Takepron OD

Lansoprazole.

The active ingredient in TAKEPRON OD Tablets is lansoprazole, a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C₁₆H₁₄F₃N₃O₂S with a molecular weight of 369.37.
Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.
Lansoprazole is stable when exposed to light for up to two months. The rate of degradation of the compound in aqueous solution increases with decreasing pH. The degradation half-life of the drug substance in aqueous solution at 25°C is approximately 0.5 hour at pH 5.0 and approximately 18 hours at pH 7.0.
TAKEPRON is supplied in OD tablets for oral administration.
TAKEPRON OD Tablets are available in two dosage strengths: 15 mg and 30 mg of lansoprazole per tablet. Each OD tablet contains enteric-coated microgranules consisting of 15 mg or 30 mg of lansoprazole (active ingredient).
Excipients/Inactive Ingredients: mannitol, methacrylic acid, hydroxypropyl cellulose, lactose monohydrate-microcrystalline cellulose sphere, triethyl citrate, crospovidone, polyacrylate, magnesium carbonate, aspartame¹, glyceryl monostearate, hypromellose, magnesium stearate, citric acid, titanium dioxide, talc, artificial strawberry flavor, polyethylene glycol, polysorbate 80 and ferric oxide.
¹Phenylketonurics: Contains Phenylalanine 2.5 mg per 15 mg Tablet and 5.1 mg per 30 mg Tablet.

Pharmacology: Pharmacodynamics: Mechanism of Action: Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H⁺, K⁺)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus.
Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.
Pharmacodynamic effects: Antisecretory Activity: After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than three and greater than four. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.
The intragastric pH results of a five-day, pharmacodynamic, crossover study of 15 mg and 30 mg of once daily lansoprazole are presented in Table 1: (See Table 1.)

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After the initial dose in this study, increased gastric pH was seen within one to two hours with 30 mg of lansoprazole and two to three hours with 15 mg of lansoprazole. After multiple daily dosing, increased gastric pH was seen within the first hour post-dosing with 30 mg of lansoprazole and within one to two hours post-dosing with 15 mg of lansoprazole.
Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above five and six was evaluated in a crossover study of TAKEPRON given daily, twice daily and three times daily (see Table 2).

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The inhibition of gastric acid secretion as measured by intragastric pH gradually returned to normal over two to four days after multiple doses.There was no indication of rebound gastric acidity.
Enterochromaffin-like (ECL) Cell Effects: During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats. Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least one year did not show evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long- term therapy with lansoprazole (see Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility in the following text).
Other Gastric Effects in Humans: Lansoprazole did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in blood flow in the antrum, pylorus, and duodenal bulb was seen. Lansoprazole significantly slowed the gastric emptying of digestible solids. Lansoprazole increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in nitrosamine concentrations was observed.
Serum Gastrin Effects: In over 2100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but remained within normal range after treatment with 15 to 60 mg of oral lansoprazole. These elevations reached a plateau within two months of therapy and returned to pretreatment levels within four weeks after discontinuation of therapy.
Endocrine Effects: Human studies for up to one year have not detected any clinically significant effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). Lansoprazole in oral doses of 15 to 60 mg for up to one year had no clinically significant effect on sexual function. In addition, lansoprazole in oral doses of 15 to 60 mg for two to eight weeks had no clinically significant effect on thyroid function. In 24-month carcinogenicity studies in Sprague-Dawley rats with daily lansoprazole dosages up to 150 mg/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rats.
Other Effects: No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems have been found in humans. Among 56 patients who had extensive baseline eye evaluations, no visual toxicity was observed after lansoprazole treatment (up to 180 mg/day) for up to 58 months. After lifetime lansoprazole exposure in rats, focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy were seen.
Microbiology: Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the Indications section (see Indications).
Helicobacter pylori Pretreatment Resistance: Clarithromycin pretreatment resistance (≥2.0 mcg/mL) was 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).
Amoxicillin pretreatment susceptible isolates (≤0.25 mcg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of 957 patients (2.2%) by E-test, and two of 100 patients (2.0%) by agar dilution, had amoxicillin pretreatment MICs of greater than 0.25 mcg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 mcg/mL by E-test and the patient was eradicated of H. pylori (see Table 3).

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Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H.pylori. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or with regimens which include clarithromycin as the sole antimicrobial agent.
Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (≤0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg three times daily/amoxicillin 1 g three times daily dual therapy and a total of 12.8% (22/172) of the patients failed the 10- and 14-day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.
Susceptibility Test for Helicobacter pylori: For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.
Clinical Studies: Duodenal Ulcer: In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15, 30, and 60 mg of TAKEPRON 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 TAKEPRON than with placebo. There was no evidence of a greater or earlier response with the two higher doses compared with TAKEPRON 15 mg.
Based on this study and the second study described as follows, the recommended dose of TAKEPRON in duodenal ulcer is 15 mg per day (see Table 4).

