Instructions for use: Tsetlo Plus film-coated tablets 12.5 mg, blister pack No. 30
Composition
active ingredients: dextromethorphan, levocetirizine;
1 tablet contains: dextromethorphan hydrobromide 7.5 mg, levocetirizine dihydrochloride 5 mg;
Excipients: corn starch, microcrystalline cellulose, magnesium stearate, talc, croscarmellose sodium, colloidal anhydrous silica, hypromellose, titanium dioxide (E171).
Dosage form
Film-coated tablets.
Main physicochemical properties: round biconvex tablets, coated with a white film coating.
Pharmacotherapeutic group
Antihistamines for systemic use.
ATX code R06A.
Pharmacological properties
Pharmacodynamics.
A combined medicinal product, the therapeutic effect of which is due to the pharmacological properties of the components that make up its composition.
Dextromethorphan is a non-opioid antitussive. It acts on the cough center in the medulla oblongata by reducing the sensitivity of receptors to stimuli from the respiratory tract, but does not suppress the respiratory center in the medulla oblongata. The antitussive effect of dextromethorphan is equivalent to that of codeine. It does not have analgesic or narcotic effects at usual dosages. It has a weak sedative effect. In therapeutic doses, dextromethorphan does not suppress ciliary activity (activity of the ciliated epithelium).
Levocetirizine is an active stable R-enantiomer of cetirizine, which belongs to the group of competitive histamine antagonists. The affinity for H1-histamine receptors of levocetirizine is 2 times higher than that of cetirizine. It affects the histamine-dependent stage of the development of an allergic reaction, reduces eosinophil migration, vascular permeability, limits the release of inflammatory mediators. It prevents the development and alleviates the course of allergic reactions, has antiexudative, anti-edematous, antipruritic, anti-inflammatory effects, has practically no anticholinergic and antiserotonin effects. In therapeutic doses, it practically does not show a sedative effect.
Pharmacokinetics.
Dextromethorphan.
Dextromethorphan is well absorbed from the digestive tract. The onset of action is observed after
15-30 minutes after oral administration. Its duration of action is approximately 3-6 hours. It is metabolized in the liver and excreted in the urine as the parent compound and demethylated metabolites, including dextrorphan, which has antitussive activity.
Levocetirizine.
The pharmacokinetic parameters of levocetirizine are linear and almost do not differ from those of cetirizine.
Absorption. The drug is rapidly and extensively absorbed after oral administration. The extent of absorption of the drug does not depend on the dose of the drug and does not change with food intake, but the maximum concentration (Cmax) of the drug decreases and reaches its maximum value later. Bioavailability reaches 100%.
In 50% of patients, the effect of the drug develops 12 minutes after taking a single dose, and in 95% - after 0.5-1 hour. Cmax in blood serum is reached 50 minutes after a single oral dose of the therapeutic dose. Equilibrium concentration in the blood is reached after 2 days of taking the drug. Cmax is 270 ng/ml after a single dose and 308 ng/ml after repeated use at a dose of 5 mg.
Distribution. There is no information on the distribution of the drug in human tissues, as well as on the penetration of levocetirizine through the blood-brain barrier. In studies, the highest concentration was recorded in the liver and kidneys, and the lowest - in the tissues of the central nervous system. The volume of distribution is 0.4 l/kg. Binding to plasma proteins is 90%.
Biotransformation. Approximately 14% of levocetirizine is metabolized in humans. The metabolic pathway includes oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation is primarily mediated by CYP3A4, while oxidation involves multiple and/or unidentified CYP isoforms. Levocetirizine does not affect the activity of cytochrome isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly above the maximum after a 5 mg oral dose. Given the low degree of metabolism and the lack of ability to inhibit metabolism, interactions of levocetirizine with other substances are unlikely.
The apparent clearance of levocetirizine in the body correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, it is recommended to adjust the dosing intervals of levocetirizine based on creatinine clearance. In anuria in patients with end-stage renal disease, total clearance is reduced by approximately 80% compared to total clearance in individuals without such impairment. The amount of levocetirizine removed during a standard 4-hour hemodialysis session was < 10%.
Indication
Short-term symptomatic treatment of respiratory diseases and nasal congestion accompanied by dry cough and associated with allergies.
Contraindication
Hypersensitivity to dextromethorphan, levocetirizine or other piperazine derivatives, as well as to other components of the drug; end-stage renal failure with an estimated glomerular filtration rate (eGFR) below 15 ml/min (requiring dialysis treatment); severe liver dysfunction; simultaneous use of the drug with monoamine oxidase inhibitors (MAOIs), specific serotonin reuptake inhibitors, other antidepressants, drugs for the treatment of Parkinson's disease or use earlier than 14 days after stopping the use of these drugs; respiratory failure, bronchial asthma, chronic obstructive pulmonary disease, pneumonia, emphysema, respiratory depression, chronic persistent productive cough.
Interaction with other medicinal products and other types of interactions
Dextromethorphan.
