Active ingredients: Hydroxyzine (Hydroxyzine hydrochloride)
ATARAX 25 mg film-coated tablets
ATARAX 20 mg / 10 ml syrup
Atarax package inserts are available for pack sizes: - ATARAX 25 mg film-coated tablets, ATARAX 20 mg / 10 ml syrup
- ATARAX 100 mg / 2 ml Solution for injection for intramuscular use
Why is Atarax used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Anxiolytic.
THERAPEUTIC INDICATIONS
Short-term treatment of anxious states. Allergic dermatitis accompanied by itching.
Contraindications When Atarax should not be used
History of hypersensitivity to the active substance or to any of the excipients, to cetirizine, to other piperazine derivatives, to aminophylline or to ethylenediamine.
In patients with porphyria.
In patients receiving monoamine oxidase inhibitors (MAOIs) (see Interactions).
In patients with pre-existing prolonged QT interval.
During pregnancy and breastfeeding (see Special warnings)
Precautions for use What you need to know before taking Atarax
Hydroxyzine should be administered with caution in patients with an increased predisposition to seizures. Young children are more prone to developing adverse events related to the central nervous system (see Undesirable Effects). The incidence of seizures is higher in children than in adults. . Due to its potential anticholinergic effects, hydroxyzine should be used with great caution in case of glaucoma, prostatic hypertrophy, bladder neck obstruction, pyloric and duodenal stenosis or other tracts of the gastrointestinal and urogenital tract, in hypomotility gastrointestinal, in myasthenia gravis, in cardiovascular diseases, in arterial hypertension, in hyperthyroidism and in cases of dementia, avoiding its use in cases of greater severity.
Particular caution is required for patients who have a known predisposition to cardiac arrhythmia including electrolyte imbalance (hypokalemia, hypomagnesaemia), who have pre-existing heart disease or who are taking concomitant medications that can induce cardiac arrhythmia. In such patients it is to be taken in consider using alternative treatments.
Interactions Which drugs or foods may change the effect of Atarax
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Hydroxyzine should not be administered together with monoamine oxidase inhibitors (see Contraindications).
The potentiating action of hydroxyzine should be considered when the drug is used in combination with other substances with anticholinergic action or with substances having a depressant effect on the central nervous system and the dose of ATARAX has to be adjusted on an individual basis.
Alcohol also enhances the effects of hydroxyzine, so its intake is not recommended during treatment with ATARAX.
Hydroxyzine antagonizes the effects of betahistine and anticholinesterases.
Treatment should be stopped at least five days prior to allergy testing or bronchial challenge test with methacholine to avoid effects on the test results.
The combination of ATARAX with other psychotropic drugs requires particular caution and vigilance on the part of the physician in order to avoid unexpected undesirable effects of interaction.
The use of antihistamines can mask the early signs of ototoxicity of certain antibiotics.
Hydroxyzine counteracts the pressure action of adrenaline.
In rats, hydroxyzine antagonizes the anticonvulsant action of phenytoin.
Cimetidine at a dosage of 600 mg twice daily has been shown to increase serum concentrations of hydroxyzine by 36% and to reduce maximal concentrations of the metabolite cetirizine by 20%.
Hydroxyzine inhibits cytochrome P450 2D6 (Ki: 3.9 μM; 1.7 μg / ml) and may cause drug interactions with other CYP2D6 substrates at high doses.
Hydroxyzine does not inhibit isoforms 1A1 and 1A6 of the UDP-glucuronyl transferase enzyme of human liver microsomes at a dose of 100 μM. It inhibits cytochrome P450 isoforms 2C9, 2C19 and 3A4 at concentrations far above the maximum plasma concentrations (CI50: 103-140 μM; 46-52 μg / ml).
Therefore, hydroxyzine is unlikely to impair the metabolism of drugs that are substrates for these enzymes. The metabolite cetirizine at 100 μM does not inhibit cytochrome P450 (1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4) nor the isoforms of "UDP-glucuronyl transferase in the human liver. Since hydroxyzine is metabolised by alcohol dehydrogenase and CYP3A4 / 5 isoenzymes, increased blood concentrations of hydroxyzine can be expected when co-administered with other drugs known to be potent inhibitors of these enzymes. However, when only one metabolic pathway is inhibited, the other can partially compensate.
Concomitant administration of hydroxyzine with a potentially arrhythmogenic drug could increase the risk of QT prolongation and torsades de pointes.
Warnings It is important to know that:
The dose should be adjusted if hydroxyzine is used concomitantly with other CNS depressants or anticholinergic properties (see Interactions).
The concomitant use of alcohol and hydroxyzine should be avoided (see Interactions).
The concomitant administration of hydroxyzine and anticoagulants requires careful surveillance, with the help of appropriate laboratory tests.
The appearance of epigastric disorders can be avoided by administering the product after meals.
Particular caution should be exercised in determining the dose in children, the elderly and in patients with renal and hepatic insufficiency (see Dose, method and time of administration).
