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Drug ATARAX have composition Hydroxyzine hydrochloride 25mg, indicated for the symptomatic treatment of pruritus, the symptomatic treatment of anxiety in adults, the premedication before surgery

Alpha Choay indications enzymatic anti-oedema and anti-inflammatory: soft tissue injuries

Medrol 4 mg indication for Rheumatic Disorders, Dermatologic Diseases, Allergic States

Conposition

EachFilm-coated tablet contains 25mg of hydrochloride

Exciprents: Lactose monohydrate, Microcrystamine cellulose. Magnesium stearate. Collcidal anhydrous silica, Opadry Y-1-7000 White (contains Titanium dioxide El7l).HP,M.C 29105cP,Macrogol 400)

ATARAX 25 - Hydroxyzine hydrochloride 25 mg

PHARMACEUTICAL FORM

White, oblong . film-coated tablet with a bisect line.

PACK SIZE

Box of 1 blister of 30 film-coated tablets.

INDICATIONS

ATARAX ( Hydroxyzine ) is indicated for

– the symptomatic treatment of anxiety in adults,

– the symptomatic treatment of pruritus,

– the premedication before surgery.

DOSAGE AND ADMINISTRATION

Route of Administration

For oral use

Adults:

– The symptomatic treatment of anxiety: 50 mg/day in 3 separate administrations of 12.5-12.5- 25 mg; in more severe cases doses up to 300 mg/day can be used.

– The symptomatic treatment of pruritus: starting dose of 25mg at night, to be followed if necessary with doses up to 25 mg three or four times daily.

– The premedicaiion before surgery: 50 to 200 mg/day in 1 or 2 administrations: single administration 1 hour before surgery, which may be preceded by 1 administration mg night before anesthesia.

The maximum single dose in adults should not exceed 200 mg whereas the maximum daily dose should not exceed 300 mg.

Children (from 12 months):

– The symptomatic treatment of pruritus:

– From 12 months to 6 years old: 1 mg/kg/day up to 2.5 mg/kg/day in divided doses.

– Over 6 years old: 1 mg/kg/day up to 2 mg/kg/day in divided doses.

– The premedication before surgery: single administration of 1 mg/kg 1 hour before surgery, which may be preceded by 1 mg/kg the night before anesthesia.

Dosage adjustments

ATARAX should be adapted within mg recommended dosage range, according to mg patient’s response.

In mg elderly, it is advised to start with half mg recommended dose due to prolonged action.

In patients with hepatic dysfunction. it is recommended to reduce mg daily dose by 33%.

Dosage should be reduced in patients with moderate or severe renal function impairment due to decreased excretion of its metabolite cetirizine.

CONTRAINDICATIONS

  1. Hydroxyzine is contraindicated in:
  2. patients with a history of hypersensitivity to hydroxyzine or any of mg excipients, to cetirizine. to other piperazine derivatives, to aminophymine, or to ethytedediammg,
  3. pregnancy and lactation (see Section Pregnaccy and Lactation),
  4. patients with porphyria,
  5. patients with pre-existing prolonged QT interval.

WARNINGS AND PRECAUTIONS

Convulsions

ATARAX should be administered cautiously in patients with increased potential for convulsions.

Children

Young children are more susceptible to develop adverse events related to the central nervous system (see Section Adverse Reactions). In children, convulsions have been more frequently reported than in adults.

Hydroxyzine anticholinergic effects

Because of its potential anticholinergic effects, hydroxyzine should be used cautiously in patients suffenng from glaucoma, bladder outflow obstruction, decreased gastrointestinal motility, myasthenia gravis, or dementia. Coadministration with CNS depressants

Dosage adjustments may be required if hydroxyzine is used simultaneously with otiier central nervous system depressant drugs or with drugs having anticholinergic properties (see Section Interactions).

Alcohol

the concomitant use of alcohol and hydroxyzine should be avoided (see Sectio Interactions).

Cardiac disorders

is needed in patients who have e known predisposing factor to csrdia arrhythmia, including electrolytes Imbalance (hypokalemia, hypomagnesaemia who have pre-existing heart disease, or who are concomitantly treated with’ potentially arrhythmogenic drug. In these patients use of alternative treatments j to be considered.

