Medications for Allergy

Drug Approvals

(British Approved Name Modified, rINNM)

INNs in main languages (French, Latin, and Spanish):

Pharmacopoeias. In Europe, Japan, and US.

European Pharmacopoeia, 6th ed. (Hydroxyzine Hydrochloride). A white or almost white, crystalline, hygroscopic powder. Freely soluble in water and in alcohol very slightly soluble in acetone. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Hydroxyzine Hydrochloride). A white, odourless, powder. Soluble 1 in 1 of water, 1 in 4.5 of alcohol, and 1 in 13 of chloroform slightly soluble in acetone practically insoluble in ether. Store in airtight containers.

Incompatibility. Hydroxyzine hydrochloride has been reported to be incompatible with aminophylline, benzylpenicillin salts, chloramphenicol sodium succinate, dimenhydrinate, doxorubicin hydrochloride (in a liposomal formulation), thioridazine, and some soluble barbiturates.

Stability. A mixture of hydroxyzine hydrochloride, chlorpromazine hydrochloride, and pethidine hydrochloride stored in glass or plastic syringes was found to be stable for 366 days at 4° and 25°.

Adverse Effects and Precautions

As for the sedating antihistamines in general. Intramuscular injection of hydroxyzine has been reported to cause marked local discomfort. Intravenous use has been associated with haemolysis.

Amputation. Accidental intra-arterial injection of hydroxyzine has led to necrosis of the extremity requiring amputation of the digits of the affected limb.

Arrhythmias. ECG abnormalities, particularly alterations in T-waves, were associated with anxiolytic doses of hydroxyzine hydrochloride and were similar to those produced by thioridazine and tricyclic antidepressants.

Effects on sexual function. A 32-year-old man had prolonged penile erections (priapism) after taking two separate doses of hydroxyzine for a skin rash. It was suggested that the effect might be due to a hydroxyzine metabolite that was found to be structurally similar to a metabolite of trazodone, a drug known to induce penile erections.

Effects on the skin. Four children given hydroxyzine hydrochloride for restlessness developed a fixed drug eruption of the penis. All recovered on drug withdrawal and subsequently had positive rechallenges.

Liver disorders. A study has suggested that hydroxyzine should only be given once daily for the relief of pruritus in patients with primary biliary cirrhosis. The mean serum elimination half-lives of hydroxyzine and its metabolite cetirizine in 8 patients with primary biliary cirrhosis were 36.6 and 25.0 hours respectively.

Porphyria. Hydroxyzine has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Interactions

As for the sedating antihistamines in general.

Pharmacokinetics

Hydroxyzine is rapidly absorbed from the gastrointestinal tract and is metabolised. Metabolites include cetirizine, which has antihistaminic activity. An elimination half-life of about 20 hours has been reported.

Liver disorders. For reference to a prolonged half-life of hydroxyzine in patients with primary biliary cirrhosis, see under Adverse Effects and Precautions, above.

Uses and Administration

Hydroxyzine, a piperazine derivative, is a sedating antihistamine with antimuscarinic and significant sedative properties it is also an antiemetic. Its main use is as an anxiolytic but see Anxiety Disorders below. It is also used as an adjunct to pre- and postoperative medication (see Anaesthesia) and in the management of pruritus and urticaria and has been used as an adjunct to opioid analgesia in the management of cancer pain. Hydroxyzine may be given orally as the hydrochloride or the embonate doses are expressed in terms of the hydrochloride. Hydroxyzine embonate 170 mg is equivalent to about 100 mg of hydroxyzine hydrochloride.

The usual oral doses in adults are: 50 to 100 mg four times daily for the short-term management of anxiety for pruritus an initial dose of 25 mg given at night, increased if necessary to 25 mg three or four times daily and 50 to 100 mg for pre- or postoperative sedation. For pruritus in children over 6 years of age the initial dose is 15 to 25 mg daily increased if necessary to 50 to 100 mg daily in divided doses for children 6 months to 6 years old the initial dose is 5 to 15 mg daily increased if necessary to 50 mg daily in divided doses.

Alternatively, 1 mg/kg daily may be given in divided doses, to a maximum of 2.5 mg/kg daily in children aged 1 to 6 years, and to a maximum of 2 mg/kg daily in those aged 6 years and over. The pre- or postoperative sedative dose in children is 600 micrograms/kg. Dosage should be reduced in patients with hepatic or renal impairment, see below.

Hydroxyzine hydrochloride may also be given by deep intramuscular injection. For prompt control of anxiety or agitation in adults 50 to 100 mg is injected intramuscularly initially, and the dose may be repeated every four to six hours as required. For other indications when oral dosage is not practical, the intramuscular dose is 25 to 100 mg for adults and 1.1 mg/kg for children. Hydroxyzine should not be given by intravenous injection since haemolysis may result.