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TAKEPRON 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 TAKEPRON 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 TAKEPRON than with placebo. There was no evidence of a greater or earlier response with the higher dose of TAKEPRON. Although the 15 mg dose of TAKEPRON 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 TAKEPRON and ranitidine leaves the comparative effectiveness of the two agents undetermined (see Table 5) (see Indications).

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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 TAKEPRON in combination with amoxicillin and clarithromycin as triple 14-day therapy or in combination with amoxicillin 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: TAKEPRON 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily; Dual therapy: TAKEPRON 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 TAKEPRON 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 (see Tables 6 and 7) (see Indications).

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Long-Term Maintenance Treatment of Duodenal Ulcers: TAKEPRON 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 TAKEPRON than in patients treated with placebo over a 12-month period (see Table 8) (see Indications).

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In trial #2, no significant difference was noted between TAKEPRON 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 TAKEPRON 15 mg and 30 mg once a day than with placebo (see Table 9) (see Short-Term Treatment of Active Benign Gastric Ulcer under Indications).

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Patients treated with any TAKEPRON 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 TAKEPRON 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 TAKEPRON 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 TAKEPRON 30 mg daily and the active control on symptom relief (i.e., abdominal pain) (see Table 10) (see Healing of NSAID-Associated Gastric Ulcer under Indications).

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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 inpatients 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 TAKEPRON 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 TAKEPRON demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcer than the 15 mg dose (see Table 11) (see Risk Reduction of NSAID-Associated Gastric Ulcer under Indications).

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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 12 and in Figures 1 and 2: (See Table 12 and Figures 1 and 2.)

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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 Gastroesophageal Reflux Disease under Indications).
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 13: (See Table 13.)

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In this study, all TAKEPRON 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.
TAKEPRON was also compared in a U.S. multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis. TAKEPRON at a dose of 30 mg was significantly more effective than ranitidine 150 mg twice daily as shown as follows (see Table 14).

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In addition, patients treated with TAKEPRON 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 TAKEPRON 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, TAKEPRON produced healing rates similar to those shown previously.
In a U.S. multicenter, double-blind, active-controlled study, 30 mg of TAKEPRON 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 H₂-receptor antagonist given at the dose indicated for symptom relief or greater, namely, cimetidine 800 mg/day, ranitidine 300 mg/day, famotidine 40 mg/day or nizatidine 300 mg/day.
TAKEPRON 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 H₂-receptor antagonists with TAKEPRON, as all patients had demonstrated unresponsiveness to the histamine H₂-receptor antagonist mode of treatment. It does indicate, however, that TAKEPRON may be useful in patients failing on a histamine H₂-receptor antagonist (see Table 15) (see Gastroesophageal Reflux Disease (GERD) under Indications).

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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 TAKEPRON than in patients treated with placebo over a 12-month period (see Table 16).

