Cetirizine hydrochloride, the active component of ZYRTEC® tablets and syrup, is an orally active and selective H₁-receptor antagonist. The chemical name is (±) - [2- [4- [ (4-chlorophenyl)phenylmethyl] -1- piperazinyl] ethoxy]acetic acid, dihydrochloride. Cetirizine hydrochloride is a racemic compound with an empirical formula of C₂₁H₂₅C_lN₂O₃•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. ZYRTEC tablets are formulated as white, film-coated, rounded-off rectangular shaped tablets for oral administration and are available in 5 and 10 mg strengths. Inactive ingredients are: lactose monohydrate; microcrystalline cellulose; colloidal silicon dioxide; croscarmellose sodium; magnesium stearate; titanium dioxide; hypromellose; and polyethylene glycol.

ZYRTEC chewable tablets are formulated as purple round tablets for oral administration and are available in 5 and 10 mg strengths. Inactive ingredients of the chewable tablets are: acesulfame potassium; artificial grape flavor; betadex, NF; blue dye; colloidal silicon dioxide; lactose monohydrate; magnesium stearate; mannitol; microcrystalline cellulose; natural flavor; red dye (carmine).

ZYRTEC syrup is a colorless to slightly yellow syrup containing cetirizine hydrochloride at a concentration of 1 mg/mL (5 mg/5 mL) for oral administration. The pH is between 4 and 5. The inactive ingredients of the syrup are: banana flavor; glacial acetic acid; glycerin; grape flavor; methylparaben; propylene glycol; propylparaben; sodium acetate; sugar syrup; and water.

Last updated on RxList: 5/16/2007

Seasonal Allergic Rhinitis: ZYRTEC is indicated for the relief of symptoms associated with seasonal allergic rhinitis due to allergens such as ragweed, grass and tree pollens in adults and children 2 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea, nasal pruritus, ocular pruritus, tearing, and redness of the eyes.

Perennial Allergic Rhinitis: ZYRTEC is indicated for the relief of symptoms associated with perennial allergic rhinitis due to allergens such as dust mites, animal dander and molds in adults and children 6 months of age and older. Symptoms treated effectively include sneezing, rhinorrhea, postnasal discharge, nasal pruritus, ocular pruritus, and tearing.

Chronic Urticaria: ZYRTEC is indicated for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 months of age and older. It significantly reduces the occurrence, severity, and duration of hives and significantly reduces pruritus.

ZYRTEC can be taken without regard to food consumption. ZYRTEC is available as 5 mg and 10 mg tablets, 1 mg/mL syrup, and 5 mg and 10 mg chewable tablets which can be taken with or without water.

Adults and Children 12 Years and Older: The recommended initial dose of ZYRTEC is 5 mg or 10 mg per day in adults and children 12 years and older, depending on symptom severity. Most patients in clinical trials started at 10 mg. ZYRTEC is given as a single daily dose. The time of administration may be varied to suit individual patient needs.

Children 6 to 11 Years: The recommended initial dose of ZYRTEC in children aged 6 to 11 years is 5 mg or 10 mg once daily depending on symptom severity. The time of administration may be varied to suit individual patient needs.

Children 2 to 5 Years: The recommended initial dose of ZYRTEC in children aged 2 to 5 years is 2.5 mg (½ teaspoon) syrup once daily. The dosage in this age group can be increased to a maximum dose of 5 mg per day given as 1 teaspoon syrup once a day or one ½ teaspoon syrup given every 12 hours, or one 5 mg chewable tablet once a day.

Children 6 months to <2 years: The recommended dose of ZYRTEC syrup in children 6 months to 23 months of age is 2.5 mg (½ teaspoon) 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 teaspoon (2.5 mg) every 12 hours. Syrup is recommended for children under the age of 2 years.

Dose Adjustment for Renal and Hepatic Impairment: In patients 12 years of age and older with decreased renal function (creatinine clearance 11-31 mL/min), patients on hemodialysis (creatinine clearance less than 7 mL/min), and in hepatically impaired patients, a dose of 5 mg once daily is recommended. Similarly, pediatric patients aged 6 to 11 years with impaired renal or hepatic function should use the lower recommended dose. Because of the difficulty in reliably administering doses of less than 2.5 mg (½ teaspoon) of ZYRTEC syrup and in the absence of pharmacokinetic and safety information for cetirizine in children below the age of 6 years with impaired renal or hepatic function, its use in this impaired patient population is not recommended.

Dose Adjustment for Geriatric Patients: In patients 77 years of age and older, a dose of 5 mg once daily is recommended.

ZYRTEC® tablets are white, film-coated, rounded-off rectangular shaped containing 5 mg or 10 mg cetirizine hydrochloride.

