CETIRIZINE: 47,655 Adverse Event Reports & Safety Profile

Cetirizine hydrochloride, the active component of QUZYTTIR, is a selective histamine-1 (H 1 ) receptor antagonist. The chemical name is (±) –[2-[4-[(4-chlorophenyl)phenylmethyl]-1- piperzinyl] ethoxy]acetic acid, dihydrochloride. Cetirizine hydrochloride is a racemic compound with an empirical formula of C 21 H 25 ClN 2 O 3

• 2HCl. The molecular weight is 461.82 and the chemical structure is shown below: Cetirizine hydrochloride is a white, crystalline powder and is water soluble. QUZYTTIR is a sterile, clear, colorless, non-pyrogenic, isotonic solution for intravenous injection. Each mL of QUZYTTIR injection contains 10 mg cetirizine hydrochloride (equivalent to cetirizine 8.42 mg) and 6.5 mg sodium chloride, USP to adjust solution tonicity, in water for injection, USP. QUZYTTIR is supplied in 2 mL size amber glass vials for single use.

Each

2 mL size amber glass vial contains 1 mL drug solution with 10 mg cetirizine hydrochloride (10 mg/mL). QUZYTTIR's pH is maintained between 4.5 to 6.5 with sodium hydroxide and/or hydrochloric acid as needed. The osmolality of QUZYTTIR injection is between 255 to 340 mOsmol.

Chemical

Structure

INDICATIONS AND USAGE Perennial Allergic Rhinitis Cetirizine hydrochloride oral solution, USP is indicated for the relief of symptoms associated with perennial allergic rhinitis due to allergens such as dust mites, animal dander and molds in children 6 to 23 months of age. Symptoms treated effectively include sneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing.

Chronic Urticaria

Cetirizine hydrochloride oral solution, USP is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months to 5 years of age. It significantly reduces the occurrence, severity, and duration of hives and significantly reduces pruritus.

Perennial Allergic Rhinitis

Cetirizine hydrochloride oral solution, USP is indicated for the relief of symptoms associated with perennial allergic rhinitis due to allergens such as dust mites, animal dander and molds in children 6 to 23 months of age. Symptoms treated effectively include sneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing.

Chronic Urticaria

Cetirizine hydrochloride oral solution, USP is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months to 5 years of age. It significantly reduces the occurrence, severity, and duration of hives and significantly reduces pruritus.

DOSAGE AND ADMINISTRATION Cetirizine hydrochloride oral solution, USP can be taken without regard to food consumption.

Children

2 to 5 Years for Chronic Urticaria: The recommended initial dose of cetirizine hydrochloride oral solution, USP in children aged 2 to 5 years is 2.5 mg (½ teaspoonful) oral solution once daily. The dosage in this age group can be increased to a maximum dose of 5 mg per day given as 1 teaspoonful oral solution once a day or one ½ teaspoonful oral solution given every 12 hours.

Children

6 months to < 2 years For Perennial Allergic Rhinitis and Chronic Urticaria: The recommended dose of cetirizine hydrochloride oral solution, USP in children 6 months to 23 months of age is 2.5 mg (½ teaspoonful) once daily. The dose in children 12 to 23 months of age can be increased to a maximum dose of 5 mg per day, given as ½ teaspoonful (2.5 mg) every 12 hours.

Children

2 to 5 Years for Chronic Urticaria: The recommended initial dose of cetirizine hydrochloride oral solution, USP in children aged 2 to 5 years is 2.5 mg (½ teaspoonful) oral solution once daily. The dosage in this age group can be increased to a maximum dose of 5 mg per day given as 1 teaspoonful oral solution once a day or one ½ teaspoonful oral solution given every 12 hours.

