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`NEXIUM
`(esomeprazole magnesium)
`DELAYED-RELEASE CAPSULES
`
`Rx only
`
`DESCRIPTION
`The active ingredient in NEXIUM (esomeprazole magnesium) Delayed-Release Capsules is bis(5-
`methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl)
`magnesium trihydrate, a compound that inhibits gastric acid secretion. Esomeprazole is the S-isomer of
`omeprazole, which is a mixture of the S- and R- isomers. Its empirical formula is (C17H18N3O3S)2Mg x
`3 H2O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. The structural
`formula is:
`
`H3C
`
`OCH3
`
`N
`
`CH3
`
`CH2
`
`N
`
`O
`S
`
`_
`
`N
`
`OCH3
`
`Mg2+
`
`.
`
`3 H2O
`
`2
`
`The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of
`solvation and is slightly soluble in water.
`The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it
`has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium
`salt is about 19 hours at 25°C and about 8 hours at 37°C.
`
`NEXIUM is supplied as Delayed-Release Capsules for oral administration. Each delayed-release
`capsule contains 20 mg or 40 mg of esomeprazole (present as 22.3 mg or 44.5 mg esomeprazole
`magnesium trihydrate) in the form of enteric-coated pellets with the following inactive ingredients:
`glyceryl monostearate 40-50, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium
`stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl citrate.
`The capsule shells have the following inactive ingredients: gelatin, FD&C Blue #1, FD&C Red #40,
`D&C Red #28, titanium dioxide, shellac, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene
`glycol, sodium hydroxide, polyvinyl pyrrolidone, and D&C Yellow #10.
`
`CLINICAL PHARMACOLOGY
`Pharmacokinetics
`Absorption
`NEXIUM Delayed-Release Capsules contain an enteric-coated pellet formulation of esomeprazole
`magnesium. After oral administration peak plasma levels (Cmax) occur at approximately 1.5 hours
`(Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase
`in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily
`dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single
`dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 µmol*hr/L on day 1 to
`
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`11.2 µmol*hr/L on day 5 after 40 mg once daily dosing.
`The AUC after administration of a single 40 mg dose of esomeprazole is decreased by 33-53% after
`food intake compared to fasting conditions. Esomeprazole should be taken at least one hour before
`meals.
`
`The pharmacokinetic profile of esomeprazole was determined in 36 patients with symptomatic
`gastroesophageal reflux disease following repeated once daily administration of 20 mg and 40 mg
`capsules of NEXIUM over a period of five days. The results are shown in the following table:
`
`Parameter
`
`Pharmacokinetic Parameters of NEXIUM Following Oral Dosing for 5 days
`NEXIUM
`NEXIUM
`40 mg
`20 mg
`AUC (µmol*h/L)
`12.6
`4.2
` Coefficient of variation 42%
`59%
`Cmax (µmol/L)
`4.7
`2.1
`Tmax (h)
`1.6
`1.6
`t1/2 (h)
`1.5
`1.2
`Values represent the geometric mean, except the Tmax, which is the arithmetic mean.
`
`Distribution
`Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the
`concentration range of 2-20 µmol/L. The apparent volume of distribution at steady state in healthy
`volunteers is approximately 16 L.
`
`Metabolism
`Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system.
`The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole’s
`metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl
`metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite.
`CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of
`Caucasians and 15-20% of Asians lack CYP2C19 and are termed Poor metabolizers. At steady state,
`the ratio of AUC in Poor metabolizers to AUC in the rest of the population (Extensive metabolizers) is
`approximately 2.
`
`Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver,
`resulting in higher plasma levels of the S- than of the R-isomer.
`
`Excretion
`The plasma elimination half-life of esomeprazole is approximately 1-1.5 hours. Less than 1% of parent
`drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as
`inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.
`Special Populations
`Geriatric
`The AUC and Cmax values were slightly higher (25% and 18%, respectively) in the elderly as compared
`to younger subjects at steady state. Dosage adjustment based on age is not necessary.
