Author: druginteractionchecker_lgaiz4

CLINICAL STUDIES

14 Adults and Adolescents ≥12 Years Old The safety and efficacy of Levalbuterol Inhalation Solution were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV 1 60% of predicted).

Approximately half of the patients were also receiving inhaled corticosteroids.

Patients were randomized to receive Levalbuterol 0.63 mg, Levalbuterol 1.25 mg, racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and a Dura-Neb ® portable compressor.

Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered-dose inhaler (MDI) was used on an as-needed basis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline FEV 1 , was demonstrated for all active treatment regimens compared with placebo on day 1 and day 29.

On both day 1 (see Figure 1) and day 29 (see Figure 2), 1.25 mg of Levalbuterol demonstrated the largest mean percent change from baseline FEV 1 compared with the other active treatments.

A dose of 0.63 mg of Levalbuterol and 2.5 mg of racemic albuterol sulfate produced a clinically comparable mean percent change from baseline FEV 1 on both day 1 and day 29.

Figure 1: Mean Percent Change from Baseline FEV 1 on Day 1, Adults and Adolescents ≥12 years old Figure 2: Mean Percent Change from Baseline FEV 1 on Day 29, Adults and Adolescents ≥12 years old The mean time to onset of a 15% increase in FEV 1 over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and 10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment.

The mean duration of effect, as measured by a >15% increase from baseline FEV 1 , was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately 6 hours after administration of 1.25 mg of levalbuterol after 4 weeks of treatment.

In some patients, the duration of effect was as long as 8 hours.

Children 6-11 Years Old A multicenter, randomized, double-blind, placebo-and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV 1 73% of predicted) (n=316).

Following a 1-week placebo run-in, subjects were randomized to Levalbuterol (0.31 or 0.63 mg), racemic albuterol (1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3 weeks using a PARI LC Plus™ nebulizer and a Dura-Neb ® 3000 compressor.

Efficacy, as measured by mean peak percent change from baseline FEV 1 , was demonstrated for all active treatment regimens compared with placebo on day 1 and day 21.

Time profile FEV 1 curves for day 1 and day 21 are shown in Figure 3 and Figure 4, respectively.

The onset of effect (time to a 15% increase in FEV 1 over test-day baseline) and duration of effect (maintenance of a >15% increase in FEV 1 over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.

Figure 3: Mean Percent Change from Baseline FEV 1 on Day 1, Children 6-11 Years of Age Figure 4: Mean Percent Change from Baseline FEV 1 on Day 21, Children 6-11 Years of Age

CLINICAL STUDIES

14 The effectiveness of oxcarbazepine as adjunctive and monotherapy for partial-onset seizures in adults, and as adjunctive therapy in children aged 2 to 16 years was established in seven multicenter, randomized, controlled trials.

The effectiveness of oxcarbazepine as monotherapy for partial-onset seizures in children aged 4 to 16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations.

14.1 Oxcarbazepine Monotherapy Trials Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of oxcarbazepine as monotherapy.

Two trials compared oxcarbazepine to placebo and 2 trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of oxcarbazepine, after substituting oxcarbazepine 2400 mg/day for 1 or more AEDs.

All doses were administered on a twice a day schedule.

A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose oxcarbazepine-treatment groups.

One placebo-controlled trial was conducted in 102 patients (11 to 62 years of age) with refractory partial-onset seizures who had completed an inpatient evaluation for epilepsy surgery.

Patients had been withdrawn from all AEDs and were required to have 2 to 10 partial-onset seizures within 48 hours prior to randomization.

Patients were randomized to receive either placebo or oxcarbazepine given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional 9 days, or until 1 of the following 3 exit criteria occurred: 1) the occurrence of a fourth partial-onset seizure, excluding Day 1, 2) 2 new-onset secondarily generalized seizures, where such seizures were not seen in the 1-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus.

The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria.

There was a statistically significant difference in favor of oxcarbazepine (see Figure 1), p = 0.0001.

Figure 1: Kaplan-Meier Estimates of Exit Rate by Treatment Group The second placebo-controlled trial was conducted in 67 untreated patients (8 to 69 years of age) with newly-diagnosed and recent-onset partial seizures.

Patients were randomized to placebo or oxcarbazepine, initiated at 300 mg twice a day and titrated to 1200 mg/day (given as 600 mg twice a day) in 6 days, followed by maintenance treatment for 84 days.

The primary measure of effectiveness was a between-group comparison of the time to first seizure.

The difference between the 2 treatments was statistically significant in favor of oxcarbazepine (see Figure 2), p = 0.046.

Figure 2: Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group A third trial substituted oxcarbazepine monotherapy at 2400 mg/day for carbamazepine in 143 patients (12 to 65 years of age) whose partial-onset seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this oxcarbazepine dose for 56 days (baseline phase).

Patients who were able to tolerate titration of oxcarbazepine to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of oxcarbazepine or 2400 mg/day oxcarbazepine.

Patients were observed for 126 days or until 1 of the following 4 exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a 2-fold increase in the highest consecutive 2-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure.

The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria.

The difference between the curves was statistically significant in favor of the oxcarbazepine 2400 mg/day group (see Figure 3), p = 0.0001.

