Amertil®

INSTRUCTIONS for medical use of the medicinal product ameritil®

Composition:

Active substance: cetirizine;

1 tablet contains 10 mg of cetirizine dihydrochloride;

Excipients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, crospovidone, magnesium stearate, hypromellose, titanium dioxide (E 171), polyethylene glycol 400.

Pharmaceutical form. Coated tablets.

Main physicochemical characteristics: white, round, biconvex coated tablets 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 selective antagonist of peripheral H1-receptors. In vitro receptor binding studies showed no affinity for other H1-receptors.

In addition to this 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 mobilization in the skin and conjunctiva of patients with atopic dermatitis who underwent allergen provocation testing.

Cetirizine at doses of 5 mg and 10 mg suppresses skin allergic reactions induced by high concentrations of histamine in the skin; however, correlation with clinical efficacy has not been established.

In a study involving children aged 5 to 12 years, no tolerance to the antihistaminic effect (suppression of skin allergic reactions) of cetirizine was observed. After discontinuation of treatment following repeated dosing, skin response to histamine typically returned to baseline within 3 days.

In a study involving patients with allergic rhinitis and mild to moderate bronchial asthma, cetirizine 10 mg once daily reduced rhinitis symptoms without affecting pulmonary function. This study confirms the safety of cetirizine use in allergic patients who have mild to moderate bronchial asthma.

Cetirizine administered at a high dose of 60 mg for 7 days did not cause a statistically significant increase in QT interval duration on ECG.

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

Pharmacokinetics.

The maximum steady-state concentration is approximately 300 ng/mL and is reached within 1 ± 0.5 hours. No accumulation was observed after administration of cetirizine 10 mg daily for 10 days.

Food intake does not reduce the extent of cetirizine absorption but decreases its absorption rate. The bioavailability of cetirizine in solution, capsule, or tablet form is equivalent.

The apparent volume of distribution is 0.5 L/kg, and plasma protein binding of cetirizine is 93 ± 0.3%. Cetirizine does not affect warfarin binding to plasma proteins.

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

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

Special patient groups

Elderly patients: After a single 10 mg oral dose, elimination half-life increased by nearly 50%, and clearance decreased by approximately 40% in elderly subjects compared to younger individuals. The reduced clearance of cetirizine in elderly volunteers was associated with impaired renal function.

Children: The elimination half-life of cetirizine is approximately 6 hours in children aged 6–12 years. In children under 7 years of age and in children aged 6 to 24 months, this value is shortened to 3.1 hours.

Patients with renal impairment: Pharmacokinetics 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, elimination half-life increased threefold and clearance decreased by 70% compared to healthy volunteers. In patients undergoing hemodialysis (creatinine clearance 7 mL/min), administration of 10 mg oral cetirizine resulted in a threefold increase in elimination half-life and a 70% reduction in clearance compared to healthy volunteers. Cetirizine is poorly removed by hemodialysis. Dose adjustment is required for patients with moderate to severe renal impairment.

Patients with hepatic impairment: In patients with chronic liver disease (hepatocellular, cholestatic, and biliary cirrhosis), following a single 10 or 20 mg dose of cetirizine, elimination half-life increased by 50% and clearance decreased by 40% compared to healthy volunteers. Dose adjustment in patients with hepatic impairment is necessary only if these patients also have concurrent renal impairment.

Clinical characteristics.

Indications.

Symptomatic treatment of nasal and ocular symptoms of seasonal and perennial allergic rhinitis, chronic idiopathic urticaria.

Contraindications.

Hypersensitivity to cetirizine, to any other component of the medicinal product, to hydroxyzine, or to any piperazine derivatives in medical history. Severe renal impairment with creatinine clearance less than 10 ml/min.

Interaction with other medicinal products and other forms of interactions.

Pharmacokinetic interaction studies have been conducted with cetirizine and pseudoephedrine, cimetidine, ketoconazole, erythromycin, and azithromycin – no pharmacokinetic interactions were observed. In a multiple-dose study of theophylline (400 mg once daily) and cetirizine, a slight (16%) reduction in cetirizine clearance was observed, while the disposition of theophylline was not affected by concomitant administration of cetirizine.

Studies of cetirizine used concomitantly with cimetidine, glipizide, diazepam, and pseudoephedrine showed no evidence of adverse pharmacodynamic interactions.

Studies of cetirizine used concomitantly 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 in ECG.

In a multiple-dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), cetirizine exposure increased by approximately 40%, while ritonavir disposition was slightly affected (–11%) with concomitant cetirizine administration.

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

There are no data regarding enhanced effects of sedatives when used at therapeutic doses. However, concomitant use of sedatives should be avoided during treatment with this medicinal product.

Concomitant administration of the medicinal product with alcohol or other central nervous system depressants may cause additional impairment of attention and deterioration of work performance, although cetirizine does not potentiate the effect of alcohol (at blood alcohol levels of 0.5 g/L).

Special precautions for use.

Use with caution in patients predisposed to urinary retention (spinal cord injury, prostate hyperplasia), as cetirizine increases the risk of developing urinary retention.