5 mg tablets are engraved with "ZYRTEC" on one side and "5" on the other. Bottles of 100: NDC 0069-0732-66
10 mg tablets are engraved with "ZYRTEC" on one side and "10" on the other. Bottles of 100: NDC 0069-0731-66

STORAGE: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

ZYRTEC chewable tablets are purple round tablets containing 5 mg or 10 mg cetirizine hydrochloride. The tablets are packaged in blister cards as follows:

5 mg tablets are engraved with "ZYRTEC C5" on one side. Boxes of 3 (Blister Cards of 10) NDC 0069-1440-03
10 mg tablets are engraved with "ZYRTEC C10" on one side. Boxes of 3 (Blister Cards of 10) NDC 0069-1450-03

STORAGE: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

ZYRTEC syrup is colorless to slightly yellow with a banana-grape flavor. Each teaspoon (5 mL) contains 5 mg cetirizine hydrochloride. ZYRTEC syrup is supplied as follows:

120 mL amber glass bottles                                    NDC 0069-5530-47
480 mL amber glass bottles                                    NDC 0069-5530-93

STORAGE: Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]; or Store refrigerated, 2-8°C (36-46°F).

Cetirizine is licensed from UCB, Inc.
Rx only
Distributed by: Pfizer Labs., Division of Pfizer Inc, NY, NY 10017
Marketed by: UCB, Inc., Smyrna, GA 30080
Revised May 2006
FDA rev date: 4/4/2006

Last updated on RxList: 5/16/2007

Controlled and uncontrolled clinical trials conducted in the United States and Canada included more than 6000 patients aged 12 years and older, with more than 3900 receiving ZYRTEC at doses of 5 to 20 mg per day. The duration of treatment ranged from 1 week to 6 months, with a mean exposure of 30 days.

Most adverse reactions reported during therapy with ZYRTEC were mild or moderate. In placebo-controlled trials, the incidence of discontinuations due to adverse reactions in patients receiving ZYRTEC 5 or 10 mg was not significantly different from placebo (2.9% vs. 2.4%, respectively).

The most common adverse reaction in patients aged 12 years and older that occurred more frequently on ZYRTEC than placebo was somnolence. The incidence of somnolence associated with ZYRTEC was dose related, 6% in placebo, 11% at 5 mg and 14% at 10 mg. Discontinuations due to somnolence for ZYRTEC were uncommon (1.0% on ZYRTEC vs. 0.6% on placebo). Fatigue and dry mouth also appeared to be treatment-related adverse reactions. There were no differences by age, race, gender or by body weight with regard to the incidence of adverse reactions.

Table 1 lists adverse experiences in patients aged 12 years and older which were reported for ZYRTEC 5 and 10 mg in controlled clinical trials in the United States and that were more common with ZYRTEC than placebo.

Table 1.
Adverse Experiences Reported in Patients Aged 12 Years and Older in
Placebo-Controlled United States ZYRTEC Trials (Maximum Dose of 10 mg)
at Rates of 2% or Greater (Percent Incidence)

Adverse Experience	ZYRTEC (N=2034)	Placebo (N=1612)
Somnolence	13.7	6.3
Fatigue	5.9	2.6
Dry Mouth	5.0	2.3
Pharyngitis	2.0	1.9
Dizziness	2.0	1.2

In addition, headache and nausea occurred in more than 2% of the patients, but were more common in placebo patients.

Pediatric studies were also conducted with ZYRTEC. More than 1300 pediatric patients aged 6 to 11 years with more than 900 treated with ZYRTEC 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 ZYRTEC 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 ZYRTEC was uncommon (0.4% on ZYRTEC vs. 1.0% on placebo).

Table 2 lists adverse experiences which were reported for ZYRTEC 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 ZYRTEC 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 and patients who received placebo. In a study of 1 week duration in children 6-11 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 2.
Adverse Experiences Reported in Pediatric Patients Aged 6 to 11 Years in Placebo-Controlled United States ZYRTEC Trials (5 or 10 mg Dose) Which Occurred at a Frequency of =2% in Either the 5-mg or the 10-mg ZYRTEC Group, and More Frequently< Than in the Placebo Group

Adverse Experiences	Placebo (N=309)	ZYRTEC
		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 ZYRTEC in U.S. trials, including an open adult study of six months duration. A causal relationship of these infrequent events with ZYRTEC 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 ZYRTEC 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 and thrombocytopenia.

Drug Abuse And Dependence

There is no information to indicate that abuse or dependency occurs with ZYRTEC.

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.

Last updated on RxList: 5/16/2007

No Information provided.

Activities Requiring Mental Alertness: In clinical trials, the occurrence of somnolence has been reported in some patients taking ZYRTEC; due caution should therefore be exercised when driving a car or operating potentially dangerous machinery. Concurrent use of ZYRTEC with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur.

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/m² basis, or approximately 7 times the maximum recommended daily oral dose in infants on a mg/m² 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/m² basis, or approximately 3 times the maximum recommended daily oral dose in infants on a mg/m² 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/m² basis, or approximately equivalent to the maximum recommended daily oral dose in infants on a mg/m² basis). The clinical significance of these findings during long-term use of ZYRTEC 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/m² basis).

Pregnancy Category B: In mice, rats, and rabbits, cetirizine was not teratogenic at oral doses up to 96, 225, and 135 mg/kg, respectively (approximately 40, 180 and 220 times the maximum recommended daily oral dose in adults on a mg/m² basis). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ZYRTEC should be used during pregnancy only if clearly needed.