In the elderly patient, it is recommended to start therapy with half the adult dosage due to the long duration of action of the drug (see Dose, method and time of administration).
The dose should be reduced in patients with hepatic insufficiency and in patients with moderate to severe renal insufficiency (see Dose, method and time of administration).
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Women of childbearing potential should use effective contraceptive measures for the prevention of pregnancy during treatment with hydroxyzine.
Pregnancy
Studies in animals have shown toxic effects on reproductive function.
Hydroxyzine crosses the placenta, reaching concentrations in the fetus that are higher than those in the mother.
There are currently no epidemiological data on the exposure of pregnant women to hydroxyzine. Therefore, hydroxyzine is contraindicated in pregnancy.
Labor and childbirth
In newborns of mothers treated with hydroxyzine during late pregnancy and / or during delivery, the following events have been observed immediately after delivery or in the first hours after birth: hypotonia, movement disorders, including extrapyramidal disorders, clonic movements, central nervous system depression, neonatal hypoxic conditions and urinary retention.
Feeding time
Cetirizine, the major metabolite of hydroxyzine, is excreted in human milk.
Although no formal studies of hydroxyzine excretion in human milk have been performed, serious adverse effects have been reported in breastfed newborns / infants of mothers treated with hydroxyzine.
Hydroxyzine is therefore contraindicated during lactation. Breastfeeding should be discontinued if the mother is to be treated with ATARAX.
Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
Hydroxyzine can cause tiredness, dizziness, sedation, visual disturbances and therefore can impair the ability to react and concentrate, particularly at higher doses and / or if administered simultaneously with alcohol or sedative drugs.
Patients should be warned of this possibility and advised that caution is required when driving and operating machinery. Concomitant use of hydroxyzine with alcohol or sedative drugs should be avoided as their intake aggravates these effects.
Important information about some of the ingredients of ATARAX
The syrup contains 0.75 g of sucrose per ml. In case of ascertained intolerance to sugars, contact your doctor before taking the medicine.
The sucrose content must also be taken into consideration when administered to patients with diabetes mellitus at doses higher than 6.5 ml of syrup. Sucrose can be bad for your teeth.
The syrup contains small amounts (0.1% by volume) of ethanol (alcohol) less than 100 mg per dose. This should be taken into consideration in patients suffering from alcoholism, in pregnant or breastfeeding women, in children and in high-risk groups such as patients with liver disease or epilepsy. The tablets contain lactose. In case of ascertained intolerance to sugars, contact your doctor before taking the medicine.
For those who carry out sporting activities, the use of medicines containing ethyl alcohol can determine positive doping tests in relation to the alcohol concentration limits indicated by some sports federations.
Dosage and method of use How to use Atarax: Dosage
The dosage is strictly individual.
Adults and adolescents: The unit dose is 12.5 mg - 25 mg (12.5 mg = 1⁄2 tablet; 25 mg = 1 tablet or 1 tablespoon not filled with syrup).
Children over 12 months of age: the unit dose is 10 mg - 20 mg depending on age (10 mg = 1 teaspoon of syrup; 20 mg = 1 tablespoon of syrup). Tablets are not suitable for administration to children.
The dosage varies from 1 to 4 daily administrations depending on the case; higher doses can be administered after careful evaluation of the doctor and on his advice.
Elderly: In the treatment of elderly patients, the posology must be carefully established by the doctor who will evaluate the possible reduction of the dosages indicated above. It is advisable to start therapy in the elderly patient with half the dosage prescribed for the adult due to the long duration of treatment. action of the drug.
Hepatic insufficiency: In patients with hepatic insufficiency, the dosage should be reduced by one third.
Renal impairment: Dosage should be reduced in patients with moderate to severe renal impairment because excretion of the metabolite cetirizine is reduced in these patients.
Method of use
Syrup: administer it, pure or diluted, in a little water or fruit juice, immediately before meals.
Tablets: swallow without chewing, with a sip of water; if necessary, follow the administration with a small amount of food (biscuits, fruit, etc.).
Overdose What to do if you have taken too much Atarax
In case of accidental ingestion / intake of an excessive dose of ATARAX, notify your doctor immediately or go to the nearest hospital.
There is no specific antidote; in case of accidents due to overdose, the treatment will therefore be symptomatic, as for all other antihistamines.
Symptoms observed after major overdose are mainly associated with excessive anticholinergic stimulation and depression or paradoxical central nervous system stimulation. Symptoms include nausea, vomiting, tachycardia, fever, somnolence, impaired pupillary reflexes, tremor, confusion and hallucinations. They may be followed by impaired consciousness, respiratory depression, convulsions, hypotension or cardiac arrhythmias. Worsening of coma and cardiorespiratory collapse may follow.
Airway patency, respiratory function and cardiocirculatory function should be carefully monitored by continuous recording of the electrocardiogram and an adequate supply of oxygen should be available. Cardiac and blood pressure monitoring should be continued until the patient has been asymptomatic for 24 hours In patients with impaired consciousness, it is necessary to check that other drugs or alcohol have not been ingested and to administer oxygen, naloxone, glucose and thiamine, as needed.