Administration in hepatic or renal impairment. In patients with hepatic impairment, UK licensed product information recommends a 33% reduction in the total oral daily dose of hydroxyzine. In patients with moderate or severe renal impairment, a dose reduction of 50% is recommended.

Anxiety disorders. Although hydroxyzine is used in the management of anxiety, there is little evidence to support its efficacy in anxious patients, and the BNF considers that use of antihistamines solely for their sedative effect in anxiety is not appropriate.

Preparations

The United States Pharmacopeia 31, 2008: Hydroxyzine Hydrochloride Injection Hydroxyzine Hydrochloride Syrup Hydroxyzine Hydrochloride Tablets Hydroxyzine Pamoate Capsules Hydroxyzine Pamoate Oral Suspension.

Proprietary Preparations

Argentina: Ataraxone; Hidroxina †; Hyderax

Austria: Atarax

Belgium: Atarax

Brazil: Hixizine; Prurizin

Canada: Atarax

Chile: Dalun; Fasarax; Nexit

Czech Republic: Atarax

Denmark: Atarax

Finland: Atarax

France: Atarax

Germany: AH 3 N; Atarax; Elroquil N

Greece: Atarax Iremofar

Hong Kong: Atarax; Qualidrozine

Hungary: Atarax

India: Atarax

Indonesia: Bestalin; Iterax

Israel: Otarex

Italy: Atarax

Malaysia: Atarax

Mexico: Atarax

The Netherlands: Atarax; Navicalm †

Norway: Atarax

New Zealand: Serecid

Philippines: Iterax

Poland: Atarax

Portugal: Atarax; Coraphene

Russia: Atarax

South Africa: Aterax; Neurax

Singapore Atarax; Hizin; Phymorax †

Spain: Atarax

Sweden: Atarax

Switzerland: Atarax

Thailand: Abacus; Allerax; Antizine; Atano; Atarax; Cerax; Daraxl; Drazine; Hadarax; Histan; Hizin; Honsa; Hydroxinl; Katrax; Masaraxf; Med-Xyzarax; Polizine; Postarax; R-Rax; Taraxin; Trandrozine; Unamine

Turkey: Atarax; Validol

UK: Atarax; Ucerax

USA: Atarax; Vistaril; Vistazine.

Multi-ingredient

Austria: Diligan

Brazil: Marax

Germany: Diligan †

India: Marax

Portugal: Diligan; Vesparax †

South Africa: Geratar

Spain: Calmoplex; Dolodens

USA: Hydrophed; Marax; Theomax D †

Venezuela: Marax.

After seven-and-one-half long years under FDA review, Pfizer’s antihistamine cetirizine (Zyrtec) has received marketing approval for the treatment of seasonal and perennial allergic rhinitis and chronic idiopathic hives. Cetirizine, a metabolite of hydroxyzine, is a selective inhibitor of peripheral histamine-1 receptors. This selectivity reportedly improves the potency and reduces the side effects of cetirizine (Zyrtec) relative to other antihistamines. According to the manufacturer, cetirizine has been used in more than 2.3 billion patient-days of therapy in more than 90 countries, and is the most frequently prescribed antihistamine in Europe.

In multicenter, randomized, double-blind trials involving adults and children (aged 12-16 years) treated for up to eight weeks, cetirizine significantly reduced symptoms of seasonal and perennial allergic rhinitis (nine trials, 5-10 mg/day) and of chronic idiopathic urticaria (two trials, 5-20 mg/day). Generally, the 10 mg dose was superior to the 5 mg dose, and the 20 mg dose gave no added benefit.

In comparative trials, cetirizine proved to be at least as effective as, and in most cases superior to, chlorpheniramine (Chlor-Trimeton, Piriton, Chlor-Tripolon), hydroxyzine (Vistaril, Atarax), astemizole, terfenadine, and loratidine (Claritin) for reducing symptoms of allergic rhinitis (nasal itching and congestion, sneezing, postnasal discharge, and redness, itching and watering of the eyes. In asthmatics with allergic rhinitis, cetirizine safely reduced allergic symptoms without exacerbating the asthma. Indeed, in healthy volunteers cetirizine actually blocked bronchoconstriction when histamine was given by nebulizer.

In clinical trials involving patients with hives, cetirizine was more effective than placebo and at least as effective as terfenadine, hydroxyzine, and aztemizole for alleviating wheal, pruritus, and erythema. Volunteers given histamine by intradermal injection responded to a single 10- mg dose of cetirizine; skin wheal and flare reaction was inhibited within 20 minutes in 50% of subjects and within one hour in 95% of subjects. This activity persisted for at least 24 hours. In studies conducted for up to 12 hours following cutaneous challenge, cetirizine inhibited the allergic inflammatory response (late phase recruitment of eosinophils, neutrophils, and basophils).

