Cetirizine-teva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CETIRIZINE-TEVA (CETIRIZINE-TEVA)

Composition:

Active substance: cetirizine;

1 tablet contains cetirizine dihydrochloride 10 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating (Opadry Y-1-7000): titanium dioxide (E 171), hydroxypropylmethylcellulose, polyethylene glycol 400.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white to almost white, round, biconvex, film-coated tablets with a score line on one side.

Pharmacotherapeutic group. Antihistamines for systemic use. Piperazine derivatives. ATC code R06AE07.

Pharmacological properties.

Pharmacodynamics.

Cetirizine, a metabolite of human hydroxyzine, is a potent selective antagonist of peripheral H1-receptors. In in vitro receptor binding studies, no measurable affinity for receptors other than H1-receptors has been observed. In addition to its antagonistic effect on H1-receptors, cetirizine exerts an antiallergic effect: at a dose of 10 mg once or twice daily, it inhibits the late-phase recruitment of eosinophils into the skin and conjunctiva of atopic patients who were challenged with antigen.

Pharmacokinetics.

Absorption. Peak plasma concentration reaches approximately 300 ng/mL and is achieved within 1.0 ± 0.5 hours. The distribution of pharmacokinetic parameters such as peak plasma concentration (Cmax) and area under the curve (AUC) is unimodal. The extent of cetirizine absorption is not reduced when taken with food, although the absorption rate is decreased. The bioavailability is similar when cetirizine is administered as a solution, capsules, or tablets.

Distribution. The apparent volume of distribution is 0.50 L/kg. Plasma protein binding of cetirizine is 93 ± 0.3%. Cetirizine does not alter warfarin protein binding.

Biotransformation. Cetirizine does not undergo extensive first-pass metabolism.

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

Linearity/Non-linearity. Cetirizine exhibits linear kinetics in the range of 5 to 60 mg.

Renal impairment. Pharmacokinetics of the drug were similar in patients with mild renal impairment (creatinine clearance (CrCl) above 40 mL/min) and healthy volunteers. In patients with moderate renal impairment, elimination half-life increased by threefold and clearance decreased by 70% compared to healthy volunteers. In patients undergoing hemodialysis (CrCl less than 7 mL/min), after a single 10 mg oral dose of cetirizine, elimination half-life increased threefold and clearance decreased by 70% compared to normal. Cetirizine is poorly removed by hemodialysis. Dose adjustment is required for patients with moderate or severe renal impairment (see section "Dosage and administration").

Hepatic impairment. In patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis), after 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 is required only for patients with hepatic impairment if concomitant renal impairment is present.

Geriatric patients. After a single 10 mg oral dose, elimination half-life increased by approximately 50% and clearance decreased by 40% in 16 elderly patients compared to younger patients. The reduced clearance of cetirizine in these elderly volunteers was apparently related to decreased renal function.

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

Clinical characteristics.

Indications.

Cetirizine is indicated for adults and children aged 6 years and older:

• for relief of nasal and ocular symptoms of seasonal and perennial allergic rhinitis,
• for relief of symptoms of chronic idiopathic urticaria.

Contraindications.

Hypersensitivity to cetirizine or to any other components of the medicinal product, as well as to hydroxyzine and to any piperazine derivatives.

Patients with end-stage renal disease with estimated glomerular filtration rate (eGFR) below 15 ml/min.

Interaction with other medicinal products and other forms of interactions.

Based on the pharmacokinetics, pharmacodynamics, and tolerability profile of cetirizine, the occurrence of any type of interaction when taking this antihistamine is unlikely. In particular, drug interaction studies have shown neither pharmacodynamic nor any clinically significant pharmacokinetic interaction when administered concomitantly with pseudoephedrine or theophylline (400 mg/day).

The extent of absorption of cetirizine is not reduced when taken with food, although the rate of absorption is decreased.

In sensitive patients, concomitant intake of alcohol or other CNS depressants may lead to additional reduction in alertness and impaired performance, although cetirizine does not potentiate the effect of alcohol (blood concentration of 0.5 g/l).

Special precautions for use

Clinically significant interactions with alcohol (with blood alcohol levels of 0.5 g/L) have not been observed at therapeutic doses. Nevertheless, caution should be exercised when using this medicinal product concurrently with alcohol.

Caution is advised when administering the drug to patients predisposed to urinary retention (e.g., due to spinal cord lesions, benign prostatic hyperplasia), as cetirizine may increase the risk of urinary retention.

The drug should be prescribed with caution to patients with epilepsy and to patients at risk of seizures.

Antihistamine medicinal products may influence the results of skin allergy tests; therefore, a washout period should be observed before testing (3 days).

Pruritus and/or urticaria may occur after discontinuation of cetirizine, even if these symptoms were not present prior to starting treatment. In some cases, symptoms may be severe and may require resumption of treatment after discontinuation. These symptoms usually resolve upon resumption of treatment.

Paediatric population. The use of tablets is not recommended in children under 6 years of age, as this formulation does not allow appropriate dose adjustment. A paediatric formulation of cetirizine is recommended.

This medicinal product should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption. This film-coated tablet contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Prospective data on cetirizine regarding pregnancy outcomes do not indicate a potential toxicity for the mother or embryo/fetus higher than background rates. Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonic/fetal development, delivery, or postnatal development. Nevertheless, caution should be exercised when prescribing to pregnant women.

