Zodak

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZODAC®

Composition:

Active substance: cetirizine dihydrochloride;

1 tablet contains cetirizine dihydrochloride 10 mg;

Excipients: lactose monohydrate, maize starch, povidone 30, magnesium stearate, hypromellose (2910/5), polyethylene glycol (macrogol 6000), talc, titanium dioxide (E 171), simethicone emulsion (SE 4).

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties: film-coated tablets, elongated shape, white or almost white, with a break line on one side.

Pharmacotherapeutic group. Antihistamines for systemic use. Piperazine derivatives. ATC code R06A E07.

Pharmacological Properties

Pharmacodynamics

Cetirizine, a metabolite of hydroxyzine formed in the human body, is a potent and selective antagonist of peripheral H1-receptors. In vitro receptor binding studies have shown no significant affinity for receptors other than H1-receptors.

In addition to its antihistaminic effect, cetirizine exerts an anti-allergic action: at a dose of 10 mg once or twice daily, it inhibits the late phase of eosinophil recruitment into the skin and conjunctiva of patients with atopic dermatitis following allergen challenge testing.

Studies in healthy volunteers have demonstrated that cetirizine at doses of 5 and 10 mg significantly inhibits histamine-induced skin responses such as wheal and flare reactions; however, correlation between this effect and clinical efficacy has not been established.

A 35-day study in children aged 5 to 12 years showed no evidence of tachyphylaxis to the antihistaminic effect of cetirizine (inhibition of wheal and flare reactions). After discontinuation of treatment following repeated dosing, normal skin response to histamine returned within 3 days.

In a 6-week placebo-controlled study involving 186 patients with allergic rhinitis and mild to moderate bronchial asthma, cetirizine 10 mg once daily reduced rhinitis symptoms without affecting lung function. This study confirms the safety of cetirizine use in allergic patients with mild to moderate bronchial asthma.

In a placebo-controlled study, administration of cetirizine at a high dose of 60 mg for 7 days did not cause statistically significant QT interval prolongation.

It has been demonstrated that at recommended doses, cetirizine improves quality of life in patients with perennial and seasonal allergic rhinitis.

Pharmacokinetics

The peak plasma concentration at steady state is approximately 300 ng/mL and is reached within 1.0 ± 0.5 hours. After administration of cetirizine 10 mg daily for 10 days, no accumulation was observed. The distribution of pharmacokinetic parameters such as maximum plasma concentration (Cmax) and area under the pharmacokinetic curve (AUC) is homogeneous among volunteers.

The extent of cetirizine absorption is not reduced when taken with food; however, the rate of absorption is decreased. The bioavailability of cetirizine in solution, capsule, or tablet form is similar.

The apparent volume of distribution is 0.50 L/kg. Plasma protein binding of cetirizine is 93 ± 0.3%. Cetirizine does not affect warfarin binding to plasma proteins.

Cetirizine undergoes minimal first-pass metabolism. Approximately two-thirds of the drug is excreted unchanged in urine. The terminal elimination half-life is approximately 10 hours.

Over the dose range of 5 to 60 mg, the pharmacokinetics of cetirizine are linear.

Special Patient Populations

Elderly patients: After a single 10 mg oral dose, the elimination half-life increased by approximately 50% and clearance decreased by 40% in 16 elderly patients compared to healthy adults. The reduced clearance of cetirizine in these elderly volunteers is likely due to decreased renal function.

Children, infants, and young children: The elimination half-life of cetirizine is approximately 6 hours in children aged 6 to 12 years, and 5 hours in children aged 2 to 6 years. In infants and young children (6 to 24 months of age), this value is reduced to 3.1 hours.

Patients with renal impairment: Pharmacokinetic parameters of the drug were similar in patients with mild renal impairment (creatinine clearance >40 mL/min) and healthy volunteers. In patients with moderate renal impairment, a threefold increase in elimination half-life and a 70% reduction in clearance were observed compared to healthy volunteers.

In patients undergoing hemodialysis (creatinine clearance <7 mL/min), a single 10 mg oral dose of cetirizine resulted in a threefold increase in elimination half-life and a 70% reduction in clearance compared to healthy subjects. Cetirizine is poorly removed by hemodialysis. Dose adjustment is required for patients with moderate to severe renal impairment (see section "Dosage and Administration").

Patients with hepatic impairment: In patients with chronic liver disease (hepatocellular, cholestatic disorders, and biliary cirrhosis) who received a single 10 or 20 mg dose of cetirizine, the elimination half-life increased by 50% and clearance decreased by 40% compared to healthy subjects. Dose adjustment in patients with hepatic impairment is required only if there is concomitant renal impairment.

Clinical characteristics.

Indications.

The medicinal product is indicated for the relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria in adults and children aged 6 years and older.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product, to hydroxyzine, or to any piperazine derivative.

