone is an active metabolite of risperidone, caution should be exercised during long-term concomitant use of Xeplion and oral risperidone or paliperidone. Data on the safety of using Xeplion with other antipsychotics are limited.

Pharmacokinetic Interactions

Risperidone is primarily metabolized by the CYP2D6 isoenzyme and to a lesser extent by CYP3A4. Both Risperidone and its active metabolite, 9-hydroxyrisperidone, are substrates of P-glycoprotein (Pgp). Substances that alter CYP2D6 activity, or substances that are strong inhibitors or inducers of CYP3A4 and/or Pgp activity, may affect the pharmacokinetics of risperidone and the active antipsychotic fraction.

Strong CYP2D6 Inhibitors

Concomitant use of Rispolept^® Consta^® with a strong CYP2D6 inhibitor may increase the plasma concentration of risperidone, but to a lesser extent the active antipsychotic fraction. Higher doses of a strong CYP2D6 inhibitor may increase the concentration of both risperidone and the active antipsychotic fraction (e.g., paroxetine, see below). Other CYP2D6 inhibitors, such as quinidine, are expected to affect risperidone plasma concentrations in a similar manner. When paroxetine, quinidine, or another strong CYP2D6 inhibitor is used concomitantly, especially at higher doses, the dose of Rispolept^® Consta^® should be adjusted.

CYP3A4 and/or P-GP Inhibitors

Concomitant administration of Rispolept^® Consta^® with a strong inhibitor of CYP3A4 and/or Pgp may significantly increase the plasma concentrations of risperidone and the active antipsychotic fraction. When itraconazole or another strong inhibitor of CYP3A4 and/or Pgp is used concomitantly, the dose of Rispolept^® Consta^® should be adjusted.

CYP3A4 and/or P-GP Inducers

Concomitant use of Rispolept^® Consta^® with a strong inducer of CYP3A4 and/or P-GP may decrease the plasma concentration of risperidone and the active antipsychotic fraction. When carbamazepine or another strong inducer of CYP3A4 and/or P-GP is used concomitantly, the dose of Rispolept^® Consta^® should be adjusted. The degree of induction may change over time, with the maximum effect achieved up to 2 weeks after initiation and the induction decreasing up to 2 weeks after discontinuation of the drug.

Drugs Highly Bound to Plasma Proteins

No clinically significant displacement from plasma proteins is observed when used concomitantly with drugs that are highly bound to plasma proteins.

When used concomitantly, refer to the prescribing information for the respective medicinal product and adjust the doses of the drugs taken if necessary.

Antibacterial Drugs

Erythromycin, a moderate CYP3A4 inhibitor and Pgp inhibitor, does not alter the pharmacokinetics of risperidone and the active antipsychotic fraction.

Rifampicin, a strong inducer of CYP3A4 and Pgp, reduces the plasma concentration of the active antipsychotic fraction.

Anticholinesterase Drugs

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

Antiepileptic Drugs

Carbamazepine, a strong inducer of CYP3A4 and Pgp, reduces the plasma levels of the active antipsychotic fraction of risperidone. A similar effect is observed with phenytoin and phenobarbital, which are also inducers of CYP3A4 and Pgp.

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

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

Antifungal Drugs

Itraconazole, a strong inhibitor of CYP3A4 and Pgp, at a dose of 200 mg/day increases the plasma concentration of the active antipsychotic fraction by approximately 70% when risperidone is used at doses from 2 to 8 mg/day.

Ketoconazole, a strong inhibitor of CYP3A4 and Pgp, at a dose of 200 mg/day increases the plasma concentration of risperidone and decreases the plasma concentration of 9-hydroxyrisperidone.

Antipsychotic Drugs

Phenothiazines may increase the plasma concentration of risperidone, but to a lesser extent the concentration of the active antipsychotic fraction.

Aripiprazole, a substrate of CYP2D6 and CYP3A4: Risperidone does not affect the pharmacokinetics of aripiprazole and its active metabolite, dehydroaripiprazole.

Antiviral Drugs

Protease inhibitors: No formal study data are available. Since ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6, ritonavir and ritonavir-boosted protease inhibitors may lead to increased concentrations of risperidone and the active antipsychotic fraction.

Beta-Blockers

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

Calcium Channel Blockers

Verapamil, a moderate inhibitor of CYP3A4 and Pgp, increases the plasma concentration of risperidone and the active antipsychotic fraction.

Cardiac Glycosides

Risperidone has no clinically significant effect on the pharmacokinetics of digoxin.

Diuretics

See the “Special Precautions” section regarding increased mortality in elderly patients with dementia when furosemide and oral forms of risperidone are used concomitantly.

Gastrointestinal Drugs

H₂ receptor antagonists: Cimetidine and ranitidine, which are weak inhibitors of CYP2D6 and CYP3A4, increase the bioavailability of risperidone but minimally affect the concentration of the active antipsychotic fraction.

Lithium Preparations

Risperidone has no clinically significant effect on the pharmacokinetics of lithium preparations.

Serotonin Reuptake Inhibitors and Tricyclic Antidepressants

Fluoxetine, a strong inhibitor of CYP2D6, increases the plasma concentration of risperidone but has a lesser effect on the concentration of the active antipsychotic fraction.

Paroxetine, a strong CYP2D6 inhibitor, increases the plasma concentration of risperidone, but at doses up to 20 mg/day, it has a lesser effect on the concentration of the active antipsychotic fraction. However, higher doses of paroxetine may increase the concentration of the active antipsychotic fraction of risperidone.

Tricyclic antidepressants may increase the plasma concentration of risperidone but do not affect the concentration of the active antipsychotic fraction. Amitriptyline does not affect the pharmacokinetics of risperidone or the active antipsychotic fraction.

Sertraline is a weak CYP2D6 inhibitor, and fluvoxamine is a weak CYP3A4 inhibitor. At doses up to 100 mg/day, sertraline and fluvoxamine do not have a clinically significant effect on the concentration of the active antipsychotic fraction of risperidone. However, the use of doses higher than 100 mg/day may lead to an increase in the concentration of risperidone and the active antipsychotic fraction.

Storage Conditions

The drug should be stored out of the reach of children, in a light-protected place at a temperature from 2°C (35.6°F) to 8°C (46.4°F).

Shelf Life

The shelf life is 3 years.

The drug must not be exposed to temperatures above 25°C (77°F). In the absence of a refrigerator, Rispolept^® Consta^® can be stored before use at a temperature not exceeding 25°C (77°F) for no more than 7 days.

The prepared suspension is physically and chemically stable for 24 hours at a temperature of 25°C (77°F). From a microbiological point of view, the suspension is preferably used immediately after preparation. If the suspension is not used immediately after preparation, it can be stored for no more than 6 hours at a temperature of 25°C (77°F).

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.