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`Pediatric
`The pharmacokinetics of esomeprazole have not been studied in patients < 18 years of age.
`
`Gender
`The AUC and Cmax values were slightly higher (13%) in females than in males at steady state. Dosage
`adjustment based on gender is not necessary.
`
`Hepatic Insufficiency
`The steady state pharmacokinetics of esomeprazole obtained after administration of 40 mg once daily to
`4 patients each with mild (Child Pugh A), moderate (Child Pugh Class B), and severe (Child Pugh Class
`C) liver insufficiency were compared to those obtained in 36 male and female GERD patients with normal
`liver function. In patients with mild and moderate hepatic insufficiency, the AUCs were within the range
`that could be expected in patients with normal liver function. In patients with severe hepatic insufficiency
`the AUCs were 2 to 3 times higher than in the patients with normal liver function. No dosage adjustment
`is recommended for patients with mild to moderate hepatic insufficiency (Child Pugh Classes A and B).
`However, in patients with severe hepatic insufficiency (Child Pugh Class C) a dose of 20 mg once daily
`should not be exceeded (See DOSAGE AND ADMINISTRATION).
`
`Renal Insufficiency
`The pharmacokinetics of esomeprazole in patients with renal impairment are not expected to be altered
`relative to healthy volunteers as less than 1% of esomeprazole is excreted unchanged in urine.
`
`Pharmacokinetics: Combination Therapy with Antimicrobials
`Esomeprazole magnesium 40 mg once daily was given in combination with clarithromycin 500 mg
`twice daily and amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The
`mean steady state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively during
`triple combination therapy compared to treatment with esomeprazole alone. The observed increase in
`esomeprazole exposure during co-administration with clarithromycin and amoxicillin is not expected
`to produce significant safety concerns.
`
`The pharmacokinetic parameters for clarithromycin and amoxicillin were similar during triple
`combination therapy and administration of each drug alone. However, the mean AUC and Cmax for 14-
`hydroxyclarithromycin increased by 19% and 22%, respectively, during triple combination therapy
`compared to treatment with clarithromycin alone. This increase in exposure to 14-
`hydroxyclarithromycin is not considered to be clinically significant.
`
`Pharmacodynamics
`Mechanism of Action
`Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the
`H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers are protonated and converted in the acidic
`compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting
`specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing
`gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of
`gastric acid secretion.
`
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`Antisecretory Activity
`The effect of esomeprazole on intragastric pH was determined in patients with symptomatic
`gastroesophageal reflux disease in two separate studies. In the first study of 36 patients, NEXIUM 40
`mg and 20 mg capsules were administered over 5 days. The results are shown in the following table:
`
`Effect on Intragastric pH On Day 5 (N=36)
`Parameter
`NEXIUM
`NEXIUM
`40 mg
`20 mg
`70%*
`53%
`% Time Gastric
`pH >4† (Hours)
` (16.8 h)
` (12.7 h)
`26%
`37%
` Coefficient of variation
`Median 24 Hour pH 4.9*
`4.1
`16%
`27%
`Coefficient of variation
`
` † Gastric pH was measured over a 24-hour period
`*p< 0.01 NEXIUM 40 mg vs NEXIUM 20 mg
`
`In a second study, the effect on intragastric pH of NEXIUM 40 mg administered once daily over a five
`day period was similar to the first study, (% time with pH>4 was 68% or 16.3 hours).
`
`Serum Gastrin Effects
`The effect of NEXIUM on serum gastrin concentrations was evaluated in approximately 2,700 patients
`in clinical trials up to 8 weeks and in over 1,300 patients for up to 6-12 months. The mean fasting
`gastrin level increased in a dose-related manner. This increase reached a plateau within two to three
`months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.
`
`Enterochromaffin-like (ECL) Cell Effects
`In 24-month carcinogenicity studies of omeprazole in rats, a dose-related significant occurrence of
`gastric ECL cell carcinoid tumors and ECL cell hyperplasia was observed in both male and female
`animals (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility). Carcinoid
`tumors have also been observed in rats subjected to fundectomy or long-term treatment with other
`proton pump inhibitors or high doses of H2-receptor antagonists.
