Cetlo® plus

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CETLO® PLUS (CETLO® PLUS)

Composition:

Active substances: dextromethorphan, levocetirizine;

1 tablet contains: dextromethorphan hydrobromide 7.5 mg, levocetirizine dihydrochloride 5 mg;

Excipients: maize starch, microcrystalline cellulose, magnesium stearate, talc, sodium croscarmellose, colloidal anhydrous silicon dioxide, hypromellose, titanium dioxide (E171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets.

Pharmacotherapeutic group.

Antihistamines for systemic use.

ATC code R06A.

Pharmacological properties.

Pharmacodynamics.

A combination medicinal product, whose therapeutic effect is determined by the pharmacological properties of its components.

Dextromethorphan is a non-opioid antitussive agent. 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 exert analgesic or narcotic effects at usual doses. It exhibits mild sedative activity. At therapeutic doses, dextromethorphan does not suppress ciliary activity (ciliated epithelium activity).

Levocetirizine is the active, stable R-enantiomer of cetirizine, belonging to the group of competitive histamine antagonists. The affinity of levocetirizine for H₁-histamine receptors is twice higher than that of cetirizine. It affects the histamine-dependent phase of the allergic reaction, reduces eosinophil migration, vascular permeability, and limits the release of inflammatory mediators. It prevents the development and alleviates the course of allergic reactions, exerting anti-exudative, anti-edematous, antipruritic, and anti-inflammatory effects. It practically lacks anticholinergic and anti-serotonergic activity. At therapeutic doses, it exhibits almost no sedative effect.

Pharmacokinetics.

Dextromethorphan.

Dextromethorphan is well absorbed from the gastrointestinal tract. The onset of action occurs within 15–30 minutes after oral administration. The duration of its effect is approximately 3–6 hours. It is metabolized in the liver and excreted in urine as the parent compound and demethylated metabolites, including dextrorphan, which possesses antitussive activity.

Levocetirizine.

The pharmacokinetic parameters of levocetirizine are linear and almost identical to those of cetirizine.

Absorption. The drug is rapidly and extensively absorbed after oral administration. The extent of absorption is independent of dose and is not altered by food intake, although the maximum concentration (C_max) is reduced and reached later. Bioavailability reaches 100%.

In 50% of patients, the effect develops within 12 minutes after a single dose, and in 95% of patients – within 0.5–1 hour. C_max in blood plasma is achieved within 50 minutes after a single oral therapeutic dose. Steady-state concentration in blood is reached after 2 days of drug administration. C_max is 270 ng/mL after a single dose and 308 ng/mL after repeated administration at a dose of 5 mg.

Distribution. There is no information available on tissue distribution in humans or on the penetration of levocetirizine through the blood-brain barrier. In studies, the highest concentrations were observed in the liver and kidneys, and the lowest – in central nervous system tissues. The volume of distribution is 0.4 L/kg. Plasma protein binding is 90%.

Metabolism. Approximately 14% of levocetirizine undergoes metabolism in the human body. The metabolic process includes oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation primarily involves cytochrome CYP3A4, whereas oxidation involves multiple and/or undefined CYP isoenzymes. Levocetirizine does not affect the activity of cytochrome isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly exceeding the maximum levels after oral administration of a 5 mg dose. Due to the low extent of metabolism and lack of inhibitory potential, drug interactions with levocetirizine are unlikely.

Excretion. The drug is primarily excreted via glomerular filtration and active tubular secretion. The elimination half-life (T_1/2) in adults is 7.9 ± 1.9 hours. The elimination half-life is shorter in younger children. Total clearance in adults is 0.63 mL/min/kg. Levocetirizine and its metabolites are mainly excreted in urine (on average, 85.4% of the administered dose). Only 12.9% of the administered dose is excreted in feces.

The apparent clearance of levocetirizine correlates with creatinine clearance. Therefore, for patients with moderate to severe renal impairment, the dosing intervals of levocetirizine should be adjusted according to creatinine clearance. In patients with end-stage renal disease and anuria, total clearance is reduced by approximately 80% compared to individuals without such impairments. The amount of levocetirizine removed during a standard 4-hour hemodialysis session is < 10%.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of respiratory tract disorders and nasal congestion associated with allergic conditions and accompanied by dry cough.

Contraindications.

Hypersensitivity to dextromethorphan, levocetirizine, or other piperazine derivatives, as well as to any excipient of the medicinal product; end-stage renal failure with a calculated glomerular filtration rate (cGFR) below 15 mL/min requiring dialysis treatment; severe hepatic impairment; concomitant use of the medicinal product with monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), other antidepressants, or drugs used for Parkinson’s disease treatment, or use within less than 14 days after discontinuation of these agents; respiratory insufficiency, bronchial asthma, chronic obstructive pulmonary disease, pneumonia, emphysema, respiratory depression, chronic persistent productive cough.

