QUZYTTIR

1 INDICATIONS AND USAGE QUZYTTIR ® is indicated for the treatment of acute urticaria in adults and children 6 months of age and older. QUZYTTIR ® is a histamine-1 (H 1 ) receptor antagonist indicated for the treatment of acute urticaria in adults and children 6 months of age and older ( 1 ) Limitations of Use : Not recommended in pediatric patients less than 6 years of age with impaired renal or hepatic function ( 1 ) Limitations of use: QUZYTTIR ® is not recommended in pediatric patients less than 6 years of age with impaired renal or hepatic function.

2 DOSAGE AND ADMINISTRATION QUZYTTIR is a single use injectable product for intravenous administration only. The recommended dosage regimen is once every 24 hours as needed for treatment of acute urticaria. Administer QUZYTTIR as an intravenous push over a period of 1 to 2 minutes. QUZYTTIR is not recommended in pediatric patients less than 6 years of age with impaired renal or hepatic function [see Pediatric Use ( 8.4 )]. If using as an antihistamine prior to infusion product administration, refer to infusion product prescribing information for instructions. For intravenous administration only ( 2 ) Recommended dosages: Adults and adolescents ≥ 12 years of age and older: 10 mg ( 2.1 ) Children 6 to 11 years: 5 mg or 10 mg ( 2.2 ) Children 6 months to 5 years: 2.5 mg ( 2.3 ) Recommended dosage regimen is once every 24 hours as needed for acute urticaria ( 2 ) 2.1 Adults and adolescents 12 years of age and older The recommended dosage is 10 mg administered by intravenous injection. 2.2 Children 6 to 11 years of age The recommended dosage is 5 mg or 10 mg depending on symptom severity administered by intravenous injection. 2.3 Children 6 months to 5 years of age The recommended dosage is 2.5 mg administered by intravenous injection.

3 DOSAGE FORMS AND STRENGTHS QUZYTTIR is a sterile, clear, colorless, non-pyrogenic, isotonic aqueous solution of cetirizine hydrochloride for intravenous injection; 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 (equivalent to 8.42 mg of cetirizine). Injection: 10 mg/mL cetirizine hydrochloride ( 3 )

4 CONTRAINDICATIONS 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 )

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: Somnolence/Sedation [see Warnings and Precautions ( 5.1 )] The most common adverse reactions (incidence less than 1%) with QUZYTTIR are dysgeusia, headache, paresthesia, presyncope, dyspepsia, feeling hot, and hyperhidrosis. Most common adverse reactions (incidence equal to or greater than 2%) with use of oral cetirizine hydrochloride are somnolence, fatigue, dry mouth, pharyngitis, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, call Esteve Pharmaceuticals, S.A. at 1-888-306-6259 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Oral cetirizine hydrochloride The following adverse reactions associated with the use of oral cetirizine hydrochloride were identified in clinical trials. In clinical trials in patients 12 years and older the most common adverse reactions to oral cetirizine hydrochloride occurring with a 2% or greater incidence and greater than placebo were somnolence (14%), fatigue (6%), dry mouth (5%), pharyngitis (2%), and dizziness (2%). In clinical trials in children 6 to 11 years of age with oral cetirizine hydrochloride the most common adverse reactions occurring with a 2% or greater incidence and greater than placebo were headache, pharyngitis, abdominal pain, coughing, somnolence, diarrhea, epistaxis, bronchospasm, nausea, and vomiting. Somnolence appeared to be dose related. Adverse reactions reported in placebo-controlled trials with oral cetirizine hydrochloride in pediatric patients 2 to 5 years were qualitatively similar in nature and generally similar in frequency to those reported in trials with children 6 to 11 years of age. In placebo-controlled trials of pediatric patients 6 to 24 months of age, the incidences of adverse experiences were similar in the oral cetirizine hydrochloride and placebo treatment groups in each trial. In a trial of 1 week duration in children 6 to 11 months of age patients who received oral cetirizine hydrochloride exhibited greater irritability/fussiness than patients on placebo. In a trial of 18 months duration in patients 12 months and older, insomnia occurred more frequently in patients who received oral cetirizine hydrochloride compared to patients who received placebo. QUZYTTIR The safety data of QUZYTTIR was evaluated in a randomized, double-blind, single-dose, non-inferiority study comparing QUZYTTIR to intravenous diphenhydramine in 262 adults with acute urticaria. The adverse reactions with QUZYTTIR occurred at an incidence of less than 1% and include: dyspepsia, feeling hot, dysgeusia, headache, paresthesia, presyncope, and hyperhidrosis. An additional randomized, double-blind, single dose study was conducted in 33 adults which showed similar safety results. Sedation Subject-rated sedation scores were assessed at baseline, 1 hr, and/or 2 hrs, and/or "Readiness for Discharge”. Sedation was rated on a 0 to 3 scale (0 = none, to 3 = severe) with lower sedation scores indicating less sedation. Subjects in the QUZYTTIR treatment group reported less sedation at all time points compared to subjects treated with diphenhydramine.