Elderly

In mg elderly, it is adwsed to start with half mg recommended dose due to a prolonged action.

Hepatic andrenalimpairment

Hydroxyzine dosage should be reduced in patients with hepatic dysfunction and in patients with moderate or severe renal impairment Excipient Lactose

Hydroxyzine film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, mg Lapp lactase deficiency or glucose- galactose malabsorption should not take the medicine.

INTERACTIONS

CNS depressants

Patients should be informed that hydroxyzine may potentiate mg effects of barbiturates, otherCNS depressants or drugs having antkhotinergic properties.

Alcohol

Alcohol also potentiates the effects of hydroxyzine.

Betahistine and anticholinesterase drugs

Hydroxyzine antagonises the effects of betahistine and anticholinesterase drugs, Tests results

The treatment should be stopped at least 5 days before allergy testing or methacholine bronchial challenge, to avoid effects on the test results.

Monoamine oxidase inhibitors

Simultaneous administration of hydroxyzine with monoamine oxidase Inhibitors should be avoided.

Epinephrine

Hydroxyzine counteracts the epinephrine pressor action.

Phenytoin

In rats, hydroxyzine antagonised the anticonvulsant action of phenytoin,

Cimetidine

Cimetidine 600 mg b.i.d. has been shown to increase the serum concentrations of hydroxyzine by 36% and to decrease peak concentrations of the metabolite cetirizine by 20%,

CYP2D6 substrates

Hydroxyzine Is an inhibitor of cytochrome P450 2D6 (Ki: 3.9 uM;1.7 pg/ml) and may cause at high doses drug-drug interactions with CYP2D6 substrates.

Effect on other drug metabolism

ATARAX ( Hydroxyzine ) has no inhibitory effect at 100 JJM on UDP-glucuronyi transferase isoforms 1A1 and 1A6 in human liver microsomes. It inhibits cytochrome P450 2C9/C10,2C19 and 3A4 isoforms at concentrations (ICH: 19 to 140   7 to 52 pg/ml) well above peak plasma concentrations. The metabolite cetirizine at 100 uM has no inhibitory effect on human liver cytochrome P450 (1A2, 2A6, 2C9/C10, 2C19, 2D6, 2E1 and 3A4) and UDP-glucuronyi transferase isoforms. Therefore, hydroxyzine is unlikely to Impair the metabolism of drugs which are substrates for these enzymes.

Potent inhibitors of liver enzymes

As hydroxyzine Is metabolised by alcohol dehydrogenase and CYP3A4/5. an increase in hydroxyzine blood concentrations may be expected when hydroxyzine is co-administered with other drugs known to be potent inhibitors of liver enzymes.

Potentially arrhythmogenic drugs

Co-administration of hydroxyzine with a potentially arrhythmogenic drug may increase the risk of QT prolongation and Torsade de Pointed.

PREGNANCY AND LACTATION

Fertility

There are no relevant data available.

Pregnancy

ATARAX is contraindicated during pregnancy (see Section Contraindications).

Animal studies have shown reproductive toxicity.

Hydroxyzine crosses the placental barrier leading to higher foetal than maternal concentrations.

To dale, no relevant epidemiological data are available relating to exposure to hydroxyzine during pregnancy.

In neonates whose mothers received hydroxyzine during late pregnancy and/or labour, the following events were observed immediately or only a few hours after birth: hypotonia, movement disorders including extrapyramidal disorders, clonic movements, CNS depression, neonatal hypoxic conditions, or urinary retention.

Lactation

ATARAX is contraindicated during lactation (see Section Contraindications). Breast-feeding should be stopped if hydroxyzine therapy is needed.

Cetirizine, the principal metabolite of hydroxyzine, is excreted in human milk. Although no formal studies have been performed on the excretion of hydroxyzine in human milk, severe adverse effects have been shown in breastfed newboms/infants of hydroxyzine treated mothers.

ABILITY TO PERFORM TASKS THAT REQUIRE JUDGEMENT, MOTOR OR COGNITIVE SKILLS

Alertness or reaction time may be impaired by hydroxyzine, therefore patients’ driving capacity or ability to use machines may be reduced. Concomitant use of hydroxyzine with alcohol or other sedative drugs should be avoided as it aggravated these effects.