Interaction with other medicinal products and other forms of interaction.

Dextromethorphan.

When dextromethorphan, a component of the medicinal product, is used concomitantly with other medicinal products, the following interactions may occur.

With amiodarone, quinidine – increased plasma concentrations of dextromethorphan.

With MAO inhibitors, drugs for Parkinson’s disease treatment, selective serotonin reuptake inhibitors, and other antidepressants – enhanced effects of the latter; concomitant use of the medicinal product with these agents is contraindicated.

Concomitant use of the medicinal product with antidepressant MAO inhibitors such as furazolidone, procarbazine, selegiline, linezolid should be avoided due to the increased risk of central nervous system (CNS) stimulation, arterial hypertension, hyperthermia, and serotonin syndrome.

CNS depressants, including psychotropic agents, antihistamines, antiparkinsonian drugs, and alcohol, may enhance the sedative effect of the medicinal product when used concomitantly.

With CYP 2D6 enzyme inhibitors. Since dextromethorphan is metabolized by cytochrome P450 isoenzymes CYP 2D6 and undergoes significant presystemic metabolism, concomitant use with CYP 2D6 enzyme inhibitors may increase dextromethorphan concentrations in the body to levels significantly exceeding therapeutic concentrations. This increases the risk of dextromethorphan toxicity and may cause CNS excitation, confusion, tremor, insomnia, diarrhea, respiratory depression, and increases the risk of serotonin syndrome. Strong CYP 2D6 inhibitors include fluoxetine, paroxetine, quinidine, and terbinafine. When used concomitantly with quinidine, plasma concentrations of dextromethorphan increase 20-fold. Amiodarone, flecainide, propafenone, sertraline, bupropion, methadone, cinacalcet, haloperidol, perphenazine, and thioridazine also have a similar effect on dextromethorphan metabolism. If concomitant use of CYP 2D6 inhibitors and dextromethorphan is necessary, careful monitoring of the patient and timely dose adjustment should be performed as needed.

With nonsteroidal anti-inflammatory drugs (NSAIDs) that are selective cyclooxygenase-2 (COX-2) inhibitors. Coxibs, such as celecoxib, parecoxib, and valdecoxib, may increase blood concentrations of dextromethorphan by inhibiting its hepatic metabolism. This medicinal product should not be used with grapefruit or grapefruit juice due to inhibition of CYP 2D6 and CYP 3A4 enzymes and subsequent elevation of dextromethorphan blood levels.

Levocetirizine.

No studies on interactions between levocetirizine and other medicinal products (including CYP 3A4 inducers) have been conducted.

Studies with the racemic compound cetirizine have shown that concomitant use with antipyrine, pseudoephedrine, cimetidine, ketoconazole, erythromycin, azithromycin, glipizide, or diazepam does not result in clinically significant adverse interactions.

Concomitant use with theophylline (400 mg/day) reduces total cetirizine clearance by 16% (theophylline pharmacokinetics remain unchanged). In a study involving multiple doses of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure increased by approximately 40%, while ritonavir exposure slightly decreased (-11%) with concomitant cetirizine use.

There are no data on enhanced sedative effects when the medicinal product is used at therapeutic doses. However, concomitant use with other sedative agents should be avoided.

Food intake does not affect the extent of absorption of the medicinal product, but co-ingestion with food reduces the rate of absorption.

Concomitant use of cetirizine or levocetirizine with alcohol or other central nervous system depressants in sensitive patients may result in additional impairment of attention and ability to perform tasks.

Special precautions for use.

Do not exceed the recommended dose of the drug.

Use the drug with caution in children with atopic dermatitis (due to histamine release), in patients with chronic renal insufficiency (dose adjustment is required), and in elderly patients with renal insufficiency (possible reduction in glomerular filtration rate).

In patients with factors predisposing to urinary retention (e.g., spinal cord injuries, benign prostatic hyperplasia), it should be considered that levocetirizine may increase the risk of urinary retention.

Concomitant use of dextromethorphan with alcohol and other central nervous system (CNS) depressants may enhance their CNS depressant effects and increase toxicity.

Levocetirizine should be used with caution in patients with epilepsy or at risk of seizures, as its use may lead to increased seizure activity.

Antihistamines suppress the response to skin allergy tests; therefore, the drug should be discontinued at least 3 days before testing (elimination period).

Pruritus may occur after discontinuation of levocetirizine, even if this symptom was not present before treatment initiation. The symptom may resolve spontaneously. In some cases, it may be intense and require re-treatment. The symptom should resolve after resuming treatment.

There have been reports of abuse and dependence associated with dextromethorphan use. 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") and to patients with a history of substance or psychotropic drug abuse.