Children

6 months to < 2 years For Perennial Allergic Rhinitis and Chronic Urticaria: The recommended dose of cetirizine hydrochloride oral solution, USP in children 6 months to 23 months of age is 2.5 mg (½ teaspoonful) once daily. The dose in children 12 to 23 months of age can be increased to a maximum dose of 5 mg per day, given as ½ teaspoonful (2.5 mg) every 12 hours.

The use of QUZYTTIR is contraindicated in patients with a known hypersensitivity to cetirizine hydrochloride or any of its ingredients, levocetirizine, or hydroxyzine. Known hypersensitivity to cetirizine hydrochloride or any of its ingredients, levocetirizine, or hydroxyzine ( 4 )

ADVERSE REACTIONS Pediatric studies were conducted with cetirizine hydrochloride. More than 1300 pediatric patients aged 6 to 11 years with more than 900 treated with cetirizine hydrochloride at doses of 1.25 to 10 mg per day were included in controlled and uncontrolled clinical trials conducted in the United States. The duration of treatment ranged from 2 to 12 weeks. Placebo-controlled trials up to 4 weeks duration included 168 pediatric patients aged 2 to 5 years who received cetirizine, the majority of whom received single daily doses of 5 mg. A placebo-controlled trial 18 months in duration included 399 patients aged 12 to 24 months treated with cetirizine (0.25 mg/kg bid), and another placebo-controlled trial of 7 days duration included 42 patients aged 6 to 11 months who were treated with cetirizine (0.25 mg/kg bid). The majority of adverse reactions reported in pediatric patients aged 2 to 11 years with cetirizine hydrochloride were mild or moderate. In placebo-controlled trials, the incidence of discontinuations due to adverse reactions in pediatric patients receiving up to 10 mg of cetirizine hydrochloride was uncommon (0.4% on cetirizine hydrochloride vs. 1.0% on placebo).

Table

1 list adverse experiences which were reported for cetirizine hydrochloride 5 and 10 mg in pediatric patients aged 6 to 11 years in placebo-controlled clinical trials in the United States and were more common with cetirizine hydrochloride than placebo. Of these, abdominal pain was considered treatment-related and somnolence appeared to be dose-related, 1.3% in placebo, 1.9% at 5 mg and 4.2% at 10 mg. The adverse experiences reported in pediatric patients aged 2 to 5 years in placebo-controlled trials were qualitatively similar in nature and generally similar in frequency to those reported in trials with children aged 6 to 11 years. In the placebo-controlled trials of pediatric patients 6 to 24 months of age, the incidences of adverse experiences were similar in the cetirizine and placebo treatment groups in each study. Somnolence occurred with essentially the same frequency in patients who received cetirizine hydrochloride and patients who received placebo. In a study of 1 week duration in children 6 to 11 months of age, patients who received cetirizine exhibited greater irritability/fussiness than patients on placebo. In a study of 18 months duration in patients 12 months and older, insomnia occurred more frequently in patients who received cetirizine compared to patients who received placebo (9.0% v. 5.3%). In those patients who received 5 mg or more per day of cetirizine as compared to patients who received placebo, fatigue (3.6% v. 1.3%) and malaise (3.6% v. 1.8%) occurred more frequently.

Table

1.

Adverse Experiences

Reported in Pediatric Patients Aged 6 to 11 Years in Placebo-Controlled United States Cetirizine Hydrochloride Trials (5 or 10 mg Dose)

Which

Occurred at a Frequency of ≥2% in Either the 5-mg or the 10-mg Cetirizine Hydrochloride Group, and More Frequently Than in the Placebo Group Adverse Experiences Placebo (N=309)

Cetirizine Hydrochloride

5 mg (N=161) 10 mg (N=215)

Headache

12.3% 11.0% 14.0% Pharyngitis 2.9% 6.2% 2.8% Abdominal pain 1.9% 4.4% 5.6% Coughing 3.9% 4.4% 2.8% Somnolence 1.3% 1.9% 4.2% Diarrhea 1.3% 3.1% 1.9% Epistaxis 2.9% 3.7% 1.9% Bronchospasm 1.9% 3.1% 1.9% Nausea 1.9% 1.9% 2.8% Vomiting 1.0% 2.5% 2.3% The following events were observed infrequently (less than 2%), in either 3982 adults and children 12 years and older or in 659 pediatric patients aged 6 to 11 years who received cetirizine hydrochloride in U.S. trials, including an open adult study of six months duration. A causal relationship of these infrequent events with cetirizine hydrochloride administration has not been established.