7 DRUG 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 )].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women with cetirizine hydrochloride the active ingredient in QUZYTTIR. In animal reproduction studies, there was no evidence of fetal harm with administration of cetirizine hydrochloride by the oral route to pregnant mice, rats, and rabbits, during the period of organogenesis, at doses that were 45 times and higher than the maximum recommended human dose (MRHD) in adults. In rats treated during late gestation and the lactation period, cetirizine hydrochloride had no effects on pup development at oral doses up to approximately 30 times the MRHD in adults. In mice treated during late gestation and the lactation period, cetirizine hydrochloride administered by the oral route to the dams had no effects on pup development at a dose that was approximately 10 times the MRHD in adults; however, lower pup weight gain during lactation was observed at a dose that was 45 times the MRHD in adults (See Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20% respectively. Data Animal Data : In embryofetal development studies conducted in mice, rats, and rabbits, cetirizine hydrochloride, administered during the period of organogenesis, was not teratogenic at doses up to 45, 220, and 260 times the MRHD, respectively (on a mg/m 2 basis with maternal oral doses up to 96, 225, and 135 mg/kg). In a prenatal and postnatal development (PPND) study conducted in mice, cetirizine hydrochloride was administered at oral doses up to 96 mg/kg/day from gestation day 15 through lactation day 21. Cetirizine hydrochloride lowered pup body weight gain during lactation at an oral dose in dams that was approximately 45 times the MRHD (on a mg/m 2 basis with a maternal oral dose of 96 mg/kg/day); however, there were no effects on pup weight gain at an oral dose in dams that was approximately 10 times the MRHD (on a mg/m 2 basis with a maternal oral dose of 24 mg/kg/day). In a PPND study conducted in rats, cetirizine hydrochloride was administered at oral doses up to 180 mg/kg/day from gestation day 17 to lactation day 22. Cetirizine hydrochloride did not have any adverse effects on rat dams or offspring development at doses up to approximately 30 times the MRHD (on a mg/m 2 basis with a maternal oral dose of 30 mg/kg/day). Cetirizine hydrochloride caused excessive maternal toxicity at an oral dose in dams that was approximately 180 times the MRHD (on a mg/m 2 basis with a maternal oral dose of 180 mg/kg/day). 8.2 Lactation Risk Summary Cetirizine hydrochloride has been reported to be present in human breast milk. In mice and beagle dogs, studies indicated that cetirizine hydrochloride was excreted in milk ( See Data ). When a drug is present in animal milk, it is likely the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for QUZYTTIR and any potential adverse effects on the breastfed child from QUZYTTIR or from the underlying maternal condition. Data Animal Data : Cetirizine hydrochloride was detected in the milk of mice. No adverse developmental effects on pups were seen when cetirizine hydrochloride was administered orally to dams during lactation at a dose that was approximately 10 times the MRHD in adults [see Use in Specific Populations ( 8.1 )] . Studies in beagle dogs indicated that approximately 3% of the dose of cetirizine hydrochloride was excreted in milk. The concentration of drug in animal milk does not necessarily predict the concentration of drug in human milk. 8.4 Pediatric Use The safety and efficacy of QUZYTTIR have be …

12.1 Mechanism of Action Cetirizine hydrochloride, a human metabolite of hydroxyzine, is an antihistamine; its principal effects are mediated via selective inhibition of peripheral H 1 -receptors. The antihistaminic activity of cetirizine hydrochloride has been clearly documented in a variety of animal and human models. In vivo and ex vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In clinical studies however, dry mouth was more common with cetirizine hydrochloride than with placebo. In vitro receptor binding studies have shown no measurable affinity for receptors other than H 1 receptors.

11 DESCRIPTION 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

10 OVERDOSAGE Cases of adult and pediatric patients with overdoses of only oral cetirizine hydrochloride have been reported, some of which resulted in adverse reactions. Adult overdose cases involved patients 18 to 81 years of age receiving oral cetirizine hydrochloride doses of 70 mg to 800 mg (7 to 80 times the maximum recommended dosage of 10 mg/day in adults). The most commonly reported adverse reactions were somnolence and fatigue. Other reported adverse reactions included tachycardia, abdominal pain, nausea, and vomiting. Pediatric overdose cases involved patients 18 months to 15 years of age receiving oral cetirizine hydrochloride doses of 90 mg to 300 mg (9 to 72 times the maximum age recommended dose). The adverse reactions reported included: somnolence, difficulty walking, agitation/irritability, hard to swallow/articulate clearly, tachycardia, vomiting, mydriasis, and elevated creatinine phosphokinase. If overdose with QUZYTTIR occurs, treatment should be symptomatic or supportive, taking into account any concomitantly ingested medications. There is no known specific antidote to cetirizine hydrochloride. Cetirizine hydrochloride is not effectively removed by dialysis, and dialysis will be ineffective unless a dialyzable agent has been concomitantly ingested.

16 HOW SUPPLIED/STORAGE AND HANDLING QUZYTTIR (cetirizine hydrochloride injection), 10 mg/mL, pH between 4.5 to 6.5, is supplied as a sterile, clear, colorless, non-pyrogenic isotonic aqueous solution in single-use 2 mL amber glass vials. The following packaging configuration is available: NDC 70720-100-01: 10 mg/mL cetirizine hydrochloride single-use vial NDC 70720-100-10: Carton containing 1 single-use vial (10 mg/mL cetirizine hydrochloride) NDC 70720-100-25: Carton containing 25 single-use vials (10 mg/mL cetirizine hydrochloride) Storage and Handling: QUZYTTIR (cetirizine hydrochloride injection) should be stored at 20°C to 25°C (68°F to 77°F), excursions permitted to 15° - 30°C (59° - 86°F) [see USP Controlled Room Temperature]. Discard unused portion.