Figure 3: Kaplan-Meier Estimates of Exit Rate by Treatment Group Another monotherapy substitution trial was conducted in 87 patients (11 to 66 years of age) whose seizures were inadequately controlled on 1 or 2 AEDs.

Patients were randomized to either oxcarbazepine 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first 6 weeks of double-blind therapy.

Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until 1 of the 4 exit criteria described for the previous study occurred.

The primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria.

The results were statistically significant in favor of the oxcarbazepine 2400 mg/day group (14/34; 41.2%) compared to the oxcarbazepine 300 mg/day group (42/45; 93.3%) (p< 0.0001).

The time to meeting one of the exit criteria was also statistically significant in favor of the oxcarbazepine 2400 mg/day group (see Figure 4), p = 0.0001.

Figure 4: Kaplan-Meier Estimates of Exit Rate by Treatment Group A monotherapy trial was conducted in 92 pediatric patients (1 month to 16 years of age) with inadequately-controlled or new-onset partial seizures.

Patients were hospitalized and randomized to either oxcarbazepine 10 mg/kg/day or were titrated up to 40 to 60 mg/kg/day within 3 days while withdrawing the previous AED on the second day of oxcarbazepine.

Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5.

Patients either completed the 5-day treatment or met 1 of the 2 exit criteria: 1) three study-specific seizures (i.e., electrographic partial-onset seizures with a behavioral correlate), 2) a prolonged study-specific seizure.

The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (p = 0.904).

The majority of patients from both dose groups completed the 5-day study without exiting.

Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable.

For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older.

Figure 1 Figure 2 Figure 3 Figure 4 14.2 Oxcarbazepine Adjunctive Therapy Trials The effectiveness of oxcarbazepine as an adjunctive therapy for partial-onset seizures was established in 2 multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15 to 66 years of age) and one in 264 pediatric patients (3 to 17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing 2 doses of oxcarbazepine in 128 pediatric patients (1 month to < 4 years of age).

Patients in the 2 placebo-controlled trials were on 1 to 3 concomitant AEDs.

In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase.

Patients who experienced at least 8 (minimum of 1 to 4 per month) partial-onset seizures during the baseline phase were randomly assigned to placebo or to a specific dose of oxcarbazepine in addition to their other AEDs.

In these studies, the dose was increased over a 2-week period until either the assigned dose was reached, or intolerance prevented increases.

Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period.

In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day.

In the pediatric trial, patients received maintenance doses in the range of 30 to 46 mg/kg/day, depending on baseline weight.

The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial-onset seizure frequency in the double-blind treatment phase relative to baseline phase.

This comparison was statistically significant in favor of oxcarbazepine at all doses tested in both trials (p = 0.0001 for all doses for both trials).

The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 8.

It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study [see Adverse Reactions ( 6 )] , an outcome not seen in the monotherapy studies.

Table 8: Summary of Percentage Change in Partial-Onset Seizure Frequency from Baseline for Placebo-Controlled Adjunctive Therapy Trials Trial Treatment Group N Baseline Median Seizure Rate** Median % Reduction 1 (pediatrics) Oxcarbazepine 136 12.5 34.8 1 Placebo 128 13.1 9.4 2 (adults) Oxcarbazepine 2400 mg/day 174 10.0 49.9 1 Oxcarbazepine 1200 mg/day 177 9.8 40.2 1 Oxcarbazepine 600 mg/day 168 9.6 26.4 1 Placebo 173 8.6 7.6 1 p=0.0001.

** = number of seizures per 28 days.

Subset analyses of the antiepileptic efficacy of oxcarbazepine with regard to gender in these trials revealed no important differences in response between men and women.

Because there were very few patients over the age of 65 years in controlled trials, the effect of the drug in the elderly has not been adequately assessed.

The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to < 4 years of age) with inadequately-controlled partial-onset seizures on 1 to 2 concomitant AEDs.

Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial-onset seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either oxcarbazepine 10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days.

Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period.

The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline.

For the entire group of patients enrolled, this comparison was statistically significant in favor of oxcarbazepine 60 mg/kg/day.

In this study, there was no evidence that oxcarbazepine was effective in patients below the age of 2 years (N = 75).

CLINICAL STUDIES

14 The safety and efficacy of LUPRON DEPOT 3.75 mg for the indicated populations has been established based on adequate and well-controlled studies in adults (See Table 8 ) of LUPRON DEPOT 3.75 mg [see Indications and Usage ( 1 ) ] .

Figure 1 14.1 Endometriosis LUPRON DEPOT 3.75 mg Monotherapy In controlled clinical studies, LUPRON DEPOT 3.75 mg monthly for six months was shown to be comparable to danazol 800 mg/day in relieving the clinical sign/symptoms of endometriosis (pelvic pain, dysmenorrhea, dyspareunia, pelvic tenderness, and induration) and in reducing the size of endometrial implants as evidenced by laparoscopy.

The clinical significance of a decrease in endometriotic lesions is not known, and laparoscopic staging of endometriosis does not necessarily correlate with the severity of symptoms.

LUPRON DEPOT 3.75 mg monthly induced amenorrhea in 74% and 98% of the women after the first and second month of treatment, respectively.