Autonomic Nervous

System: anorexia, flushing, increased salivation, urinary retention. Cardiovascular: cardiac failure, hypertension, palpitation, tachycardia. Central and Peripheral Nervous Systems: abnormal coordination, ataxia, confusion, dysphonia, hyperesthesia, hyperkinesia, hypertonia, hypoesthesia, leg cramps, migraine, myelitis, paralysis, paresthesia, ptosis, syncope, tremor, twitching, vertigo, visual field defect. Gastrointestinal: abnormal hepatic function, aggravated tooth caries, constipation, dyspepsia, eructation, flatulence, gastritis, hemorrhoids, increased appetite, melena, rectal hemorrhage, stomatitis including ulcerative stomatitis, tongue discoloration, tongue edema. Genitourinary: cystitis, dysuria, hematuria, micturition frequency, polyuria, urinary incontinence, urinary tract infection. Hearing and Vestibular: deafness, earache, ototoxicity, tinnitus. Metabolic/Nutritional: dehydration, diabetes mellitus, thirst. Musculoskeletal: arthralgia, arthritis, arthrosis, muscle weakness, myalgia. Psychiatric: abnormal thinking, agitation, amnesia, anxiety, decreased libido, depersonalization, depression, emotional lability, euphoria, impaired concentration, insomnia, nervousness, paroniria, sleep disorder.

Respiratory

System: bronchitis, dyspnea, hyperventilation, increased sputum, pneumonia, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection. Reproductive: dysmenorrhea, female breast pain, intermenstrual bleeding, leukorrhea, menorrhagia, vaginitis. Reticuloendothelial: lymphadenopathy. Skin: acne, alopecia, angioedema, bullous eruption, dermatitis, dry skin, eczema, erythematous rash, furunculosis, hyperkeratosis, hypertrichosis, increased sweating, maculopapular rash, photosensitivity reaction, photosensitivity toxic reaction, pruritus, purpura, rash, seborrhea, skin disorder, skin nodule, urticaria.

