Sedex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SЕDEX (SЕDІX)

Composition:

Active substance: hydroxyzine hydrochloride;

One film-coated tablet contains hydroxyzine hydrochloride 25 mg;

Excipients: anhydrous lactose, microcrystalline cellulose (PH 112), colloidal anhydrous silicon dioxide, magnesium stearate,

Film coating: Opadry White OY-58900 (hypromellose, titanium dioxide (E 171), macrogol 400).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets, white to almost white, oblong, biconvex, with a score line on both sides.

The tablet can be divided into equal doses.

Pharmacotherapeutic group. Anxiolytics. Diphenylmethane derivatives. ATC code N05B В01.

Pharmacological Properties.

Pharmacodynamics.

Hydroxyzine hydrochloride is a diphenylmethane derivative, chemically unrelated to phenothiazines, reserpine, meprobamate, or benzodiazepines.

Mechanism of action

Hydroxyzine is not a cortical depressant, but its effects may be related to suppression of activity in certain key subcortical regions of the central nervous system (CNS).

Pharmacodynamic effects

Antihistaminic and bronchodilating effects have been demonstrated experimentally and confirmed clinically. Antiemetic effect has been demonstrated in both apomorphine- and veratrum alkaloid-induced tests. Pharmacological and clinical studies indicate that hydroxyzine, at therapeutic doses, does not increase gastric secretion or acidity and in most cases exhibits mild antisecretory activity. Reduction of wheals and erythema has been demonstrated in healthy adult volunteers and in children following intradermal injections of histamine or antigens. Hydroxyzine has also shown efficacy in relieving pruritus associated with various forms of urticaria, eczema, and dermatitis.

In patients with hepatic impairment, the antihistaminic effect of a single dose may be prolonged up to 96 hours after administration.

EEG data in healthy volunteers demonstrate an anxiolytic-sedative profile of the drug. The anxiolytic effect has been confirmed in patients using various classical psychometric tests.

Polysomnographic data in anxious patients and in patients suffering from insomnia show an increase in total sleep time, reduction in total time of nocturnal awakenings, and reduction in sleep latency after single or repeated daily doses of 50 mg. Reduction in muscle tone has been demonstrated in anxious patients receiving a daily dose of 3 × 50 mg. No memory impairment was observed. No withdrawal symptoms or signs were reported after 4 weeks of treatment in anxious patients.

Onset of action

Following administration of oral pharmaceutical forms, the antihistaminic effect begins approximately 1 hour after intake. The sedative effect begins 5–10 minutes after administration of oral liquid forms and 30–45 minutes after tablet intake. Hydroxyzine also exhibits spasmolytic and sympatholytic effects. It has weak affinity for muscarinic receptors. Hydroxyzine exerts mild analgesic activity.

Pharmacokinetics.

Absorption

Hydroxyzine is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration (C_max) is reached approximately 2 hours after oral administration. After single oral doses of 25 mg and 50 mg in adults, C_max is typically 30 and 70 ng/mL, respectively. Following repeated once-daily administration, plasma concentration increases by 30%. The bioavailability of hydroxyzine after oral administration compared to intramuscular (i.m.) administration is approximately 80%. After a single 50 mg intramuscular dose, C_max is 65 ng/mL.

Distribution

Hydroxyzine is widely distributed throughout the body and generally achieves higher tissue concentrations than plasma concentrations. In adults, the apparent volume of distribution ranges from 7 to 16 L/kg. Hydroxyzine penetrates into the skin after oral administration. Both after single and multiple doses, the concentration of hydroxyzine in the skin is higher than in blood serum. Hydroxyzine crosses the blood-brain and placental barriers, resulting in higher concentrations in the fetus than in the pregnant woman.

Biotransformation

Hydroxyzine undergoes extensive metabolism. The formation of the main metabolite, cetirizine—a carboxylic acid metabolite (approximately 45% of the oral dose)—is catalyzed by alcohol dehydrogenase. This metabolite is a potent peripheral H₁-antagonist. Other identified metabolites include N-dealkylated and O-dealkylated metabolites, with a half-life of 59 hours. These metabolic pathways are primarily mediated by CYP3A4/5.

Elimination

The elimination half-life of hydroxyzine in adults is approximately 14 hours (range: 7–20 hours). The apparent total body clearance, calculated during studies, is 13 mL/min/kg. Only 0.8% of the dose is excreted unchanged in urine. The main metabolite, cetirizine, is primarily excreted unchanged in urine (25% and 16% of hydroxyzine dose after oral and intramuscular administration, respectively).

