Alertec

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALLELTEC® (ALLERTEC®)

Composition:

Active ingredient: cetirizine dihydrochloride;

One film-coated tablet contains 10 mg of cetirizine dihydrochloride;

Excipients: lactose monohydrate; microcrystalline cellulose; maize starch; povidone K-25; magnesium stearate; sodium starch glycolate (type C); colloidal anhydrous silicon dioxide; sodium lauryl sulfate;

Coating composition: hypromellose, polyethylene glycol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white to creamy in color, elongated, biconvex, with a smooth surface, with a break line on one side.

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

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

Cetirizine, a metabolite of hydroxyzine, is a potent, selective antagonist of peripheral histamine H1 receptors. In vitro receptor binding studies showed no significant affinity for other receptors except H1.

Pharmacodynamic effects

In addition to its H1-receptor antagonistic activity, cetirizine exerts anti-allergic effects: at a dose of 10 mg once or twice daily, the drug inhibits the late-phase migration of inflammatory cells (predominantly eosinophils) into the skin and conjunctiva of atopic individuals following antigen challenge.

Clinical efficacy and safety

Studies in healthy volunteers demonstrated that cetirizine at doses of 5 and 10 mg strongly inhibits histamine-induced wheal and flare reactions in the skin, even at very high histamine concentrations, although the correlation between this effect and clinical efficacy has not been established.

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

A placebo-controlled study in which cetirizine was administered at a high daily dose (60 mg) for 7 days showed no statistically significant QT interval prolongation.

Administration of cetirizine at standard doses improves quality of life in patients with chronic and seasonal allergic rhinitis.

Pharmacokinetics.

Absorption

The steady-state peak plasma concentration is approximately 300 ng/mL and is reached within 1±0.5 hours. The distribution of pharmacokinetic parameters such as peak plasma concentrations (Cmax) and area under the curve (AUC) is homogeneous.

The extent of cetirizine absorption is not reduced when taken with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is administered as a solution, capsules, or tablets.

Distribution

The apparent volume of distribution is 0.5 L/kg. Plasma protein binding of cetirizine is 93±0.3%. Cetirizine does not affect warfarin protein binding in blood.

Biotransformation

Cetirizine undergoes no extensive first-pass metabolism.

Elimination

The terminal elimination half-life is approximately 10 hours. No accumulation of cetirizine was observed after administration of a 10 mg daily dose for 10 days. Approximately two-thirds of the dose is excreted unchanged in urine.

Linearity/Non-linearity

Cetirizine exhibits linear kinetics over the dose range of 5 to 60 mg.

Special patient populations

Patients with renal impairment

Pharmacokinetics of the drug in patients with mild renal impairment (creatinine clearance below 40 mL/min) were similar to those in healthy volunteers. In patients with moderate renal impairment, the elimination half-life was three times longer and clearance was 70% lower than in healthy volunteers.

In patients undergoing hemodialysis (creatinine clearance below 7 mL/min), following a single 10 mg dose of cetirizine, the elimination half-life was three times longer and clearance was 70% lower compared to healthy volunteers. Cetirizine is only minimally removed from plasma by hemodialysis. Dose adjustment is required in patients with moderate or severe renal impairment (see section "Dosage and administration").

Patients with hepatic impairment

In patients with chronic liver disease (biliary cirrhosis, cholestatic liver disorders) receiving a single 10 or 20 mg dose of cetirizine, the elimination half-life was prolonged by 50% and clearance was reduced by 40% compared to healthy volunteers. Dose adjustment is required only if both hepatic and renal impairments are present simultaneously.

Elderly patients

In sixteen elderly patients, after a single 10 mg oral dose, the elimination half-life increased by approximately 50% and clearance decreased by 40% compared to younger subjects. The reduced clearance of cetirizine in elderly volunteers may be related to impaired renal function.