Cetirizine (Zyrtec) is well tolerated. The most common side effects in clinical trials were somnolence, fatigue, dry mouth, pharyngitis, and dizziness. These effects were mild or moderate and, except for sedation, their incidence was not significantly different from placebo. Because some of the newer antihistamines can cause adverse cardiac effects, cetirizine has been evaluated extensively for eletcrophysiologic activity and drug interactions. Terfenadine (Seldane/Dow) and astemizole (Hismanal/Janssen) can cause conduction abnormalities when administered concurrently with a variety of drugs. By contrast, cetirizine did not demonstrate any clinically significant effects on the QTc interval, even in high doses (60 mg, six times the recommended dose) and in combination with ketoconazole, erythromcyin, or azithromycin. No pharmacokinetic interactions were observed with pseudoephedrine, antipyrine, ketoconazole, erythromycin or azithromycin. The only drug interaction found was with theophylline, which reduced cetirizine clearance by 16%. Cetirizine had no effect on theophylline pharmacokinetics.

Cetirizine (Zyrtec) is rapidly absorbed orally, with peak serum concentrations achieved within one hour. Food delays absorption and reduces the peak blood concentration, but has no effect on the extent of absorption. The mean elimination half-life is about eight hours. Cetirizine undergoes minimal hepatic metabolism and is excreted primarily in the urine; 70% of the dose is recovered in the urine and 10% in the feces, for a combined total recovery of about 80%. Approximately 50% of the dose is excreted in the urine as unchanged drug. Because of low first-pass metabolism and extended half-life, cetirizine can be given once daily. The drug is available in 5 and 10 mg tablets, but most patients respond best to the 10 mg, given once daily with or without food. Since cetirizine (Zyrtec) has the potential to cause somnolence, patients should be cautioned against driving or operating dangerous machinery. Concurrent use with alcohol or other CNS depressants should be avoided.

Allergy refers to a broad state of altered reactivity to a foreign substance, resulting from prior experience with the same substance. Used today, the term allergy generally refers to the unfavorable clinical consequences of an antigen-antibody interaction. Although the term allergic disorder implies an immune mechanism, in many allergic disorders, most notably bronchial asthma and atopic dermatitis, non-immune mechanisms may be of great importance. Many of the clinical conditions being treated by an allergist may be aggravated by non-immune factors such as pollution, psychic stress, cold air, and exertion -for example, exercise-induced asthma. We must always remember that there are three main principles in the therapy of allergic diseases:

1. Most important: avoidance of allergens and irritants known or suspected to be causing or aggravating the disorder.

2. The use of pharmacologic agents, restricted to as few as possible.

3. The use of specific immunotherapy or hyposensitization.

We must use a drug appropriate to the patient’s symptoms; antihistamines, for example, are useful for ear and nose complaints as well as pruritis of the skin (i.e. urticaria, eczema).

Drugs Used in the Treatment of Allergic Disorders

Antihistamines have been used in the treatment of allergic conditions for the past 30 years. They compete with the histamine released through either an antigen-antibody reaction, by physical trauma or by a histamine-liberating agent (eg. morphine, codeine). This histamine is released from the mast cells. The antihistamines compete for the cellular receptor sites, but they do not combine with the histamines in vivo or in vitro.

There are many commercially available antihistamines, which can be classified into five major groups. Physicians should be familiar with one member of each group. If the initial drug chosen does not give a good therapeutic response, use an antihistamine in another group. At times, it is necessary to try an antihistamine of one group after another, often in various combinations with sympathomimetic agents, to obtain reasonable results.

The classes of antihistamines are as follows:

1. Ethanolamines, e.g. diphenhydramine (Benadryl), dosage five mg/kg/day in three or four divided doses. A side effect is marked sedation.

2. Ethylenediamine; e.g. tripelennamine (Pyribenzamine), dosage five mg/kg/day in three or four divided doses. Side effects include moderate sedation.

3. Alkylamine; e.g. chlorpheniramine (Chlor-Tripolon), dosage 0.3 mg/kg/day in three or four divided doses. There is minimal sedation.

4. Piperazines; e.g. hydroxyzine (Atarax).

5.Phenothiazine, e.g. promethazine (Phenergan), dosage 0.5 mg/kg before retiring or 0.3 mg/kg/day. This has side effects of marked sedation.

Remember that antihistamines compete with the histamine already released in the body of the cell receptors, thus blocking the effect of the released histamine on the effector organs. Antihistamines do not combine chemically with the histamine, and they do not interfere with the antigen antibody reaction.

The sympathomimetic amine drugs or beta adrenergic agonists and theophylline are useful bronchodilators for bronchospasm.

The antibiotics used for infection in an allergic individual are tetracycline after age seven (five to ten mg/kg every six hours) and erythromycin, an unusually safe drug, orally, 10 mg/kg every six hours.

Steroids are used for more severe and acute symptoms.