Allervay

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALLE RWAY (ALLERWAY)

Composition:

Active substance: levocetirizine dihydrochloride;

One film-coated tablet contains levocetirizine dihydrochloride 5 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry White OY-58900 (containing hypromellose (E 464), titanium dioxide (E 171), polyethylene glycol (E 1521)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval, white to almost white, film-coated, biconvex tablets with engraving «R 5» on one side and smooth on the other side.

Pharmacotherapeutic group. Antihistamines for systemic use. Piperazine derivatives. ATC code R06A E09.

Pharmacological properties.

Pharmacodynamics.

Levocetirizine is the active, stable R-enantiomer of cetirizine and belongs to the group of competitive histamine antagonists. Its pharmacological effect is due to blockade of H1-histamine receptors. The affinity of levocetirizine for H1-histamine receptors is twice as high as that of cetirizine. Levocetirizine affects the histamine-dependent phase of allergic reactions, 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-pruritic, and anti-inflammatory effects. It has almost no anticholinergic or anti-serotonergic activity.

Pharmacokinetics.

The pharmacokinetic parameters of levocetirizine exhibit linear kinetics and are independent of dose and time, with low variability among different patients. The pharmacokinetic profile after administration of a single enantiomer is the same as that observed with cetirizine. No chiral inversion occurs during absorption or elimination.

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; however, the maximum concentration (Cmax) is reduced and reaches its peak later. Bioavailability is 100%.

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

Distribution. Data on tissue distribution and penetration through the blood-brain barrier in humans are currently unavailable. In animal studies, the highest concentrations were observed in the liver and kidneys, while the lowest were found in central nervous system tissues. The volume of distribution is limited, with a value of 0.4 L/kg, indicating restricted distribution of levocetirizine. Plasma protein binding in humans is 90%.

Metabolism. In humans, the extent of metabolism is less than 14% of the administered dose of levocetirizine. Therefore, differences due to genetic polymorphism or concomitant use of enzyme inhibitors are expected to be minimal. Metabolic pathways include aromatic oxidation, N- and O-dealkylation, and conjugation with taurine. Dealkylation is primarily mediated by cytochrome CYP3A4, while aromatic oxidation involves multiple and/or undefined CYP isoforms. Levocetirizine does not affect the activity of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 at concentrations significantly exceeding the maximum plasma levels achieved after a 5 mg oral dose. Due to the low extent of metabolism and lack of inhibitory potential, drug interactions involving levocetirizine are unlikely.

Elimination. Levocetirizine is eliminated via two pathways: glomerular filtration and active tubular secretion. The elimination half-life (T1/2) in plasma of adults is 7.9 ± 1.9 hours. The T1/2 is shorter in younger children. The mean apparent total clearance in adults is 0.63 mL/min/kg. The majority of levocetirizine and its metabolites are excreted in urine—on average, 85.4% of the administered dose—while only 12.9% is eliminated via feces.

Special populations

Renal impairment

The apparent clearance of levocetirizine correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, the dosing interval should be adjusted based on creatinine clearance. In patients with end-stage renal disease and anuria, total clearance is reduced by approximately 80% compared to individuals with normal renal function. Less than 10% of levocetirizine is removed during a standard 4-hour hemodialysis session.

Clinical characteristics.

Indications.

Symptomatic treatment of allergic rhinitis (including perennial allergic rhinitis) and urticaria.

Contraindications. Hypersensitivity to levocetirizine, cetirizine, hydroxyzine, to any other piperazine derivatives, or to any other component of the medicinal product. Severe form of chronic renal insufficiency (creatinine clearance ˂ 10 mL/min). Rare hereditary disorders manifesting as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Interaction with other medicinal products and other types of interactions.

Studies on interactions of levocetirizine (including with CYP3A4 inducers) have not been conducted. Studies on cetirizine (the racemate compound) have shown that concomitant administration with antipyrine, azithromycin, cimetidine, diazepam, erythromycin, glipizide, ketoconazole, or pseudoephedrine does not cause clinically significant adverse interactions. In a multiple-dose study, concomitant administration with theophylline (400 mg/day) resulted in a slight reduction (by 16%) in cetirizine clearance (theophylline distribution remained unchanged). In multiple-dose studies with ritonavir (600 mg twice daily) and cetirizine (10 mg daily), exposure to cetirizine increased by approximately 40%, while ritonavir distribution was slightly altered (-11%) with concomitant cetirizine use. There are no data on enhanced effects of sedatives when used at therapeutic doses. However, concomitant use of sedatives with levocetirizine should be avoided.

Food intake does not affect the extent of drug absorption, but simultaneous food intake reduces the rate of its 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.

Use this medicinal product with caution in patients with chronic renal insufficiency (dose adjustment is required) and in elderly patients with renal insufficiency (possible reduction in glomerular filtration rate).

Alcohol consumption should be avoided during treatment with this medicinal product (see section "Interaction with other medicinal products and other forms of interaction").

When prescribing the medicinal product to patients with factors predisposing to urinary retention (e.g., spinal cord injury, benign prostatic hyperplasia), it should be taken into account that levocetirizine may increase the risk of urinary retention.

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

Antihistamines suppress the response to skin allergy tests; therefore, administration of the medicinal product should be discontinued 3 days prior to 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, the symptom may be intense and re-treatment may be necessary. The symptom should resolve after re-initiation of treatment.

