LANSOPOMP

The active ingredient in Lansoprazole Delayed-Release

Capsules, USP 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

C 16 H 14 F 3 N 3 O 2 S with a molecular weight of 369.37.

Lansoprazole has the following structure

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.

Capsules, USP are supplied in delayed-release capsules for oral administration.The delayed-release capsules are available in two dosage strengths: 15 mg and 30 mg of lansoprazole per capsule.

Each delayed-release capsule contains enteric-coated granules consisting of 15 mg or 30 mg of lansoprazole (active ingredient) and the following inactive ingredients: methacrylic acid copolymer dispersion, hypromellose, magnesium carbonate, mannitol, polyethylene glycol, polysorbate, sodium lauryl sulfate, sodium starch glycolate, sugar spheres, talc, titanium dioxide.

The capsule shell contains

FD&C blue #2, gelatin, titanium dioxide and yellow iron oxide.

Capsules are printed with edible black ink which contains black iron oxide, n-butyl alcohol, isopropyl alcohol, propylene glycol and shellac. formula-structure.jpg.

The treatment of duodenal ulcer and gastric ulcer is indicated in adults.

• Treatment of reflux-related oesophagitis.

• Prevention of reflux-induced oesophagitis.

• Eradication of Helicobacter pylori ( H. pylori) by concomitant administration of appropriate antibiotic therapy for the treatment of H. pylori-associated ulcers.

• Treatment of duodenal ulcer and benign gastric ulcer induced by NSAIDs in patients requiring continuous NSAID therapy.

• Prevention of duodenal ulcer and gastric ulcer induced by NSAIDs in patients at risk requiring continuous NSAID treatment.

• Gastroesophageal reflux symptomatic.

• Zollinger-Ellison syndrome.

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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. 12.2 Pharmacodynamics An tisecretory 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 6: Table 6.

Mean Antisecretory Effects After Single and Multiple Daily Lansoprazole Dosing Lansoprazole Parameter Baseline Value 15 mg 30 mg Day 1 Day 5 Day 1 Day 5 Mean 24 Hour pH 2.1 2.7 4.0 3.6 † 4.9 † Mean Nighttime pH 1.9 2.4 3.0 2.6 3.8 † % Time Gastric pH>3 18 33 59 51 † 72 † % Time Gastric pH>4 12 22 49 41 † 66 † NOTE: An intragastric pH of greater than 4 reflects a reduction in gastric acid by 99%. (p<0.05) versus baseline only. † (p<0.05) versus baseline and lansoprazole 15 mg. 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 lansoprazole given daily, twice daily and three times daily ( Table 7 ).

Table 7.

Mean Antisecretory Effects After Five Days of Twice Daily and Three Times Daily Dosing Lansoprazole Parameter 30 mg daily 15 mg twice daily 30 mg twice daily 30 mg three times daily % Time Gastric pH>5 43 47 59 77 † % Time Gastric pH>6 20 23 28 45 † (p<0.05) versus lansoprazole 30 mg daily. † (p<0.05) versus lansoprazole 30 mg daily, 15 mg twice daily and 30 mg twice daily.

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.

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.

In over 2100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but remained within normal range after treatment with 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.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels.

The increased

CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors.

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 (T 3 ), thyroxine (T 4 ), and somatotropic hormone (STH).

Lansoprazole in oral doses of to 60 mg for up to one year had no clinically significant effect on sexual function.

In addition, lansoprazole in oral doses of 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.

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. 12.3 Pharmacokinetics Absorption: Lansoprazole delayed-release capsules contain an enteric-coated granule formulation of lansoprazole (because lansoprazole is acid-labile), so that absorption of lansoprazole begins only after the granules leave the stomach.

The mean peak plasma levels of lansoprazole occur at 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 the administered dose.

Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.

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.

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.

Following single-dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine.

In one study, after a single oral dose of 14 C-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.

One year to 17 years of age The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged one year to 11 years and 12 years to 17 years in two separate clinical studies.

In children aged one year 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 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 years 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 year to 17 years were similar to those observed in healthy adult subjects.

Ger iatric Patients

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.