Most of the remaining women reported episodes of only light bleeding or spotting.

In the first, second and third post-treatment months, normal menstrual cycles resumed in 7%, 71% and 95% of women, respectively, excluding those who became pregnant.

Figure 1 illustrates the percent of women with symptoms at baseline, final treatment visit and sustained relief at 6 and 12 months following discontinuation of treatment for the various symptoms evaluated during the two controlled clinical studies.

A total of 166 women received LUPRON DEPOT 3.75 mg.

Seventy-five percent (N=125) of these elected to participate in the follow-up period.

Of these women, 36% and 24% are included in the 6-month and 12-month follow-up analysis, respectively.

All the women who had a pain evaluation at baseline and at least of one treatment visit are included in the Baseline (B) and final treatment visit (F) analysis.

Figure 1.

Percent of Women with Signs/Symptoms of Endometriosis at Baseline, Final Treatment Visit, and After 6 and 12 Months of Follow-Up, LUPRON DEPOT 3.75 mg Monthly for Six Months LUPRON DEPOT with Norethindrone Acetate Add-Back Therapy Two clinical studies with treatment duration of 12 months were conducted to evaluate the effect of co-administration of LUPRON DEPOT 3.75 mg and norethindrone acetate on the loss of bone mineral density (BMD) associated with LUPRON DEPOT 3.75 mg and on the efficacy of LUPRON DEPOT in relieving symptoms of endometriosis.

All women in these studies received calcium supplementation with 1000 mg elemental calcium.

A total of 242 women were treated with monthly administration of LUPRON DEPOT 3.75 mg (13 injections) and 191 of them were co-administered 5 mg norethindrone acetate taken daily.

The population age range was 17-43 years old.

The majority of women were Caucasian (87%).

One co-administration study was a controlled, randomized and double-blind study included 51 women treated monthly with LUPRON DEPOT 3.75 mg alone and 55 women treated monthly with LUPRON DEPOT 3.75 mg plus norethindrone acetate daily.

Women in this trial were followed for up to 24 months after completing one year of treatment.

The other study was an open-label single arm clinical study in 136 women of one year of treatment with LUPRON DEPOT 3.75 mg monthly and daily norethindrone acetate 5 mg, with follow-up for up to 12 months after completing treatment.

See Table 8 .

The assessment of efficacy was based on the investigator’s or the woman’s monthly assessment of five signs or symptoms of endometriosis (dysmenorrhea, pelvic pain, deep dyspareunia, pelvic tenderness and pelvic induration).

Table 8 below provides detailed efficacy data regarding relief of symptoms of endometriosis based on the two studies of co-administration of LUPRON DEPOT 3.75 mg monthly and norethindrone acetate 5 mg daily.

Table 8.

Effect of LUPRON DEPOT and Norethindrone Acetate on the Symptoms of Endometriosis and Mean Clinical Severity Scores Percent of Women with Symptoms Clinical Pain Severity Score Baseline Final Baseline Final Variable Study Group N 1 (%) 2 (%) N 1 Value 3 Change Dysmenorrhea Controlled Study LD* 4 51 (100) (4) 50 3.2 -2.0 LD/N† 55 (100) (4) 54 3.1 -2.0 Open Label Study LD/N 5 136 (99) (9) 134 3.3 -2.1 Pelvic Pain Controlled Study LD 4 51 (100) (66) 50 2.9 -1.1 LD/N 55 (96) (56) 54 3.1 -1.1 Open Label Study LD/N 5 136 (99) (63) 134 3.2 -1.2 Deep Dyspareunia Controlled Study LD 4 42 (83) (37) 25 2.4 -1.0 LD/N 43 (84) (45) 30 2.7 -0.8 Open Label Study LD/N 5 102 (91) (53) 94 2.7 -1.0 Pelvic Tenderness Controlled Study LD 4 51 (94) (34) 50 2.5 -1.0 LD/N 54 (91) (34) 52 2.6 -0.9 Open Label Study LD/N 5 136 (99) (39) 134 2.9 -1.4 Pelvic Induration Controlled Study LD 4 51 (51) (12) 50 1.9 -0.4 LD/N 54 (46) (17) 52 1.6 -0.4 Open Label Study LD/N 5 136 (75) (21) 134 2.2 -0.9 * LD = LUPRON DEPOT 3.75 mg assessment † LD/N = LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg 1 Number of women that were included in the assessment 2 Percentage of women with the symptom/sign 3 Value description: 1=none; 2= mild; 3= moderate; 4= severe 4 12-month treatment followed by up to 24 months of follow up 5 12-month treatment followed by up to 12 months of follow up Suppression of menses (menses was defined as three or more consecutive days of menstrual bleeding) was maintained throughout treatment in 84% and 73% of women receiving leuprolide acetate and norethindrone acetate, in the controlled study and open label study, respectively.

The median time for menses resumption after treatment with leuprolide acetate and norethindrone acetate was 8 weeks.

Changes in Bone Density The effect of LUPRON DEPOT 3.75 mg and norethindrone acetate on bone mineral density was evaluated by dual energy x-ray absorptiometry (DEXA) scan in the two clinical trials.