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Regardless of initial grade of erosive esophagitis, TAKEPRON 15 mg and 30 mg were similar in maintaining remission.
In a U.S., randomized, double-blind, study, TAKEPRON 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 TAKEPRON 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, TAKEPRON was significantly more effective than ranitidine in providing complete relief ofboth daytime and nighttime heartburn. Patients treated with TAKEPRON remained asymptomatic for a significantly longer period of time than patients treated with ranitidine (see Maintenance of Healing of Erosive Esophagitis under Indications).
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, TAKEPRON 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 & Administration). TAKEPRON 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 TAKEPRON. However, in some patients, serum gastrin increased to levels greater than those present prior to initiation of lansoprazole therapy (see Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (ZES) under Indications).
Pharmacokinetics: TAKEPRON OD Tablets contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. After a single-dose administration of 15 mg to 60 mg of oral lansoprazole, the peak plasma concentrations (C_max) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to theadministered dose. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.
Absorption: The absorption of lansoprazole is rapid, with the mean C_max occurring approximately 1.7 hours after oral dosing, and the absolute bioavailability is over 80%. In healthy subjects, the mean (±SD) plasma half-life was 1.5 (±1.0) hours. Both the C_max and AUC are diminished by about 50% to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.
Distribution: Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0 mcg/mL.
Metabolism: Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by blocking the proton pump [(H⁺, K⁺)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of lansoprazole is less than two hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.
Elimination: Following single-dose oral administration of TAKEPRON, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of ¹⁴C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.
Specific Populations: Pediatric Use: One to 17 years of age: The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged one to 11 years and 12 to 17 years in two separate clinical studies. In children aged one to 11 years, lansoprazole was dosed 15 mg daily for subjects weighing ≤30 kg and 30 mg daily for subjects weighing greater than 30 kg. Mean C_max and AUC values observed on Day 5 of dosing were similar between the two dose groups and were not affected by weight or age within each weight-adjusted dose group used in the study. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15 mg or 30 mg daily. Mean C_max and AUC values of lansoprazole were not affected by body weight or age; and nearly dose-proportional increases in mean C_max and AUC values were observed between the two dose groups in the study. Overall, lansoprazole pharmacokinetics in pediatric patients aged 1 to 17 years were similar to those observed in healthy adult subjects.
Neonate to less than one year of age: Refer to Use in Children under Precautions for the pharmacokinetics of lansoprazole in pediatric patients with GERD aged less than 28 days and one to 11 months.
Geriatric Use: The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly. No dosage adjustment is necessary in the elderly (see Precautions).
Renal Impairment: In patients with severe renal impairment, plasma protein binding decreased by 1.0% to 1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the C_max and T_max (time to reach the maximum concentration) were not different than the C_max and T_max from subjects with normal renal function. No dosage adjustment is necessary inpatients with renal impairment (see Renal impairment under Precautions).
Hepatic Impairment: In patients with various degrees of chronic hepatic impairment, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2 to 7.2 hours. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment (see Hepatic impairment under Precautions).
Gender: In a study comparing 12 male and six female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results (see Gender under Precautions).
Drug-Drug Interactions: TAKEPRON may interfere with the absorption of other drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, digoxin).
Lansoprazole is metabolized through the cytochrome P₄₅₀ system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that TAKEPRON does not have clinically significant interactions with other drugs metabolized by the cytochrome P₄₅₀ system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P₄₅₀ isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.
Atazanavir and Nelfinavir: Lansoprazole causes long-lasting inhibition of gastric acid secretion. Lansoprazole substantially decreases the systemic concentrations of HIV protease inhibitors, such as atazanavir and nelfinavir, which are dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir or nelfinavir and the development of HIV resistance. Therefore, TAKEPRON, or other proton pump inhibitors, should not be co-administered with atazanavir or nelfinavir.
Theophylline: When TAKEPRON was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be of clinical concern. Nonetheless, individual patients may require additional titration of their theophylline dosage when TAKEPRON is started or stopped to ensure clinically effective blood levels.
Warfarin: In a study of healthy subjects neither the pharmacokinetics of warfarin enantiomers nor prothrombin time were affected following single or multiple 60 mg doses of lansoprazole. However, there have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving proton pump inhibitors, including TAKEPRON, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
Methotrexate and 7-hydromethotrexate: In an open-label, single-arm, eight-day, pharmacokinetic study of 28 adult rheumatoid arthritis patients (who required the chronic use of 7.5 to 15 mg of methotrexate given weekly), administration of seven days of naproxen 500 mg twice daily and TAKEPRON 30 mg daily had no effect on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate. While this study was not designed to assess the safety of this combination of drugs, no major adverse reactions were noted. However, this study was conducted with low doses of methotrexate. A drug interaction study with high doses of methotrexate has not been conducted.
Amoxicillin: TAKEPRON has also been shown to have no clinically significant interaction with amoxicillin.
Sucralfate: In a single-dose crossover study examining TAKEPRON 30 mg and omeprazole 20 mg each administered alone and concomitantly with sucralfate 1 gram, absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17% and 16%, respectively, when administered concomitantly with sucralfate. Therefore, proton pump inhibitors should be taken at least 30 minutes prior to sucralfate. In clinical trials, antacids were administered concomitantly with TAKEPRON and there was no evidence of a change in the efficacy of TAKEPRON.
Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with TAKEPRON 30 mg (n=40),for nine days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (mean AUC ratio was 86%, with 90% CI of 80 to 92%) when TAKEPRON was coadministered compared to administration of clopidogrel alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated with oral lansoprazole doses of five to 150 mg/kg/day, about one to 40 times the exposure on a body surface (mg/m²) basis of a 50 kg person of average height [1.46 m² body surface area (BSA)] given the recommended human dose of 30 mg/day. Lansoprazole produced dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. It also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg/kg/day (four to 40 times the recommended human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.
In a 24-month carcinogenicity study, CD-1 mice were treated with oral lansoprazole doses of 15 to 600 mg/kg/day, two to 80 times there commended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg/kg/day (40 to 80 times the recommended human dose based on BSA) and female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg/kg/day (10 to 80 times the recommended human dose based on BSA).
A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.
Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxicin the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test, or the rat bone marrow cell chromosomal aberration test.
Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on BSA) was found to have no effect onfertility and reproductive performance of male and female rats.
Animal Toxicology and/or Pharmacology: Reproductive Toxicology Studies: Reproduction studies have been performed in pregnant rats at oral lansoprazole doses up to 150 mg/kg/day [40 times the recommended human dose (30 mg/day) based on body surface area (BSA)] and pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human dose based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.