Special populations

Elderly patients

The pharmacokinetics of hydroxyzine were studied in 9 healthy elderly volunteers (69.5 ± 3.7 years) after a single 0.7 mg/kg dose. The elimination half-life of hydroxyzine was prolonged to 29 hours, and the apparent volume of distribution increased to 22.5 L/kg. A reduced daily dose of hydroxyzine is recommended for elderly patients (see section "Dosage and administration").

Children

The pharmacokinetics of hydroxyzine were evaluated in 12 children (6.1 ± 4.6 years; 22 ± 12 kg) after a single 0.7 mg/kg dose. The apparent plasma clearance was approximately 2.5 times higher than in adults. The elimination half-life was shorter than in adults, being approximately 4 hours in 1-year-old patients and 11 hours in 14-year-old patients. The dose should be adjusted when administered to children (see section "Dosage and administration").

Hepatic impairment

In subjects with secondary hepatic dysfunction due to primary biliary cirrhosis, total clearance was approximately 66% of that in healthy volunteers. The elimination half-life increased to 37 hours, and serum concentrations of the carboxylic acid metabolite cetirizine were higher than in young patients with normal liver function. The daily dose or dosing frequency should be reduced in patients with impaired liver function (see section "Dosage and administration").

Renal impairment

The pharmacokinetics of hydroxyzine were studied in 8 patients with severe renal impairment (creatinine clearance 24 ± 7 mL/min). The area under the pharmacokinetic curve (AUC) for hydroxyzine did not change significantly, whereas the AUC for the carboxylic acid metabolite cetirizine was increased. This metabolite is not effectively removed by hemodialysis.

To avoid significant accumulation of the cetirizine metabolite after repeated doses of hydroxyzine, the daily dose of hydroxyzine should be reduced in patients with impaired renal function (see section "Dosage and administration").

Clinical characteristics.

Indications.

Due to its sedative, tranquilizing, and antihistaminic properties, the medicinal product Sedex is indicated for:

• symptomatic treatment of anxiety states in adults;
• symptomatic therapy of allergic pruritus.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product, to any of their metabolites, cetirizine, other piperazine derivatives, aminophylline, or ethylenediamine;
• porphyria;
• diagnosed acquired or congenital QT interval prolongation;
• presence of risk factors for QT interval prolongation, including diagnosed cardiovascular diseases, significant electrolyte imbalance (hypokalemia, hypomagnesemia), sudden cardiac death in family history, marked bradycardia, known concomitant use with medicinal products that prolong the QT interval and/or induce polymorphic ventricular tachycardia of the torsades de pointes type (see sections "Interaction with other medicinal products and other types of interactions" and "Special warnings and precautions for use");
• pregnancy or breastfeeding period (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Contraindicated concomitant use

Concomitant administration of hydroxyzine with medicinal products that prolong the QT interval and/or induce polymorphic ventricular tachycardia of the torsades de pointes type, such as class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g., amiodarone, sotalol), some antihistamines, some neuroleptics (e.g., haloperidol), some antidepressants (e.g., citalopram, escitalopram), some antimalarials (e.g., mefloquine, hydroxychloroquine), some antibiotics (e.g., erythromycin, levofloxacin, moxifloxacin), some antifungals (e.g., pentamidine), some gastrointestinal medicinal products (e.g., prucalopride), some anticancer drugs (e.g., toremifene, vandetanib), methadone, increases the risk of cardiac arrhythmia. Therefore, such combinations are contraindicated (see section "Contraindications").

Combinations requiring precautions

Medicinal products causing bradycardia and hypokalemia should be used with caution.

Hydroxyzine should be used with caution at doses exceeding the recommended ones when administered concomitantly with medicinal products capable of inducing cardiac arrhythmia, such as quinidine, lithium, thioridazine, tricyclic antidepressants, atropine, and similar agents.

Enhancement of Sedex's effect should be considered when used concomitantly with medicinal products that depress the CNS or have anticholinergic properties. In such cases, dosage should be individually adjusted.

Alcohol also enhances the effect of hydroxyzine.

Concomitant administration with MAO inhibitors should be avoided.

When treating with anticoagulants, hemostasis should be checked prior to initiation of therapy. Hydroxyzine antagonizes the pressor effect of histamine and anticholinesterase drugs.

Sedex interferes with the pressor action of adrenaline, acts as an antagonist of the anticonvulsant activity of phenytoin in rats, and also interferes with the action of betahistine and cholinesterase inhibitor drugs.

If allergic testing or methacholine bronchial challenge testing is required, Sedex intake should be discontinued 5 days before the tests to prevent interference with test results.