Severe renal impairment with creatinine clearance less than 10 ml/min.

Rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Interaction with other medicinal products and other types of interactions.

Due to the pharmacokinetic and pharmacodynamic properties of cetirizine and its safety profile, no interactions are expected for this antihistamine. Throughout the period of drug interaction studies, including with pseudoephedrine or theophylline at a dose of 400 mg per day, no pharmacodynamic or statistically significant pharmacokinetic interactions were observed.

Pharmacokinetic interaction studies were conducted with cetirizine and pseudoephedrine, antipyrine, cimetidine, ketoconazole, erythromycin, and azithromycin — no pharmacokinetic interactions were observed. In a study of multiple dosing of theophylline (400 mg once daily) and cetirizine, a slight (16%) reduction in cetirizine clearance was observed, while theophylline distribution remained unchanged when cetirizine was co-administered.

Studies with cetirizine co-administered with cimetidine, glipizide, diazepam, and pseudoephedrine showed no evidence of adverse pharmacodynamic interactions.

Studies with cetirizine co-administered with azithromycin, erythromycin, ketoconazole, theophylline, and pseudoephedrine showed no evidence of adverse clinical interactions. Furthermore, concomitant administration of cetirizine with macrolides or ketoconazole has never led to clinically significant changes on the ECG.

In a study of multiple dosing of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure increased by approximately 40%, while ritonavir distribution was slightly altered (–11%) when cetirizine was co-administered.

The extent of cetirizine absorption is not reduced when taken with food, although the rate of absorption is delayed by 1 hour.

In sensitive patients, concomitant use of alcohol or other central nervous system depressants may cause additional impairment of attention and worsening of performance. However, cetirizine does not potentiate the effect of alcohol (at a blood alcohol concentration of 0.5 g/L).

Special precautions for use

Clinically significant interactions with alcohol have not been observed when administered at therapeutic doses (at blood alcohol levels of 0.5 g/L). However, concomitant use of alcohol is not recommended.

Use with caution in patients predisposed to urinary retention (e.g., spinal cord injury, prostate hyperplasia), as cetirizine may increase the risk of urinary retention.

Exercise caution when prescribing the drug to patients with epilepsy and to patients at risk of seizures.

Antihistamines suppress skin allergic reactions; therefore, administration of the medicinal product should be discontinued at least 3 days before skin testing (elimination period).

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

Cetirizine in film-coated tablets should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Pruritus and/or urticaria may occur after discontinuation of cetirizine, even if these symptoms were not present before treatment initiation. In some cases, symptoms may be severe and may require re-initiation of treatment after discontinuation.

Pediatric population

The use of the drug in the form of film-coated tablets is not recommended in children under 6 years of age, as this dosage form does not allow for appropriate dose adjustment.

Use during pregnancy or breastfeeding.

Pregnancy. There is insufficient data on the effects of the drug during pregnancy. Animal studies have not indicated any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. The drug should be prescribed to pregnant women only with caution and solely when, in the opinion of the physician, the benefit of treatment outweighs the potential risk to the fetus.

Breastfeeding period. Cetirizine passes into breast milk at concentrations ranging from 25–90% of plasma levels, depending on the time interval after drug administration. Therefore, the drug should be prescribed with caution to breastfeeding women.

Fertility. Limited data are available on the effect of cetirizine on human fertility; however, no adverse effects have been reported. Animal studies have shown no harmful effects on fertility.

Ability to affect reaction speed when driving or operating machinery.

Objective assessment of the ability to drive, presence of hidden drowsiness, and capacity to work on assembly lines revealed no clinically significant effects with the recommended 10 mg dose of the drug.

Patients intending to drive, engage in potentially hazardous activities, or operate machinery should not exceed the recommended dose and should consider their individual response to the drug. In sensitive patients, concomitant use of the drug with other central nervous system depressants may additionally impair attention and reduce performance.

Method of Administration and Dosage

Children aged 6 to 12 years: 5 mg twice daily (½ tablet twice daily).

Adults and children aged 12 years and older: 10 mg once daily (1 tablet once daily).

Tablets should be swallowed with a glass of water.

Elderly patients: if renal function is normal, dosage reduction is not required.

Patients with moderate to severe renal impairment: data on the benefit-risk ratio of the drug in patients with renal impairment are lacking. Since cetirizine is primarily excreted by the kidneys (see section "Pharmacological Properties"), in cases where alternative treatment methods cannot be used, dosing intervals should be individually adjusted. The dosage should be adjusted according to the table below. To use this dosing table, the patient's creatinine clearance (CC) in mL/min must be calculated. This can be calculated using a formula based on serum creatinine level in mg/dL:

Dosage adjustment of the drug for adult patients with renal impairment

For children with impaired kidney function, the dose should be individually adjusted based on each patient's renal clearance, age, and body weight.