Norepinephrine or metaramirole should be used if a vasopressor is needed.
You don't have to use adrenaline.
Ipecac syrup should not be given to patients who are symptomatic or at risk of dullness, coma or convulsions, as this could lead to aspiration pneumonia. In case of clinically important ingestion, gastric lavage can be performed after endotracheal intubation. Activated charcoal can be administered, but its effectiveness is poorly documented.
The usefulness of hemodialysis or hemoperfusion is questionable.
There are data in the literature indicating that in the presence of severe anticholinergic effects that do not respond to other therapies and place the patient at risk of life, an attempt with a therapeutic dose of physostigmine may be useful. This drug should not be used only to keep the patient awake. If tricyclic antidepressants are also ingested at the same time, the use of physostigmine can trigger seizures and lead to intractable cardiac arrest. Physostigmine should also be avoided in patients with cardiac conduction defects.
If you have any questions about the use of ATARAX, ask your doctor or pharmacist.
Side Effects What are the side effects of Atarax
Like all medicines, ATARAX can cause side effects, although not everybody gets them.
At common therapeutic doses, antihistamines exhibit highly variable undesirable effects from compound to compound and from subject to subject.
Undesirable effects are mainly related to depression or paradoxical stimulation of the central nervous system, anticholinergic activity or hypersensitivity reactions.
A Clinical studies
The table below lists undesirable effects that occurred with hydroxyzine, at a frequency of at least 1%, in placebo-controlled clinical trials including 735 subjects exposed to hydroxyzine administered orally up to 50 mg per day and 630 subjects exposed to placebo. Frequency was assessed using the following definitions: very common (≥1 / 10), common (≥1 / 100 to <1/10), uncommon (≥1 / 1,000 to <1/100), rare (≥1 /10,000, <1 / 1,000), very rare (<1 / 10,000), not known (cannot be estimated from the available data).
The following adverse reactions have been observed with the major metabolite of hydroxyzine cetirizine and could potentially occur with hydroxyzine: thrombocytopenia, aggression, depression, tics, dystonia, paraesthesia, oculogyric crisis, diarrhea, dysuria, enuresis, asthenia, edema, increased weight.
B Post-marketing experience
The undesirable effects reported during the marketing of the medicine are listed below, by system and by frequency class.
Frequency was assessed using the following definitions: very common (≥1 / 10), common (≥1 / 100 to <1/10), uncommon (≥1 / 1,000 to <1/100), rare (≥1 /10,000, <1 / 1,000), very rare (<1 / 10,000), not known (cannot be estimated from the available data).
Cardiac disorders:
Rare: tachycardia
Not known: prolonged QT electrocardiogram, torsades de pointes
Eye disorders:
Rare: accommodation disorder, blurred vision
Ear and labyrinth disorders:
Not known: dry nose, ringing in the ears
Gastrointestinal disorders:
Common: dry mouth
Uncommon: nausea
Rare: constipation, vomiting
Hepatobiliary disorders:
Rare: liver function tests abnormal
Not known: hepatitis
General disorders and administration site conditions:
Common: fatigue
Uncommon: asthenia, malaise, fever, injection site pain or inflammation, phlebitis, buttock abscess
Immune system disorders:
Rare: hypersensitivity
Very rare: anaphylactic shock
Nervous system disorders:
Very common: somnolence
Common: headache, sedation
Uncommon: dizziness, insomnia, tremor
Rare: convulsions, dyskinesias, nervousness, difficulty coordinating movements
Psychiatric disorders:
Uncommon: agitation, confusion
Rare: disorientation, hallucinations
Renal and urinary disorders:
Rare: urinary retention
Respiratory, thoracic and mediastinal disorders:
Very rare: bronchospasm
Skin and subcutaneous tissue disorders:
Rare: pruritus, erythematous rash, maculo-papular rash, urticaria, dermatitis
Very rare: Stevens-Johnson syndrome, erythema multiforme, acute generalized exanthematous pustulosis, angioneurotic edema, fixed drug eruption, increased sweating
Vascular disorders:
Rare: hypotension
Disorders of the blood and lymphatic system:
Exceptionally agranulocytosis and other severe haematological reactions (thrombocytopenia, haemolytic anemia).
In rare cases, intramuscular administration of the solution for injection induces long-lasting moderate pain.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
See the expiry date printed on the package. The expiry date indicated refers to the product in intact and correctly stored packaging.
WARNING: do not use the medicine after the expiry date indicated on the package. The expiry date refers to the last day of the month.
Special precautions for storage
Keep the blisters and the bottle in the outer carton to protect the medicine from light.
Keep this medicine out of the reach and sight of children.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
COMPOSITION
ATARAX 20 mg / 10 ml syrup
10 ml of syrup contain:
Active ingredient: hydroxyzine dihydrochloride 20 mg.