For the open-label study, success in mitigating BMD loss was defined as the lower bound of the 95% confidence interval around the change from baseline at one year of treatment not to exceed -2.2%.

The bone mineral density data of the lumbar spine from these two studies are presented in Table 9 .

Table 9.

Mean Percent Change from Baseline in Bone Mineral Density of Lumbar Spine LUPRON DEPOT 3.75 mg (LD only) LUPRON DEPOT 3.75 mg plus norethindrone acetate 5 mg daily (LD/N) Controlled Study Controlled Study Open Label Study N Change Mean (95% CI) # N Change Mean (95% CI) # N Change Mean (95% CI) # Week 24* 41 -3.2% (-3.8, -2.6) 42 -0.3% (-0.8, 0.3) 115 -0.2% (-0.6, 0.2) Week 52† 29 -6.3% (-7.1, -5.4) 32 -1.0% (-1.9, -0.1) 84 -1.1% (-1.6, -0.5) * Includes on-treatment measurements that fell within 2 to 252 days after the first day of treatment.

† Includes on-treatment measurements >252 days after the first day of treatment.

# 95% CI: 95% Confidence Interval The change in BMD following discontinuation of treatment is shown in Table 10 .

Table 10.

Mean Percent Change from Baseline in BMD of Lumbar Spine in Post-Treatment Follow-up Period 1 Post Treatment Measurement Controlled Study Open Label Study LD-Only LD/N LD/N N Mean % Change 95% CI (%) 2 N Mean % Change 95% CI (%) N Mean % Change 95% CI (%) 2 Month 8 19 -3.3 (-4.9, -1.8) 23 -0.9 (-2.1, 0.4) 89 -0.6 (-1.2, 0.0) Month 12 16 -2.2 (-3.3, -1.1) 12 -0.7 (-2.1, 0.6) 65 0.1 (-0.6, 0.7) 1 Patients with post treatment measurements 2 95% CI (2-sided) of percent change in BMD values from baseline These clinical studies demonstrated that co-administration of leuprolide acetate and norethindrone acetate 5 mg daily is effective in significantly reducing the loss of bone mineral density that occurs with LUPRON DEPOT 3.75 mg and in relieving symptoms of endometriosis.

14.2 Fibroids LUPRON DEPOT 3.75 mg monthly for a period of three to six months was studied in four controlled clinical trials.

In one of these clinical studies, enrollment was based on hematocrit ≤ 30% and/or hemoglobin ≤ 10.2 g/dL.

Administration of LUPRON DEPOT 3.75 mg monthly, concomitantly with iron, produced an increase of ≥ 6% hematocrit and ≥ 2 g/dL hemoglobin in 77% of women at three months of therapy.

The mean change in hematocrit was 10.1% and the mean change in hemoglobin was 4.2 g/dL.

Clinical response was judged to be a hematocrit of ≥ 36% and hemoglobin of ≥ 12 g/dL, thus allowing for autologous blood donation prior to surgery.

At two and three months, respectively, 71% and 75% of women met this criterion (Table 11 ).

These data suggest however, that some women may benefit from iron alone or 1 to 2 months of LUPRON DEPOT 3.75 mg.

Table 11.

Percent of Women Achieving Hematocrit ≥ 36% and Hemoglobin ≥ 12 g/dL Treatment Group Week 4 Week 8 Week 12 LUPRON DEPOT 3.75 mg with Iron (N=104) 40* 71† 75* Iron Alone (N=98) 17 39 49 * P-Value < 0.01 † P-Value < 0.001 Excessive vaginal bleeding (menorrhagia or menometrorrhagia) decreased in 80% of women at three months.

Episodes of spotting and menstrual-like bleeding were noted in 16% of women at final visit.

In this same study, a decrease in uterine volume and myoma volume of ≥25% was seen in 60% and 54% of women, respectively.

The mean fibroid diameter was 6.3 cm at pretreatment and decreased to 5.6 cm at the end of treatment.

LUPRON DEPOT 3.75 mg was found to relieve symptoms of bloating, pelvic pain, and pressure.

In three other controlled clinical trials, enrollment was not based on hematologic status.

Mean uterine volume decreased by 41% and myoma volume decreased by 37% at final visit as evidenced by ultrasound or MRI.

The mean fibroid diameter was 5.6 cm at pretreatment and decreased to 4.7 cm at the end of treatment.

These women also experienced a decrease in symptoms including excessive vaginal bleeding and pelvic discomfort.

Ninety-five percent of these women became amenorrheic with 61%, 25%, and 4% experiencing amenorrhea during the first, second, and third treatment months respectively.

In addition, post-treatment follow-up was carried out in one clinical trial for a small percentage of women on LUPRON DEPOT 3.75 mg (N=46) among the 77% who demonstrated a ≥ 25% decrease in uterine volume while on therapy.

Menses usually returned within two months of cessation of therapy.

Mean time to return to pretreatment uterine size was 8.3 months.

Regrowth did not appear to be related to pretreatment uterine volume.

Changes in Bone Density In one of the studies for fibroids described above, when LUPRON DEPOT 3.75 mg was administered for three months in women with uterine fibroids, vertebral trabecular bone mineral density, as assessed by quantitative digital radiography (QDR), revealed a mean decrease of 2.7% compared with baseline.