In a study comparing 12 male and six female human subjects who received lansoprazole, no sex-related differences were found in pharmacokinetics and intragastric pH results.

The pooled mean pharmacokinetic parameters of Lansoprazole from twelve U.S. studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20).

The mean AUCs of Lansoprazole in

Asian subjects were approximately twice those seen in pooled U.S. data; however, the interindividual variability was high.

C max values were comparable.

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).

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.

Therefore, the pharmacokinetics of lansoprazole were not.

The pharmacotherapeutic class

Inhibitors of the proton pump, the ATC code: A02BC03.

Lansoprazole is an inhibitor of the gastric proton pump.

It allows to inhibit the last stage of formation of gastric acid by inhibiting the activity of the proton pump H + /K + ATPase in the parietal cells of the stomach.

The inhibition is reversible and dose dependent.

Its effects are exercised both on the secretions of basal and stimulated gastric acid.

Lansoprazole concentrates in the parietal cells and becomes active in their acidic environment and reacts with the single sulfohydral group of the proton pump H + /K + ATPase causing a low-level of the symptoms of the enzyme to inhibit the activity of the enzyme.

Effect on the secretion of gastric acid: Lansoprazole is a specific inhibitor of the proton pump of the parietal cells.

A single dose of the lansoprazole is reduced by a low-level of the drugs that cause a low-level of the symptoms of the enzyme to inhibit the activity of the process.

The following are not possible: for all post-marketing adverse reactions, it is not possible to apply any frequency of adverse reactions, therefore, they are mentioned with an "undetermined" frequency.

Within each frequency group, the adverse reactions are presented in decreasing order of severity.

Common Very rare Very rare Blood and lymphatic disorders Thrombopenia, eosinophilia, leukopenia Anemia Agranulocyteosis, partial disorder, fenthemia, fenthemia, hallucination, nervous disorder Hyponatremia , Hypocalcaemia otensive anaemia *otensive disorder, hypertensive disorder, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision, shortness of vision.

Lansoprazole is not removed from the circulation by hemodialysis.

In one reported overdose, a patient consumed 600 mg of lansoprazole 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.

In the event of over-exposure, treatment should be symptomatic and supportive.

If over-exposure occurs, call your poison control center at 1-800-222-1222 for current information on the management of poisoning or over-exposure.

Lansoprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to any component of the formulation.

Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria.

Inhibitors (PPIs), including lansoprazole, are contraindicated with rilpivirine-containing products.

For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with lansoprazole, refer to the CONTRAINDICATIONS section of their prescribing information.

Contraindicated in patients with known hypersensitivity to any component of the lansoprazole delayed-release capsules formulation.

Patients receiving rilpivirine-containing products.

See full prescribing information for complete dosing information for lansoprazole delayed-release capsules by indication and and dosage adjustment in patients with severe hepatic impairment.

Administration Instructions Lansoprazole delayed-release capsules

Should be swallowed whole.

See full prescribing information for alternative administration options 2.1 Recommended Adult Dosage by Indication Indication Recommended Dose Frequency Duodenal Ulcers Short-Term Treatment 15 mg Once daily for 4 weeks Maintenance of Healed 15 mg Once daily Eradication of H. pylori to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: Lansoprazole 30 mg Twice daily for 10 or 14 days Amoxicillin 1 gram Twice daily for 10 or 14 days Clarithromycin 500 mg Twice daily for 10 or 14 days Dual Therapy: Lansoprazole 30 mg Three times daily for 14 days Amoxicillin 1 gram Three times daily for 14 days Benign Gastric Ulcer Short-Term Treatment 30 mg Once daily for up to 8 weeks NSAID-associated Gastric Ulcer Healing 30 mg Once daily for 8 weeks † Risk Reduction 15 mg Once daily for up to 12 weeks † Gastroesophageal Reflux Disease (GERD) Short-Term Treatment of Symptomatic GERD 15 mg Once daily for up to 8 weeks Short-Term Treatment of Erosive Esophagitis 30 mg Once daily for up to 8 weeks ‡ Maintenance of Healing of Erosive Esophagitis 15 mg Once daily # Pathological Hypersecretory Conditions including Zollinger-Ellison Syndrome 60 mg Once daily ¶ Please refer to the amoxicillin and clarithromycin full prescribing information CONTRAINDICATIONS and WARNINGS and PRECAUTIONS sections, and for information regarding dosing in elderly and renally-impaired patients. † Controlled studies did not extend beyond indicated duration. ‡ For patients who do not heal with lansoprazole 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 lansoprazole may be considered. ¶ Varies with individual patient.

