REACTINE Tablet, Capsule, Syrup Ref.[27789] Active ingredients: Cetirizine

General

Severe skin reactions such as acute generalized exanthematous pustulosis (AGEP) have been reported very rarely with cetirizine-containing products. This acute pustular eruption may exhibit an early or delayed onset with numerous small, mostly non-follicular pustules arising on a widespread edematous erythema mainly localized on the skin folds, trunk, and upper extremities, which may be accompanied by fever. Patients should be carefully monitored.

If symptoms persist or worsen, or if new symptoms occur, the patient should discontinue use and consult a physician.

Activities Requiring Mental Alertness: Studies using objective measurements have shown no effect of REACTINE (cetirizine hydrochloride) on cognitive function, motor performance or sleep latency in healthy volunteers. However, in clinical trials the appearance of some CNS effects, particularly somnolence, have been observed. If drowsiness occurs, patients should be advised not to drive or operate machinery and to avoid concurrent use of REACTINE with sedating substances because additional reductions in alertness and additional impairment of CNS performance may occur (See Drug Interactions).

Special Populations

Pregnant Women: No teratogenic effects were caused by oral doses as high as 60, 188 and 133 times the maximum clinically studied human dose in mice, rats and rabbits, respectively. No effects on reproduction and fertility were observed at doses as high as 40 and 10 times the maximum recommended human dose in male and female mice, respectively. An oral dose 60 times the maximum clinically studied human dose in female mice did not affect parturition or lactation. Although the animal studies are not indicative of any adverse effects during pregnancy at clinically relevant doses, such studies are not always predictive of a human response. There are no adequate and well-controlled studies in pregnant women. Until such data become available, REACTINE (cetirizine hydrochloride) should not be used during pregnancy, unless advised otherwise by a physician.

Nursing Women: Studies in beagle dogs indicate that approximately 3% of the dose is excreted in milk. The extent of excretion in human milk is unknown. Use of REACTINE in nursing mothers is not recommended, unless directed otherwise by a physician.

Pediatrics: Unless directed otherwise by a physician, REACTINE should not be administered to children below 2 years of age (See DOSAGE AND ADMINISTRATION.)

Geriatrics: REACTINE (cetirizine hydrochloride) was well tolerated by patients aged 65 and over. Clearance of REACTINE is reduced in proportion to creatinine clearance. In patients whose creatinine clearance is reduced (i.e., those with moderate renal impairment), a starting dose of 5 mg/day is recommended (see HUMAN PHARMACOKINETICS).

Occasional instances of liver function test (transaminase) elevations have occurred during REACTINE (cetirizine hydrochloride) therapy. This incidence was 1.6% in the short-term trials and 4.4% in the 6 month trials. These liver enzyme elevations, mainly ALT, were generally reversible. There was no evidence of jaundice or hepatitis, and the clinical significance is presently unknown. Consequently, Reactine should be used with caution in patients with preexisting liver disease. In patients with moderate hepatic impairment, a starting dose of 5 mg is recommended.

Use in Asthmatics: REACTINE has been safely administered to patients with mild to moderate asthma. REACTINE did not cause exacerbation of asthma symptoms.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In clinical development programs (domestic and international), REACTINE (cetirizine hydrochloride) has been evaluated in more than 6000 treated patients at daily doses ranging from 5 to 20 mg. The most common adverse reactions were headache and somnolence (see paragraph below). The incidence of headache associated with REACTINE (cetirizine hydrochloride) was not different from placebo. The incidence of somnolence associated with REACTINE was dose related and predominantly mild to moderate. The adverse reaction profile in children shows a lower incidence of somnolence.

Incidence of somnolence reported in placebo controlled efficacy trials with cetirizine should not be misinterpreted as these studies were not designed or powered to assess somnolence or lack of somnolence. Several placebo controlled studies involving objective and subjective tests in healthy volunteers have demonstrated that REACTINE at doses up to 10 mg did not significantly differ from placebo with respect to CNS impairment or task performance.

