Hydroxyzine Canon, 25 mg, film-coated tablets, 25 pcs.
Pharmacotherapeutic group: anxiolytic agent (tranquilizer)
ATX code: [N05BB01]
Pharmacological properties
Pharmacodynamics Hydroxyzine is a first-generation H1-histamine receptor blocker, a derivative of phenothiazine with antimuscarinic and sedative properties and diphenylmethane, which helps inhibit the activity of certain subcortical zones. It has H1-histamine blocking, bronchodilating and antiemetic effects, and has a moderate inhibitory effect on gastric secretion. Hydroxyzine significantly reduces itching in patients with urticaria, eczema and dermatitis. Hydroxyzine has a positive effect on cognitive abilities, improves attention and memory. Hydroxyzine does not cause addiction or mental dependence; with prolonged use, no withdrawal syndrome has been observed. Hydroxyzine is capable of depressing the central nervous system, and also has anticholinergic, antihistamine, antispasmodic, local anesthetic, sympatholetic effects, and has muscle relaxant activity. In case of liver failure, the H1-histamine blocking effect can be prolonged up to 96 hours after a single dose. Has moderate anxiolytic activity. Polysomnography in patients with insomnia and anxiety demonstrates an increase in sleep duration and a decrease in the frequency of night awakenings after single or repeated administration of hydroxyzine at a dose of 50 mg. A decrease in muscle tension in patients with anxiety was noted when taking the drug at a dose of 50 mg 3 times a day. The H1-histamine blocking effect occurs approximately 1 hour after taking the tablets orally. The sedative effect appears after 30-45 minutes.
Pharmacokinetics.
Absorption: Absorption is high. The time to reach maximum concentration (TCmax) after oral administration is 2 hours. After taking an average dose of 50 mg, the Tmax in adults is 70 mg/ml. Distribution: The distribution coefficient is 7-16 l/kg in adults. Hydroxyzine penetrates the blood-brain barrier and the placenta, concentrating more in fetal than maternal tissues. After oral administration, hydroxyzine penetrates well into the skin, with hydroxyzine concentrations in the skin far exceeding serum concentrations after both single and multiple doses. Plasma concentration of hydroxyzine does not necessarily reflect its tissue binding or distribution at skin receptors. It has an effect on skin inflammation depending on serum concentration. Metabolism: Hydroxyzine is metabolized in the liver. Cetirizine - the main metabolite (45%) is a blocker of H1-histamine receptors. Metabolites are found in breast milk. Elimination: Half-life (T1/2) in adults is 14 hours (range: 7-20 hours). The total clearance of hydroxyzine is 13 ml/min/kg. About 0.8% of hydroxyzine is excreted unchanged through the kidneys. The main metabolite cetirizine is excreted mainly in the urine, also unchanged (25% of the dose of hydroxyzine). Pharmacokinetics in special groups of patients. In elderly patients In elderly patients T1/2 was 29 hours. The volume of distribution is 22.5 l/kg. It is recommended to reduce the daily dose of hydroxyzine when prescribed to elderly patients. Children under 1 year In children, the total clearance is 2.5 times higher than in adults. The dose must be adjusted. The half-life is 4 hours. Children from 1 year to 14 years The half-life is 11 hours. In patients with liver failure In patients with liver dysfunction secondary to primary biliary cirrhosis, the total clearance was approximately 66% of the value recorded in healthy volunteers. In patients with liver diseases, T1/2 increased to 37 hours, the concentration of metabolites in the blood serum was higher than in young patients with normal liver function. For patients with liver failure, a reduction in the daily dose or frequency of administration is recommended. In patients with renal failure The pharmacokinetics of hydroxyzine was studied in 8 patients with severe renal failure (creatinine clearance 24+7 ml/min). The duration of exposure to hydroxyzine did not change significantly, while the duration of exposure to cetirizine was increased. To avoid any significant accumulation of cetirizine metabolite after repeated use of hydroxyzine in patients with impaired renal function, the daily dose of hydroxyzine should be reduced.
HYDROXYZINE
Contraindications for co-administration
Co-administration of hydroxyzine with drugs known to prolong the QT interval and/or cause torsade de pointes (TdP), for example, class IA (such as quinidine, disopyramide) and class III antiarrhythmics (such as amiodarone, sotalol), some antihistamines drugs, some antipsychotics (eg, haloperidol), some antidepressants (eg, citalopram, escitalopram), some antimalarials (such as mefloquine and hydroxychloroquine), some antibiotics (such as erythromycin, levofloxacin, moxifloxacin), some antifungals (eg, pentamidine ), certain drugs used to treat gastrointestinal problems (such as prucalopride), certain drugs used to treat cancer (such as toremifene, vandetanib), and methadone, which increase the risk of heart rhythm problems. Therefore, such combinations are contraindicated.
Co-prescription of drugs requiring special precautions during use
Caution is required when using drugs that cause bradycardia and hypokalemia.
Caution is required when using hydroxyzine in doses higher than recommended in patients receiving concomitant treatment with drugs with arrhythmogenic effects: quinidine, lithium, thioridazine, tricyclic antidepressants, atropine, etc.
The potentiating effect of hydroxyzine should be taken into account when using the drug together with drugs that have a depressant effect on the central nervous system or have anticholinergic properties; in this case, the dose should be selected individually.