Short-Term Treatment of Active Duodenal Ulcer: TAKEPRON is indicated for short-term treatment (for four weeks) for healing and symptom relief of active duodenal ulcer (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence: Triple Therapy: TAKEPRON/amoxicillin/clarithromycin: TAKEPRON in combination with amoxicillin plus clarithromycin as triple therapy is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one-year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Please refer to the full prescribing information for amoxicillin and clarithromycin.
Dual Therapy: TAKEPRON/amoxicillin: TAKEPRON in combination with amoxicillin as dual therapy is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one-year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected (see the clarithromycin prescribing information, Microbiology section). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Please refer to the full prescribing information for amoxicillin.
Maintenance of Healed Duodenal Ulcers: TAKEPRON is indicated to maintain healing of duodenal ulcers. Controlled studies do not extend beyond 12 months (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Short-Term Treatment of Active Benign Gastric Ulcer: TAKEPRON is indicated for short-term treatment (up to eight weeks) for healing and symptom relief of active benign gastric ulcer (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Healing of NSAID-Associated Gastric Ulcer: TAKEPRON is indicated for the treatment of NSAID-associated gastric ulcer in patients who continue NSAID use. Controlled studies did not extend beyond eight weeks (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Risk Reduction of NSAID-Associated Gastric Ulcer: TAKEPRON is indicated for reducing the risk of NSAID-associated gastric ulcers in patients with a history of a documented gastric ulcer who require the use of an NSAID. Controlled studies did not extend beyond 12 weeks (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Gastroesophageal Reflux Disease (GERD): Short-Term Treatment of Symptomatic GERD: TAKEPRON is indicated for the treatment of heartburn and other symptoms associated with GERD for up to eight weeks (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Short-Term Treatment of Erosive Esophagitis: TAKEPRON is indicated for short-term treatment (up to eight weeks) for healing and symptom relief of all grades of erosive esophagitis. For patients who do not heal with TAKEPRON for eight weeks (5 to 10%), it may be helpful to give an additional eight weeks of treatment. If there is a recurrence of erosive esophagitis an additional eight-week course of TAKEPRON may be considered (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Maintenance of Healing of Erosive Esophagitis (EE): TAKEPRON is indicated to maintain healing of erosive esophagitis. Controlled studies did not extend beyond 12 months (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (ZES): TAKEPRON is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).

TAKEPRON is available as a capsule and as an OD tablet. Both are available in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration for each of these dosage forms is presented as follows. TAKEPRON should be taken before eating.
TAKEPRON capsule and OD tablet should not be crushed or chewed. In the clinical trials, antacids were used concomitantly with. (See Table 17.)

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Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take two doses at one time to make up for a missed dose.
Special Populations: Renal impairment patients and geriatric patients do not require dosage adjustment. However, consider dose adjustment in patients with severe liver impairment (see Use in Children, Use in Elderly and Renal Impairment under Precautions).
Important Administration Information: Administration Options: TAKEPRON OD Tablets - Orally Disintegrating Tablets: TAKEPRON OD should not be broken or cut.
TAKEPRON OD should not be chewed.
Place the tablet on the tongue and allow it to disintegrate, with or without water, until the particles can be swallowed.
The tablet typically disintegrates in less than one minute.
Alternatively, for children or other patients who have difficulty swallowing tablets, TAKEPRON OD can be delivered in two different ways.
TAKEPRON OD Tablets - Oral Syringe: For administration via oral syringe, TAKEPRON OD can be administered as follows: Place a 15 mg tablet in oral syringe and draw up 4 mL of water, or place a 30 mg tablet in oral syringe and draw up 10 mL of water.
Shake gently to allow for a quick dispersal.
After the tablet has dispersed, administer the contents within 15 minutes.
Refill the syringe with approximately 2 mL (5 mL for the 30 mg tablet) of water, shake gently, and administer any remaining contents.
TAKEPRON OD Tablets - Nasogastric Tube (≥8 French) Administration: For administration via a nasogastric tube, TAKEPRON OD Tablets can be administered as follows: Place a 15 mg tablet in a syringe and draw up 4 mL of water, or place a 30 mg tablet in a syringe and draw up 10 mL of water.
Shake gently to allow for a quick dispersal.
After the tablet has dispersed, inject through the nasogastric tube into the stomach within 15 minutes.
Refill the syringe with approximately 5 mL of water, shake gently, and flush the nasogastric tube.

TAKEPRON is not removed from the circulation by hemodialysis. In one reported overdose, a patient consumed 600 mg of TAKEPRON with no adverse reaction. Oral lansoprazole doses up to 5000 mg/kg in rats [approximately 1300 times the 30 mg human dose based on body surface area (BSA)] and in mice (about 675.7 times the 30 mg human dose based on BSA) did not produce deaths or any clinical signs.