Recommended adult starting dose is 60 mg once daily.

Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated.

Dosages up to 90 mg twice daily have been administered.

Daily dose of greater than 120 mg should be administered in divided doses.

Some patients with

Zollinger-Ellison syndrome have been treated continuously with lansoprazole for more than four years. # Controlled studies did not extend beyond 12 months 2.2 Recommended Pediatric Dosage by Indication Pediatric Patients to 11 Years of Age In clinical studies, Lansoprazole delayed-release capsules was not administered beyond 12 weeks in to 11 year olds.

It is not known if

Lansoprazole delayed-release capsules are safe and effective if used longer than the recommended duration.

Do not exceed the recommended dose and duration of use in pediatric patients as outlined below.

Indication Recommended Dose Frequency Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of Erosive Esophagitis ≤ 30 kg 15 mg Once daily for up to 12 weeks > 30 kg 30 mg Once daily for up to 12 weeks Pediatric Patients to 17 Years of Age Indication Recommended Dose Frequency Short-Term Treatment of Symptomatic GERD Non-erosive GERD 15 mg Once daily for up to 8 weeks Erosive Esophagitis 30 mg Once daily for up to 8 weeks 2.3 Hepatic Impairment The recommended dosage is 15 mg orally daily in patients with severe liver impairment (Child-Pugh C) 2.4 Important Administration Information Take Lansoprazole delayed-release capsules before meals.

Do not crush or chew Lansoprazole delayed-release capsules Take Lansoprazole delayed-release capsules at least 30 minutes prior to sucralfate.

Antacids may be used concomitantly with

Lansoprazole delayed-release capsules.

Missed doses

If a dose is missed, administer as soon as possible.

However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time.

Do not take two doses at one time to make up for a missed dose.

Swallow whole; do not chew.

For patients who have difficulty swallowing capsules, Lansoprazole delayed-release capsules can be opened and administered orally or via a nasogastric tube in the soft foods or liquids specified below.

Administration of

Lansoprazole delayed-release capsules in foods or liquids other than those discussed below have not been studied clinically and therefore are not recommended.

Foods (applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears): 1.Open capsule. 2.Sprinkle intact granules on one tablespoon of either applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears. 3.Swallow immediately.

Administration in

Liquids (apple juice, orange juice or tomato juice): 1.Open capsule. 2.Sprinkle intact granules into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately two ounces). 3.Mix briefly. 4.Swallow immediately. 5.To ensure complete delivery of the dose, rinse the glass with two or more volumes of juice and swallow the contents immediately.

Administration with Apple Juice Through a Nasogastric Tube (≥16 French) 1.Open capsule. 2.Sprinkle intact granules into 40 mL of apple juice. 3.Mix briefly 4.Using a catheter tipped syringe, draw up the mixture 5.Inject through the nasogastric tube into the stomach. 6.Flush with additional apple juice to clear the tube.

Capsules, USP, 15 mg, are hard gelatin capsules N o 3, opaque white body and green cap, with black printing “A262” over “15 mg” on the body and cap containing white or almost white spherical pellets.

The 30 mg capsules are hard gelatin capsules N o 1, opaque white body and light blue cap, with black printing “A263” over “30 mg” on the body and cap containing white or almost white spherical pellets.

They are available as follows: 15 mg: Bottle of 30.NDC# 70700-262-30 30 mg: Bottle of 30.NDC# 70700-263-30 Bottle of 90.NDC# 70700-263-90 Bottle of 500.NDC# 70700-263-05 Store at 20°C to 25°C (68°F to 77°F) .

Available data from published observational studies overall do not indicate an association of adverse pregnancy outcomes with lansoprazole treatment.