Patients with hepatic impairment: dose adjustment is not required for patients with hepatic impairment only.

Patients with both hepatic and renal impairment: dose adjustment is recommended (see above, "Patients with moderate to severe renal impairment").

The duration of treatment is determined individually by the physician depending on the course of the disease.

Children. The drug can be administered to children aged 6 years and older. The tablet formulation with coating is not recommended for children under 6 years of age, as this medicinal form does not allow for appropriate dose adjustment.

Overdose.

Symptoms. Symptoms observed in cetirizine overdose are mainly related to its effect on the central nervous system or manifestations resembling an anticholinergic effect.

Adverse events observed after ingestion of doses at least five times higher than the recommended daily dose include: confusion, diarrhea, vertigo, increased fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedative effect, somnolence, stupor, tachycardia, tremor, and urinary retention.

Treatment. There is no specific antidote for cetirizine. In case of overdose, symptomatic or supportive therapy is recommended. Gastric lavage should be performed as soon as possible after drug intake. Removal of cetirizine by dialysis is ineffective.

Adverse Reactions

Clinical trials have shown that the use of cetirizine at recommended doses may cause minor adverse effects on the central nervous system, including somnolence, increased fatigue, vertigo, and headache. In some cases, there have been reports of paradoxical stimulation of the central nervous system.

Although cetirizine is a selective antagonist of peripheral H1-receptors with no significant anticholinergic activity, there have been reports of isolated cases of urinary retention, accommodation disorders, and dry mouth.

Cases of hepatic function abnormalities with increased levels of liver enzymes in combination with elevated bilirubin levels have been reported. In most cases, these symptoms resolved after discontinuation of treatment with cetirizine dihydrochloride.

In double-blind, placebo-controlled clinical or pharmacological studies comparing cetirizine with placebo or other antihistamines at recommended doses (10 mg daily for cetirizine), more than 3,200 patients receiving cetirizine were included in safety evaluations where quantitative safety data were available. In placebo-controlled studies, the following adverse effects were observed with cetirizine 10 mg in at least 1.0% of patients:

Although somnolence occurred statistically more frequently than in the placebo group, in most cases its severity was mild or moderate. Other studies have shown that when the drug was administered at the recommended daily doses in healthy young volunteers, everyday activity was not impaired.

In children aged 6 months to 12 years who were included in placebo-controlled clinical or pharmacokinetic studies, the following adverse drug reactions were observed, with a frequency of 1% or higher:

Post-marketing experience

During post-marketing use, the following adverse reactions have been observed. The reactions are categorized by frequency: uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Very rare: thrombocytopenia.

Immune system disorders

Rare: hypersensitivity.

Very rare: anaphylactic shock.

Psychiatric disorders

Uncommon: psychomotor agitation with anxiety (agitation).

Rare: aggression, confusion, depression, hallucinations, insomnia.

Very rare: tic.

Frequency not known: suicidal thoughts, nightmares.

Nervous system disorders

Uncommon: paraesthesia.

Rare: seizures, movement disorders.

Very rare: dysgeusia, syncope, tremor, dystonia, dyskinesia.

Frequency not known: amnesia, memory impairment.

Eye disorders

Very rare: accommodation disorders, blurred vision, disturbances in eye movement.

Cardiac disorders

Rare: tachycardia.

Aural and vestibular disorders

Frequency not known: vertigo.

Gastrointestinal disorders

Uncommon: diarrhoea.

Hepatobiliary disorders

Rare: liver function abnormalities (increased levels of transaminases, alkaline phosphatase, gamma-glutamyl transferase and bilirubin).

Frequency not known: hepatitis.

Skin and subcutaneous tissue disorders

Uncommon: pruritus, rash.

Rare: urticaria.

Very rare: angioedema, fixed drug eruption.

Frequency not known: acute generalized exanthematous pustulosis.

After discontinuation of cetirizine, cases of pruritus and (or) urticaria have been reported.

Musculoskeletal and connective tissue disorders

Frequency not known: arthralgia.

Renal and urinary disorders

Very rare: dysuria, enuresis.

Frequency not known: urinary retention.

Metabolism and nutrition disorders

Frequency not known: increased appetite.

General disorders

Uncommon: asthenia, malaise.

Rare: oedema.

Frequency not known: increased appetite.

Investigations

Rare: weight gain.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Packaging.

No. 30 (10×3): 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Over-the-counter.

Manufacturer.

ZENTIVA, s.r.o.

Manufacturer's address.

U Kabelovny 130, 102 37 Prague 10, Dolni Měcholupy, Czech Republic.

Marketing Authorization Holder.

Opella Health Ukraine LLC.

Address of Marketing Authorization Holder.

48-50A Zhylianska Street, Kyiv, 01033, Ukraine.