`
`Human gastric biopsy specimens have been obtained from more than 3,000 patients treated with
`omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased
`with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these
`patients.
`
`In over 1,000 patients treated with NEXIUM (10, 20 or 40 mg/day) up to 6-12 months, the prevalence
`of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids,
`dysplasia, or neoplasia in the gastric mucosa.
`
`Endocrine Effects
`NEXIUM had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other
`effects of NEXIUM on the endocrine system were assessed using omeprazole studies. Omeprazole
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`given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism,
`circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or
`secretin.
`
`Microbiology
`Esomeprazole magnesium, amoxicillin and clarithromycin triple therapy has been shown to be active
`against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections as described in
`the Clinical Studies and INDICATIONS AND USAGE sections.
`
`Helicobacter
`Helicobacter pylori
`Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar
`dilution methodology, and minimum inhibitory concentrations (MICs) were determined.
`
`Pretreatment Resistance
`Clarithromycin pretreatment resistance rate (MIC ≥ 1 µg/mL) to H. pylori was 15% (66/445) at
`baseline in all treatment groups combined. A total of > 99% (394/395) of patients had H. pylori
`isolates which were considered to be susceptible (MIC ≤ 0.25 µg/mL) to amoxicillin at baseline. One
`patient had a baseline
`H. pylori isolate with an amoxicillin MIC = 0.5 µg /mL.
`
`Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes
`The baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results at the
`Day 38 visit are shown in the table below:
`
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`H. pylori
`negative
`(Eradicated)
`
`Clarithromycin
`Pretreatment
`Results
`
`Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes a for Triple
`Therapy - (Esomeprazole magnesium 40 mg once daily/amoxicillin
`1000 mg twice daily/clarithromycin 500 mg twice daily for
`10 days)
`H. pylori positive
`(Not Eradicated)
`Post-treatment susceptibility
`results
`Rb No MIC
`Ib
`Sb
`Susceptibleb 182
`2
`14
`0
`4
`162
`Intermediateb 1
`0
`0
`0
`0
`1
`Resistantb 29
`13
`2
`0
`1
`13
`aIncludes only patients with pretreatment and post-treatment clarithromycin susceptibility test results
`bSusceptible (S) MIC ≤ 0.25 µg/mL, Intermediate (I) MIC =0.5 µg/mL, Resistant (R) MIC ≥ 1.0 µg /mL
`
`Patients not eradicated of H. pylori following esomeprazole magnesium/amoxicillin/clarithromycin
`triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin
`susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori
`should not be re-treated with a clarithromycin-containing regimen.
`
`Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes
`In the esomeprazole magnesium/amoxicillin/clarithromycin clinical trials, 83% (176/212) of the
`patients in the esomeprazole magnesium/amoxicillin/clarithromycin treatment group who had
`pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were eradicated of H. pylori, and 17%
`(36/212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori on
`triple therapy, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori
`isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori
`on triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There
`were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin.
`
`Susceptibility Test for Helicobacter pylori
`The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. 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 Campylobacter.
`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:
`
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`Clarithromycin MIC (µg/mL) a
`≤ 0.25
`0.5
`≥1.0
`
`Interpretation
`Susceptible
`Intermediate
`Resistant
`
`(S)
`(I)
`(R)
`
`Amoxicillin MIC (µg/mL) a,b
`Interpretation
`≤ 0.25
`(S)
`Susceptible
`These are breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative
`methods.
`There were not enough organisms with MICs > 0.25 µg /mL to determine a resistance breakpoint.
`
`a
`
`b
`
`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:
`
`Antimicrobial
`Agent
`Clarithromycin
`
`Microorganism
`
`MIC (µg/mL) a
`
`H. pylori ATCC
`0.016 – 0.12
`(µg/mL)
`43504
`H. pylori ATCC
`0.016 – 0.12
`(µg/mL)
`43504
`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.