Excipients: sucrose, sodium benzoate (E211), levomentol, hazelnut essence (containing among others propylene glycol, vanillin, ethylvanillin, fenugreek seed extract, lovage oil), ethanol, purified water.
ATARAX 25 mg film-coated tablets
Each tablet contains:
Active ingredient: hydroxyzine dihydrochloride 25 mg.
Excipients: Core: lactose monohydrate, microcrystalline cellulose, magnesium stearate, anhydrous colloidal silica. Coating: Opadry Y-1-7000 [titanium dioxide (E171), hypromellose (E464), macrogol 400].
PHARMACEUTICAL FORM AND CONTENT
Syrup. Bottle of 150 ml of syrup 20 mg / 10 ml
Film-coated tablets. Box of 20 divisible tablets of 25 mg.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
ATARAX
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
ATARAX 20 mg / 10 ml syrup
10 ml of syrup contain:
Active principle: hydroxyzine dihydrochloride 20 mg.
Excipients: sucrose, ethanol (alcohol).
ATARAX 25 mg film-coated tablets
Each tablet contains:
Active principle: hydroxyzine dihydrochloride 25 mg.
Excipients: lactose.
ATARAX 100 mg / 2 ml solution for injection for intramuscular use
Each vial contains:
Active principle: hydroxyzine dihydrochloride 100 mg.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Syrup: clear, colorless solution.
Film-coated tablets: White, oblong shaped, scored film-coated tablets.
Solution for injection: clear, colorless solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Tablets and syrup
Short-term treatment of anxious states. Allergic dermatitis accompanied by itching.
Injectable solution
Emergency treatment of states of agitation, preparation for surgical interventions. Post-operative medication: postoperative nausea and vomiting, adjuvant treatment of systemic allergies (serum sickness, anaphylaxis) and general reactions to transfusions or medications.
04.2 Posology and method of administration
Tablets and syrup
The dosage is strictly individual.
Adults and adolescents
The unit dose is 12.5 mg - 25 mg (12.5 mg = ½ tablet; 25 mg = 1 tablet or 1 tablespoon not filled with syrup).
Children over 12 months of age
The unit dose is 10 mg - 20 mg depending on age (10 mg = 1 teaspoon of syrup; 20 mg = 1 tablespoon of syrup). The tablets are not suitable for administration to children.
The dosage varies from 1 to 4 daily administrations depending on the case; higher doses can be administered after careful consideration.
Injectable solution
The solution for injection is intended for intramuscular administration only.
to) Emergency treatment of states of agitation
Adults
The unit dose is 50 mg - 200 mg to be repeated, if necessary, every 4-6 hours, without exceeding the maximum total daily dose of 300 mg.
b) Preparation for surgery
The unit dose is 25 mg - 200 mg to be administered half an hour before surgery.
c) Post-operative dressing; post-operative nausea and vomiting and adjuvant treatment of systemic allergies (serum sickness, anaphylaxis) and general reactions from transfusions or drugs
The unit dose is 25 mg - 50 mg for a single administration.
The treatment will eventually be continued orally.
Senior citizens
In the treatment of elderly patients, the posology must be carefully established, evaluating the possible reduction of the dosages indicated above. It is advisable to start therapy in the elderly patient with half the dosage prescribed for the adult due to the long duration of action of the drug.
Hepatic insufficiency
In patients with hepatic insufficiency, the dosage should be reduced by one third.
Kidney failure
Dosage should be reduced in patients with moderate to severe renal impairment because excretion of the metabolite cetirizine is reduced in these patients.
04.3 Contraindications
History of hypersensitivity to the active substance or to any of the excipients, to cetirizine, to other piperazine derivatives, to aminophylline or to ethylenediamine.
In patients with porphyria.
In patients receiving monoamine oxidase inhibitors (MAOIs) (see section 4.5).
In patients with pre-existing prolonged QT interval.
During pregnancy and lactation (see section 4.6).
The solution for injection must not be administered intravenously, intra-arterially and subcutaneously.
04.4 Special warnings and appropriate precautions for use
Hydroxyzine should be administered with caution in patients with an increased predisposition to seizures. Young children are more prone to developing central nervous system adverse events (see section 4.8). The incidence of seizures is higher in children than in adults. .
Due to its potential anticholinergic effects, hydroxyzine should be used with caution in case of glaucoma, prostatic hypertrophy, bladder neck obstruction, pyloric and duodenal stenosis or other tracts of the gastrointestinal and urogenital tract, in gastrointestinal hypomotility. , in myasthenia gravis, in cardiovascular diseases, in arterial hypertension, in hyperthyroidism and in cases of dementia, avoiding its use in cases of greater severity.
Particular caution is required for patients who have a known predisposition to cardiac arrhythmia including electrolyte imbalance (hypokalemia, hypomagnesaemia), who have pre-existing heart disease or who are taking concomitant medications that can induce cardiac arrhythmia. In such patients it is to be taken in consider using alternative treatments.
The dose should be adjusted if hydroxyzine is used concomitantly with other CNS depressants or anticholinergic properties (see section 4.5).