Special

Senses: parosmia, taste loss, taste perversion. Vision: blindness, conjunctivitis, eye pain, glaucoma, loss of accommodation, ocular hemorrhage, xerophthalmia. Body as a Whole: accidental injury, asthenia, back pain, chest pain, enlarged abdomen, face edema, fever, generalized edema, hot flashes, increased weight, leg edema, malaise, nasal polyp, pain, pallor, periorbital edema, peripheral edema, rigors. Occasional instances of transient, reversible hepatic transaminase elevations have occurred during cetirizine therapy. Hepatitis with significant transaminase elevation and elevated bilirubin in association with the use of cetirizine hydrochloride has been reported. Post-Marketing Experience In the post-marketing period, the following additional rare, but potentially severe adverse events have been reported: aggressive reaction, anaphylaxis, cholestasis, convulsions, glomerulonephritis, hallucinations, hemolytic anemia, hepatitis, orofacial dyskinesia, severe hypotension, stillbirth, suicidal ideation, suicide, thrombocytopenia, acute generalized exanthematous pustulosis (AGEP), and new onset pruritus within a few days after discontinuation of cetirizine, usually after long-term use (e.g., few months to years) of cetirizine. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Warnings Severe Allergy Warning Severe Allergy Warning: Get emergency help immediately if you have hives along with any of the following symptoms: ■ trouble swallowing ■ dizziness or loss of consciousness ■ swelling of tongue ■ swelling in or around mouth ■ trouble speaking ■ drooling ■ wheezing or problems breathing These symptoms may be signs of anaphylactic shock. This condition can be life threatening if not treated by a health professional immediately. Symptoms of anaphylactic shock may occur when hives first appear or up to a few hours later. Not a Substitute for Epinephrine . If your doctor has prescribed an epinephrine injector for anaphylaxis or severe allergy symptoms that could occur with your hives, never use this product as a substitute for the epinephrine injector. If you have been prescribed an epinephrine injector, you should carry it with you at all times. Do not use ■ to prevent hives from any known cause such as: ■ foods ■ insect stings ■ medicines ■ latex or rubber gloves because this product will not stop hives from occurring. Avoiding the cause of your hives is the only way to prevent them. Hives can sometimes be serious. If you do not know the cause of your hives, see your doctor for a medical exam. Your doctor may be able to help you find a cause. ■ if you have ever had an allergic reaction to this product or any of its ingredients or to an antihistamine containing hydroxyzine. Ask a doctor before use if you have ■ liver or kidney disease. Your doctor should determine if you need a different dose. ■ hives that are an unusual color, look bruised or blistered ■ hives that do not itch Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives. When using this product ■ drowsiness may occur ■ avoid alcoholic drinks ■ alcohol, sedatives, and tranquilizers may increase drowsiness ■ be careful when driving a motor vehicle or operating machinery Stop use and ask a doctor if ■ an allergic reaction to this product occurs. Seek medical help right away. ■ symptoms do not improve after 3 days of treatment ■ the hives have lasted more than 6 weeks If pregnant or breast-feeding : ■ if breast-feeding: not recommended ■ if pregnant: ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)

PRECAUTIONS Activities Requiring Mental Alertness: In clinical trials, the occurrence of somnolence has been reported in some patients taking cetirizine hydrochloride; due caution should therefore be exercised when driving a car or operating potentially dangerous machinery. Concurrent use of cetirizine hydrochloride with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur. Risk of New Onset Pruritus After Discontinuation of Cetirizine : Cases of pruritus after discontinuation of cetirizine have been reported in the postmarketing setting in patients where pruritus was not present before initiation of cetirizine. Pruritus occurred within a few days of discontinuing cetirizine among patients who used cetirizine long-term (e.g., few months to years). Reported cases of pruritus were infrequent, but some were serious with patients experiencing widespread severe pruritus. If pruritus occurs after discontinuation of cetirizine, symptoms may improve with restarting or tapering cetirizine. Drug-Drug Interactions: No clinically significant drug interactions have been found with theophylline at a low dose, azithromycin, pseudoephedrine, ketoconazole, or erythromycin. There was a small decrease in the clearance of cetirizine caused by a 400-mg dose of theophylline; it is possible that larger theophylline doses could have a greater effect. Carcinogenesis, Mutagenesis and Impairment of Fertility: In a 2-year carcinogenicity study in rats, cetirizine was not carcinogenic at dietary doses up to 20 mg/kg (approximately 15 times the maximum recommended daily oral dose in adults on a mg/m 2 basis, or approximately 7 times the maximum recommended daily oral dose in infants on a mg/m 2 basis). In a 2-year carcinogenicity study in mice, cetirizine caused an increased incidence of benign liver tumors in males at a dietary dose of 16 mg/kg (approximately 6 times the maximum recommended daily oral dose in adults on a mg/m 2 basis, or approximately 3 times the maximum recommended daily oral dose in infants on a mg/m 2 basis). No increase in the incidence of liver tumors was observed in mice at a dietary dose of 4 mg/kg (approximately 2 times the maximum recommended daily oral dose in adults on a mg/m 2 basis, or approximately equivalent to the maximum recommended daily oral dose in infants on a mg/m 2 basis). The clinical significance of these findings during long-term use of cetirizine hydrochloride is not known. Cetirizine was not mutagenic in the Ames test, and not clastogenic in the human lymphocyte assay, the mouse lymphoma assay, and in vivo micronucleus test in rats. In a fertility and general reproductive performance study in mice, cetirizine did not impair fertility at an oral dose of 64 mg/kg (approximately 25 times the maximum recommended daily oral dose in adults on a mg/m 2 basis).