Six months after discontinuation of therapy, a trend toward recovery was observed.

CLINICAL STUDIES

Clini cal Studies Head & Neck Cancer Patients A 12 week randomized, double-blind, placebo-controlled study in 207 patients (142 men, 65 women) was conducted in patients whose mean age was 58.5 years with a range of 19 to 77; the racial distribution was Caucasian 95%, Black 4%, and other 1%.

In this population, a statistically significant improvement in mouth dryness occurred in the 5 and 10 mg pilocarpine hydrochloride tablet treated patients compared to placebo treated patients.

The 5 and 10 mg treated patients could not be distinguished.

(See Pharmacodynamics section for flow study details.) Another 12 week, double-blind, randomized, placebo-controlled study was conducted in 162 patients whose mean age was 57.8 years with a range of 27 to 80; the racial distribution was Caucasian 88%, Black 10%, and other 2%.

The effects of placebo were compared to 2.5 mg three times a day of pilocarpine hydrochloride tablets for 4 weeks followed by adjustment to 5 mg three times a day and 10 mg three times a day.

Lowering of the dose was necessary because of adverse events in 3 of 67 patients treated with 5 mg of pilocarpine hydrochloride tablets and in 7 of 66 patients treated with 10 mg of pilocarpine hydrochloride tablets.

After 4 weeks of treatment, 2.5 mg of pilocarpine hydrochloride tablets three times a day was comparable to placebo in relieving dryness.

In patients treated with 5 mg and 10 mg of pilocarpine hydrochloride tablets, the greatest improvement in dryness was noted in patients with no measurable salivary flow at baseline.

In both studies, some patients noted improvement in the global assessment of their dry mouth, speaking without liquids, and a reduced need for supplemental oral comfort agents.

In the two placebo-controlled clinical trials, the most common adverse events related to drug, and increasing in rate as dose increases, were sweating, nausea, rhinitis, diarrhea, chills, flushing, urinary frequency, dizziness, and asthenia.

The most common adverse experience causing withdrawal from treatment was sweating (5 mg t.i.d.

≤1%; 10 mg t.i.d.

=12%).

Sjogren’s Syndrome Patients Two separate studies were conducted in patients with primary or secondary Sjogren’s Syndrome.

In both studies, the majority of patients best fit the European criteria for having primary Sjogren’s Syndrome.

[“Criteria for the Classification of Sjogren’s Syndrome” (Vitali C, Bombardieri S, Moutsopoulos HM, et al: Preliminary criteria for the classification of Sjogren’s syndrome.

Arthritis Rheum 36:340-347, 1993.)] A twelve week, randomized, double-blind, parallel-group, placebo-controlled study was conducted in 256 patients (14 men, 242 women) whose mean age was 57 years with a range of 24 to 85 years.

The racial distribution was as follows: Caucasian 91%, Black 6%, and other 3%.

The effects of placebo were compared with those of pilocarpine hydrochloride tablets 5 mg four times a day (20 mg/day) for 6 weeks.

At 6 weeks, the patients’ dosage was increased from 5 mg pilocarpine hydrochloride tablets q.i.d.

to 7.5 mg q.i.d.

The data collected during the first 6 weeks of the trial were evaluated for safety and efficacy, and the data of the second 6 weeks of the trial were used to provide additional evidence of safety.

After 6 weeks of treatment, statistically significant global improvement of dry mouth was observed compared to placebo.

“Global improvement” is defined as a score of 55 mm or more on a 100 mm visual analogue scale in response to the question, “Please rate your present condition of dry mouth (xerostomia) compared with your condition at the start of this study.

Consider the changes to your dry mouth and other symptoms related to your dry mouth that have occurred since you have taken this medication.” Patients’ assessments of specific dry mouth symptoms such as severity of dry mouth, mouth discomfort, ability to speak without water, ability to sleep without drinking water, ability to swallow food without drinking, and a decreased use of saliva substitutes were found to be consistent with the significant global improvement described.

Another 12 week randomized, double-blind, parallel-group, placebo-controlled study was conducted in 373 patients (16 men, 357 women) whose mean age was 55 years with a range of 21 to 84.

The racial distribution was Caucasian 80%, Oriental 14%, Black 2%, and 4% of other origin.

The treatment groups were 2.5 mg pilocarpine tablets, 5 mg pilocarpine hydrochloride tablets, and placebo.

All treatments were administered on a four times a day regimen.

After 12 weeks of treatment, statistically significant global improvement of dry mouth was observed at a dose of 5 mg compared with placebo.

The 2.5 mg (10mg/day) group was not significantly different than placebo.

However, a subgroup of patients with rheumatoid arthritis tended to improve in global assessments at both the 2.5 mg q.i.d.

(9 patients) and 5 mg q.i.d.

(16 patients) dose (10-20 mg/day).

The clinical significance of this finding is unknown.

Patients’ assessments of specific dry mouth symptoms such as severity of dry mouth, mouth discomfort, ability to sleep without drinking water, and decreased use of saliva substitutes were also found to be consistent with the significant global improvement described when measured after 6 weeks and 12 weeks of pilocarpine hydrochloride tablets use.