TAKEPRON is contraindicated in patients with known severe hypersensitivity to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria (see Adverse Reactions).
For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with TAKEPRON, refer to the Contraindications section of their prescribing information.

Presence of Gastric Malignancy: In adults, symptomatic response to therapy with TAKEPRON does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.
Acute Interstitial Nephritis: Acute interstitial nephritis has been observed in patients taking PPIs including TAKEPRON. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue TAKEPRON if acute interstitial nephritis develops (see Contraindications).
Clostridium difficile Associated Diarrhea: Published observational studies suggest that proton pump inhibitor (PPI) therapy like TAKEPRON may be associated with an increased risk of Clostridium difficile associated diarrhea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve (see Postmarketing Experience under Adverse Reactions).
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with TAKEPRON, refer to Warnings and Precautions sections of those prescribing information.
Bone Fracture: Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines (see Dosage & Administration and Postmarketing Experience under Adverse Reactions).
Cutaneous and Systemic Lupus Erythematosus: Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including lansoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.
The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.
Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.
Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving TAKEPRON, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in four to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.
Cyanocobalamin (Vitamin B-12) Deficiency: Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than three years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.
Hypomagnesemia: Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically (see Postmarketing Experience under Adverse Reactions).
Concomitant Use of TAKEPRON with Methotrexate: Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients (see Methotrexate under Interactions and Pharmacology: Pharmacokinetics under Actions).
Renal Impairment: No dosage adjustment of TAKEPRON is necessary in patients with renal impairment. The pharmacokinetics of lansoprazole in patients with various degrees of renal impairment were not substantially different compared to those in subjects with normal renal function (see Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: In patients with various degrees of chronic hepatic impairment, an increase in the mean AUC of up to 500% was observed at steady state compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Gender: Over 4,000 women were treated with TAKEPRON. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse reactions in females were similar to those seen in males (see Pharmacology: Pharmacokinetics under Actions).
Race: The pooled mean pharmacokinetic parameters of TAKEPRON from twelve U.S. Phase 1 studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of TAKEPRON in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The C_max values were comparable.
Use in Children: The safety and effectiveness of TAKEPRON have been established in pediatric patients one to 17 years of age for short-term treatment of symptomatic GERD and erosive esophagitis, however, lansoprazole was not effective in patients with symptomatic GERD one month to less than one year of age in a multicenter, double-blind, placebo controlled study.
Neonate to less than one year of age: The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged less than 28 days and one to 11 months. Compared to healthy adults receiving 30 mg, neonates had higher exposure (mean weight-based normalized AUC values 2.04- and 1.88-fold higher at doses of 0.5 mg/kg/day and 1 mg/kg/day, respectively). Infants aged ≤10 weeks had clearance and exposure values that were similar to neonates. Infants aged greater than 10 weeks who received 1 mg/kg/day had mean AUC values that were similar to adults who received a 30 mg dose.
Lansoprazole was not found to be effective in a U.S. and Polish four week multicenter, double-blind, placebo-controlled, parallel-group study of 162 patients between one month and less than 12 months of age with symptomatic GERD based on a medical history of crying/fussing/irritability associated with feedings who had not responded to conservative GERD management (i.e., non-pharmacologic intervention) for seven to 14 days. Patients received lansoprazole as a suspension daily (0.2 to 0.3 mg/kg/day in infants ≤10 weeks of age or 1.0 to 1.5 mg/kg/day in infants greater than 10 weeks or placebo) for up to four weeks of double-blind treatment.
The primary efficacy endpoint was assessed by greater than 50% reduction from baseline in either the percent of feedings with a crying/fussing/irritability episode or the duration (minutes) of a crying/fussing/irritability episode within one hour after feeding.
There was no difference in the percentage of responders between the lansoprazole pediatric suspension group and placebo group (54% in both groups).
There were no adverse events reported in pediatric clinical studies (one month to less than 12 months of age) that were not previously observed in adults.
Based on the results of the Phase 3 efficacy study, lansoprazole was not shown to be effective. Therefore, these results do not support the use of lansoprazole in treating symptomatic GERD in infants.
One to 11 years of age: In an uncontrolled, open-label, U.S. multicenter study, 66 pediatric patients (one to 11 years of age) with GERD were assigned, based on body weight, to receive an initial dose of either TAKEPRON 15 mg daily if ≤30 kg or TAKEPRON 30 mg daily if greater than 30 kg administered for eight to 12 weeks. The TAKEPRON dose was increased (up to 30 mg twice daily) in 24 of 66 pediatric patients after two or more weeks of treatment if they remained symptomatic. At baseline 85% of patients had mild to moderate overall GERD symptoms (assessed by investigator interview), 58% had non-erosive GERD and 42% had erosive esophagitis (assessed by endoscopy).
After eight to 12 weeks of TAKEPRON treatment, the intent-to-treat analysis demonstrated an approximate 50% reduction in frequency and severity of GERD symptoms.
Twenty-one of 27 erosive esophagitis patients were healed at eight weeks and 100% of patients were healed at 12 weeks by endoscopy (see Table 18.)

