 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Lansoprazole
The active ingredient in lansoprazole delayed-release capsules is a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluroethoxy)-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 compound degrades in aqueous solution, the rate of degradation increasing with decreasing pH. At 25°C the t½ is approximately 0.5 hour at pH 5.0 and approximately 18 hours at pH 7.0. Prevacid is supplied in delayed-release capsules for oral administration. The delayed-release capsules contain the active ingredient, lansoprazole, in the form of enteric-coated granules and 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 lansoprazole, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium carbonate, methacrylic acid copolymer, starch, talc, sugar sphere, sucrose, polyethylene glycol, polysorbate 80, and titanium dioxide. Components of the gelatin capsule include gelatin, titanium dioxide, D&C red no. 28, FD&C blue no. 1, FD&C green no. 3 (Prevacid 15 mg capsules only), and FD&C red no. 40.
Pharmacokinetics and Metabolism Lansoprazole delayed-release capsules 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. Peak plasma concentrations of lansoprazole (Cmax) and the area under plasma concentration curve (AUC) of lansoprazole are approximately proportional in doses from 15 mg to 60 mg after single-oral administration. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing. Absorption: The absorption of lansoprazole is rapid, with mean Cmax occurring approximately 1.7 hours after oral dosing, and relatively complete with absolute bioavailability over 80%. In healthy subjects, the mean (± SD) plasma half-life was 1.5 (± 1.0) hours. Both Cmax and AUC are diminished by about 50% if the drug is given 30 minutes after food as opposed to the fasting condition. There is no significant food effect if the drug is given before meals. Distribution: Lansoprazole is 97% bound 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 (H+,K+)-ATPase within the parietal cell canaliculus, but are not present in the systemic circulation. The plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion. Thus, the plasma elimination half-life is less than two hours, while the acid inhibitory effect lasts more than 24 hours. Elimination: 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 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 metabolites of lansoprazole. Special Populations Geriatric: The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly. Pediatric: The pharmacokinetics of lansoprazole has not been investigated in patients <18 years of age. Gender: In a study comparing 12 male and six female human subjects, no gender differences were found in pharmacokinetics and intragastric pH results (also see PRECAUTIONS, Use in Women). Renal Insufficiency: In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-1.5% after administration of 60 mg of lansoprazole. Patients with renal insufficiency had a shortened elimination half-life and decreased total AUC (free and bound). AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment, and Cmax and Tmax were not different from subjects with healthy kidneys. Hepatic Insufficiency: In patients with various degrees of chronic hepatic disease, the mean plasma half-life of the drug was prolonged from 1.5 hours to 3.2-7.2 hours. An increase in mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Dose reduction in patients with severe hepatic disease should be considered. Race: The pooled mean pharmacokinetic parameters of lansoprazole 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 lansoprazole in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable. Pharmacodynamics Mechanism of Action Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but 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. 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 >3 and >4. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin. In a crossover study comparing lansoprazole 15 and 30 mg with omeprazole 20 mg for five days, the effects on intragastric pH are shown inTABLE 1.
After the initial dose in this study, increased gastric pH was seen within 1-2 hours with lansoprazole 30 mg, 2-3 hours with lansoprazole 15 mg, and 3-4 hours with omeprazole 20 mg. After multiple daily dosing, increased gastric pH was seen within the first hour postdosing with lansoprazole 30 mg and within 1-2 hours postdosing with lansoprazole 15 mg and omeprazole 20 mg. Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of lansoprazole given qd, bid and tid.
The inhibition of gastric acid secretion as measured by intragastric pH returns gradually to normal over two to four days after multiple doses. There is no indication of rebound gastric acidity. Enterochromaffin-Like (ECL) Cell Effects During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats (see PRECAUTIONS, Carcinogenesis, Mutagenesis, and Impairment of Fertility) . Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least one year have not shown evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with lansoprazole. Other Gastric Effects in Humans Lansoprazole did not significantly affect mucosal blood wflow 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 nitrate 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 lansoprazole given orally in doses of 15 mg to 60 mg. 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 in 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 on Sprague-Dawley rats with daily dosages up to 150 mg/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rates. Other Effects No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular or respiratory systems have been found in humans. No visual toxicity was observed among 56 patients who had extensive baseline eye evaluations, were treated with up to 180 mg/day of lansoprazole and were observed for up to 58 months. Other rat-specific findings after lifetime exposure included focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus, and spontaneous retinal atrophy. 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 INDICATIONS AND USAGE. Helicobacter pylori Pretreatment Resistance: Clarithromycin pretreatment resistance (³ 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 2 of 100 patients (2.0%) by agar dilution had amoxicillin pretreatment MICs of > 0.25 mcg/ml. One patient on the 14 day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 mcg/ml by E-test and the patient was eradicated of H. pylori.. See TABLE 3
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 > 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 tid/amoxicillin 1 gm tid dual therapy and a total of 12.8% (22/172) of the patients failed the 10-and-14 day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates. Susceptibility Test for Helicobacter pylori The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.1 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 ´ 107 - 1 ´ 108 CFU/ml for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (³2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for campylobacters. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the criteria shown in TABLE 4.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the MIC values shown in TABLE 5.