When dextromethorphan, which is part of the drug, is used simultaneously with other drugs, the following interactions are possible.
With amiodarone, quinidine - increased plasma concentrations of dextromethorphan.
With MAO inhibitors, drugs for the treatment of Parkinson's disease, specific serotonin reuptake inhibitors and other antidepressants - increased effect of the latter; simultaneous use of the drug with these drugs is contraindicated.
The simultaneous use of the drug with antidepressants - MAO inhibitors furazolidone, procarbazine, selegiline, linezolid should be avoided due to the increased risk of central nervous system (CNS) excitation, the development of arterial hypertension and hyperthermia, and serotonin syndrome.
CNS depressants, including psychotropic, antihistamine and antiparkinsonian drugs, as well as alcohol, when used together, enhance the sedative effect of the drug.
With CYP 2D6 enzyme inhibitors. Since dextromethorphan is metabolized by the cytochrome P450 isoenzyme CYP 2D6 and has a pronounced presystemic metabolism, simultaneous use with CYP 2D6 enzyme inhibitors can increase the concentration of dextromethorphan in the body to a level that significantly exceeds therapeutic concentrations. This increases the risk of toxic effects of dextromethorphan on the patient and can cause agitation, confusion, tremor, insomnia, diarrhea and respiratory failure, and also increases the risk of serotonin syndrome. Strong inhibitors of CYP 2D6 enzymes are fluoxetine, paroxetine, quinidine and terbinafine. With simultaneous use with quinidine, the concentration of dextromethorphan increases in blood plasma by 20 times. Amiodarone, flecainide, propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine, and thioridazine also have similar effects on the metabolism of dextromethorphan. If concomitant use of CYP 2D6 inhibitors and dextromethorphan is necessary, the patient should be carefully monitored and the dose adjusted promptly, if necessary.
With nonsteroidal anti-inflammatory drugs of the cyclooxygenase-2 (COX-2) inhibitor group. Coxibs, namely celecoxib, parecoxib and valdecoxib, may increase blood concentrations of dextromethorphan due to inhibition of its hepatic metabolism. This medicinal product should not be used with grapefruit and grapefruit juice due to inhibition of CYP 2D6 and CYP 3A4 enzymes and increased blood levels of dextromethorphan.
Levocetirizine.
No studies have been conducted on the interaction of levocetirizine with other drugs (including CYP 3A4 inducers).
Studies of the racemic compound of cetirizine have shown that concomitant use with antipyrine, pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide, or diazepam does not cause clinically significant adverse interactions.
Co-administration with theophylline (400 mg/day) reduced the total clearance of cetirizine by 16% (theophylline kinetics were not altered). In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the exposure of cetirizine increased by approximately 40%, while the distribution of ritonavir was slightly reduced (-11%) with concomitant cetirizine administration.
There is no evidence of an increase in the effect of sedatives when used in therapeutic doses. However, the use of these drugs should be avoided.
Concomitant use of cetirizine or levocetirizine with alcohol or other central nervous system depressants in susceptible patients may cause additional impairment of attention and ability to perform work.
Application features
Do not exceed the recommended dose of the drug.
The drug should be used with caution in children with atopic dermatitis (due to histamine release), patients with chronic renal failure (dosage regimen correction is required), and elderly patients with renal failure (possible decrease in glomerular filtration).
If patients have factors that provoke urinary retention (e.g. spinal cord injury, prostatic hyperplasia), it should be taken into account that levocetirizine may increase the risk of urinary retention.
The use of dextromethorphan concomitantly with alcohol and other central nervous system (CNS) depressants may potentiate their CNS depressant effects and increase toxicity.
Levocetirizine should be used with caution in patients with epilepsy and at risk of seizures, as its use may lead to increased seizures.
Antihistamines suppress the response to skin allergy testing; the drug should be discontinued 3 days before testing (withdrawal period).
Itching may occur after discontinuation of levocetirizine, even if this symptom was not present before treatment. The symptom may disappear on its own. In some cases, the symptom may be intense and re-treatment may be necessary. The symptom should disappear after re-treatment.
There have been reports of abuse and dependence with dextromethorphan. Although the dose of dextromethorphan in this medicinal product is low, this should be taken into account when prescribing the drug to children (see section "Children"), as well as to patients with a history of drug and psychotropic substance use.
Dextromethorphan is metabolized in the liver by cytochrome P450 isoenzyme CYP 2D6, the activity of which is genetically determined. In about 10% of the world's population, the activity of this enzyme is low ("slow metabolizers"). In such individuals, as well as in patients taking drugs that block CYP 2D6 (see section "Interaction with other medicinal products and other types of interactions"), signs of overdose and/or prolonged exposure to dextromethorphan may occur.
Serotonin syndrome.
Serotonergic effects of dextromethorphan, including the development of potentially life-threatening serotonin syndrome, have been reported with concomitant use of serotonergic drugs such as selective serotonin reuptake inhibitors, drugs that impair serotonin metabolism (including monoamine oxidase inhibitors and CYP 2D6 inhibitors).
Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, treatment should be discontinued.
Use during pregnancy or breastfeeding
The drug is contraindicated for use during pregnancy or breastfeeding.
Fertility
There are no clinical data (including animal studies) on the effects of levocetirizine on fertility.
The ability to influence the reaction speed when driving or working with other mechanisms
Given the possible adverse reactions, it is advisable to refrain from driving and operating other mechanisms.
Some patients may experience drowsiness, fatigue and asthenia during treatment with levocetirizine. Therefore, patients who intend to drive vehicles, operate machinery or engage in other potentially hazardous activities should take into account their reaction to the drug.
Method of administration and doses
The drug is administered orally to adults and children over 12 years of age at a dose of 1 tablet once a day. Swallow the tablet without chewing, with a small amount of water, regardless of food intake. The duration of treatment is determined by the doctor.
Elderly patients.
Elderly patients with normal renal function do not require dosage adjustment.
Patients with liver failure.
No dosage adjustment is required in patients with normal renal function and hepatic impairment. Dose adjustment is recommended in elderly patients with moderate to severe renal impairment (see section “Patients with renal impairment” below).
Patients with impaired renal function.
For patients with impaired renal function, the dose interval should be calculated individually, taking into account creatinine clearance (eGFR) according to the table.
Dose adjustment for patients with renal impairment
| Kidney function | Creatinine clearance, ml/min | Dosage and number of doses |
| Normal kidney function | ≥ 90 | 1 tab. 1 time per day |
| Mild impairment | 60 < 90 | 1 tab. 1 time per day |
| Moderate impairment | 30 < 60 | 1 tab. 1 time in 2 days |
| A sharp decline in kidney function | 15 < 30 (no need for dialysis) | 1 tab. 1 time in 3 days |
| End-stage renal failure | < 15 (dialysis required) | Contraindicated |
For children with impaired renal function, the dose of the drug should be adjusted individually, taking into account renal clearance and body weight.
Children
The drug should be used in children over 12 years of age.
Children may experience serious side effects in case of overdose, including neurological disorders. Do not exceed the recommended dose.
Overdose
Symptoms.
Overdose of levocetirizine may cause drowsiness in adults, and in children - initial agitation and increased irritability with subsequent drowsiness.
Dextromethorphan overdose may cause nausea, vomiting, dystonia, central nervous system depression, dizziness, dysarthria, myoclonus, nystagmus, drowsiness, stupor, tremor, agitation, confusion, toxic psychosis with visual hallucinations, respiratory depression, cardiotoxicity (tachycardia, abnormal ECG, including QTc prolongation), ataxia, toxic psychosis with visual hallucinations, increased excitability. In case of severe overdose, the following symptoms may be observed: coma, respiratory depression, convulsions.
Treatment.
Symptomatic and supportive therapy. Gastric lavage and the use of sorbents may be effective shortly after overdose. There is no specific antidote for levocetirizine. Activated charcoal may be given to asymptomatic patients in whom dextromethorphan overdose has occurred within the last hour. Naloxone in usual doses, as used for the treatment of opioid overdose, may be given to patients in whom dextromethorphan has caused mental depression or coma.
If seizures develop, benzodiazepines should be used, and for hyperthermia caused by serotonin syndrome, benzodiazepines and external cooling measures should be used.
Naloxone, as well as infusion therapy, can be used as an antidote to dextromethorphan in children.
Side effects
Immune system disorders: hypersensitivity reactions, including anaphylaxis.
Metabolism and nutrition disorders: increased appetite.
Psychiatric: sleep disturbances, agitation, hallucinations, depression, aggression, insomnia, suicidal thoughts, confusion, nightmares.
Nervous system: drowsiness, headache, fatigue, weakness, asthenia, convulsions, paresthesia, dizziness, fainting, tremor, dysgeusia.
On the part of the organs of vision: visual impairment, blurred vision, oculogyration.
From the organs of hearing and balance: vertigo.
From the cardiovascular system: increased heartbeat, tachycardia.
Respiratory, thoracic and mediastinal disorders: dyspnea.
On the part of the digestive tract: diarrhea, vomiting, constipation, dry mouth, nausea, abdominal pain.
From the hepatobiliary system: hepatitis.
From the urinary system: dysuria, urinary retention.
Skin and subcutaneous tissue disorders: angioedema, persistent drug eruptions, pruritus, rash, urticaria.
Musculoskeletal and connective tissue disorders: myalgia, arthralgia.
General disorders and administration site conditions: edema.
Research results: weight gain, abnormal liver function tests.
Reporting adverse reactions after registration of a medicinal product is of great importance. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the link: https://aisf.dec.gov.ua
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
10 tablets in a blister; 1 blister in a cardboard box.
10 tablets in a blister; 2 blisters in a cardboard box.
10 tablets in a blister; 3 blisters in a cardboard box.
Vacation category
Without a prescription.
Producer
Evertogen Life Sciences Limited.
Location of the manufacturer and its business address.
Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.