ADVERSE REACTIONS

Undesirable effects are mainly related to CNS depressant or paradoxical CNS stimulation effects, to anticholinergic activity, or tohyperaensitivity reactions. Adverse reactions are ranked under headings of frequency using the following

Convention:

Very common  >=1/10

Common >= 1/100 to <1/10

Uncommon >=1/1000  To <1/100

Rare  >=1/10000 to <1/1000

Very rate   <1/10000

Notknown  (cannot be estimated from the avaliable data)

Clinical Trial Data

Nervous system disorders

Very common      somnolence

Common     headache

Uncommon-         dizziness, insomma.Adisturbance in attention

General disorders

Common     dry mouth

Uncommon constipation.        nausea

General disorders and administration site conditions

Common:    fatigue

Uncommon:         asthenia

Post Marketing Data

Immune system disorders

Notknown: hypersensitivity, anaphytactic shock

Psychiatric disorders

Notknown: agitation, confoston, disorientation. hallucination

Nervous system disorders

Not known: sedation, tremor, convulsions, dyskinesia

Eye disorders

Notknown: accommodation disorder, vision blurred

Cardiac disorders

Notknown: tachycardia, electrocardiogram         QT prolonged,

torsades depointes

Vasoular disorders

Notknown: hypotension

Respiratory, thoracic and mediastinal disorders Notknown   bronchospasm

Gastrointestinal disorders Notknown:        vomiting

Hepatobiliary disorders

Notknown: liver function tests abnormal

Skin and subcutaneous tissue disorders

Not known: pruritus, erythematous  rash, maculo-papular rash.

urticaria, dermatitis, angioneurotic oedema, hypeihidrosis, fixed drug eruption Renal and urinary disorders Notknown-  urinary retention

Genera/disorders and administration site conditions

Notknown  malaise, pyrexia

The following adverse reactions have been observed with cefirizine. the principal metabolite of hydroxyzine: thrombocytopenia, aggression, depression, tic, dystonia, paraestfiesta, oculogyric crisis, diarrhoea, dysuria, enuresis, asthenia, oedema, weight increased and could potentially occur with hydroxyzine.

OVERDOSAGE

Symptoms and signs

Symptoms observed after an important overdose are mainly associated with excessive anticholinergic load, Central Nervous System (CNS) depression or CNS paradoxical stimulation. They include nausea, vomiting, tachycardia, pyrexia, somnolence, impaired pupillary reflex, tremor, confusion, or hallucination. This may be followed by depressed level of consciousness, respiratory depression, convulsions, hypotension, or cardiac arrhythmia. Deepening coma and cardiorespiratory collapse may ensue.

Treatment

Airway, breathing and circulatory status must be closely monitored with continuous ECG recording and an adequate oxygen supply should be available. Cardiac and blood pressure monitoring should be maintained until the patient is free of symptoms for 24 hours Patients with altered mental status should be checked for simultaneous intake of other drugs or alcohol and should be given oxygen, naloxone, glucose, and thiamine if deemed necessary.

Norepinephrine or metarammol should be used if vasopressor Is needed Epinephrine should not be used.

Syrup of ipecac should not be administered in symptomatic patients or those who could rapidly become obtunded, comatose or convulsing, as this could lead to aspiration pneumonitis Activated charcoal may be left In the stomach but there are scant data to support its efficacy.

It is doubtful that haemodialysis or haemopertusion would be of any value.

There is no specific antidote.

Literature data indicate that in the presence of severe, life-threatening, intractable anticholinergic effects unresponsive to other agents, a therapeutic Inal dose of physostigmlne may be useful Physostigmine should not be used just to keep the patient awake If cyclic antidepressants have been coingested, use of physostigmine may precipitate seizures and intractable cardiac arrest Also avoid physostigmine in patients with cardiac conduction defects.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Pharmacotherapeutic group

Antihistamines with sedative effect, Diphenytmethane derivatives

ATC Code

N05BB01

Mechanism of Action

ATARAX is a first generation antihistamine that crosses extensively the blood/brain bamer and has a high affinity for histaminic receptors Info the brain, thereby producing sedative-anxiolytic effects.