`
`Amoxicillin
`
`Clinical Studies
` Healing of Erosive Esophagitis
`The healing rates of NEXIUM 40 mg, NEXIUM 20 mg, and omeprazole 20 mg (the approved dose for this
`indication) were evaluated in patients with endoscopically diagnosed erosive esophagitis in four
`multicenter, double-blind, randomized studies. The healing rates at weeks 4 and 8 were evaluated and are
`shown in the table below:
`
`Erosive Esophagitis Healing Rate (Life-Table Analysis)
`No. of
`Significance
`Patients Treatment Groups
`Level *
`588
`NEXIUM 20 mg
`N.S.
`588
`Omeprazole 20 mg
`654
`NEXIUM 40 mg
`656
`NEXIUM 20 mg
`650
`Omeprazole 20 mg
`576
`NEXIUM 40 mg
`572
`Omeprazole 20 mg
`1216
`NEXIUM 40 mg
`1209
`Omeprazole 20 mg
`
`p < 0.001
`p < 0.05
`
`N.S.
`
`p < 0.001
`
`Week 4 Week 8
`68.7% 90.6%
`69.5% 88.3%
`75.9% 94.1%
`70.5% 89.9%
`64.7% 86.9%
`71.5% 92.2%
`68.6% 89.8%
`81.7% 93.7%
`68.7% 84.2%
`
`Study
`1
`
`2
`
`3
`
`4
`
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`*log-rank test vs omeprazole 20 mg
`N.S. = not significant (p > 0.05).
`
`In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to
`sustained heartburn resolution were evaluated and are shown in the table below:
`
`Sustained Resolution‡ of Heartburn (Erosive Esophagitis Patients)
`
`Study
`1
`
`2
`
`3
`
`4
`
`p <0.001
`N.S.
`
`N.S.
`
`p <0.001
`
`Cumulative Percent#
`with Sustained
`Resolution
`
`Significance
`Level *
`N.S.
`
`No. of
`Day 28
`Day 14
`Patients Treatment Groups
`72.7%
`64.3%
`573
`NEXIUM 20 mg
`70.9%
`64.1%
`555
`Omeprazole 20 mg
`74.2%
`64.8%
`621
`NEXIUM 40 mg
`70.1%
`62.9%
`620
`NEXIUM 20 mg
`66.6%
`56.5%
`626
`Omeprazole 20 mg
`73.9%
`65.4%
`568
`NEXIUM 40 mg
`73.1%
`65.5%
`551
`Omeprazole 20 mg
`75.1%
`67.6%
`1187
`NEXIUM 40 mg
`70.8%
`62.5%
`1188
`Omeprazole 20 mg
`‡Defined as 7 consecutive days with no heartburn reported in daily patient diary.
`#Defined as the cumulative proportion of patients who have reached the start of sustained resolution
`*log-rank test vs omeprazole 20 mg
`N.S. = not significant (p > 0.05).
`
`In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive
`days with no heartburn) was 5 days for NEXIUM 40 mg, 7-8 days for NEXIUM 20 mg and 7-9 days for
`omeprazole 20 mg.
`
`There are no comparisons of 40 mg of NEXIUM with 40 mg of omeprazole in clinical trials assessing
`either healing or symptomatic relief of erosive esophagitis.
`
`Long-Term Maintenance of Healing of Erosive Esophagitis
`Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients
`with endoscopically confirmed, healed erosive esophagitis to evaluate NEXIUM 40 mg (n=174), 20 mg
`(n=180), 10 mg (n= 168) or placebo (n=171) once daily over six months of treatment.
`
`No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.