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In a study of 66 pediatric patients in the age group one year to 11 years old after treatment with TAKEPRON given orally in doses of 15 mg daily to 30 mg twice daily, increases in serum gastrin levels were similar to those observed in adult studies. Median fasting serum gastrin levels increased 89% from 51 pg/mL at baseline to 97 pg/mL [interquartile range (25^th to 75^th percentile) of 71 to 130 pg/mL] at the final visit.
The pediatric safety of TAKEPRON Capsules has been assessed in 66 pediatric patients aged one to 11 years of age. Of the 66 patients with GERD 85% (56/66) took TAKEPRON for 8 weeks and 15% (10/66) took it for 12 weeks.
The most frequently reported (two or more patients) treatment-related adverse reactions in patients one to 11 years of age (N=66) were constipation (5%) and headache (3%).
Twelve to 17 years of age: In an uncontrolled, open-label, U.S. multicenter study, 87 adolescent patients (12 to 17 years of age) with symptomatic GERD were treated with TAKEPRON for 8 to 12 weeks. Baseline upper endoscopies classified these patients into two groups: 64 (74%) nonerosive GERD and 23 (26%) erosive esophagitis (EE). The nonerosive GERD patients received TAKEPRON 15 mg daily for eight weeks and the EE patients received TAKEPRON 30 mg daily for eight to 12 weeks. At baseline, 89% of these patients had mild to moderate overall GERD symptoms (assessed by investigator interviews). During 8 weeks of TAKEPRON treatment, adolescent patients experienced a 63% reduction in frequency and a 69% reduction in severity of GERD symptoms based on diary results.
Twenty-one of 22 (95.5%) adolescent erosive esophagitis patients were healed after eight weeks of TAKEPRON treatment. One patient remained unhealed after 12 weeks of treatment (see Table 19).

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In these 87 adolescent patients, increases in serum gastrin levels were similar to those observed in adult studies, median fasting serum gastrin levels increased 42% from 45 pg/mL at baseline to 64 pg/mL [interquartile range (25^th to 75^th percentile) of 44 to 88 pg/mL] at the final visit. (Normal serum gastrin levels are 25 to 111 pg/mL.)
The safety of TAKEPRON Capsules has been assessed in these 87 adolescent patients. Of the 87 adolescent patients with GERD, 6% (5/87) took TAKEPRON for less than six weeks, 93% (81/87) for 6 to 10 weeks, and 1% (1/87) for greater than 10 weeks.
The most frequently reported (at least 3%) treatment-related adverse reactions in these patients were headache (7%), abdominal pain (5%), nausea (3%) and dizziness (3%). Treatment-related dizziness, reported in this prescribing information as occurring in less than 1% of adult patients, was reported in this study by three adolescent patients with nonerosive GERD, who had dizziness concurrently with other reactions (such as migraine, dyspnea, and vomiting).
Use in Elderly: No dosage adjustment of TAKEPRON is necessary in geriatric patients. The incidence rates of adverse reactions and laboratory test abnormalities are similar to those seen in younger patients (see Pharmacology: Pharmacokinetics under Actions).

Pregnancy: Teratogenic effects: Pregnancy Category B. Reproduction studies have been performed in pregnant rats at oral doses up to 40 times the recommended human dose and in pregnant rabbits at oral doses up to 16 times the recommended human dose and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed (see Pharmacology: Nonclinical Toxicology: Animal Toxicology and/or Pharmacology under Actions).
See full prescribing information for clarithromycin before using in pregnant women.
Nursing Mothers: Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions in nursing infants from lansoprazole, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue lansoprazole, taking into account the importance of lansoprazole to the mother.

The following serious adverse reactions are described as follows and in Precautions: Acute Interstitial Nephritis (see Acute Interstitial Nephritis under Precautions); Clostridium difficile Associated Diarrhea (Clostridium difficile& Associated Diarrhea under Precautions); Bone Fracture (see Bone Fractures under Precautions); Cutaneous and Systemic Lupus Erythematosus (see Cutaneous and Systemic Lupus Erythematosus under Precautions); Cyanocobalamin (Vitamin B-12) Deficiency (see Cyanocobalamin (Vitamin B-12) Deficiency under Precautions); Hypomagnesemia (see Hypomagnesemia under Precautions).
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Worldwide, over 10,000 patients have been treated with TAKEPRON in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, TAKEPRON treatment has been well-tolerated in both short-term and long-term trials.
The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of TAKEPRON-treated patients and occurred at a greater rate in TAKEPRON-treated patients than placebo-treated patients in Table 20. (See Table 20.)