Nursing Mothers: In mice, cetirizine caused retarded pup weight gain during lactation at an oral dose in dams of 96 mg/kg (approximately 40 times the maximum recommended daily oral dose in adults on a mg/m² basis). Studies in beagle dogs indicated that approximately 3% of the dose was excreted in milk. Cetirizine has been reported to be excreted in human breast milk. Because many drugs are excreted in human milk, use of ZYRTEC in nursing mothers is not recommended.

Geriatric Use: Of the total number of patients in clinical studies of ZYRTEC, 186 patients were 65 years and older, and 39 patients were 75 years and older. No overall differences in safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. With regard to efficacy, clinical studies of ZYRTEC for each approved indication did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients.

ZYRTEC is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. (See Geriatric Patients and Renal Impairment subsections in CLINICAL PHARMACOLOGY.)

Pediatric Use: The safety of ZYRTEC has been demonstrated in pediatric patients aged 6 months to 11 years. The safety of ZYRTEC, at daily doses of 5 or 10 mg, has been demonstrated in 376 pediatric patients aged 6 to 11 years in placebo-controlled trials lasting up to four weeks and in 254 patients in a non-placebo-controlled 12-week trial. The safety of cetirizine 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 HCl. The safety of cetirizine 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 to 11 mg/day. The safety of ZYRTEC syrup 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 to 6.2 mg/day.

The effectiveness of ZYRTEC for the treatment of allergic rhinitis and chronic idiopathic urticaria in pediatric patients aged 6 months to 11 years is based on an extrapolation of the demonstrated efficacy of ZYRTEC 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 and down to 2 years of age for seasonal allergic rhinitis because these diseases are 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 Cmax 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 syrup and in pediatric subjects aged 6 to 11 years who received a single dose of 10 mg of cetirizine syrup were estimated to be intermediate between that observed in adults who received a single dose of 10 mg of cetirizine tablets and those who received a single dose of 20 mg of cetirizine tablets.

The safety and effectiveness of cetirizine in pediatric patients under the age of 6 months have not been established.

Last updated on RxList: 5/17/2007

Overdosage has been reported with ZYRTEC. In one adult patient who took 150 mg of ZYRTEC, the patient was somnolent but did not display any other clinical signs or abnormal blood chemistry or hematology results. In an 18 month old pediatric patient who took an overdose of ZYRTEC (approximately 180 mg), restlessness and irritability were observed initially; this was followed by drowsiness. Should overdose occur, treatment should be symptomatic or supportive, taking into account any concomitantly ingested medications. There is no known specific antidote to ZYRTEC. ZYRTEC is not effectively removed by dialysis, and dialysis will be ineffective unless a dialyzable agent has been concomitantly ingested. The acute minimal lethal oral doses were 237 mg/kg in mice (approximately 95 times the maximum recommended daily oral dose in adults on a mg/m² basis, or approximately 40 times the maximum recommended daily oral dose in infants on a mg/m² basis) and 562 mg/kg in rats (approximately 460 times the maximum recommended daily oral dose in adults on a mg/m² basis, or approximately 190 times the maximum recommended daily oral dose in infants on a mg/m² basis). In rodents, the target of acute toxicity was the central nervous system, and the target of multiple-dose toxicity was the liver.

ZYRTEC is contraindicated in those patients with a known hypersensitivity to it or any of its ingredients or hydroxyzine.

Last updated on RxList: 5/17/2007

Pharmacokinetics and Metabolism

PREVACID Delayed-Release Capsules, PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets and PREVACID for Delayed-Release Oral Suspension contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. After a single-dose administration of 15 mg to 60 mg of oral lansoprazole, the peak plasma concentrations (Cmax) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to the administered dose. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.

Absorption

The absorption of lansoprazole is rapid, with the mean Cmax occurring approximately 1.7 hours after oral dosing, and the absolute bioavailability is over 80%. In healthy subjects, the mean (±SD) plasma half-life was 1.5 (±1.0) hours. Both the Cmax and AUC are diminished by about 50% to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.

Distribution

Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0 µg/mL.

Metabolism

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into

two active species which inhibit acid secretion by blocking the proton pump [(H⁺,K⁺)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of lansoprazole is less than 2 hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.

Elimination

Following single-dose oral administration of PREVACID, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of ¹⁴C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.

Special Populations

Geriatric

The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly. No dosage adjustment is necessary in the elderly.

Pediatric

The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged 1 to 11 years and 12 to 17 years in two separate clinical studies. In children aged 1 to 11 years, lansoprazole was dosed 15 mg daily for subjects weighing ≤ 30 kg and 30 mg daily for subjects weighing greater than 30 kg. Mean Cmax and AUC values observed on Day 5 of dosing were similar between the two dose groups and were not affected by weight or age within each weight-adjusted dose group used in the study. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15 mg or 30 mg daily. Mean Cmax and AUC values of lansoprazole were not affected by body weight or age; and nearly dose-proportional increases in mean Cmax and AUC values were observed between the two dose groups in the study. Overall, lansoprazole pharmacokinetics in pediatric patients aged 1 to 17 years were similar to those observed in healthy adult subjects.

Gender

In a study comparing 12 male and 6 female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results. (Also see Use in Women).