Breastfeeding. Cetirizine passes into breast milk. The risk of adverse effects in breastfed infants cannot be excluded. Cetirizine penetrates into human breast milk at concentrations ranging from 25–90% of plasma concentrations, depending on the time interval after drug administration. Therefore, cetirizine should be used with caution in breastfeeding women.

Fertility. Limited data are available on human fertility, but no safety concerns have been identified. Animal data do not indicate a risk to human reproductive function.

Ability to affect reaction speed when driving or operating machinery.

Objective assessment of the ability to drive, operate machinery, and degree of somnolence showed no clinically relevant effect when the drug was used at the recommended dose of 10 mg. However, patients who experience drowsiness should refrain from driving, engaging in potentially hazardous activities, or operating machinery. Patients should not exceed the recommended doses and should take into account their individual response to the drug.

Dosage and Administration

Administer orally, taking with one glass of liquid. The tablet may be divided into two equal doses.

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

Children aged 6 to 12 years: 5 mg (1/2 tablet) twice daily.

Elderly patients: Data do not indicate the need for dose reduction in elderly patients, provided normal renal function.

Patients with renal impairment: There are no data confirming the benefit-risk ratio for patients with impaired renal function. Since cetirizine is primarily excreted by the kidneys, in cases where alternative treatment cannot be used, dosing intervals should be individually adjusted according to renal function.

For dose adjustment, refer to Table 1.

Table 1

Dosage adjustment for adult patients with renal impairment

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

Patients with hepatic impairment. Dose adjustment is not required in patients with isolated hepatic impairment.

Patients with concomitant hepatic and renal impairment. Dose adjustment is recommended (see section above, "Patients with renal impairment").

Children.

The use of the drug in tablet form is not recommended for children under 6 years of age, as this pharmaceutical form does not allow appropriate dose adjustment.

Overdose.

Symptoms. Symptoms observed following cetirizine overdose are mainly related to effects on the central nervous system or to effects indicating anticholinergic activity. Adverse effects reported after ingestion of doses at least five times higher than the recommended daily dose include: confusion, diarrhea, dizziness, increased fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.

Treatment. There is no specific antidote for cetirizine. Symptomatic and supportive treatment is recommended in case of overdose. Gastric lavage should be performed as soon as possible after drug ingestion. Cetirizine is not effectively removed by hemodialysis.

Adverse Reactions

Clinical studies have shown that cetirizine has minimal central nervous system (CNS) effects at recommended doses, including somnolence, increased fatigue, dizziness, and headache. In some cases, paradoxical CNS stimulation 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 hepatic function impairment with elevated liver enzymes and increased bilirubin levels have also been reported. These conditions usually resolved after discontinuation of cetirizine dihydrochloride.

Safety data are available from studies involving more than 3,200 subjects who participated in double-blind, controlled trials comparing cetirizine with placebo or other antihistamines at the recommended dose (10 mg of cetirizine daily). Based on a summary of these data, adverse events occurring at an incidence rate of 1.0% or greater with cetirizine 10 mg in placebo-controlled trials are listed in Table 2.

Table 2

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

Table 3

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

Post-marketing surveillance

In addition to the adverse reactions reported during clinical trials and listed above, the following adverse reactions have been reported in the post-marketing period.

The adverse reactions are listed by system organ class (MedDRA system) and frequency of occurrence. Frequency data are defined as follows: uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from available data).

Blood and lymphatic system disorders. Very rare: thrombocytopenia.

Immune system disorders. Rare: hypersensitivity. Very rare: anaphylactic shock.

Metabolism and nutrition disorders. Frequency not known: increased appetite.

Psychiatric disorders. Uncommon: agitation. Rare: aggression, confusion, depression, hallucinations, insomnia. Very rare: nervous tic. Frequency not known: suicidal thoughts, nightmares.

Nervous system disorders. Uncommon: paraesthesia. Rare: seizures. Very rare: dysgeusia, loss of consciousness, tremor, dystonia, dyskinesia. Frequency not known: amnesia, memory impairment.

Eye disorders. Very rare: accommodation disorder, blurred vision, oculogyration.

Ear and labyrinth disorders. Frequency not known: vertigo.

Cardiac disorders. Rare: tachycardia.

Gastrointestinal disorders. Uncommon: diarrhoea.

Hepatobiliary disorders. Rare: liver function abnormalities (elevated levels of transaminases, alkaline phosphatase, GGT, and bilirubin). Frequency not known: hepatitis.

Skin and subcutaneous tissue disorders. Uncommon: pruritus, rash. Rare: urticaria. Very rare: angioneurotic oedema, persistent drug erythema. Frequency not known: acute generalized exanthematous pustulosis.

Musculoskeletal and connective tissue disorders. Frequency not known: arthralgia, myalgia.

Renal and urinary disorders. Very rare: dysuria, enuresis. Frequency not known: urinary retention.

General disorders and administration site conditions. Uncommon: asthenia, malaise. Rare: oedema.

Investigations. Rare: weight increased.

Description of selected adverse reactions. Pruritus (intense itching) and/or urticaria have been reported after discontinuation of cetirizine.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach and sight of children.

Packaging. 7 tablets in a blister, 1 blister in a carton; 10 tablets in a blister, 1, 2, 3, or 5 blisters per carton.

Classification. Over-the-counter (without prescription).

Manufacturer. Merckle GmbH.

Manufacturer's address and place of business.
Ludwig-Merckle-Straße 3, 89143 Blaubeuren, Germany.