Pediatric population, including infants

In children aged 6–12 years, the elimination half-life of cetirizine is approximately 6 hours, and in children aged 2–6 years, it is 5 hours. In infants and children aged 6 to 24 months, the half-life is reduced to 3.1 hours.

Clinical Characteristics

Indications

Symptomatic treatment of:

• nasal and ocular symptoms of seasonal and perennial allergic rhinitis;
• chronic idiopathic urticaria.

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 (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 forms of interaction

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

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, and theophylline 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 with ritonavir (600 mg twice daily) and cetirizine (10 mg once daily), cetirizine exposure increased by approximately 40%, while ritonavir exposure was slightly reduced (-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 about 1 hour.

There are no data indicating an enhanced effect of sedatives when used at therapeutic doses. However, concomitant use of sedatives should be avoided during treatment.

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

Special precautions for use

No clinically significant interactions with alcohol have been observed when administered at therapeutic doses (with blood alcohol levels of 0.5 g/L); however, concomitant use of alcohol should be avoided.

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.

Use with caution in patients with epilepsy and in patients at risk of seizures.

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

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. Repeated treatment may only be started once symptoms have completely resolved.

Use during pregnancy or breastfeeding

Pregnancy

Available data from human studies do not indicate a causal association between cetirizine use and congenital malformations or fetal/neonatal toxicity. Animal studies have not revealed any direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition, or postnatal development. The drug should be prescribed to pregnant women only if, in the opinion of the physician, the benefit outweighs the potential risk to the fetus.

Breastfeeding period

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

Fertility

Data on the effect of cetirizine on human fertility are limited; however, no adverse effects on fertility have been identified.

Animal studies have not revealed any adverse effects on human fertility.

Ability to affect reaction speed when driving vehicles or operating machinery

Objective studies with cetirizine have shown that at the standard dose (10 mg daily), the drug does not cause significant drowsiness or reduction in psychomotor performance; therefore, its effect on the ability to drive vehicles is negligible.

Patients who plan to drive vehicles, operate moving mechanical equipment, or perform tasks requiring high levels of psychomotor alertness should not exceed the standard daily dose and should take into account their individual response to the drug. In sensitive patients, concomitant use of cetirizine with other central nervous system depressants may lead to additional impairment of attention and reduced performance.

Dosage and Administration.

Administer orally, swallowing the tablet with a glass of water. Tablets should be swallowed whole, not chewed.

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

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

Elderly patients

There are no data indicating the need for dose reduction in elderly patients with normal renal function.

Patients with moderate or severe renal impairment

There are no sufficient data on the benefit-risk ratio in patients with renal impairment. However, since cetirizine is primarily excreted by the kidneys, if alternative treatment cannot be used, the dosing intervals should be individually adjusted according to renal function.

Dosage should be adjusted as indicated in the table below.

To use the table, determine creatinine clearance (Clcr) in mL/min. Clcr (mL/min) can be calculated based on serum creatinine concentration (mg/dL) using the following formula:

Dosage adjustment for adult patients with renal impairment

Table 1

For children with renal function disorders, the dose should be individually adjusted based on creatinine clearance, age, and body weight.

Patients with hepatic impairment

There is no need for dose adjustment in patients with impaired liver function.

Patients with renal and hepatic impairment

Dose adjustment should be based on the patient's condition (see above, "Patients with moderate or severe renal impairment").

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

Children

The drug is indicated for children aged 6 years and older. The film-coated tablet formulation is not recommended for children under 6 years of age, as this dosage form does not allow for appropriate dose adjustment.

Overdose

Symptoms

Symptoms of cetirizine overdose are primarily related to effects on the central nervous system or manifestations resembling an anticholinergic effect.

Following significant overdose (at least fivefold exceeding the usual daily dose), symptoms such as confusion, diarrhea, dizziness, increased fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedative effect, somnolence, stupor, tachycardia, tremor, and urinary retention have been reported.

Treatment

There is no specific antidote.