In animal reproduction studies, oral administration of lansoprazole to rats during organogenesis through lactation at 6.4 times the maximum recommended human dose produced reductions in the offspring in femur weight, femur length, crown-rump length and growth plate thickness (males only) on postnatal Day 21.

These effects were associated with reduction in body weight gain.

Advise pregnant women of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

If lansoprazole delayed release capsules are administered with clarithromycin, the pregnancy information for clarithromycin also applies to the combination regimen.

Refer to the prescribing information for clarithromycin for more information on use in pregnancy.

Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and lansoprazole use.

Methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy.

In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 62 pregnant women administered median daily doses of 30 mg of lansoprazole were compared to a control group of 868 pregnant women who did not take any PPIs.

There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=1.04, [95% Confidence Interval (CI) 0.25-4.21. In a population-based retrospective cohort study covering all live births in Denmark from to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to lansoprazole in 794 live births. A meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations Odds Ratio (OR)=1.12, [95% CI 0.86-1.45] and for spontaneous abortions OR=1.29, [95% CI 0.84-1.97]).

No adverse effects on embryo-fetal development occurred in studies 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) administered during organogenesis and pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human dose based on body surface area) administered during organogenesis.

A pre.

• and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with lansoprazole at oral doses of to 100 mg/kg/day (0.7 to 6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC [area under the plasma concentration-time curve]) administered during organogenesis through lactation.

Maternal effects observed at 100 mg/kg/day (6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC) included increased gestation period, decreased body weight gain during gestation, and decreased food consumption.

The number of stillbirths was increased at this dose, which may have been secondary to maternal toxicity.

Body weight of pups was reduced at 100 mg/kg/day starting on postnatal Day 11.

Femur weight, femur length, and crown-rump length were reduced at 100 mg/kg/day on postnatal Day 21.

Femur weight was still decreased in the 100 mg/kg/day group at age to 18 weeks.

Growth plate thickness was decreased in the 100 mg/kg/day males on postnatal Day 21, and was increased in the and 100 mg/kg/day males at age to 18 weeks.

The effects on bone parameters were associated with reduction in body weight gain.

The safety and effectiveness of

Lansoprazole delayed-release capsules has been established in pediatric patients one year to 17 years of age for short-term treatment of symptomatic GERD and erosive esophagitis.

In clinical studies of symptomatic

GERD and erosive esophagitis, Lansoprazole delayed-release capsules were not administered beyond 12 weeks in patients one year to 11 years of age.

It is not known if

Lansoprazole delayed-release capsules are safe and effective if used longer than the recommended duration.

Do not exceed the recommended dose and duration of use in pediatric patients.

Lansoprazole delayed-release capsules were not effective in pediatric patients with symptomatic GERD one month to less than one year of age in a multicenter, double-blind, placebo-controlled study.

Therefore, safety and effectiveness have not been established in patients less than one year of age.

Nonclinical studies in juvenile rats have demonstrated an adverse effect of heart valve thickening and bone changes at lansoprazole doses higher than the maximum recommended equivalent human dose.

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 month 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 year to 11 years of age In an uncontrolled, open-label, U.S. multicenter study, 66 pediatric patients (one year to 11 years of age) with GERD were assigned, based on body weight, to receive an initial dose of either lansoprazole 15 mg daily if ≤30 kg or lansoprazole 30 mg daily if greater than 30 kg administered for eight to 12 weeks.

The lansoprazole delayed-release capsules dose was increased (up to 30 mg twice daily) in 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 lansoprazole delayed-release capsules 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 ( Table 4 ).

Table 4.

GERD Symptom Improvement and Erosive Esophagitis Healing Rates in Pediatric Patients Age 1 Year to 11 Years of Age GERD Final Visit % (n/N) Symptomatic GERD Improvement in Overall GERD Symptoms † 76% (47/62 ‡ ) Erosive Esophagitis Improvement in Overall GERD Symptoms † 81% (22/27) Healing Rate 100% (27/27) At Week 8 or Week 12 † Symptoms assessed by patients diary kept by caregiver. ‡ No data were available for 4 pediatric patients.