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Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 15 mg and 30 mg of TAKEPRON, but higher in the patients who received 60 mg of TAKEPRON (2.9%, 1.4%, 4.2%, and 7.4%, respectively).
The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.
In the risk reduction study of TAKEPRON for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with TAKEPRON, misoprostol, and placebo was 5%, 22%, and 3%, respectively.
Another study for the same indication, where patients took either a COX-2 inhibitor or lansoprazole and naproxen, demonstrated that the safety profile was similar to the prior study. Additional reactions from this study not previously observed in other clinical trials with TAKEPRON included contusion, duodenitis, epigastric discomfort, esophageal disorder, fatigue, hunger, hiatal hernia, hoarseness, impaired gastric emptying, metaplasia, and renal impairment.
Additional adverse experiences occurring in less than 1% of patients or subjects who received TAKEPRON in domestic trials are shown as follows: Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills,edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain.
Cardiovascular System: angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/hypotension, migraine,myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation.
Digestive System: abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, gastrointestinal moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis.
Endocrine System: diabetes mellitus, goiter, hypothyroidism.
Hemic and Lymphatic System: anemia, hemolysis, lymphadenopathy.
Metabolism and Nutritional Disorders: avitaminosis, gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss.
Musculoskeletal System: arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, ptosis, synovitis.
Nervous System: abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, dementia, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo.
Respiratory System: asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, lung fibrosis, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor.
Skin and Appendages: acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria.
Special Senses: abnormal vision, amblyopia, blepharitis, blurred vision, cataract, conjunctivitis, deafness, dry eyes, ear/eye disorder, eye pain, glaucoma, otitis media, parosmia, photophobia, retinal degeneration/disorder, taste loss, taste perversion, tinnitus, visual field defect.
Urogenital System: abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary retention, urinary tract infection, urinary urgency, urination impaired, vaginitis.
Postmarketing Experience: Additional adverse experiences have been reported since TAKEPRON has been marketed. The majority of these cases are foreign-sourced and a relationship to TAKEPRON has not been established. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events are listed as follows by COSTART body system.
Body as a Whole: anaphylactic/anaphylactoid reactions, systemic lupus erythematosus.
Digestive System: hepatotoxicity, pancreatitis, vomiting.
Hemic and Lymphatic System: agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura.
Infections and Infestations: Clostridium difficile associated diarrhea.
Metabolism and Nutritional Disorders: hypomagnesemia.
Musculoskeletal System: bone fracture, myositis.
Skin and Appendages: severe dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus.
Special Senses: speech disorder.
Urogenital System: interstitial nephritis, urinary retention.
Combination Therapy with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with TAKEPRON plus amoxicillin and clarithromycin, and TAKEPRON plus amoxicillin, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with TAKEPRON, amoxicillin, or clarithromycin.
Triple Therapy: TAKEPRON/amoxicillin/clarithromycin: The most frequently reported adverse reactions for patients who received triple therapy for 14 days were diarrhea (7%), headache (6%), and taste perversion (5%). There were no statistically significant differences in the frequency of reported adverse reactions between the 10- and 14-day triple therapy regimens. No treatment-emergent adverse reactions were observed at significantly higher rates with triple therapy than withany dual therapy regimen.
Dual Therapy: TAKEPRON/amoxicillin: The most frequently reported adverse reactions for patients who received TAKEPRON three times daily plus amoxicillin three times daily dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse reactions were observed at significantly higher rates with TAKEPRON three times daily plus amoxicillin three times daily dual therapy than with TAKEPRON alone.
For information about adverse reactions with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with TAKEPRON, refer to the Adverse Reactions section of their prescribing information.
Laboratory Values: The following changes in laboratory parameters in patients who received TAKEPRON were reported as adverse reactions: Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.
In the placebo controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and TAKEPRON, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received TAKEPRON reported jaundice at any time during the study.
In clinical trials using combination therapy with TAKEPRON plus amoxicillin and clarithromycin, and TAKEPRON plus amoxicillin, no increased laboratory abnormalities particular to these drug combinations were observed.
For information about laboratory value changes with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with TAKEPRON, refer to the Adverse Reactions section of their prescribing information.