Administration of hydroxyzine may interfere with the determination of 17-hydroxycorticosteroids in urine.

Cimetidine 600 mg twice daily increased serum hydroxyzine concentration by 36% and reduced the maximum concentration of the metabolite cetirizine by 20%.

Sedex is an inhibitor of CYP2D6 (Ki: 3.9 µmol; 1.7 µg/mL) and at high doses may cause 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).

Sedex has no inhibitory effect at a concentration of 100 µmol on UDP-glucuronosyltransferase isoforms 1A1 and 1A6 in human liver microsomes. It inhibits cytochrome P450 isoforms 2C9/C10, 2C19, and 3A4 at concentrations exceeding the maximum plasma concentration (IC50: 103–140 µmol; 46–52 µg/mL). Therefore, it is unlikely that Sedex may disrupt the metabolism of medicinal products that are substrates for these enzymes.

The metabolite cetirizine at a concentration of 100 µmol does not exhibit inhibitory effects on human liver cytochrome P450 (1A2, 2A6, 2C9/C10, 2C19, 2D6, 2E1, and 3A4) or UDP-glucuronosyltransferase isoforms.

Hydroxyzine is metabolized by alcohol dehydrogenase and CYP3A4/5; increased plasma hydroxyzine concentrations can be expected when hydroxyzine is co-administered with medicinal products known as potent 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, other pathways may partially compensate for this.

Special precautions for use

Hydroxyzine should be used with caution in patients prone to seizures.

Due to the anticholinergic effect of the medicinal product, it should be administered with caution in patients with glaucoma, prostate hypertrophy, urinary retention, decreased gastrointestinal motility, myasthenia gravis, or dementia.

Dosage adjustment is required in patients concurrently using other medicinal products that depress the central nervous system (CNS) or anticholinergic agents (see section "Interaction with other medicinal products and other forms of interaction").

Alcohol or other sedative medicinal products should be avoided during treatment with Sedex (see section "Interaction with other medicinal products and other forms of interaction").

Effects on the cardiovascular system

Hydroxyzine has been associated with QT interval prolongation on ECG. During post-marketing surveillance, cases of QT interval prolongation and polymorphic ventricular tachycardia of the torsades de pointes type have been reported in patients taking hydroxyzine. Most of these patients had other risk factors, including electrolyte imbalances and concomitant medications, which may have contributed to the development of these symptoms (see section "Undesirable effects").

Hydroxyzine should be used at the lowest effective dose and for the shortest duration possible. If signs or symptoms suggestive of cardiac arrhythmia occur, treatment with hydroxyzine should be discontinued and patients should seek immediate medical attention.

Patients should be advised to promptly report any cardiac symptoms.

Skin reactions

Life-threatening skin/immunological reactions such as Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema have been reported during the use of Sedex.

Patients should be informed about these signs and symptoms and should be closely monitored for the development of skin/immunological reactions. The highest risk of developing Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema occurs within the first few days to several weeks after starting treatment.

If symptoms or signs of Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema (e.g., progressive skin rash often accompanied by pain, blisters, or mucosal lesions, and sometimes fever) occur, Sedex should be discontinued immediately and medical help should be sought.

Optimal outcomes in treating Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema are achieved through early diagnosis and treatment, as well as immediate discontinuation of the suspected medicinal product. Early withdrawal of the drug is associated with a better prognosis.

If a patient develops Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, or angioedema while taking Sedex, this medicinal product must never be used again in that patient.

Elderly patients

Hydroxyzine is not recommended for use in elderly patients due to reduced clearance of hydroxyzine in this population compared to younger patients and an increased risk of adverse reactions (e.g., anticholinergic effects) (see sections "Dosage and administration" and "Undesirable effects"). It is recommended to initiate treatment with half the recommended dose due to prolonged effect.

Hepatic and/or renal impairment

Dosage reduction is required in patients with hepatic impairment or with moderate to severe renal impairment (see section "Dosage and administration").

Sedex contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Pediatric population

Young children are more susceptible to CNS-related adverse reactions (see section "Undesirable effects"). Seizures have been reported more frequently in children than in adults.

Use during pregnancy or breastfeeding

Pregnancy

Animal studies have demonstrated reproductive toxicity of the medicinal product. Hydroxyzine crosses the placental barrier, resulting in higher concentrations in the fetus compared to the mother. Currently, there are no relevant epidemiological data on the effects of hydroxyzine during pregnancy; therefore, Sedex is contraindicated during pregnancy.