In case of overdose, gastric lavage should be performed if less than one hour has passed since drug intake, along with symptomatic treatment.

Dialysis is not an effective method for removing cetirizine from the body.

Adverse reactions.

Clinical studies have shown that cetirizine at usual doses (10 mg per day) may cause undesirable effects on the central nervous system, including drowsiness, increased fatigue, headache, and dizziness. These effects are mild and transient in nature.

In some cases, paradoxical excitation of the central nervous system has been observed.

Although cetirizine is a selective H1-receptor antagonist and is practically devoid of cholinolytic activity, isolated cases of urinary retention, accommodation disorders of the eye, and dryness of the oral mucosa have been reported. Hepatic function disorders have also been observed, including increased activity of liver enzymes and elevated bilirubin concentration. In most cases, these symptoms resolved after discontinuation of cetirizine.

Clinical studies

In patients participating in studies comparing cetirizine with placebo or other antihistamines at recommended doses, adverse events were observed following administration of cetirizine 10 mg (see Table 2):

Table 2

Although somnolence occurred statistically more frequently than in the placebo group, in most cases its severity was mild or moderate. Objective tests, as demonstrated in other studies, have shown that administration of the drug at the recommended daily doses in healthy young volunteers did not impair daily activities.

In children aged 6 months to 12 years who were included in placebo-controlled clinical or pharmacokinetic studies, adverse drug reactions with an incidence of 1% or higher were observed (see Table 3):

Table 3

Post-marketing experience

In addition to the adverse effects reported during clinical trials and listed above, isolated cases of the following adverse reactions have been reported during post-marketing use. These adverse effects, reported less frequently, were assessed for frequency of occurrence (uncommon: ≥ 1/1,000 to < 1/100, rare: ≥ 1/10,000 to < 1/1,000, very rare: < 1/10,000, or not known: frequency cannot be estimated based on available data) based on post-marketing experience.

Blood and lymphatic system disorders

Very rare: thrombocytopenia.

Immune system disorders

Rare: hypersensitivity.

Very rare: anaphylactic shock.

Metabolism and nutrition disorders

Not known: increased appetite.

Nervous system disorders

Uncommon: mental stimulation with anxiety (agitation).

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

Very rare: nervous tic.

Not known: suicidal thoughts.

Sensory organ disorders

Eye disorders

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

Ear and labyrinth disorders

Not known: vertigo.

Cardiac disorders

Rare: tachycardia.

Gastrointestinal disorders

Uncommon: diarrhea.

Hepatobiliary disorders

Rare: liver function abnormalities (elevated levels of transaminases, alkaline phosphatase, gamma-glutamyltransferase, and bilirubin).

Skin and subcutaneous tissue disorders

Uncommon: pruritus, rash.

Rare: urticaria.

Very rare: angioneurotic edema, fixed drug eruption.

Not known: acute generalized exanthematous pustulosis.

Musculoskeletal and connective tissue disorders

Not known: arthralgia.

Renal and urinary disorders

Very rare: dysuria, enuresis.

Not known: urinary retention.

General disorders

Uncommon: asthenia, malaise.

Rare: edema.

Laboratory and diagnostic test findings

Rare: weight gain.

Description of selected adverse reactions

Cases of pruritus (intense itching) and/or urticaria have been reported following discontinuation of cetirizine.

Shelf life. 4 years.

Storage conditions.

Store at a temperature not exceeding 25 °C in a place protected from moisture, light, and out of the reach of children.

Packaging.

7 or 20 film-coated tablets in a PVC/Al blister;

1 blister pack in a cardboard box.

Pharmaceutical category. Over-the-counter.

Manufacturer.

Pharmaceutical Works «POLPHARMA» S.A.

Pharmaceutical Works «POLPHARMA» S.A.

Manufacturer's name and address of the place of business.

Production Department in Nowa Deba, 2 Metalowca Str., 39-460 Nowa Deba, Poland.