CLINICAL STUDIES

Effects on the endometrium In a randomized, double-blind clinical trial, 358 postmenopausal women, each with an intact uterus, received treatment for up to 36 months.

The treatment groups were: PROMETRIUM Capsules at the dose of 200 mg per day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg per day (n=120); conjugated estrogens 0.625 mg per day only (n=119); or placebo (n=119).

The subjects in all three treatment groups were primarily Caucasian women (87 percent or more of each group).

The results for the incidence of endometrial hyperplasia in women receiving up to 3 years of treatment are shown in Table 3 .

A comparison of the PROMETRIUM Capsules plus conjugated estrogens treatment group to the conjugated estrogens only group showed a significantly lower rate of hyperplasia (6 percent combination product versus 64 percent estrogen alone) in the PROMETRIUM Capsules plus conjugated estrogens treatment group throughout 36 months of treatment.

TABLE 3.

Incidence of Endometrial Hyperplasia in Women Receiving 3 Years of Treatment a Most advanced result to least advanced result: Adenocarcinoma > atypical hyperplasia > complex hyperplasia > simple hyperplasia Endometrial Diagnosis Treatment Group Conjugated Estrogens 0.625 mg + PROMETRIUM Capsules 200 mg (cyclical) Conjugated Estrogens 0.625 mg (alone) Placebo Number of patients % of patients Number of patients % of patients Number of patients % of patients n=117 n=115 n=116 HYPERPLASIA a 7 6 74 64 3 3 Adenocarcinoma 0 0 0 0 1 1 Atypical hyperplasia 1 1 14 12 0 0 Complex hyperplasia 0 0 27 23 1 1 Simple hyperplasia 6 5 33 29 1 1 The times to diagnosis of endometrial hyperplasia over 36 months of treatment are shown in Figure 1 .

This figure illustrates graphically that the proportion of patients with hyperplasia was significantly greater for the conjugated estrogens group (64 percent) compared to the conjugated estrogens plus PROMETRIUM Capsules group (6 percent).

Figure 1.

Time to Hyperplasia in Women Receiving up to 36 Months of Treatment The discontinuation rates due to hyperplasia over the 36 months of treatment are as shown in Table 4 .

For any degree of hyperplasia, the discontinuation rate for patients who received conjugated estrogens plus PROMETRIUM Capsules was similar to that of the placebo only group, while the discontinuation rate for patients who received conjugated estrogens alone was significantly higher.

Women who permanently discontinued treatment due to hyperplasia were similar in demographics to the overall study population.

TABLE 4.

Discontinuation Rate Due to Hyperplasia Over 36 Months of Treatment Most Advanced Biopsy Result Through 36 Months of Treatment Treatment Group Conjugated Estrogens + PROMETRIUM Capsules (cyclical) Conjugated Estrogens (alone) Placebo n=120 n=119 n=119 Number of patients % of patients Number of patients % of patients Number of patients % of patients Adenocarcinoma 0 0 0 0 1 1 Atypical hyperplasia 1 1 10 8 0 0 Complex hyperplasia 0 0 21 18 1 1 Simple hyperplasia 1 1 13 11 0 0 Figure 1 Effects on secondary amenorrhea In a single-center, randomized, double-blind clinical study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of PROMETRIUM Capsules therapy resulted in 80 percent of women experiencing withdrawal bleeding within 7 days of the last dose of PROMETRIUM Capsules, 300 mg per day (n=20), compared to 10 percent of women experiencing withdrawal bleeding in the placebo group (n=21).

In a multicenter, parallel-group, open label, postmarketing dosing study that included premenopausal women with secondary amenorrhea for at least 90 days, administration of 10 days of PROMETRIUM Capsules during two 28-day treatment cycles, 300 mg per day (n=107) or 400 mg per day (n=99), resulted in 73.8 percent and 76.8 percent of women, respectively, experiencing withdrawal bleeding.

The rate of secretory transformation was evaluated in a multicenter, randomized, double-blind clinical study in estrogen-primed postmenopausal women.

PROMETRIUM Capsules administered orally for 10 days at 400 mg per day (n=22) induced complete secretory changes in the endometrium in 45 percent of women compared to 0 percent in the placebo group (n=23).

A second multicenter, parallel-group, open label postmarketing dosing study in premenopausal women with secondary amenorrhea for at least 90 days also evaluated the rate of secretory transformation.

All subjects received daily oral conjugated estrogens over 3 consecutive 28-day treatment cycles and PROMETRIUM Capsules, 300 mg per day (n=107) or 400 mg per day (n=99) for 10 days of each treatment cycle.

The rate of complete secretory transformation was 21.5 percent and 28.3 percent, respectively.

Women’s Health Initiative Studies The Women’s Health Initiative (WHI) enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral conjugated estrogens (CE) [0.625 mg]-alone or in combination with medroxyprogesterone acetate (MPA) [2.5 mg] compared to placebo in the prevention of certain chronic diseases.

The primary endpoint was the incidence of coronary heart disease [(CHD) defined as nonfatal myocardial infarction (MI), silent MI and CHD death], with invasive breast cancer as the primary adverse outcome.

A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause.

These sub studies did not evaluate the effects of CE–alone or CE plus MPA on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy The WHI estrogen plus progestin substudy was stopped early.