Alcohol also potentiates the effect of hydroxyzine.
Concomitant use of hydroxyzine with monoamine oxidase inhibitors should be avoided.
In the case of treatment with anticoagulants, control of hemostasis is necessary at the beginning of therapy.
Hydroxyzine exhibits antagonistic properties towards Betahistine and anticholinesterase drugs.
Treatment should be stopped at least 5 days before an allergy test or a provocative test for bronchial reactivity with methacholine to avoid interfering with the study results. The administration of hydroxyzine may affect the results of determining 17-hydrocorticosteroids in urine.
Hydroxyzine counteracts the pressor effect of adrenaline.
When used in rats, hydroxyzine antagonized the anticonvulsant effects of phenytoin.
Cimetidine at a dose of 600 mg, divided into 2 doses per day, caused an increase in the concentration of hydroxyzine in the blood serum by 36% and a decrease in the maximum concentration of the cetirizine metabolite by 20%.
Hydroxyzine is a CYP2D6 inhibitor (enzyme release rate constant (Ki): 3.9 µmol; 1.7 µg/ml) and in high doses can lead to drug interactions with CYP2D6 substrates (metoprolol, propafenone, timolol, amitriptyline, clomipramine, desipramine , imipramine, paroxetine, haloperidol, risperidone, thioridazine, aripiprazole, codeine, dextromethorphan, duloxetine, flecainide, mexiletine, ondansetron, tamoxifen, tramadol, venlafaxine).
Hydroxyzine at a concentration of 100 μmol does not have an inhibitory effect on uridine diphosphate (UDP)-glucuronyltransferase isoforms 1A1 and 1A6 in human liver microsomes. It inhibits cytochrome P450 isoforms 2C9/C10, 2C19 and 3A4 at plasma concentrations exceeding the maximum (IC50 (mean concentration required to achieve half maximum inhibition): 103-140 µmol; 46-52 µg/ml). Therefore, it is unlikely that hydroxyzine can disrupt the metabolism of drugs that are substrates for these enzymes. The cetirizine metabolite at a concentration of 100 µmol does not have an inhibitory effect on liver cytochrome P450 (1A2, 2A6, 2C9/C10, 2C19, 2D6, 2E1 and 3A4) and isoforms of UDP-glucuronyltransferase.
Hydroxyzine is metabolized by alcohol dehydrogenase and CYP3A4/5. An increase in the concentration of hydroxyzine in the blood can be expected when it is used simultaneously with drugs that are inhibitors of these enzymes (telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and some HIV protease inhibitors, including atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, lopinavir/ritonavir, saquinavir/ritonavir and tipranavir/ritonavir). However, when only one metabolic pathway is inhibited, the effect can be partially compensated by other metabolic pathways.
HYDROXYZINE CANON
Pharmacokinetics
Absorption:
Absorption is high. The time to reach maximum concentration (Tcmax) after oral administration is 2 hours. After taking an average dose of 50 mg, Tcmax in adults is 70 mg/ml.
Distribution:
The distribution coefficient is 7-16 l/kg in adults. Hydroxyzine penetrates the blood-brain barrier and the placenta, concentrating more in fetal than maternal tissues. After oral administration, hydroxyzine penetrates well into the skin, with hydroxyzine concentrations in the skin far exceeding serum concentrations after both single and multiple doses. Plasma concentration of hydroxyzine does not necessarily reflect its tissue binding or distribution at skin receptors. It has an effect on skin inflammation depending on serum concentration.
Metabolism:
Hydroxyzine is metabolized in the liver. Cetirizine - the main metabolite (45%) is a blocker of H1-histamine receptors. Metabolites are found in breast milk.
Removal:
The half-life (T1/2) in adults is 14 hours (range: 7-20 hours). The total clearance of hydroxyzine is 13 ml/min/kg. About 0.8% of hydroxyzine is excreted unchanged through the kidneys. The main metabolite cetirizine is excreted mainly in the urine, also unchanged (25% of the dose of hydroxyzine).
Pharmacokinetics in special groups of patients
In elderly patients
In elderly patients T1/2 was 29 hours. The volume of distribution is 22.5 l/kg. It is recommended to reduce the daily dose of hydroxyzine when prescribed to elderly patients.
Children under 1 year
In children, the total clearance is 2.5 times higher than in adults. The dose must be adjusted. The half-life is 4 hours.
Children from 1 year to 14 years
The half-life is 11 hours.
In patients with liver failure
In patients with liver dysfunction secondary to primary biliary cirrhosis, the total clearance was approximately 66% of the value recorded in healthy volunteers. In patients with liver diseases, T1/2 increased to 37 hours, the concentration of metabolites in the blood serum was higher than in young patients with normal liver function. For patients with liver failure, a reduction in the daily dose or frequency of administration is recommended.
In patients with renal failure
The pharmacokinetics of hydroxyzine was studied in 8 patients with severe renal failure (creatinine clearance 24±7 ml/min). The duration of exposure to hydroxyzine did not change significantly, while the duration of exposure to cetirizine was increased. To avoid any significant accumulation of cetirizine metabolite after repeated use of hydroxyzine in patients with impaired renal function, the daily dose of hydroxyzine should be reduced.