Renal Insufficiency

In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-1.5% after administration of 60 mg of lansoprazole. Patients with renal insufficiency had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function. No dosage adjustment is necessary in patients with renal insufficiency.

Hepatic Insufficiency

In patients with various degrees of chronic hepatic disease, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2-7.2 hours. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Dose reduction in patients with severe hepatic disease should be considered.

Race

The pooled mean pharmacokinetic parameters of PREVACID from twelve U.S. Phase 1 studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of PREVACID in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.

Pharmacodynamics

Mechanism of Action

PREVACID (lansoprazole) belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H⁺,K⁺)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.

Antisecretory Activity

After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than 3 and greater than 4. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin. The intragastric pH results of a five-day, pharmacodynamic, crossover study of 15 mg and 30 mg of once daily lansoprazole are presented in Table 1:

Table 1: Mean Antisecretory Effects After Single and Multiple Daily PREVACID Dosing

		PREVACID
Parameter	Baseline Value	15 mg		30 mg
		Day 1	Day 5	Day 1	Day 5
Mean 24-Hour pH	2.1	2.7+	4.0+	3.6*	4.9*
Mean Nighttime pH	1.9	2.4	3.0+	2.6	3.8*
% Time Gastric pH>3	18	33+	59+	51*	72*
% Time Gastric pH>4	12	22+	49+	41*	66*
NOTE: An intragastric pH of greater than 4 reflects a reduction in gastric acid by 99%. *(p<0.05) versus baseline and lansoprazole 15 mg. +(p<0.05) versus baseline only.

After the initial dose in this study, increased gastric pH was seen within 1-2 hours with 30 mg of lansoprazole and 2-3 hours with 15 mg of lansoprazole. After multiple daily dosing, increased gastric pH was seen within the first hour post-dosing with 30 mg of lansoprazole and within 1-2 hours post-dosing with 15 mg of lansoprazole.

Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of PREVACID given daily, b.i.d. and t.i.d (Table 2).

Table 2: Mean Antisecretory Effects After 5 Days of b.i.d. and t.i.d. Dosing

	PREVACID
Parameter	30 mg daily	15 mg b.i.d.	30 mg b.i.d.	30 mg t.i.d.
% Time Gastric pH>5	43	47	59+	77*
% Time Gastric pH>6	20	23	28	45*
+(p<0.05) versus PREVACID 30 mg daily *(p<0.05) versus PREVACID 30 mg daily, 15 mg b.i.d. and 30 mg b.i.d.

The inhibition of gastric acid secretion as measured by intragastric pH gradually returned to normal over two to four days after multiple doses. There was no indication of rebound gastric acidity.

Enterochromaffin-like (ECL) Cell Effects

During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility).

Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least one year did not show evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with lansoprazole.

Other Gastric Effects in Humans

Lansoprazole did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in blood flow in the antrum, pylorus, and duodenal bulb was seen. Lansoprazole significantly slowed the gastric emptying of digestible solids. Lansoprazole increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in nitrosamine concentrations was observed.

Serum Gastrin Effects

In over 2100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but remained within normal range after treatment with 15 to 60 mg of oral lansoprazole. These elevations reached a plateau within two months of therapy and returned to pretreatment levels within four weeks after discontinuation of therapy.

Endocrine Effects

Human studies for up to one year have not detected any clinically significant effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). Lansoprazole in oral doses of 15 to 60 mg for up to one year had no clinically significant effect on sexual function. In addition, lansoprazole in oral doses of 15 to 60 mg for two to eight weeks had no clinically significant effect on thyroid function.

In 24-month carcinogenicity studies in Sprague-Dawley rats with daily lansoprazole dosages up to 150 mg/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rates.

Other Effects

No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems have been found in humans. Among 56 patients who had extensive baseline eye evaluations, no visual toxicity was observed after lansoprazole treatment (up to 180 mg/day) for up to 58 months.

After lifetime lansoprazole exposure in rats, focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy were seen.

Microbiology

Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Helicobacter
Helicobacter pylori

Pretreatment Resistance

Clarithromycin pretreatment resistance (≥ 2.0 µg/mL) was 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates (≤ 0.25 µg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of 957 patients (2.2%) by E-test and 2 of 100 patients (2.0%) by agar dilution had amoxicillin pretreatment MICs of greater than 0.25 µg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 µg/mL by E-test and the patient was eradicated of H. pylori (Table 3).

Table 3: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes^a

Clarithromycin Pretreatment Results		Clarithromycin Post-treatment Results
		H. pylori negative - eradicated	H. pylori positive - not eradicated
			Post-treatment susceptibility results
			Sb	Ib	Rb	No MIC
Triple Therapy 14-Day (lansoprazole 30 mg b.i.d./amoxicillin 1 gm b.i.d./clarithromycin 500 mg b.i.d.) (M95-399, M93-131, M95-392)
Susceptible	112	105				7
Intermediate	3	3
Resistant	17	6			7	4
Triple Therapy 10-Day (lansoprazole 30 mg b.i.d./amoxicillin 1 gm b.i.d./clarithromycin 500 mg b.i.d.) (M95-399)
Susceptibleb	42	40	1		1
Intermediateb
Resistantb	4	1			3
aIncludes only patients with pretreatment clarithromycin susceptibility test results bSusceptible (S) MIC ≤ 0.25 µg/mL, Intermediate (I) MIC 0.5 - 1.0 µg/mL, Resistant (R) MIC ≥ 2 µg/mL

Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant

H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or with regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 µg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg t.i.d./amoxicillin 1 gm t.i.d. dual therapy and a total of 12.8% (22/172) of the patients failed the 10- and 14-day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.¹ One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 10⁷ - 1 x 10⁸ CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial-containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for campylobacters. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Clarithromycin MIC (µg/mL)a	Interpretation
≤ 0.25	Susceptible (S)
0.5-1.0	Intermediate (I)
≥ 2.0	Resistant (R)
Amoxicillin MIC (µg/mL)	Interpretation
≤ 0.25	Susceptible (S)
aThese are tentative breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods. b There were not enough organisms with MICs greater than 0.25 µg/mL to determine a resistance breakpoint.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

Microorganism	Antimicrobial Agent	MIC (µg/mL)a
H. pylori ATCC 43504	Clarithromycin	0.015-0.12 µg/mL
H. pylori ATCC 43504	Amoxicillin	0.015-0.12 µg/mL
a These are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.

Clinical Studies

In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15, 30, and 60 mg of PREVACID once daily) study of 284 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after two and four weeks was significantly higher with all doses of PREVACID than with placebo. There was no evidence of a greater or earlier response with the two higher doses compared with PREVACID 15 mg. Based on this study and the second study described below, the recommended dose of PREVACID in duodenal ulcer is 15 mg per day (Table 4).

Table 4: Duodenal Ulcer Healing Rates

	PREVACID			Placebo
Week	15 mg daily (N=68)	30 mg daily (N=74)	60 mg daily (N=70)	(N=72)
2	42.4%*	35.6%*	39.1%*	11.3%
4	89.4%*	91.7%*	89.9%*	46.1%
* (p ≤ 0.001) versus placebo.

PREVACID 15 mg was significantly more effective than placebo in relieving day and nighttime abdominal pain and in decreasing the amount of antacid taken per day.

In a second U.S. multicenter study, also double-blind, placebo-controlled, dose-comparison (15 and 30 mg of PREVACID once daily), and including a comparison with ranitidine, in 280 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after four weeks was significantly higher with both doses of PREVACID than with placebo. There was no evidence of a greater or earlier response with the higher dose of PREVACID. Although the 15 mg dose of PREVACID was superior to ranitidine at 4 weeks, the lack of significant difference at 2 weeks and the absence of a difference between 30 mg of PREVACID and ranitidine leaves the comparative effectiveness of the two agents undetermined (Table 5).

Table 5: Duodenal Ulcer Healing Rates

	PREVACID		Ranitidine	Placebo
Week	15 mg daily (N=80)	30 mg daily (N=77)	300 mg h.s. (N=82)	(N=41)
2	35.0%	44.2%	30.5%	34.2%
4	92.3%**	80.3%*	70.5%*	47.5%
* (p ≤ 0.05) versus placebo. ** (p ≤ 0.05) versus placebo and ranitidine.

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Randomized, double-blind clinical studies performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of PREVACID in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy or in combination with amoxicillin capsules as dual 14-day therapy for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of two different eradication regimens were established:

Triple therapy: PREVACID 30 mg b.i.d./
                          amoxicillin 1 gm b.i.d./ clarithromycin 500 mg b.i.d.

Dual therapy: PREVACID 30 mg t.i.d./
                          amoxicillin 1 gm t.i.d.

All treatments were for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at 4-6 weeks following the end of treatment.

Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of PREVACID triple therapy for 10 and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori (Tables 6 and 7).

Table 6
H. pylori Eradication Rates - Triple Therapy
(PREVACID/amoxicillin/clarithromycin)
Percent of Patients Cured
[95% Confidence Interval]
(Number of patients)

		Triple Therapy	Triple Therapy
Study	Duration	Evaluable Analysis*	Intent-to-Treat Analysis#
M93-131	14 days	92†	86†
		[80.0-97.7]	[73.3-93.5]
		(N=48)	(N=55)
M95-392	14 days	86‡	83‡
		[75.7-93.6]	[72.0-90.8]
		(N=66)	(N=70)
M95-399+	14 days	85	82
		[77.0-91.0]	[73.9-88.1]
		(N=113)	(N=126)
	10 days	84	81
		[76.0-89.8]	[73.9-87.6]
		(N=123)	(N=135)
* Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy. # Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy. † (p<0.05) versus PREVACID/amoxicillin and REVACID/clarithromycin dual therapy ‡ (p<0.05) versus clarithromycin/amoxicillin dual therapy + The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.

Table 7 H. pylori Eradication Rates - 14-Day Dual Therapy
(PREVACID/amoxicillin)
Percent of Patients Cured
[95% Confidence Interval]
(Number of patients)

	Dual Therapy	Dual Therapy
Study	Evaluable Analysis*	Intent-to-Treat Analysis#
M93-131	77†	70†
	[62.5-87.2]	[56.8-81.2]
	(N=51)	(N=60)
M93-125	66‡	61‡
	[51.9-77.5]	[48.5-72.9]
	(N=58)	(N=67)
* Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection atbaseline defined as at least two of three positive endoscopic tests from CLOtest®, histology and/or culture.Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of thestudy due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. # Patients were included in the analysis if they had documented H. pylori infection at baseline as defined aboveand had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures oftherapy. † (p<0.05) versus PREVACID alone. ‡ (p<0.05) versus PREVACID alone or amoxicillin alone.