Levocetirizine, film-coated tablets should not be administered to children under 6 years of age, as this dosage form does not allow for appropriate dose adjustment. Children under 6 years of age should be administered a medicinal product formulation suitable for pediatric use.

The medicinal product contains lactose monohydrate. In case of diagnosed intolerance to certain sugars, consult a physician before taking this medicinal product.

Use during pregnancy or breastfeeding. Levocetirizine is contraindicated in women during pregnancy. Cetirizine passes into breast milk; therefore, breastfeeding should be discontinued if the medicinal product is used.

Fertility

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

Ability to affect reaction speed when driving or operating machinery. Patients should refrain from driving or operating potentially dangerous machinery while taking this medicinal product.

Method of Administration and Dosage

The medication is intended for adults and children aged 6 years and older.

Recommended Doses

Adults and children aged 12 years and older: the daily dose is 5 mg (1 film-coated tablet) once daily.

Elderly Patients

Elderly patients with normal renal function do not require dose adjustment. Dose adjustment is recommended for elderly patients with moderate to severe renal impairment.

Renal Impairment

For patients with impaired renal function, dosage must be calculated based on creatinine clearance (CrCl) according to the table below.

To do this, determine the patient's creatinine clearance (CrCl) in mL/min using serum creatinine concentration (mg/dL) by applying the following formula:

Dosage adjustment of the drug for patients with renal function impairment

In children with renal impairment, the dose of the drug should be individually adjusted according to the patient's renal clearance and body weight.

There are no specific data regarding use in children with renal impairment.

Hepatic impairment

Dose adjustment is not required in patients with hepatic impairment. In patients with both hepatic and renal impairment, dosage regimen should be adjusted according to the table above.

Paediatric population

Children aged 6 to 12 years: recommended daily dose – 5 mg (1 film-coated tablet).

For children aged 2 to 6 years, dose adjustment is not feasible with the film-coated tablet dosage form. It is recommended to prescribe levocetirizine in a dosage form suitable for paediatric use.

Method of administration

The tablet should be taken orally, independently of food intake. The tablet must be swallowed whole, with a small amount of water. The daily dose is recommended to be administered once daily.

Duration of treatment

Patients with intermittent allergic rhinitis (disease symptoms lasting less than 4 days per week or less than 4 weeks per year) should take levocetirizine according to the course of the disease and medical history; treatment may be discontinued upon symptom resolution and resumed upon symptom recurrence.

Patients with persistent allergic rhinitis (disease symptoms lasting more than 4 days per week or more than 4 weeks per year) may be offered continuous therapy during allergen exposure periods.

There is clinical experience with levocetirizine use for at least a 6-month treatment period. In chronic conditions (chronic allergic rhinitis, chronic urticaria), treatment duration may extend up to 1 year (data available from clinical studies using the racemate).

Children. The tablet form of the drug should not be used in children under 6 years of age, as this dosage form does not allow for appropriate dose adjustment. This patient group should be prescribed levocetirizine in a dosage form suitable for paediatric use.

Overdose.

Symptoms. Symptoms of overdose in adults may include somnolence. In children, initial excitation and increased irritability may occur, followed by somnolence.

Treatment. There is no specific antidote for levocetirizine. Symptomatic and supportive therapy is recommended in case of overdose symptoms. Gastric lavage may be considered shortly after drug intake. Haemodialysis is not effective for removing levocetirizine from the body.

Adverse Reactions

Immune system disorders: hypersensitivity, including anaphylaxis.

Metabolism and nutrition disorders: increased appetite.

Nervous system disorders: somnolence, headache, fatigue, weakness, asthenia, convulsions, paraesthesia, dizziness, loss of consciousness, tremor, dysgeusia.

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

Cardiac disorders: palpitations, tachycardia.

Eye disorders: visual disturbance, blurred vision, nystagmus.

Ear and labyrinth disorders: vertigo.

Hepatobiliary disorders: hepatitis.

Renal and urinary disorders: dysuria, urinary retention.

Respiratory, thoracic and mediastinal disorders: dyspnea.

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

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

Musculoskeletal, connective tissue and bone disorders: myalgia, arthralgia.

General disorders: edema.

Investigations: weight gain, abnormal liver function tests.

The medication should be discontinued if any of the above adverse effects occur and when the cause of their development cannot be clearly identified.

Description of selected adverse reactions

Pruritus has been reported after discontinuation of levocetirizine.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is highly important. It allows continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are asked to report any suspected adverse reactions through the national reporting system.

Shelf life: 2 years.

Storage conditions: Store in a dry, light-protected place, out of reach of children, at a temperature not exceeding 25 °C.

Packaging: 10 tablets per blister pack. 1 or 2 blisters per cardboard box.

Availability category: Over-the-counter (without prescription).

Manufacturer 1: Dr. Reddy’s Laboratories Ltd, FTO – 3

Manufacturer’s location and address of the site of operation: Survey Nos. 41, 42r, 45r and 46r, Bachupally and Mandal, Medchal-Malkajgiri District – 500090, Telangana, India.

Manufacturer 2: Dr. Reddy’s Laboratories Limited

Manufacturer’s location and address of the site of operation: Unit-VI, Khol Village, Nalagarh Road, Baddi, Solan District, Himachal Pradesh, 173205, India.