Dextromethorphan is metabolized in the liver by cytochrome P450 isoenzymes CYP 2D6, the activity of which is genetically determined. Approximately 10% of the population have low activity of this enzyme ("poor metabolizers"). In these individuals, as well as in patients taking drugs that inhibit CYP 2D6 (see section "Interaction with other medicinal products and other forms of interaction"), signs of dextromethorphan overdose and/or prolonged effects may occur.

Serotonin syndrome.

Serotonergic effects of dextromethorphan, including potentially life-threatening serotonin syndrome, have been reported when used concomitantly with serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs), and 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 abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, treatment should be discontinued.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy and breastfeeding.

Fertility

There are no clinical data (including animal studies) on the effect of levocetirizine on fertility.

Ability to affect reaction speed when driving or operating machinery.

Due to possible adverse reactions, patients should refrain from driving vehicles or operating machinery.

Some patients may experience somnolence, fatigue, and asthenia during treatment with levocetirizine. Therefore, patients intending to drive vehicles, operate machinery, or engage in other potentially hazardous activities should assess their individual response to the medicinal product.

Dosage and Administration

The drug should be administered orally to adults and children aged 12 years and older at a dose of 1 tablet once daily. The tablet should be swallowed whole with a small amount of water, regardless of food intake. The duration of treatment is determined by the physician.

Elderly patients

For elderly patients with normal renal function, dosage adjustment is not required.

Patients with hepatic impairment

For patients with normal renal function and hepatic impairment, dosage adjustment is not required. Dose adjustment is recommended for elderly patients with moderate to severe renal impairment (see section "Patients with renal impairment" below).

Patients with renal impairment

For patients with renal impairment, the dosing interval should be individually adjusted based on creatinine clearance (eGFR) according to the table.

Dosage adjustment of the drug for patients with renal impairment

Dose adjustment in children with impaired renal function should be individualized according to creatinine clearance and body weight.

Children

The drug may be administered to children aged 12 years and older.

Serious adverse effects, including neurological disturbances, may occur in children in case of overdose. The recommended dose should not be exceeded.

Overdose

Symptoms

Levocetirizine overdose may cause drowsiness in adults and initial excitation and increased irritability followed by drowsiness in children.

Dextromethorphan overdose may cause nausea, vomiting, dystonia, central nervous system depression, dizziness, dysarthria, myoclonus, nystagmus, somnolence, stupor, tremor, excitation, confusion, toxic psychosis with visual hallucinations, respiratory depression, cardiotoxicity (tachycardia, abnormal ECG including QTc prolongation), ataxia, and toxic psychosis with visual hallucinations and increased excitability. In cases of severe overdose, symptoms such as coma, respiratory depression, and seizures may occur.

Treatment

Symptomatic and supportive therapy. Gastric lavage and administration of adsorbents may be effective shortly after overdose. There is no specific antidote for levocetirizine. Activated charcoal may be administered to asymptomatic patients who have ingested dextromethorphan within the past hour. Patients who have developed dextromethorphan-induced depression of consciousness or coma may be treated with naloxone in usual doses, as in opioid overdose management.

In case of seizures, benzodiazepines should be administered. For hyperthermia associated with serotonin syndrome, benzodiazepines and external cooling measures should be used.

Naloxone may be used as an antidote to dextromethorphan in children, along with infusion therapy.

Adverse Reactions

Immune system disorders: hypersensitivity reactions, including anaphylaxis.

Metabolism and nutrition disorders: increased appetite.

Psychiatric disorders: sleep disorders, excitement, hallucinations, depression, aggression, insomnia, suicidal thoughts, confusion, nightmares.

Nervous system disorders: somnolence, headache, increased fatigue, weakness, asthenia, seizures, paraesthesia, dizziness, syncope, tremor, dysgeusia.

Eye disorders: visual disturbances, blurred vision, nystagmus.

Ear and labyrinth disorders: vertigo.

Cardiac disorders: palpitations, tachycardia.

Respiratory, thoracic and mediastinal disorders: dyspnoea.

Gastrointestinal disorders: diarrhoea, vomiting, constipation, dry mouth, nausea, abdominal pain.

Hepatobiliary disorders: hepatitis.

Renal and urinary disorders: dysuria, urinary retention.

Skin and subcutaneous tissue disorders: angioneurotic oedema, fixed drug eruptions, pruritus, rash, urticaria.

Musculoskeletal and connective tissue disorders: myalgia, arthralgia.

General disorders and administration site conditions: oedema.

Investigations: weight gain, abnormal liver function tests.

Reporting of suspected adverse reactions after marketing authorization is highly important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life: 3 years.

Storage conditions:

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach and sight 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.

Supply category:

Over-the-counter (without prescription).

Manufacturer:

Evertogen Life Sciences Limited.

Manufacturer's 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.