Most adverse reactions reported during REACTINE (cetirizine hydrochloride) therapy in clinical trials were mild to moderate. The incidence of discontinuation due to adverse reactions in patients receiving REACTINE was not significantly different from placebo (1.0% vs 0.6%, respectively, in placebo-controlled trials). There was no difference by gender or by body weight with regard to the incidence of adverse reactions.

Occasional instances of transient, reversible hepatic transaminase elevations have occurred during REACTINE therapy, without evidence of jaundice, hepatitis or other clinical findings.

Adverse events which were reported at an incidence of greater than 1/50 (2%) in clinical trials are listed in Tables 1 and 2.

TABLE 1. ADVERSE REACTIONS REPORTED IN PLACEBO-CONTROLLED REACTINE TRIALS (MAXIMUM DOSE OF 10 mg) AT RATES OF 2% OR GREATER (Percent Incidence):

( )* = Higher frequency in placebo group.

TABLE 2. ADVERSE REACTIONS REPORTED IN PLACEBO-CONTROLLED UNITED STATES REACTINE TRIALS (TOTAL DAILY DOSE 20 mg) AT RATES OF 2% OR GREATER (Percent Incidence):

( )* = Higher frequency in placebo group.

The following events were observed infrequently (equal to or less than 2%), in 3982 patients who received REACTINE in worldwide trials, including an open study of 6 months duration; a causal relationship with REACTINE administration has not been established.

Application Site: application site reaction, injection site inflammation

Autonomic Nervous System: anorexia, urinary retention, flushing, saliva increased

Cardiovascular: palpitation, tachycardia, hypertension, arrhythmia, cardiac failure

Central and Peripheral Nervous Systems: fatigue, dizziness, insomnia, nervousness paresthesia, confusion, hyperkinesia, hypertonia, migraine, tremor, vertigo, leg cramps, ataxia, dysphonia, coordination abnormal, hyperesthesia, hypoesthesia, myelitis, paralysis, ptosis, speech disorder, twitching, visual field defect

Endocrine: thyroid disorder

Gastrointestinal: nausea, pharyngitis, appetite increased, dyspepsia, abdominal pain, diarrhea, flatulence, constipation, vomiting, stomatitis ulcerative, tongue disorder, tooth caries aggravated, stomatitis, tongue discoloration, tongue edema, gastritis, hemorrhage rectum, hemorrhoids, melena, hepatic function abnormal

Genitourinary: polyuria, urinary tract infection, cystitis, dysuria, hematuria, urine abnormal

Hearing and vestibular: earache, tinnitus, deafness, ototoxicity

Metabolic/Nutritional: thirst, edema, dehydration, diabetes mellitus

Musculoskeletal: myalgia, arthralgia, bone disorder, arthrosis, tendon disorder, arthritis, muscle weakness,

Psychiatric: depression, emotional lability, concentration impaired, anxiety, depersonalization, paroniria, thinking abnormal, agitation, amnesia, libido decreased, euphoria

Resistance Mechanism: healing impaired, herpes simplex, infection, infection fungal, infection viral

Respiratory System: epistaxis, rhinitis, coughing, respiratory disorder, bronchospasm, dyspnea, upper respiratory tract infection, hyperventilation, sinusitis, sputum increased, bronchitis, pneumonia

Reproductive: dysmenorrhea, menstrual disorder, breast pain female, intermenstrual bleeding, leukorrhea, menorrhagia, pregnancy unintended, vaginitis, testes disorder

Reticuloendothelial: lymphadenopathy

Skin: pruritus, rash, skin disorder, skin dry, urticaria, acne, dermatitis, rash erythematous, sweating increased, alopecia, angioedema, furunculosis, bullous eruption, eczema, hyperkeratosis, hypertrichosis, photosensitivity reaction, photosensitivity toxic reaction, rash maculopapular, seborrhea, purpura

Special Senses: taste perversion, taste loss, parosmia

Vision: eye abnormality, vision abnormal, eye pain, conjunctivitis, xerophthalmia, glaucoma, ocular hemorrhage