The concomitant use of alcohol and hydroxyzine should be avoided (see section 4.5).
The concomitant administration of hydroxyzine and anticoagulants requires careful surveillance, with the help of appropriate laboratory tests.
The appearance of epigastric disorders can be avoided by administering the product after meals.
Particular caution should be exercised in determining the dose in children, the elderly and in patients with renal and hepatic insufficiency (see section 4.2).
In elderly patients, it is recommended to start therapy with half the adult dosage due to the long duration of action of the drug (see section 4.2).
The dose should be reduced in patients with hepatic impairment and in patients with moderate to severe renal impairment (see section 4.2).
Before intramuscular administration of the solution for injection, a thorough check should be made to ensure that the needle has not entered a blood vessel.
The solution for injection should not be administered subcutaneously, intravenously and intra-arterially due to adverse reactions at the injection site, such as local tissue necrosis or long-lasting residual pain and the possibility of thrombophlebitis and arterial thrombosis (see section 4.3).
Important information about some of the ingredients
ATARAX syrup contains 0.75 g of sucrose per ml. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase isomaltase insufficiency should not take this medicinal product (see section 6.1).
The sucrose content must also be taken into consideration when administered to patients with diabetes mellitus at doses higher than 6.5 ml of syrup. Sucrose can be bad for your teeth.
The syrup contains small amounts (0.1% by volume) of ethanol (alcohol) less than 100 mg per dose. This should be taken into consideration in patients suffering from alcoholism, in pregnant or breastfeeding women, in children and in high-risk groups such as patients with liver disease or epilepsy.
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product (see section 6.1).
04.5 Interactions with other medicinal products and other forms of interaction
Hydroxyzine must not be administered together with monoamine oxidase inhibitors (see section 4.3).
The potentiating action of hydroxyzine should be considered when used in combination with other substances with anticholinergic action or with substances with central nervous system depressant effect and the dose should be adjusted on an individual basis. Alcohol also enhances the effects of hydroxyzine, so its intake is not recommended during treatment with ATARAX.
Hydroxyzine antagonizes the effects of betahistine and anticholinesterases.
Treatment should be stopped at least five days prior to allergy testing or bronchial challenge test with methacholine to avoid effects on the test results.
The combination of ATARAX with other psychotropic drugs requires particular caution and vigilance on the part of the physician in order to avoid unexpected undesirable effects of interaction.
The use of antihistamines can mask the early signs of ototoxicity of certain antibiotics.
Hydroxyzine counteracts the pressure action of adrenaline.
In rats, hydroxyzine antagonizes the anticonvulsant action of phenytoin.
Cimetidine at a dosage of 600 mg twice daily has been shown to increase serum concentrations of hydroxyzine by 36% and to reduce maximal concentrations of the metabolite cetirizine by 20%.
Hydroxyzine inhibits cytochrome P450 2D6 (Ki: 3.9 mM; 1.7 mg / ml) and may cause drug interactions with other CYP2D6 substrates at high doses.
Hydroxyzine does not inhibit isoforms 1A1 and 1A6 of the UDP-glucuronyl transferase enzyme of human liver microsomes at a dose of 100 mM. It inhibits the cytochrome P450 isoforms 2C9, 2C19 and 3A4 at concentrations much higher than the maximum plasma concentrations (CI50: 103-140 mM; 46-52 mg / ml).Therefore, hydroxyzine is unlikely to impair the metabolism of drugs that are substrates for these enzymes. The metabolite cetirizine at 100 mM does not inhibit cytochrome P450 (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4) nor isoforms of UDP-glucuronyl transferase in the human liver. Since hydroxyzine is metabolised by alcohol dehydrogenase and CYP3A4 / 5 isoenzymes, increased blood concentrations of hydroxyzine can be expected when co-administered with other drugs known to be potent inhibitors of these enzymes. However, when only one pathway is inhibited, the other can partially compensate.
Concomitant administration of hydroxyzine with a potentially arrhythmogenic drug could increase the risk of QT prolongation and torsades de pointes.
04.6 Pregnancy and lactation
Women of childbearing potential should use effective contraceptive measures for the prevention of pregnancy during treatment with hydroxyzine.
Pregnancy
Studies in animals have shown toxic effects on reproductive function.
Hydroxyzine crosses the placenta, reaching concentrations in the fetus that are higher than those in the mother.
There are currently no epidemiological data on the exposure of pregnant women to hydroxyzine. Therefore, hydroxyzine is contraindicated in pregnancy.
Labor and childbirth
In newborns of mothers treated with hydroxyzine during late pregnancy and / or during delivery, the following events have been observed immediately after delivery or in the first hours after birth: hypotonia, movement disorders, including extrapyramidal disorders, clonic movements, central nervous system depression, neonatal hypoxic conditions and urinary retention.
Feeding time
Cetirizine, the major metabolite of hydroxyzine, is excreted in human milk.
Although no formal studies of hydroxyzine excretion in human milk have been performed, serious adverse effects have been reported in breastfed newborns / infants of mothers treated with hydroxyzine.