`
`The percentage of patients that maintained healing of erosive esophagitis at the various time points are
`shown in the figures below:
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`Maintenance of Healing Rates by Month (Study 177)
`
`NEXIUM 40 mg (n=92)
`TM
`NEXIUM 20 mg (n=98)
`TM
`NEXIUM 10 mg (n=91)
`TM
`Placebo (n=94)
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`Percent Maintained
`
`0
`
`0
`
`s
`
`1
`
`2
`
`s
`
`3
`
`Month
`
`4
`
`5
`
`s
`
`6
`
`s= scheduled visit
`
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`Maintenance of Healing Rates by Month (Study 178)
`
`Nexium 40 mg (n=82)
`Nexium 20 mg (n=82)
`Nexium 10 mg (n=77)
`Placebo (n=77)
`S
`1
`
`2
`
`S
`3
`Month
`
`4
`
`5
`
`S
`
`6
`
`
`
`Percent Maintained
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`0
`
`s= scheduled visit
`
`Patients remained in remission significantly longer and the number of recurrences of erosive
`esophagitis was significantly less in patients treated with NEXIUM compared to placebo.
`
`In both studies, the proportion of patients on NEXIUM who remained in remission and were free of
`heartburn and other GERD symptoms was well differentiated from placebo.
`
`In a third multicenter open label study of 808 patients treated for 12 months with NEXIUM 40 mg, the
`percentage of patients that maintained healing of erosive esophagitis was 93.7% for six months and 89.4%
`for one year.
`
`Symptomatic Gastroesophageal Reflux Disease (GERD)
`Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of
`717 patients comparing four weeks of treatment with NEXIUM 20 mg or 40 mg once daily versus
`placebo for resolution of GERD symptoms. Patients had ≥ 6-month history of heartburn episodes, no
`erosive esophagitis by endoscopy, and heartburn on at least four of the seven days immediately
`preceding randomization.
`
`The percentage of patients that were symptom-free of heartburn was significantly higher in the
`NEXIUM groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).
`
`No additional clinical benefit was seen with NEXIUM 40 mg over NEXIUM 20 mg.
`
`The percent of patients symptom-free of heartburn by day are shown in the figures below:
`
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`

`

`Percent of Patients Symptom-Free of Heartburn by Day
`(Study 225)
`
`N e x iu m 4 0 m g
`N e x iu m 2 0 m g
`P la c e b o
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`1 0 0
`
`7 5
`
`5 0
`
`2 5
`
`Percent of Patients Symptom-Free
`
`0
`
`0
`
`7
`
`1 4
`D ia ry D a y
`
`2 1
`
`2 8
`
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`Percent of Patients Symptom-Free of Heartburn by Day
`(Study 226)
`
`N e x iu m 4 0 m g
`N e x iu m 2 0 m g
`P la c e b o
`
`1 0 0
`
`7 5
`
`5 0
`
`2 5
`
`Percent of Patients Symptom-Free
`
`0
`
`0
`
`7
`
`1 4
`D ia ry D a y
`
`2 1
`
`2 8
`
`In three European symptomatic GERD trials, NEXIUM 20 mg and 40 mg and omeprazole 20 mg were
`evaluated. No significant treatment related differences were seen.