Body as a Whole: weight increase, back pain, malaise, pain, chest pain, fever, asthenia, edema generalized, edema periorbital, edema peripheral, rigors, edema legs, face edema, hot flushes, abdomen enlarged, allergic reaction, nasal polyp

The adverse reaction profile in children is similar to the one in adults with, however, a lower incidence of somnolence (3.7% overall vs. 0.84% for children receiving placebo) and higher incidences of abdominal pain, pharyngitis, coughing and epistaxis, as indicated in Table 3 below. Adverse drug reactions at rates of 1% or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical or pharmacoclinical trials are:

TABLE 3. MOST COMMON ADVERSE REACTIONS REPORTED IN PLACEBO-CONTROLLED PEDIATRIC TRIALS:

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Weight gain was reported as an adverse event in 0.4% of cetirizine patients in placebo controlled trials. In an open study of 6 months duration, the mean weight gain was 2.8% after 20 weeks, with no further increase at 26 weeks.

In a 6-week, placebo-controlled study of 186 patients with allergic rhinitis and mild to moderate asthma, REACTINE 10 mg o.d. improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering REACTINE to allergic rhinitis patients with mild to moderate asthma.

Abnormal Hematologic and Clinical Chemistry Findings

Occasional instances of transient, reversible hepatic transaminase elevations have occurred during cetirizine therapy.

Post-Market Adverse Drug Reactions

Additional adverse drug reactions identified during post-marketing experience with cetirizine include: blurred vision, eye swelling, feeling abnormal, enuresis, hepatic function abnormal (increased transaminases, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase), erectile dysfunction, hallucination, dysgeusia, dyskinesia, dystonia, memory impairment, tremor, arthralgia, urinary retention, pruritus upon withdrawal and weight increased.

In post-marketing experience the following additional rare, but potential severe adverse events have been reported: hemolytic anemia, thrombocytopenia, orofacial dyskinesia, severe hypotension, anaphylaxis, hepatitis, glomerulonephritis, stillbirth, cholestasis and acute generalized exanthematous pustulosis. In addition, isolated cases of the following adverse drug reactions have been reported: convulsions, syncope, aggression, and hypersensitivity.

Overview

Interaction studies with REACTINE and alcohol or diazepam indicate that at therapeutic doses, REACTINE does not increase alcohol-induced or diazepam-induced impairment of motor and mental performance.

The drug should not be used with sedating substances such as alcohol and some other medications, including antianxiety medications, sleep aids, antihistamines, antidepressants, muscle relaxants or prescription analgesics due to possible interactions.

Drug-Drug Interactions

No clinically significant drug interactions have been found with theophylline, pseudoephedrine, cimetidine, erythromycin and ketoconazole. Epidemiologic data suggests that there also would not be interaction with other macrolide antibiotics or imidazole antifungals. In clinical trials, REACTINE (cetirizine hydrochloride) has been safely administered with beta-agonists, non-steroidal anti-inflammatory drugs, oral contraceptives, narcotic analgesics, corticosteroids, H2-antagonists, cephalosporins, penicillins, thyroid hormones and thiazide diuretics. If drowsiness occurs, concurrent use of REACTINE with sedating substances should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur. (See Activities Requiring Mental Alertness).

Based on (1) its relatively low level of metabolic elimination, (2) no effect on corrected QT intervals at plasma concentrations three times the maximal therapeutic levels, and (3) no apparent interactions with ketoconazole or erythromycin, cetirizine is unlikely to have clinically significant interactions with other macrolides such as clarithromycin or other imidazole antifungals such as itraconazole in patients with normal renal and hepatic function. Although no data with these other drugs are available at the present time, there is no epidemiological evidence (the safety database comprised 6,490 patients evaluated in U.S. and Canadian studies) of interactions between macrolide antibiotics and/or imidazole antifungals taken orally, and cetirizine/hydroxyzine. The epidemiologic data do not suggest an increase of adverse events, cardiac or non-cardiac, in patients treated with cetirizine and concomitant macrolide or imidazole antifungal medication.