In a study of 66 pediatric patients in the one year to 11 years old after treatment with lansoprazole 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 (25th to 75th percentile) of to 130 pg/mL] at the final visit.

The pediatric safety of lansoprazole delayed-release capsules has been assessed in 66 pediatric patients aged one year to 11 years of age.

Of the 66 patients with GERD 85% (56/66) took lansoprazole 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 year to 11 years of age (N=66) were constipation (5%) and headache (3%).

Twelve years to 17 years of age In an uncontrolled, open-label, U.S. multicenter study, 87 adolescent patients (12 years to 17 years of age) with symptomatic GERD were treated with lansoprazole for 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 lansoprazole 15 mg daily for eight weeks and the EE patients received lansoprazole 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 lansoprazole 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 lansoprazole treatment.

One patient remained unhealed after 12 weeks of treatment ( Table 5 ).

Table 5.

GERD Symptom Improvement and Erosive Esophagitis Healing Rates in Pediatric Patients Age 12 Years to 17 Years of Age GERD Final Visit % (n/N) Symptomatic GERD (All Patients) Improvement in Overall GERD Symptoms 73.2% (60/82) † Nonerosive GERD Improvement in Overall GERD Symptoms 71.2% (42/59) † Erosive Esophagitis Improvement in Overall GERD Symptoms 78.3% (18/23) Healing Rate ‡ 95.5% (21/22) ‡ Symptoms assessed by patient diary (parents/caregivers as necessary). † No data available for five patients. ‡ Data from one healed patient was excluded from this analysis due to timing of final endoscopy.

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 (25th to 75th percentile) of to 88 pg/mL] at the final visit. (Normal serum gastrin levels are to 111 pg/mL). The safety of lansoprazole delayed-release capsules has been assessed in these 87 adolescent patients.

Of the 87 adolescent patients with GERD, 6% (5/87) took lansoprazole for less than six weeks, 93% (81/87) for six 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).

Juvenile Animal Toxicity Data Heart Valve Thickening In two oral toxicity studies, thickening of the mitral heart valve occurred in juvenile rats treated with lansoprazole.

Heart valve thickening was observed primarily with oral dosing initiated on postnatal Day 7 (age equivalent to neonatal humans) and postnatal Day 14 (human age equivalent of approximately one year) at doses of 250 mg/kg/day and higher (at postnatal Day and postnatal Day 14, respectively 6.2 times and 4.2 times the daily pediatric dose of 15 mg in pediatric patients age one year to 11 years weighing 30 kg or less, based on AUC).

The treatment durations associated with heart valve thickening ranged from 5 days to 8 weeks.

The findings reversed or trended towards reversibility after a 4-week drug-free recovery period.

The incidence of heart valve thickening after initiation of dosing on postnatal Day 21 (human age equivalent of approximately two years) was limited to a single rat (1/24) in groups given 500 mg/kg/day for 4 or 8 weeks (approximately 5.2 times the daily pediatric dose of 15 mg in pediatric patients age one year to 11 years weighing 30 kg or less, based on AUC).

Based on exposure margins, the risk of heart valve injury does not appear to be relevant to patients one year of age and older.

In an eight-week oral toxicity study in juvenile rats with dosing initiated on postnatal Day 7, doses equal to or greater than 100 mg/kg/day (2.5 times the daily pediatric dose of 15 mg in children age one year to 11 years weighing 30 kg or less, based on AUC) produced delayed growth, with impairment of weight gain observed as early as postnatal Day 10 (age equivalent to neonatal humans).

At the end of treatment, the signs of impaired growth at 100 mg/kg/day and higher included reductions in body weight (14 to 44% compared to controls), absolute weight of multiple organs, femur weight, femur length, and crown-rump length.

Femoral growth plate thickness was reduced only in males and only at the 500 mg/kg/day dose.

The effects related to delayed growth persisted through the end of the four-week recovery period.

Longer term data were not collected.

Of the total number of patients (n=21,486) in clinical studies of Lansoprazole, 16% of patients were aged 65 years and over, while 4% were 75 years and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.