Long-Term Maintenance Treatment of Duodenal Ulcers

PREVACID has been shown to prevent the recurrence of duodenal ulcers. Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed duodenal ulcers. Patients remained healed significantly longer and the number of recurrences of duodenal ulcers was significantly less in patients treated with PREVACID than in patients treated with placebo over a 12-month period (Table 8).

Table 8: Endoscopic Remission Rates

Trial	Drug	No. of Pts.	Percent in Endoscopic Remission
			0-3 mo.	0-6 mo.	0-12 mo.
#1	PREVACID 15 mg daily	86	90%*	87%*	84%*
	Placebo	83	49%	41%	39%
#2	PREVACID 30 mg daily	18	94%*	94%*	85%*
	PREVACID 15 mg daily	15	87%*	79%*	70%*
	Placebo	15	33%	0%	0%
%=Life Table Estimate * (p ≤ 0.001) versus placebo.

In trial #2, no significant difference was noted between PREVACID 15 mg and 30 mg in maintaining remission.

Gastric Ulcer

In a U.S. multicenter, double-blind, placebo-controlled study of 253 patients with endoscopically documented gastric ulcer, the percentage of patients healed at four and eight weeks was significantly higher with PREVACID 15 mg and 30 mg once a day than with placebo (Table 9).

Table 9: Gastric Ulcer Healing Rates

	PREVACID			Placebo
Week	15 mg daily (N=65)	30 mg daily (N=63)	60 mg daily (N=61)	(N=64)
4	64.6%*	58.1%*	53.3%*	37.5%
8	92.2%*	96.8%*	93.2%*	76.7%
* (p ≤ 0.05) versus placebo.

Patients treated with any PREVACID dose reported significantly less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets used per day than the placebo group. Independent substantiation of the effectiveness of PREVACID 30 mg was provided by a meta-analysis of published and unpublished data.

Healing of NSAID-Associated Gastric Ulcer

In two U.S. and Canadian multicenter, double-blind, active-controlled studies in patients with endoscopically confirmed NSAID-associated gastric ulcer who continued their NSAID use, the percentage of patients healed after 8 weeks was statistically significantly higher with 30 mg of PREVACID than with the active control. A total of 711 patients were enrolled in the study, and 701 patients were treated. Patients ranged in age from 18 to 88 years (median age 59 years), with 67% female patients and 33% male patients. Race was distributed as follows: 87% Caucasian, 8% Black, 5% other. There was no statistically significant difference between PREVACID 30 mg daily and the active control on symptom relief (i.e., abdominal pain) (Table 10).

Table 10: NSAID-Associated Gastric Ulcer Healing Rates ¹

Study #1
	PREVACID 30 mg daily	Active Control 2
Week 4	60% (53/88) 3	28% (23/83)
Week 8	79% (62/79) 3	55% (41/74)
Study #2
	PREVACID 30 mg daily	Active Control 2
Week 4	53% (40/75)	38% (31/82)
Week 8	77% (47/61) 3	50% (33/66)
1  Actual observed ulcer(s) healed at time points + 2 days 2  Dose for healing of gastric ulcer 3  (p ≤ 0.05) versus the active control

Risk Reduction of NSAID-Associated Gastric Ulcer

In one large U.S., multicenter, double-blind, placebo- and misoprostol-controlled (misoprostol blinded only to the endoscopist) study in patients who required chronic use of an NSAID and who had a history of an endoscopically documented gastric ulcer, the proportion of patients remaining free from gastric ulcer at 4, 8, and 12 weeks was significantly higher with 15 or 30 mg of PREVACID than placebo. A total of 537 patients were enrolled in the study, and 535 patients were treated. Patients ranged in age from 23 to 89 years (median age 60 years), with 65% female patients and 35% male patients. Race was distributed as follows: 90% Caucasian, 6% Black, 4% other. The 30 mg dose of PREVACID demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcer than the 15 mg dose (Table 11).

Table 11: Proportion of Patients Remaining Free of Gastric Ulcers¹

Week	PREVACID15 mg daily (N=121)	PREVACID 30 mg daily (N=116)	Misoprostol 200 jig q.i.d. (N=106)	Placebo (N=112)
4	90%	92%	96%	66%
8	86%	88%	95%	60%
12	80%	82%	93%	51%
1 % = Life Table Estimate (p<0.001) PREVACID 15 mg daily versus placebo; PREVACID 30 mg daily versus placebo; and misoprostol 200 µg q.i.d. versus placebo. (p<0.05) Misoprostol 200 µg q.i.d. versus PREVACID 15 mg daily; and misoprostol 200 µg q.i.d. versus PREVACID 30 mg daily

Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD

In a U.S. multicenter, double-blind, placebo-controlled study of 214 patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, significantly greater relief of heartburn associated with GERD was observed with the administration of lansoprazole 15 mg once daily up to 8 weeks than with placebo. No significant additional benefit from lansoprazole 30 mg once daily was observed.