According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other) are presented in Table 5 .

These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 5.

Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of WHI at an Average of 5.6 Years a, b a Adapted from numerous WHI publications.

WHI publications can be viewed at www.nhlbi.nih.gov/whi.

b Results are based on centrally adjudicated data.

c Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.

d Not included in Global Index.

e Includes metastatic and non-metastatic breast cancer with the exception of in situ breast cancer.

f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE or cerebrovascular disease.

g A subset of the events was combined in a “global index” defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.

Event Relative Risk CE/MPA versus Placebo (95% nCI c ) CE/MPA n = 8,506 Placebo n = 8,102 Absolute Risk per 10,000 Women-Years CHD events 1.23 (0.99-1.53) 41 34 Non-fatal MI 1.28 (1.00-1.63) 31 25 CHD death 1.10 (0.70-1.75) 8 8 All stroke 1.31 (1.03-1.88) 33 25 Ischemic Stroke 1.44 (1.09-1.90) 26 18 Deep vein thrombosis d 1.95 (1.43-2.67) 26 13 Pulmonary embolism 2.13 (1.45-3.11) 18 8 Invasive breast cancer e 1.24 (1.01-1.54) 41 33 Colorectal cancer 0.61 (0.42-0.87) 10 16 Endometrial cancer d 0.81 (0.48-1.36) 6 7 Cervical cancer d 1.44 (0.47-4.42) 2 1 Hip fracture 0.67 (0.47-0.96) 11 16 Vertebral fractures d 0.65 (0.46-0.92) 11 17 Lower arm/wrist fractures d 0.71 (0.59-0.85) 44 62 Total fractures d 0.76 (0.69-0.83) 152 199 Overall mortality f 1.00 (0.83-1.19) 52 52 Global Index g 1.13 (1.02-1.25) 184 165 Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile.

The WHI estrogen plus progestin substudy stratified for age showed in women 50 to 59 years of age a non-significant trend toward reducing risk of overall mortality [hazard ratio (HR) 0.69 (95 percent CI, 0.44-1.07)].

Women’s Health Initiative Memory Study The estrogen plus progestin Women’s Health Initiative Memory Study (WHIMS), an ancillary study of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; and 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 – 3.48).

The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years.

Probable dementia as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD).

The most common classification of probable dementia in the treatment group and the placebo group was AD.

Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

(See WARNINGS, Probable dementia and PRECAUTIONS, Geriatric Use .)

CLINICAL STUDIES

14 Duodenal Ulcer 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 7 ).

Table 7: Duodenal Ulcer Healing Rates Week PREVACID Placebo 15 mg daily 30 mg daily 60 mg daily (N=68) (N=74) (N=70) (N=72) 2 42.4% (p≤0.001) versus placebo.

35.6% 39.1% 11.3% 4 89.4% 91.7% 89.9% 46.1% 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 four weeks, the lack of significant difference at two weeks and the absence of a difference between 30 mg of PREVACID and ranitidine leaves the comparative effectiveness of the two agents undetermined ( Table 8 ) [see Indications and Usage (1.1) ].

Table 8: Duodenal Ulcer Healing Rates PREVACID Ranitidine Placebo Week 15 mg daily 30 mg daily 300 mg h.s.

(N=80) (N=77) (N=82) (N=41) 2 35.0% 44.2% 30.5% 34.2% 4 92.3% (p≤0.05) versus placebo and ranitidine.

80.3% (p≤0.05) versus placebo.

70.5% 47.5% 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 twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily Dual therapy: PREVACID 30 mg three times daily/amoxicillin 1 g three times daily All treatments were for 14 days.

H.

pylori eradication was defined as two negative tests (culture and histology) at four to six 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 9 and 10 ) [see Indications and Usage (1.2) ].

Table 9: H.

pylori Eradication Rates – Triple Therapy (PREVACID/amoxicillin/clarithromycin) Percent of Patients Cured [95% Confidence Interval] (Number of patients) Study Duration Triple Therapy Evaluable Analysis 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.

Triple Therapy Intent-to-Treat Analysis 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.

M93-131 14 days 92 (p<0.05) versus PREVACID/amoxicillin and PREVACID/clarithromycin dual therapy.

[80.0-97.7] (N=48) 86 [73.3-93.5] (N=55) M95-392 14 days 86 (p<0.05) versus clarithromycin/amoxicillin dual therapy.

[75.7-93.6] (N=66) 83 [72.0-90.8] (N=70) M95-399 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.

14 days 85 [77.0-91.0] (N=113) 82 [73.9-88.1] (N=126) 10 days 84 [76.0-89.8] (N=123) 81 [73.9-87.6] (N=135) Table 10: H.

pylori Eradication Rates – 14 Day Dual Therapy (PREVACID/amoxicillin) Percent of Patients Cured [95% Confidence Interval] (Number of patients) Study Dual Therapy Evaluable Analysis 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 analysis as failures of therapy.

Dual Therapy Intent-to-Treat Analysis 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.

M93-131 77 (p<0.05) versus PREVACID alone.

[62.5-87.2] (N=51) 70 [56.8-81.2] (N=60) M93-125 66 (p<0.05) versus PREVACID alone or amoxicillin alone.