Hydroxyzine is therefore contraindicated during lactation. Breastfeeding should be discontinued if the mother is to be treated with hydroxyzine.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed.
Hydroxyzine can cause tiredness, dizziness, sedation, visual disturbances and therefore can impair the ability to react and concentrate, particularly at higher doses and / or if administered simultaneously with alcohol or sedative drugs.
Patients should be warned of this possibility and advised that caution is required when driving and operating machinery. Concomitant use of hydroxyzine with alcohol or sedative drugs should be avoided as their intake aggravates these effects.
04.8 Undesirable effects
At common therapeutic doses, antihistamines exhibit highly variable undesirable effects from compound to compound and from subject to subject.
Undesirable effects are mainly related to depression or paradoxical stimulation of the central nervous system, anticholinergic activity or hypersensitivity reactions.
TO) Clinical studies
The table below lists undesirable effects that occurred with hydroxyzine, at a frequency of at least 1%, in placebo-controlled clinical trials including 735 subjects exposed to hydroxyzine administered orally up to 50 mg per day and 630 subjects exposed to placebo.
Frequency was assessed using the following definitions: very common (≥1 / 10), common (≥1 / 100,
The following adverse reactions have been observed with the major metabolite of hydroxyzine cetirizine and could potentially occur with hydroxyzine: thrombocytopenia, aggression, depression, tics, dystonia, paraesthesia, oculogyric crisis, diarrhea, dysuria, enuresis, asthenia, edema, increased weight.
B) Post-marketing experience
The undesirable effects reported during the marketing of the medicine are listed below, by system and by frequency class.
Frequency was assessed using the following definitions: very common (≥1 / 10), common (≥1 / 100,
Cardiac pathologies
Rare: tachycardia.
Not known: prolonged QT electrocardiogram, torsades de pointes.
Eye disorders
Rare: accommodation disorder, blurred vision.
Ear and labyrinth disorders
Not known: dry nose, ringing in the ears.
Gastrointestinal disorders
Common: dry mouth.
Uncommon: nausea.
Rare: constipation, vomiting.
Hepatobiliary disorders
Rare: liver function tests abnormal.
Not known: hepatitis.
General disorders and administration site conditions
Common: fatigue.
Uncommon: asthenia, malaise, fever, pain or inflammation at the injection site, phlebitis, buttock abscess.
Disorders of the immune system
Rare: hypersensitivity.
Very rare: anaphylactic shock.
Nervous system disorders
Very common: somnolence.
Common: headache, sedation.
Uncommon: dizziness, insomnia, tremor.
Rare: convulsions, dyskinesias, nervousness, difficulty coordinating movements.
Psychiatric disorders
Uncommon: agitation, confusion.
Rare: disorientation, hallucinations.
Renal and urinary disorders
Rare: urinary retention.
Respiratory, thoracic and mediastinal disorders:
Very rare: bronchospasm.
Skin and subcutaneous tissue disorders
Rare: pruritus, erythematous rash, maculo-papular rash, urticaria, dermatitis.
Very rare: Stevens-Johnson syndrome, erythema multiforme, acute generalized exanthematous pustulosis, angioneurotic edema, fixed drug eruption, increased sweating.
Vascular pathologies
Rare: hypotension.
Disorders of the blood and lymphatic system
Exceptionally agranulocytosis and other severe haematological reactions (thrombocytopenia, haemolytic anemia).
In rare cases, intramuscular administration of the solution for injection induces long-lasting moderate pain.
04.9 Overdose
There is no specific antidote; in case of accidents due to overdose, the treatment will therefore be symptomatic, as for all other antihistamines.
Symptoms observed after major overdose are mainly associated with excessive anticholinergic stimulation and depression or paradoxical central nervous system stimulation. Symptoms include nausea, vomiting, tachycardia, fever, somnolence, impaired pupillary reflexes, tremor, confusion and hallucinations. They may be followed by impaired consciousness, respiratory depression, convulsions, hypotension or cardiac arrhythmias. Worsening of coma and cardiorespiratory collapse may follow.
Airway patency, respiratory function and cardiocirculatory function should be closely monitored by continuous electrocardiogram recording and adequate oxygen supply should be available. Cardiac and blood pressure monitoring should be continued as long as the patient has been asymptomatic for 24 hours. In patients with impaired consciousness, it is necessary to check that other drugs or alcohol have not been ingested and to administer oxygen, naloxone, glucose and thiamine, as needed.
Norepinephrine or metaramirole should be used if a vasopressor is needed. You don't have to use adrenaline.
Ipecac syrup should not be given to patients who are symptomatic or at risk of dullness, coma or seizures, as this could lead to pneumonia. ab ingestis. In case of clinically important ingestion, gastric lavage can be performed after endotracheal intubation. Activated charcoal can be administered, but its effectiveness is poorly documented.
The usefulness of hemodialysis or hemoperfusion is questionable.