Pediatric

Use: The safety of cetirizine hydrochloride has been demonstrated in pediatric patients aged 6 months to 5 years. The safety of cetirizine hydrochloride has been demonstrated in 168 patients aged 2 to 5 years in placebo-controlled trials of up to 4 weeks duration. On a mg/kg basis, most of the 168 patients received between 0.2 and 0.4 mg/kg of cetirizine hydrochloride. The safety of cetirizine hydrochloride in 399 patients aged 12 to 24 months has been demonstrated in a placebo-controlled 18-month trial, in which the average dose was 0.25 mg/kg bid, corresponding to a range of 4 mg/day to 11 mg/day. The safety of cetirizine hydrochloride oral solution has been demonstrated in 42 patients aged 6 to 11 months in a placebo-controlled 7-day trial. The prescribed dose was 0.25 mg/kg bid, which corresponded to a mean of 4.5 mg/day, with a range of 3.4 mg/day to 6.2 mg/day. The effectiveness of cetirizine hydrochloride for the treatment of allergic rhinitis and chronic idiopathic urticaria in pediatric patients aged 6 months to 5 years is based on an extrapolation of the demonstrated efficacy of cetirizine hydrochloride in adults with these conditions and the likelihood that the disease course, pathophysiology and the drug’s effect are substantially similar between these two populations. Efficacy is extrapolated down to 6 months of age for perennial allergic rhinitis because this disease is thought to occur down to these ages in children. The recommended doses for the pediatric population are based on cross-study comparisons of the pharmacokinetics and pharmacodynamics of cetirizine in adult and pediatric subjects and on the safety profile of cetirizine in both adult and pediatric patients at doses equal to or higher than the recommended doses. The cetirizine AUC and C max in pediatric subjects aged 6 to 23 months who received a mean of 2.3 mg in a single dose, and in subjects aged 2 to 5 years who received a single dose of 5 mg of cetirizine hydrochloride oral solution, was estimated to be intermediate between that observed in adults who received a single dose of 10 mg of cetirizine hydrochloride tablets and those who received a single dose of 20 mg of cetirizine hydrochloride tablets. The safety and effectiveness of cetirizine hydrochloride in pediatric patients under the age of 6 months have not been established.

INTERACTIONS No clinically significant drug interactions with oral cetirizine hydrochloride, the active ingredient in QUZYTTIR, have been found with theophylline at a low dose, azithromycin, pseudoephedrine, ketoconazole, or erythromycin. There was a small decrease in the clearance of oral cetirizine hydrochloride caused by a 400-mg dose of theophylline; it is possible that larger theophylline doses could have a greater effect [see Clinical Pharmacology ( 12.3 )].

Active Ingredients Active Ingredients (in each tablet)

Purpose

Cetirizine HCl 10 mg..............................................................................................Antihistimine

Inactive ingredients betadex, citric acid anhydrous, colloidal silicon dioxide, crospovidone, dl-alpha-tocopherol, hydroxypropyl cellulose, magnesium stearate, maize maltodextrin, mannitol, microcrystalline cellulose, natural flavourings, sodium bicarbonate, sodium starch glycolate and sucralose. Questions or comments? call 1-855-274-4122 (Monday - Friday 8:30 AM to 5:00 PM EST) Distributed by: CVS Pharmacy, Inc. One CVS Drive, Woonsocket, RI 02895 © 2021 CVS/pharmacy CVS.com ® 1-800-SHOP CVS Made in India Code: AP/DRUGS/04/2016