The intent-to-treat analyses demonstrated significant reduction in frequency and severity of day and night heartburn. Data for frequency and severity for the 8-week treatment period are presented in Table 12 and in Figures 1 and 2:

Table 12: Frequency of Heartburn

Variable	Placebo (n=43)	PREVACID 15 mg (n=80)	PREVACID 30 mg (n=86)
	Median
% of Days without Heartburn
Week 1	0%	71%*	46%*
Week 4	11%	81%*	76%*
Week 8	13%	84%*	82%*
% of Nights without Heartburn
Week 1	17%	86%*	57%*
Week 4	25%	89%*	73%*
Week 8	36%	92%*	80%*
* (p<0.01) versus placebo.

Figure 1
Mean Severity of Day Heartburn By Study Day For Evaluable Patients (3=Severe, 2=Moderate, 1=Mild, 0=None)

 

Figure 2
Mean Severity of Night Heartburn By Study Day For Evaluable Patients (3=Severe, 2=Moderate, 1=Mild, 0=None)

 

In two U.S., multicenter double-blind, ranitidine-controlled studies of 925 total patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, lansoprazole 15 mg was superior to ranitidine 150 mg (b.i.d.) in decreasing the frequency and severity of day and night heartburn associated with GERD for the 8-week treatment period. No significant additional benefit from lansoprazole 30 mg once daily was observed.

Erosive Esophagitis

In a U.S. multicenter, double-blind, placebo-controlled study of 269 patients entering with an endoscopic diagnosis of esophagitis with mucosal grading of 2 or more and grades 3 and 4 signifying erosive disease, the percentages of patients with healing are presented in Table 13:

Table 13: Erosive Esophagitis Healing Rates

	PREVACID			Placebo
Week	15 mg daily (N=69)	30 mg daily (N=65)	60 mg daily (N=72)	(N=63)
4	67.6%*	81.3%*†	80.6%*†	32.8%
6	87.7%*	95.4%*	94.3%*	52.5%
8	90.9%*	95.4%*	94.4%*	52.5%
* (p ≤ 0.001) versus placebo. † (p ≤ 0.05) versus PREVACID 15 mg.

In this study, all PREVACID groups reported significantly greater relief of heartburn and less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets taken per day than the placebo group.

Although all doses were effective, the earlier healing in the higher two doses suggests 30 mg daily as the recommended dose.

PREVACID was also compared in a U.S. multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis. PREVACID at a dose of 30 mg was significantly more effective than ranitidine 150 mg b.i.d. as shown below (Table 14).

Table 14: Erosive Esophagitis Healing Rates

Week	PREVACID30 mg daily (N=115)	Ranitidine150 mg b.i.d. (N=127)
2	66.7%*	38.7%
4	82.5%*	52.0%
6	93.0%*	67.8%
8	92.1%*	69.9%
* (p ≤ 0.001) versus ranitidine.

In addition, patients treated with PREVACID reported less day and nighttime heartburn and took less antacid tablets for fewer days than patients taking ranitidine 150 mg b.i.d.

Although this study demonstrates effectiveness of PREVACID in healing erosive esophagitis, it does not represent an adequate comparison with ranitidine because the recommended ranitidine dose for esophagitis is 150 mg q.i.d., twice the dose used in this study.

In the two trials described and in several smaller studies involving patients with moderate to severe erosive esophagitis, PREVACID produced healing rates similar to those shown above.

In a U.S. multicenter, double-blind, active-controlled study, 30 mg of PREVACID was compared with ranitidine 150 mg b.i.d. in 151 patients with erosive reflux esophagitis that was poorly responsive to a minimum of 12 weeks of treatment with at least one H2-receptor antagonist given at the dose indicated for symptom relief or greater, namely, cimetidine 800 mg/day, ranitidine 300 mg/day, famotidine 40 mg/day or nizatidine 300 mg/day. PREVACID 30 mg was more effective than ranitidine 150 mg b.i.d. in healing reflux esophagitis, and the percentage of patients with healing were as follows. This study does not constitute a comparison of the effectiveness of histamine H2-receptor antagonists with PREVACID, as all patients had demonstrated unresponsiveness to the histamine H2-receptor antagonist mode of treatment. It does indicate, however, that PREVACID may be useful in patients failing on a histamine H2-receptor antagonist (Table 15).

Table 15: Reflux Esophagitis Healing Rates in
Patients Poorly Responsive to Histamine H2-Receptor
Antagonist Therapy

Week	PREVACID30 mg daily (N=100)	Ranitidine150 mg b.i.d. (N=51)
4	74.7%*	42.6%
8	83.7%*	32.0%
* (p ≤ 0.001) versus ranitidine.

Long-Term Maintenance Treatment of Erosive Esophagitis

Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed esophagitis. Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with PREVACID than in patients treated with placebo over a 12-month period (Table 16).