There are data in the literature indicating that in the presence of severe anticholinergic effects that do not respond to other therapies and place the patient at risk of life, an attempt with a therapeutic dose of physostigmine may be useful. This drug should not be used only to keep the patient awake. If tricyclic antidepressants are also ingested at the same time, the use of physostigmine can trigger seizures and lead to intractable cardiac arrest. Physostigmine should also be avoided in patients with cardiac conduction defects.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: psycholeptic and anxiolytic (ataraxic)
ATC code: N05BB01
The active substance hydroxyzine dihydrochloride is a derivative of diphenylmethane which is not chemically related to either the phenothiazine or benzodiazepine class, nor to reserpine or meprobamate.
Mechanism of action
Hydroxyzine dihydrochloride does not depress the cerebral cortex, but its action may be due to the suppression of activity in some key areas of the subcortical area of the central nervous system.
Pharmacodynamic effects
Antihistamine and bronchodilator activities have been experimentally demonstrated and confirmed in the clinic. An antiemetic effect has also been demonstrated, both with the apomorphine test and with that with Veriloid. Pharmacological and clinical studies indicate that hydroxyzine at therapeutic dosage does not increase gastric secretion or acidity and that in most cases it exerts a modest antisecretory activity. The reduction of the erythemato-wheal reaction to the intradermal injection of histamine or antigens has been demonstrated in healthy volunteers both adults and children. Hydroxyzine has also been shown to be effective in relieving itching in various forms of urticaria, eczema and dermatitis.
In hepatic insufficiency, the antihistamine effect of a single dose can last up to 96 hours after administration.
Electroencephalographic traces in healthy volunteers have a profile similar to drugs with an anxiolytic and sedative effect. The anxiolytic effect has been confirmed in patients through the use of various classical psychometric tests.
Polysomnographic traces in anxious and insomniac patients showed an increase in the total duration of sleep, a reduction in the total time of nocturnal awakenings and a reduction in the latency time to sleep after both single and repeated daily doses of 50 mg. A reduction in muscle tension has been demonstrated in anxious patients at the daily dosage of 50 mg three times a day. No memory deficit was observed. No withdrawal signs or symptoms appeared after 4 weeks of treatment in anxious patients.
The antihistamine effect sets in after about 1 hour following oral administration. The sedative effect begins after 5-10 minutes with the oral solution and after 30-45 minutes with the tablets.
Hydroxyzine also exerts spasmolytic and sympatholytic effects. It has a weak affinity for muscarinic receptors. It exerts a modest analgesic activity.
05.2 Pharmacokinetic properties
Absorption
Hydroxyzine is rapidly absorbed from the gastrointestinal tract.
Peak plasma (Cmax) is reached approximately 2 hours after oral administration. After single doses of 25 mg and 50 mg in adults the Cmax concentrations are 30 and 70 ng / ml, respectively. The rate and extent of exposure to hydroxyzine is very similar with tablets and syrup. Following repeated once daily administration, concentrations increased by 30%. The oral bioavailability of hydroxyzine relative to intramuscular administration is approximately 80%. After a single 50 mg intramuscular dose, the Cmax concentration is generally 65 ng / ml.
Distribution
Hydroxyzine is widely distributed in the body and generally concentrates more in tissues than in plasma. The apparent volume of distribution varies between 7 and 16 l / kg in adults. Hydroxyzine penetrates the skin after oral administration. Concentrations in the skin are higher than those in serum following both single and multiple dosing.
Hydroxyzine crosses the blood brain and placental barrier, reaching higher concentrations in the fetus than in the mother.
Metabolism
Hydroxyzine is extensively metabolised. The formation of the major metabolite cetirizine, a carboxylic metabolite (45% of the oral dose), is mediated by alcohol dehydrogenase. This metabolite possesses important antagonistic properties of peripheral H1 receptors. Several other metabolites have been identified, including an N-dealkylated metabolite and an O-dealkylated metabolite with a plasma half-life of 59 hours. These metabolic pathways are mainly mediated by CYP3A4 / 5 isoenzymes.
Elimination
In the "adult" the half-life of hydroxyzine is approximately 14 hours (range: 7-20 hours). The total apparent clearance calculated in the various available studies amounts to 13 ml / min / kg. Only 0.8% of the dose is excreted unchanged in the urine. The major metabolite cetirizine is mainly excreted unchanged in the urine (25% and 16% of the oral and intramuscular dose, respectively).
Special populations
Senior citizens
The pharmacokinetics of hydroxyzine were studied in 9 healthy elderly subjects (69.5 ± 3.7 years) following administration of a single oral dose of 0.7 mg / kg. The elimination half-life of hydroxyzine was prolonged to 29 hours and the apparent volume of distribution increased to 22.5 L / kg. It is recommended that the daily dose of hydroxyzine be reduced in the elderly (see section 4.2).
Children
The pharmacokinetics of hydroxyzine were studied in 12 pediatric patients 6.1 ± 4.6 years; (22.0 ± 12.0 kg) following administration of a single oral dose of 0.7 mg / kg. Apparent plasma clearance was approximately 2.5 times that in adults. The half-life was shorter than in adults: approximately 4 hours in 1-year-olds and 11 hours in 14-year-olds. The dosage should be adapted in the pediatric patient population (see section 4.2).