`
`Helicobacter pylori (H. pylori) Eradication in Patients with Duodenal Ulcer Disease
`Triple Therapy (NEXIUM/amoxicillin/clarithromycin): Two multicenter, randomized, double-blind
`studies were conducted using a 10 day treatment regimen. The first study (191) compared NEXIUM 40
`mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice
`daily to NEXIUM 40 mg once daily plus clarithromycin 500 mg twice daily. The second study (193)
`compared NEXIUM 40 mg once daily in combination with amoxicillin 1000 mg twice daily and
`clarithromycin 500 mg twice daily to NEXIUM 40 mg once daily. H. pylori eradication rates, defined
`as at least two negative tests and no positive tests from CLOtest, histology and/or culture, at 4 weeks
`post-therapy were significantly higher in the NEXIUM plus amoxicillin and clarithromycin group than
`in the NEXIUM plus clarithromycin or NEXIUM alone group. The results are shown in the following
`table:
`
`MYLAN PHARMS. INC. EXHIBIT 1043 PAGE 12
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`

`

`NDA 21-153
`NDA 21-154
`Page 16
`
`Study
`191
`
`193
`
`Treatment Group
`NEXIUM plus
`amoxicillin and
`clarithromycin
`NEXIUM plus
`clarithromycin
`
`NEXIUM plus
`amoxicillin and
`clarithromycin
`NEXIUM
`
`H. pylori Eradication Rates at 4 Weeks after 10 Day Treatment Regimen
`% of Patients Cured
`[95% Confidence Interval]
`(Number of patients)
`Per-Protocol†
`Intent-to-Treat ‡
`77%*
`84%*
`[71, 82]
`[78, 89]
`(n=233)
`(n=196)
`55%
`52%
`[48, 62]
`[45, 59]
`(n=187)
`(n=215)
`85%**
`78%**
`[74, 93]
`[67, 87]
`(n=67)
`(n=74)
`5%
`4%
`[0, 23]
`[0, 21]
`(n=22)
`(n=24)
`† Patients were included in the analysis if they had H. pylori infection documented at baseline, had at least one endoscopically verified
`duodenal ulcer ≥ 0.5 cm in diameter at baseline or had a documented history of duodenal ulcer disease within the past 5 years, and were
`not protocol violators. Patients who dropped out of the study due to an adverse event related to the study drug were included in the
`analysis as not H. pylori eradicated.
`‡ Patients were included in the analysis if they had documented H. pylori infection at baseline, had at least one documented duodenal
`ulcer at baseline, or had a documented history of duodenal ulcer disease, and took at least one dose of study medication. All dropouts
`were included as not H. pylori eradicated.
`*p < 0.05 compared to NEXIUM plus clarithromycin
`**p < 0.05 compared to NEXIUM alone
`
`The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment
`regimen in the NEXIUM plus amoxicillin and clarithromycin group was 75% (n=156) and 57% (n=60)
`respectively, in the 191 and 193 studies (per-protocol analysis).
`
`INDICATIONS AND USAGE
`Treatment of Gastroesophageal Reflux Disease (GERD)
`Healing of Erosive Esophagitis
`NEXIUM is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic
`resolution of diagnostically confirmed erosive esophagitis. For those patients who have not healed after
`4-8 weeks of treatment, an additional 4-8-week course of NEXIUM may be considered.
`
`Maintenance of Healing of Erosive Esophagitis
`NEXIUM is indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled
`studies do not extend beyond 6 months.
`
`Symptomatic Gastroesophageal Reflux Disease
`NEXIUM is indicated for treatment of heartburn and other symptoms associated with GERD.
`
`MYLAN PHARMS. INC. EXHIBIT 1043 PAGE 13
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`NDA 21-153
`NDA 21-154
`Page 17
`
`H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
`Triple Therapy (NEXIUM plus amoxicillin and clarithromycin): NEXIUM, in combination with
`amoxicillin and clarithromycin, is indicated for the treatment of patients with H. pylori infection and
`duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. Eradication of
`H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. (See CLINICAL STUDIES
`and DOSAGE AND ADMINISTRATION.)
`
`In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is
`demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be
`instituted. (See CLINICAL PHARMACOLOGY, Microbiology and the clarithromycin package
`insert, CLINICAL PHARMACOLOGY, Microbiology.)
`
`CONTRAINDICATIONS
`NEXIUM is contraindicated in patients with known hypersensitivity to any component of the
`formulation or to substituted benzimidazoles.
`
`Clarithromycin is contraindicated in patients with a known hypersensitivity to any macrolide antibiotic.
`
`Concomitant administration of clarithromycin with pimozide is contraindicated. There have been post-
`marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered
`with pimozide resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular
`fibrillation, and torsade de pointes) most likely due to inhibition of hepatic metabolism of pimozide by
`erythromycin and clarithromycin. Fatalities have been reported. (Please refer to full prescribing
`information for clarithromycin.)
`
`Amoxicillin is contraindicated in patients with a known hypersensitivity to any penicillin. (Please refer
`to full prescribing information for amoxicillin.)