Pharmacodynamic effects

Anlihistamimc and bronchodilator activities have been demonstrated experimentally and confirmed dimcally. An antiemetic effect both by die apomorphine test and the verifoid test has been demonstrated. Pharmacological and clinical studies indicate that hydroxyzine at therapeutic dosage does not

increase gastric secretion or acidity and in most cases has mild antiseretory activity. Wheal an flare reduction have been demonstrated in adult healthy volunteers and in chilren after intradermal injections of histamine or antigens Hydroxyzine has also revealed its efficacy in relieving pryritus in various forms of urticaria, eczema and dermatitis.

Onset of action

The antihistaminic effect begins approximately affter 1 hour with oral pharmaceutical forms. The sedative effect starts after 30-45 minutes with tablets Hydroxyzine has a weak affinity for muscarinic receptors

Pharmacokinetics

Absorption

ATARAX is rapidly absorbed from (he gasmnteshnat tract The peon plasma level (Cmaxi ts reached approximately two hours after oral mutke Alter  doses of 25 mg end 50 mg . Cmax concentrations,respectively.

Following repeat administration once a day, concentrations are increased by 30%.

The oral of hydroxyzine with rasped to intramuscular

Distribution

Hydroxyzine is widely distributed in the body and generally more concentrate.! m the tissues foan m plasma The apparent volume is 7 to 16 l/kg in adults

Hydroxyzine enters the skin following oral Skin concentrations of hydroxyzine are higher than serum concentrations, following both Single and multiple administration. Hydroxyzine crosses the Wood-brain and placental barriers leading to higher foetal than maternal concentrations

Metabolism

Hydroxyzine is extensively metabolised The formation of the cetinzme. a carboxylic and metabolite (approximately 45% of the oral dose), is mediated by alcohol dehydrogenase. This metabotite mine significant penpheral Hl-antagonist properties The other metabolites identified include a N- deatkyiated metabolite, and an O-deefkyfated metabofife with a plasma half-life of 59 hours. These pathwaysare mediated principally by CYP3A4/5

Elimination

Hydroxyzine half-life In adults is approximately 14 hours (range 7 – 20 hrs) The apparent total body clearance calculated across studies is 13 Oily 0.8% of the dose is excreted unchanged in urine The major metabolite cetinzme is excreted mainly unchanged in urine (25% and 16 % of the hydroxyzine oral end IM dose, respectively).

Special patient populations

Children

The pharmacokinetics of ATARAX was evaluated in 12 paediatnc patients (mean 6.1 ± 4.6 yrs. 22.0 ± 12.0 kg) following a single oral dose of 0.7 mg/fcg. The apparent plasma clearance was approximately 2.5 times that in adults. The half- life was shorter than in adults It was approximately 4 hours m the 1 year-old patients and 11 hours in the 14 year-old-patrents. Dosage should be adjusted in paediatric population (see Section Dosage and Admministration)

Elderly

The pharmacokinetics of hydroxyzine was investigated in 9 healthy  subjeds(69.5i 3.7 years) following a single 0 7 mg/kg oral dose The elimination half-life of hydroxyzine was prolonged to 29 hours and the apparent volume of distribution was increased to 22.5 l/kg. It b recommended to reduce by half the daliy dose of hydroxyzine in elderly patients (see Section Oosege and Administration).

Renal impairment

The pharmacokinetics of ATARAX was studied in 6 severe ranatty impaired subjects (Creatinine clearance: 2417 ml/min) The extent ol exposure (AUC) to hydroxyzine was not altered in a relevant manner while that to toe carboxylic metabolite, cetinzme, was increased. This metabolite is not removed affluently by haemodialysis In order to avoid any important accumulation of the metabolite following multiple doses of hydroxyzme. the deity dose of hydroxyzine should be reduced in subjects with impaired renal function isee Sedan Dosage and administration).

Hepatic impairment

In subjects with hepatic dysfunction secondary to primary biliary emboss total body clearance was approximately 66% that of normal subtexts The half-life was increased to 37 hours and the serum concentrations of the carboryve metabolite, cetinzme. were higher than m young patients with a normal liver funchon. tarty dose or dose frequency should be reduced in patients with impaired lever function (see Section Dosage and administration)

SHELF LIFE: 60 months.

Do not use after expiry date indicated on the packaging

STORAGE: Keep at room temperature (150 C – 250 C), Keep container in the outer carton

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