Hepatic insufficiency
In subjects with hepatic insufficiency secondary to primary biliary cirrhosis, the total body clearance was approximately 66% of that observed in normal subjects. An increase in the half-life of up to 37 hours and an increase in serum concentrations of the carboxylic metabolite cetirizine were observed compared to young patients with normal hepatic function.
In patients with hepatic insufficiency the daily dosage or frequency of administration should be reduced (see section 4.2).
Kidney failure
The pharmacokinetics of hydroxyzine was studied in 8 subjects with severe renal insufficiency (creatinine clearance: 24 ± 7 ml / min). The extent of exposure (AUC) to hydroxyzine was not significantly altered, while that to carboxylic metabolite cetirizine, is increased. This metabolite is not removed efficiently by hemodialysis. In order to avoid any relevant accumulation of the metabolite cetirizine following multiple doses of hydroxyzine, the daily dose of the drug should be reduced in subjects with impaired function renal (see section 4.2).
05.3 Preclinical safety data
In isolated dog Purkinje fibers, 3 mcM hydroxyzine increased the duration of the action potential suggesting that there was an interaction with the potassium channels involved in the repolarization phase. At concentrations higher than 30 mcM c "was a marked decrease in the duration of the action potential suggesting a possible interaction with calcium and / or sodium currents. The" hydroxyzine produced inhibition of the potassium current (Ikr) in the channels of the human hERG gene expressed in breast cells, with a CI50 of 0.62 mcM, a concentration that is 10 to 60 times higher than the therapeutic concentrations. Furthermore, the concentrations of hydroxyzine required to produce effects on cardiac electrophysiology are 10 to 100 times higher than those required to block H1 and 5-HT2 receptors. In free awake dogs monitored by telemetry hydroxyzine and its metabolites produced similar cardiovascular profiles although there was some minimal difference. In a first telemetry study in dogs, hydroxyzine (21 mg / kg orally) increased heart rate mildly and decreased PR and QT intervals. There was no effect on the QRS and QTc intervals and therefore at normal therapeutic doses of 25 - 100 mg these slight changes are unlikely to be of clinical interest. Similar effects on heart rate and PR interval were observed over one second. telemetry study in dogs where the absence of effects of hydroxyzine on the QTc interval was confirmed up to a single oral dose of 36 mg / kg.
Acute and chronic toxicity data are as follows:
Acute toxicity
The LD50 in the rat is equal to 1000 mg / kg per os or 45 mg / kg per i.v.
Chronic toxicity
It is practically absent; in dogs, daily oral doses from 5 to 20 mg / kg, for 6-7 months, do not cause haematological alterations, hepatic and renal functions, nor histological alterations of the main parenchyma.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Syrup
Sucrose, sodium benzoate (E211), levomenthol, hazelnut essence (containing propylene glycol, vanillin, ethylvanillin, fenugreek seed extract, lovage oil), ethanol, purified water.
Film-coated tablets
Core: lactose monohydrate, microcrystalline cellulose, magnesium stearate, anhydrous colloidal silica.
Coating: Opadry Y-1-7000 [titanium dioxide (E 171), hypromellose (E 464), macrogol 400].
Injectable solution
Sodium hydroxide, water for injections.
06.2 Incompatibility
The solution for injection must not be mixed with other substances / solutions.
06.3 Period of validity
Syrup: 2 years.
Tablets and solution for injection: 5 years.
06.4 Special precautions for storage
Syrup and film-coated tablets: keep the bottle and blisters in the outer carton to protect the medicine from light.
Injectable solution: do not store above 25 ° C. Keep the ampoules in the outer carton to protect the medicine from light.
06.5 Nature of the immediate packaging and contents of the package
Syrup: 150 ml amber glass bottle.
Film-coated tablets: PVC / aluminum blister. Pack of 20 divisible tablets.
Injectable solution: 2 ml vials. Pack of 6 ampoules.
06.6 Instructions for use and handling
Syrup: administer it, pure or diluted, in a little water or fruit juice, immediately before meals.
Tablets: swallow without chewing, with a sip of water; if necessary, follow the administration with a small amount of food (biscuits, fruit, etc.).
07.0 MARKETING AUTHORIZATION HOLDER
UCB Pharma S.p.A. - Via Gadames 57 - Milan (MI)
08.0 MARKETING AUTHORIZATION NUMBER
ATARAX 20 mg / 10 ml syrup - 150 ml bottle - AIC 010834012
ATARAX 25 mg film-coated tablets - 20 divisible tablets - AIC 010834024
ATARAX 100 mg / 2 ml solution for injection for intramuscular use - 6 ampoules 2 ml - AIC 010834051
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 4 February 1956
Date of last renewal: 1 June 2010
10.0 DATE OF REVISION OF THE TEXT
November 20, 2012