In newborns whose mothers received Sedex in late pregnancy and/or during labor, the following effects were observed immediately or several hours after birth: hypotonia, movement disorders including extrapyramidal disorders, clonic movements, CNS depression, neonatal hypoxic state, or urinary retention. Therefore, Sedex is contraindicated during pregnancy.

Breastfeeding period

Cetirizine, the main metabolite of hydroxyzine, is excreted into breast milk.

Although formal studies on the excretion of hydroxyzine into breast milk are lacking, severe adverse reactions have been observed in newborns/infants whose mothers were treated with hydroxyzine.

Hydroxyzine is contraindicated during breastfeeding. If treatment with Sedex is necessary, breastfeeding should be discontinued.

Fertility

There are no adequate data on the effects of hydroxyzine on human fertility.

Ability to affect reaction speed when driving or operating machinery

Hydroxyzine may impair the ability to react and concentrate. Patients should be aware of this and exercise caution when driving or operating machinery.

Concomitant use of Sedex with alcohol or other sedative medicinal products should be avoided, as this may potentiate the aforementioned effects.

Method of Administration and Dosage

The medicinal product Sedex is taken orally. Hydroxyzine should be used at the lowest effective dose for the shortest duration possible.

Adults

For symptomatic treatment of anxiety states: 50–100 mg per day, i.e., 2–4 tablets of 25 mg or ½–1 tablet of 100 mg at bedtime, particularly in cases of anxiety associated with insomnia.

For symptomatic treatment of allergic pruritus: 25–100 mg per day, i.e., 1–4 tablets of 25 mg per day.

The maximum daily dose for adults and children with body weight of 40 kg or more is 100 mg.

The duration of treatment is determined by the physician based on symptoms, and the lowest possible maintenance dose is prescribed.

Since patient response to hydroxyzine may vary, it is recommended to initiate treatment with low doses and gradually increase the dose until the optimal dose adjusted to the patient's response to therapy is achieved.

Children

For symptomatic treatment of allergic pruritus:

Children aged 12 years (with body weight over 40 kg): 25–100 mg/day, i.e., 1–4 tablets of 25 mg per day.

Children aged 9 to 12 years (with body weight 28–40 kg): 25–75 mg/day, i.e., 1–3 tablets of 25 mg per day.

Children aged 7 to 9 years (with body weight 23–28 kg): 25–50 mg/day, i.e., 1–2 tablets of 25 mg per day.

Children aged 4 to 7 years (with body weight 17–23 kg): 25–37.5 mg/day, i.e., 1–1½ tablets of 25 mg per day.

Children aged 3 to 4 years (with body weight 12.5–17 kg): 12.5–25 mg/day, i.e., ½–1 tablet of 25 mg per day.

The dose is calculated according to body weight, ranging from 1 mg/kg/day to a maximum of 2 mg/kg/day, administered in divided doses.

For children with body weight up to 40 kg, the maximum daily dose is 2 mg/kg/day. For children with body weight exceeding 40 kg, the maximum daily dose is 100 mg per day.

Special Populations

Elderly Patients

The maximum daily dose for elderly patients is 50 mg per day (see section "Special Warnings and Precautions for Use").

Renal Impairment

If a temporary effect is required, the dose may be halved. This may also apply to patients with renal impairment.

Dose adjustment for adults with impaired renal function:

• For patients with mild renal impairment (glomerular filtration rate (GFR) 60 – < 90 mL/min), no dose adjustment is required.
• For patients with moderate renal impairment (GFR 30–60 mL/min), a 50% dose reduction is recommended.
• For patients with severe renal impairment (GFR < 30 mL/min, not requiring dialysis), a 25% dose reduction is recommended.
• For patients with end-stage renal disease (ESRD) (GFR < 15 mL/min, requiring dialysis), a 25% dose reduction is recommended, administered three times per week.

Hepatic Impairment

Patients with hepatic impairment should have their daily dose reduced by 33%.

Children

The use of the medicinal product Sedex in children is described in detail in the section "Method of Administration and Dosage".

Overdose

Symptoms

Symptoms observed after significant overdose of the medicinal product are primarily related to excessive anticholinergic effects, CNS depression, or paradoxical CNS stimulation. Symptoms of significant overdose may include nausea, vomiting, tachycardia, hyperthermia, drowsiness, pupillary reflex abnormalities, tremor, confusion, or hallucinations. This may be followed by decreased level of consciousness, respiratory depression, seizures, arterial hypotension, or cardiac arrhythmias, including bradycardia. Increased depth of coma and cardiorespiratory collapse are possible.

Treatment

Careful monitoring of airways, respiration, and circulatory status with continuous ECG recording and adequate oxygen supply is required. Cardiac monitoring and blood pressure should be maintained for 24 hours after symptom resolution.