[51.9-77.5] (N=58) 61 [48.5-72.9] (N=67) 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 11 ) [see Indications and Usage (1.3) ].

Table 11: Endoscopic Remission Rates Percent in Endoscopic Remission %=Life Table Estimate Trial Drug No.

of Pts.

0-3 0-6 0-12 #1 PREVACID 15 mg daily 86 90% (p≤0.001) versus placebo.

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% 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 12 ) [see Indications and Usage (1.4) ].

Table 12: Gastric Ulcer Healing Rates PREVACID Placebo (N=64) Week 15 mg daily (N=65) 30 mg daily (N=63) 60 mg daily (N=61) 4 64.6% (p≤0.05) versus placebo 58.1% 53.3% 37.5% 8 92.2% 96.8% 93.2% 76.7% 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 eight 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 13 ) [see Indications and Usage (1.5) ].

Table 13: NSAID-Associated Gastric Ulcer Healing Rates Actual observed ulcer(s) healed at time points ±2 days Study #1 PREVACID 30 mg daily Active Control Dose for healing of gastric ulcer Week 4 60% (53/88) (p≤0.05) versus the active control 28% (23/83) Week 8 79% (62/79) 55% (41/74) Study #2 PREVACID 30 mg daily Active Control Week 4 53% (40/75) 38% (31/82) Week 8 77% (47/61) 50% (33/66) 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 four, eight, 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 14 ) [see Indications and Usage (1.6) ].

Table 14: Proportion of Patients Remaining Free of Gastric Ulcers % = Life Table Estimate Week PREVACID 15 mg daily (N=121) PREVACID 30 mg daily (N=116) Misoprostol 200 mcg four times daily (N=106) Placebo (N=112) 4 90% 92% 96% 66% 8 86% 88% 95% 60% 12 80% 82% 93% 51% (p<0.001) PREVACID 15 mg daily versus placebo; PREVACID 30 mg daily versus placebo; and misoprostol 200 mcg four times daily versus placebo.

(p<0.05) Misoprostol 200 mcg four times daily versus PREVACID 15 mg daily; and misoprostol 200 mcg four times daily 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 eight 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 eight week treatment period are presented in Table 15 and in Figures 1 and 2 : Table 15: 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% (p<0.01) versus placebo.

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% Figure 1 Figure 2 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 (twice daily) in decreasing the frequency and severity of day and night heartburn associated with GERD for the eight week treatment period.

No significant additional benefit from lansoprazole 30 mg once daily was observed [see Indications and Usage (1.7) ].

Figure 1 Figure 2 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 two or more and grades three and four signifying erosive disease, the percentages of patients with healing are presented in Table 16 : Table 16: Erosive Esophagitis Healing Rates Week PREVACID Placebo (N=63) 15 mg daily (N=69) 30 mg daily (N=65) 60 mg daily (N=72) 4 67.6% (p≤0.001) versus placebo.

81.3% , (p≤0.05) versus PREVACID 15 mg.

80.6% , 32.8% 6 87.7% 95.4% 94.3% 52.5% 8 90.9% 95.4% 94.4% 52.5% 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 twice daily as shown below ( Table 17 ).

Table 17: Erosive Esophagitis Healing Rates Week PREVACID 30 mg daily (N=115) Ranitidine 150 mg twice daily (N=127) 2 66.7% (p≤0.001) versus ranitidine.

38.7% 4 82.5% 52.0% 6 93.0% 67.8% 8 92.1% 69.9% 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 twice daily.

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 four times daily, 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 twice daily in 151 patients with erosive reflux esophagitis that was poorly responsive to a minimum of 12 weeks of treatment with at least one H 2 -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 twice daily 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 H 2 -receptor antagonists with PREVACID, as all patients had demonstrated unresponsiveness to the histamine H 2 -receptor antagonist mode of treatment.

It does indicate, however, that PREVACID may be useful in patients failing on a histamine H 2 -receptor antagonist ( Table 18 ) [see Indications and Usage (1.7) ].

Table 18: Reflux Esophagitis Healing Rates in Patients Poorly Responsive to Histamine H 2 -Receptor Antagonist Therapy Week PREVACID 30 mg daily (N=100) Ranitidine 150 mg twice daily (N=51) 4 74.7% (p≤0.001) versus ranitidine.

42.6% 8 83.7% 32.0% 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 19 ).

Table 19: Endoscopic Remission Rates Percent in Endoscopic Remission Trial Drug No.

of Pts.

0-3 mo.

0-6 mo.

0-12 mo.

%=Life Table Estimate PREVACID 15 mg daily 59 83% (p≤0.001) versus placebo.

81% 79% #1 PREVACID 30 mg daily 56 93% 93% 90% Placebo 55 31% 27% 24% PREVACID 15 mg daily 50 74% 72% 67% #2 PREVACID 30 mg daily 49 75% 72% 55% Placebo 47 16% 13% 13% 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 twice daily (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 than those 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 [see Indications and Usage (1.8) ].

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome In open studies of 57 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome (ZES) 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 (2.1) ].

PREVACID was well tolerated at these high dose levels for prolonged periods (greater than four years in some patients).

In most ZES 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 [see Indications and Usage (1.9) ].