Table 16: Endoscopic Remission Rates

Trial	Drug	Percent in Endoscopic Remission
		No. of Pts.	0-3 mo.	0-6 mo.	0-12 mo.
#1	PREVACID 15 mg daily	59	83%*	81%*	79%*
	PREVACID 30 mg daily	56	93%*	93%*	90%*
	Placebo	55	31%	27%	24%
#2	PREVACID 15 mg daily	50	74%*	72%*	67%*
	PREVACID 30 mg daily	49	75%*	72%*	55%*
	Placebo	47	16%	13%	13%
%=Life Table Estimate * (p ≤ 0.001) versus placebo.

Regardless of initial grade of erosive esophagitis, PREVACID 15 mg and 30 mg were similar in maintaining remission.

In a U.S., randomized, double-blind, study, PREVACID 15 mg daily (n = 100) was compared with ranitidine 150 mg b.i.d. (n = 106), at the recommended dosage, in patients with endoscopically-proven healed erosive esophagitis over a 12-month period. Treatment with PREVACID resulted in patients remaining healed (Grade 0 lesions) of erosive esophagitis for significantly longer periods of time thanthose treated with ranitidine (p<0.001). In addition, PREVACID was significantly more effective than ranitidine in providing complete relief of both daytime and nighttime heartburn. Patients treated with PREVACID remained asymptomatic for a significantly longer period of time than patients treated with ranitidine.

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

In open studies of 57 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, PREVACID significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia and pain. Doses ranging from 15 mg every other day to 180 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients (see DOSAGE AND ADMINISTRATION). PREVACID was well tolerated at these high dose levels for prolonged periods (greater than four years in some patients). In most ZE patients, serum gastrin levels were not modified by PREVACID. However, in some patients, serum gastrin increased to levels greater than those present prior to initiation of lansoprazole therapy.

Reference

1. National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL, January 11-13, 1998.

Last updated on RxList: 5/16/2007

No information provided. Please refer to the PRECAUTIONS sections.

Last updated on RxList: 5/17/2007

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

CETIRIZINE - ORAL

(seh-TEER-ah-zeen)

COMMON BRAND NAME(S): Zyrtec

USES: This medication is an antihistamine that treats symptoms such as itching, runny nose, watery eyes, and sneezing from "hay fever" and other allergies. It is also used to relieve itching from hives.

Cetirizine does not prevent hives or prevent/treat a serious allergic reaction (e.g., anaphylaxis). Therefore, if your doctor has prescribed epinephrine to treat allergic reactions, always carry your epinephrine injector with you. Do not use cetirizine in place of your epinephrine.

If you are self-treating with this medication, it is important to read the manufacturer's package instructions carefully so you know when to consult your doctor or pharmacist. (See also Precautions section.)

HOW TO USE: If you are self-treating with the over-the-counter product, read all the directions on the product package before taking this medication. If your doctor has prescribed this medication, follow your doctor's directions and the instructions on your prescription label. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth with or without food, usually once a day or as directed by your doctor. If you are using the chewable tablets, chew the tablets well and swallow.

Dosage is based on your age, condition, and response to treatment. Do not increase your dose or take this drug more often than directed. Do not take more of this medication than recommended for your age.

Tell your doctor if your allergy symptoms do not improve after 3 days of treatment or if your hives last more than 6 weeks. Seek immediate medical attention if your condition worsens or if you think you have a serious medical problem (e.g., very serious allergic reaction/anaphylaxis).

SIDE EFFECTS: Drowsiness, tiredness, and dry mouth may occur. In children, stomach pain and vomiting may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

If your doctor has prescribed this medication, he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking cetirizine, tell your doctor or pharmacist if you are allergic to it; or to hydroxyzine; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history. Do not self-treat with this medication without consulting your doctor first if you have certain medical conditions such as: kidney disease, liver disease.

This drug may make you drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

If you have hives and your doctor has prescribed cetirizine, or if you are considering using this drug to treat your own hives, tell your doctor immediately if you have any of these other symptoms because they may be signs of a more serious condition: hives that are an unusual color, hives that look bruised or blistered, hives that do not itch.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, older adults may be at greater risk for side effects (e.g., drowsiness) while using this drug.

During pregnancy, this medication should be used only when clearly needed and as directed by your doctor. Discuss the risks and benefits with your doctor before taking this drug.

This medication passes into breast milk. Breast-feeding is not recommended while using this drug.

DRUG INTERACTIONS: If you are taking this medication under your doctor's direction, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription products you may use, especially of drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), anti-seizure drugs (e.g., carbamazepine), medicine for sleep or anxiety (e.g., alprazolam, diazepam, zolpidem), muscle relaxants, narcotic pain relievers (e.g., codeine), psychiatric medicines (e.g., chlorpromazine, risperidone, amitriptyline, trazodone).

Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain ingredients that cause drowsiness. Ask your pharmacist about using those products safely.

If you are scheduled for allergy testing, ask your doctor if you should stop taking this medication for several days before testing. This drug may affect your allergy test results.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: severe drowsiness. In children, symptoms may include: restlessness and irritability followed by drowsiness.

NOTES: If your doctor has prescribed this medication for you, do not share it with others.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Different brands/strengths of this medication may have different storage requirements. Read the package labeling or ask your pharmacist for the storage requirements for the product you are using. Protect from light. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.