Drugs with pH-Dependent Absorption: Due to its effects on gastric acid secretion, lansoprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. As with other drugs that decrease the intragastric acidity, the absorption of drugs such as ampicillin esters, ketoconazole, atazanavir, nelfinavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with TAKEPRON (see Pharmacology: Pharmacokinetics under Actions).
TAKEPRON is likely to substantially decrease the systemic concentrations of HIV protease inhibitors such as atazanavir and nelfinavir, which are dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir or nelfinavir and the development of HIV resistance. Therefore, TAKEPRON should not be co-administered with atazanavir or nelfinavir (see Pharmacology: Pharmacokinetics under Actions).
Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use TAKEPRON with caution in transplant patients receiving MMF.
Warfarin: In a study of healthy subjects, co-administration of single or multiple 60 mg doses of TAKEPRON and warfarin did not affect the pharmacokinetics of warfarin nor prothrombin time (see Pharmacology: Pharmacokinetics under Actions). However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time (see Pharmacology: Pharmacokinetics under Actions).
Tacrolimus: Concomitant administration of lansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Theophylline: A minor increase (10%) in the clearance of theophylline was observed following the administration of TAKEPRON concomitantly with theophylline. Although the magnitude of the effect on theophylline clearance is small, individual patients may require additional titration of their theophylline dosage when TAKEPRON is started or stopped to ensure clinically effective blood levels (see Pharmacology: Pharmacokinetics under Actions).
Clopidogrel: Concomitant administration of lansoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition (see Pharmacology: Pharmacokinetics under Actions). No dose adjustment of clopidogrel is necessary when administered with an approved dose of TAKEPRON.
Methotrexate: Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of high dose methotrexate with PPIs have been conducted (see Concomitant Use of TAKEPRON with Methotrexate under Precautions)
In a study of rheumatoid arthritis patients receiving low-dose methotrexate, TAKEPRON and naproxen, no effect on pharmacokinetics of methotrexate was observed (see Pharmacology: Pharmacokinetics under Actions).
Combination Therapy with Clarithromycin: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for coadministration with certain drugs [see Contraindications in prescribing information for clarithromycin].
For information about drug interactions of antibacterial agents (amoxicillin and clarithromycin) indicated in combination with TAKEPRON, refer to the Interactions section of their prescribing information.

Advise the patient to read the FDA approved patient labeling (Medication Guide and Instructions for Use).
Adverse Reactions: Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with: Hypersensitivity Reactions (see Contraindications); Acute Interstitial Nephritis (see Acute Interstitial Nephritis under Precautions); Clostridium difficile Associated Diarrhea (Clostridium difficile Associated Diarrhea under Precautions); Bone Fracture (see Bone Fractures under Precautions); Cutaneous and Systemic Lupus Erythematosus (see Cutaneous and Systemic Lupus Erythematosus under Precautions); Cyanocobalamin (Vitamin B-12) Deficiency (see Cyanocobalamin (Vitamin B-12) Deficiency under Precautions); Hypomagnesemia (see Hypomagnesemia under Precautions).
Administration: TAKEPRON is available as an orally disintegrating tablet. Both are available in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration for each of these dosage forms is presented as follows (see Important Administration Information under Dosage & Administration).
TAKEPRON should be taken before eating.
TAKEPRON OD Tab should not be crushed or chewed.
Phenylketonurics: Contains Phenylalanine 2.5 mg per 15 mg Tablet and 5.1 mg per 30 mg Tablet.
Administration Options: TAKEPRON OD Tablets - Orally Disintegrating Tablets: TAKEPRON OD Tablets should not be broken or cut.
TAKEPRON OD Tablets should not be chewed.
Place the tablet on the tongue and allow it to disintegrate, with or without water, until the particles can be swallowed.
The tablet typically disintegrates in less than one minute.
Alternatively, for children or other patients who have difficulty swallowing tablets, TAKEPRON OD Tablets can be delivered in two different ways.
TAKEPRON OD Tablets - Oral Syringe: For administration via oral syringe, TAKEPRON OD Tablets can be administered as follows: Place a 15 mg tablet in oral syringe and draw up 4 mL of water, or place a 30 mg tablet in oral syringe and draw up 10 mL of water.
Shake gently to allow for a quick dispersal.
After the tablet has dispersed, administer the contents within 15 minutes.
Refill the syringe with approximately 2 mL (5 mL for the 30 mg tablet) of water, shake gently, and administer any remaining contents.
TAKEPRON OD Tablets - Nasogastric Tube (≥8 French) Administration: For administration via a nasogastric tube, TAKEPRON OD Tablets can be administered as follows: Place a 15 mg tablet in a syringe and draw up 4 mL of water, or place a 30 mg tablet in a syringe and draw up 10 mL of water.
Shake gently to allow for a quick dispersal.
After the tablet has dispersed, inject through the nasogastric tube into the stomach within 15 minutes.
Refill the syringe with approximately 5 mL of water, shake gently, and flush the nasogastric tube.

Antacids, Antireflux Agents & Antiulcerants

A02BC03 - lansoprazole ; Belongs to the class of proton pump inhibitors. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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