The medicinal product should be prescribed with caution in patients with epilepsy and in patients at risk of seizures.

Antihistamines suppress skin allergy tests; therefore, administration of the drug must be discontinued at least 3 days before the test (elimination period).

Use with caution in patients with chronic renal impairment (dose adjustment required) and in elderly patients with renal impairment (possible reduction in glomerular filtration rate). The daily dose should be halved in patients with renal and hepatic impairment.

The product contains lactose and therefore should not be used in patients with hereditary galactose intolerance, Lapp 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 resumption of treatment after discontinuation. Reinitiation of treatment should only occur after complete resolution of symptoms.

Use during pregnancy or breastfeeding.

Pregnancy.

There is insufficient data on the effects of the drug during pregnancy. The drug should be prescribed to pregnant women only with caution and only when, in the opinion of the physician, the benefit of use outweighs the potential risk to the fetus.

Breastfeeding period.

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

Fertility.

According to limited data, no harmful effect on human fertility has been observed. Animal studies did not reveal any adverse effects on fertility.

Ability to affect reaction speed when driving or operating machinery.

Objective assessment of the ability to drive, sleep latency, and performance on an assembly line showed no clinically significant impairment when the medicinal product was used at the recommended dose of 10 mg.

Patients who drive vehicles, perform potentially hazardous work, or operate machinery should not exceed the recommended doses and should consider their individual response to the drug.

In sensitive patients, concomitant use of the drug with other central nervous system depressants may cause additional impairment of attention.

Dosage and Administration

Administer orally.

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

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

Tablets should be swallowed with a glass of water.

Elderly patients. Dose adjustment in elderly patients is not required if renal function is normal.

Patients with moderate to severe renal impairment. There are no data regarding the benefit-risk ratio in patients with renal impairment. Since cetirizine is primarily excreted via the kidneys (see section "Pharmacological Properties"), in cases where alternative treatment methods are not available, the dosing intervals should be adjusted individually. Dose adjustments should be made according to the table below. To use this dosing table, the patient's creatinine clearance (CrCl) in mL/min must be calculated. CrCl (mL/min) can be calculated from serum creatinine levels (mg/dL) using the following formula:

[140 – age (years)] × body weight (kg)
CrCl = −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− (× 0.85 for women)
72 × serum creatinine (mg/dL)

Table 1

Dosage adjustment for adult patients with renal impairment

The dose for children with renal impairment should be individually adjusted based on renal clearance values, as well as age and body weight.

Patients with hepatic impairment. Dose adjustment is not required for patients with hepatic impairment alone.

Patients with concomitant hepatic and renal impairment. Dose adjustment is recommended.

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

Children.

The medicinal product 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 pharmaceutical form does not allow appropriate dose adjustment.

Overdose.

Symptoms. Symptoms observed in cetirizine overdose are primarily related to its effects on the central nervous system or manifestations resembling anticholinergic effects.

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

Treatment. There is no specific antidote known 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.

Cetirizine has minimal central nervous system effects when used at recommended doses, including drowsiness, increased fatigue, dizziness, and headache. In some cases, paradoxical stimulation of the central nervous system has been reported.

Although cetirizine is a selective antagonist of peripheral H1-receptors and exhibits almost no anticholinergic activity, isolated cases of urinary retention, accommodation disorders of the eye, and dry mouth have been reported.

Cases of liver function abnormalities have been reported, characterized by elevated liver enzyme levels associated with increased bilirubin levels. These conditions usually resolved after discontinuation of the drug.

Clinical studies

Safety data are available from more than 3,200 subjects who participated in double-blind, controlled studies comparing cetirizine with placebo or other antihistamines at the recommended dose (10 mg of cetirizine daily).

Summarizing these data, adverse events occurring with a frequency of 1.0% or greater during treatment with 10 mg cetirizine in placebo-controlled studies are listed in Table 2.

Table 2

Although somnolence occurred more frequently from a statistical standpoint than in the placebo group, in most cases it was of mild or moderate severity. As with other studies, results of objective assessments confirmed that administration of the recommended daily dose did not cause negative effects on everyday activities in healthy subjects.

Table 3

Adverse reactions with an incidence of 1% or more in children aged 6 months to 12 years during placebo-controlled clinical trials

Post-marketing surveillance

In addition to adverse reactions reported during clinical trials and listed above, the following adverse reactions have been reported after marketing of the medicinal product.

Adverse reactions reported after marketing of the medicinal product are listed below according to system organ class (MedDRA system) and frequency of occurrence.

Frequency data are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (frequency cannot be estimated from the available data).

Table 4

Description of individual adverse reactions

Pruritus (severe itching) and/or urticaria have been reported after discontinuation of cetirizine.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

7 tablets in a blister pack, 1 blister pack in a cardboard box.

10 tablets in a blister pack, 1, 2, or 3 blister packs in a cardboard box.

Supply category. Over-the-counter (without prescription).

Manufacturer.

Biofarm Ltd.

Manufacturer's address and place of business.

13 Walbrzyska Street, 60-198 Poznan, Poland.