`
`WARNINGS
`CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN
`CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS
`APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING CLARITHROMYCIN, THE
`PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. (See
`WARNINGS in prescribing information for clarithromycin.)
`
`Amoxicillin: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been
`reported in patients on penicillin therapy. These reactions are more apt to occur in individuals with a
`history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.
`
`There have been well documented reports of individuals with a history of penicillin hypersensitivity
`reactions who have experienced severe hypersensitivity reactions when treated with a cephalosporin.
`Before initiating therapy with any penicillin, careful inquiry should be made concerning previous
`hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an allergic reaction
`occurs, amoxicillin should be discontinued and the appropriate therapy instituted.
`
`MYLAN PHARMS. INC. EXHIBIT 1043 PAGE 14
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`

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`NDA 21-153
`NDA 21-154
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`
`SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT
`WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY
`MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS
`INDICATED.
`
`Pseudomembranous colitis has been reported with nearly all antibacterial agents, including
`clarithromycin and amoxicillin, and may range in severity from mild to life threatening.
`Therefore, it is important to consider this diagnosis in patients who present with diarrhea
`subsequent to the administration of antibacterial agents.
`
`Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of
`clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of
`“antibiotic-associated colitis”.
`
`After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be
`initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug
`alone. In moderate to severe cases, consideration should be given to management with fluids and
`electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective
`against Clostridium difficile colitis.
`
`PRECAUTIONS
`General
`Symptomatic response to therapy with NEXIUM does not preclude the presence of gastric malignancy.
`
`Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-
`term with omeprazole, of which NEXIUM is an enantiomer.
`
`Information for Patients
`Patients should be informed of the following:
`NEXIUM Delayed-Release Capsules should be taken at least one hour before meals.
`
`For patients who have difficulty swallowing capsules, one tablespoon of applesauce can be added to an
`empty bowl and the NEXIUM Delayed-Release Capsule can be opened, and the pellets inside the
`capsule carefully emptied onto the applesauce. The pellets should be mixed with the applesauce and
`then swallowed immediately. The applesauce used should not be hot and should be soft enough to be
`swallowed without chewing. The pellets should not be chewed or crushed. The pellet/applesauce
`mixture should not be stored for future use.
`
`Antacids may be used while taking NEXIUM.
`
`Drug Interactions
`Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
`
`In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9,
`2D6, 2E1 and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes
`
`MYLAN PHARMS. INC. EXHIBIT 1043 PAGE 15
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`

`NDA 21-153
`NDA 21-154
`Page 19
`
`would be expected. Drug interaction studies have shown that esomeprazole does not have any
`clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin or amoxicillin.
`
`Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme.
`Coadministration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45%
`decrease in clearance of diazepam. Increased plasma levels of diazepam were observed 12 hours after
`dosing and onwards. However, at that time, the plasma levels of diazepam were below the therapeutic
`interval, and thus this interaction is unlikely to be of clinical relevance.
`
`Esomeprazole inhibits gastric acid secretion. Therefore, esomeprazole may interfere with the
`absorption of drugs where gastric pH is an important determinant of bioavailability (eg, ketoconazole,
`iron salts and digoxin).
`
`Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the
`pharmacokinetic profile of esomeprazole.
`
`Combination Therapy with Clarithromycin
`Co-administration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the
`plasma levels of esomeprazole and 14-hydroxyclarithromycin. (See CLINICAL
`PHARMACOLOGY, Pharmacokinetics: Combination Therapy with Antimicrobials.)
`
`Concomitant administration of clarithromycin with pimozide is contraindicated. (See clarithromycin
`package insert.)
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`The carcinogenic potential of esomeprazole was assessed using omeprazole studies. In two 24-month oral
`carcinogenicity studies
`in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and
`140.8 mg/kg/day (about 0.7 to 57 times the human dose of 20 mg/day expressed on a body surface area
`basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the
`incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole.
` Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all
`treated groups of both