Patients with altered mental status should be evaluated for concomitant alcohol intake or use of other medicinal products; oxygen, naloxone, glucose, and thiamine should be administered as needed.

If vasopressor support is required, norepinephrine or metaraminol should be administered. Epinephrine must not be used.

Syrup of ipecac should not be administered to patients with symptoms or predisposition to rapid deterioration in consciousness, coma, or seizures, as this may lead to aspiration pneumonia.

In cases of ingestion of a clinically significant amount of the medicinal product, gastric lavage may be performed following endotracheal intubation. Activated charcoal may be used, although data supporting its efficacy are limited. Hemodialysis or hemoperfusion is not indicated. There is no specific antidote.

Published data suggest that trial therapeutic doses of physostigmine may be beneficial in cases of severe, life-threatening anticholinergic effects that are refractory to standard treatments and do not respond to conventional antidotes. Physostigmine should not be used solely to maintain consciousness. If tricyclic antidepressants have been co-ingested, physostigmine administration may precipitate seizures and cardiac arrest that are difficult to treat. Physostigmine should not be administered in patients with conduction system abnormalities of the heart.

Adverse reactions.

Adverse reactions are mainly related to CNS depression or paradoxical stimulatory effects on the CNS, anticholinergic activity, or hypersensitivity reactions.

The table below lists adverse reactions reported during post-marketing use, as well as those reported in placebo-controlled clinical trials with an incidence of at least 1% for hydroxyzine (735 patients treated with hydroxyzine at doses up to 50 mg daily and 630 patients receiving placebo). The frequency of adverse reactions observed in clinical studies is provided as a percentage where possible; however, for adverse reactions reported during post-marketing use, frequency categories cannot be reliably estimated.

The adverse reactions listed below, observed during drug use, are categorized by MedDRA system organ classes and frequency as follows: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1000 to < 1/100); rare (> 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Some adverse reactions were identified during clinical trials with the frequency indicated below. However, certain adverse reactions were reported spontaneously during post-marketing use. When the frequency cannot be estimated from available data, it is listed as "not known."

Adverse Reactions	Frequency (%) of adverse reactions
Immune system disorders:
hypersensitivity	uncommon
anaphylactic shock	very rare
Psychiatric disorders:
excitation	uncommon
confusion	uncommon
disorientation	rare
hallucinations	rare
Nervous system disorders:
drowsiness	very common (13.74)
headache	common (1.63)
sedation	common
dizziness	uncommon
insomnia	uncommon
tremor	uncommon
seizures	rare
dyskinesia	rare
loss of consciousness (syncope)	frequency not known
Eye disorders:
accommodation disorder	rare
blurred vision	rare
Cardiac disorders:
tachycardia	rare
QT interval prolongation (see section "Special precautions")	frequency not known
ventricular arrhythmia (e.g., torsades de pointes)	frequency not known
Vascular disorders:
arterial hypotension	rare
Respiratory, thoracic and mediastinal disorders:
bronchospasm	very rare
Gastrointestinal disorders:
dry mouth	common (1.22)
nausea	uncommon
constipation	rare
vomiting	rare
Hepatobiliary disorders:
hepatitis	frequency not known
liver function test abnormalities	rare
Skin and subcutaneous tissue disorders:
itching	rare
erythematous rash	rare
maculopapular rash	rare
urticaria	rare
dermatitis	rare
Stevens-Johnson syndrome	very rare
multiform erythema	very rare
bullous conditions (e.g., toxic epidermal necrolysis, pemphigoid)	frequency not known
acute generalized exanthematous pustulosis	very rare
angioneurotic edema	very rare
fixed drug eruption	very rare
increased sweating	very rare
Renal and urinary disorders:
urinary retention	rare
General disorders:
increased fatigue	common (1.36)
generalized weakness	uncommon
fever	uncommon
Investigations:
weight gain	frequency not known

Description of individual adverse reactions

The adverse reactions listed below are associated with cetirizine, the main metabolite of hydroxyzine: thrombocytopenia, aggression, depression, tic, dystonia, paresthesia, oculogyric crisis, diarrhea, dysuria, urinary incontinence, asthenia, edema, weight gain – and thus may potentially occur during the use of hydroxyzine.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after the authorization of a medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system (https://aisf.dec.gov.ua).

Shelf life. 2 years.

Storage conditions.

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

Packaging.

10 film-coated tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. INFARMASCI

Address of manufacturer and location of its business operations.

Zone Industrielle No. 2, 1 Rue Nangesse, Provin, 59121, France