CLINICAL STUDIESDuodenal Ulcer In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15, 30, and 60 mg of lansoprazole 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 lansoprazole than with placebo. There was no evidence of a greater or earlier response with the two higher doses compared with lansoprazole 15 mg. Based on this study and the second study described below, the recommended dose of lansoprazole in duodenal ulcer is 15 mg per day. (See TABLE 6)
Lansoprazole 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 lansoprazole 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 lansoprazole than with placebo. There was no evidence of a greater or earlier response with the higher dose of lansoprazole. Although the 15 mg dose of lansoprazole was superior to ranitidine at 4 weeks, the lack of significant difference at 2 weeks and the absence of a difference between 30 mg of lansoprazole and ranitidine leaves the comparative effectiveness of the two agents undetermined. (See TABLE 7)
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 lansoprazole in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy or in combination with amoxicillin capsules as dual 14-day therapy for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of two different eradication regimens were established: Triple Therapy: Lansoprazole 30 mg bid/amoxicillin 1 gm bid/clarithromycin 500 mg bid. Dual Therapy: Lansoprazole 30 mg tid/amoxicillin 1 gm tid. All treatments were for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at 4-6 weeks following the end of treatment. Triple therapy was shown to be more effective than all possible dual therapy combinations (see TABLE 8). Dual therapy was shown to be more effective than both monotherapies (see TABLE 9) . 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 lansoprazole 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. Long-Term Maintenance Treatment of Duodenal Ulcers Lansoprazole 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 lansoprazole than in patients treated with placebo over a 12-month period. See TABLE 10.
In trial #2, no significant difference was noted between lansoprazole 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 lansoprazole 15 mg and 30 mg once a day than with placebo. See TABLE 11.
Patients treated with any lansoprazole 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 lansoprazole 30 mg was provided by a meta-analysis of published and unpublished data. Gastroesophageal Reflux Disease (GERD) Symptomatic GERD: In a U.S. multicenter, double-blind, placebo-controlled study of 214 patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, significantly greater relief of heartburn associated with GERD was observed with the administration of lansoprazole 15 mg once daily up to 8 weeks than with placebo. No significant additional benefit from lansoprazole 30 mg once daily was observed. The intent-to-treat analyses demonstrated significant reduction in frequency and severity of day and night heartburn. Data for frequency and severity for the 8-week treatment period are found in TABLE 12.
Erosive Esophagitis In a U.S. multicenter, double-blind, placebo-controlled study of 269 patients entering with an endoscopic diagnosis of esophagitis with mucosal grading of 2 or more and grades 3 and 4 signifying erosive disease, the percentages of patients with healing are in TABLE 13.
In this study, all lansoprazole 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 suggest 30 mg qd as the recommended dose. Lansoprazole was also compared in a U.S. multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis. Lansoprazole at a dose of 30 mg was significantly more effective than ranitidine 150 mg b.i.d. as shown in TABLE 14.
In addition, patients treated with lansoprazole reported less day and nighttime heartburn and took less antacid tablets for fewer days than patients taking ranitidine 150 mg bid. Although this study demonstrates effectiveness of lansoprazole in healing erosive esophagitis, it does not represent an adequate comparison with ranitidine because the recommended ranitidine dose for esophagitis is 150 mg q.i.d., twice the dose used in this study. In the two trials described and in several smaller studies involving patients with moderate to severe erosive esophagitis, lansoprazole produced healing rates similar to those shown above. In a U.S. multicenter, double-blind, active-controlled study, 30 mg of lansoprazole was compared with ranitidine 150 mg bid 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. Lansoprazole 30 mg was more effective than ranitidine 150 mg bid 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 lansoprazole, as all patients had demonstrated unresponsiveness to the histamine H2-receptor antagonist mode of treatment. It does indicate, however, that lansoprazole may be useful in patients failing on a histamine H2-receptor antagonist (TABLE 15).
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 lansoprazole than in patients treated with placebo over a 12-month period. See TABLE 16.
Regardless of initial grade of erosive esophagitis, lansoprazole 15 mg and 30 mg were similar in maintaining remission. Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome In open studies of 57 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, lansoprazole 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 m/Eq/hr in patients with prior gastric surgery. Initial dose were titrated to the individual patient need, and adjustments were necessary with time in some patients (see DOSAGE AND ADMINISTRATION). Lansoprazole was well tolerated at these high dose levels for prolonged periods (greater than four years in some patients). In most ZE patients, serum gastrin levels were not modified by lansoprazole. However, in some patients serum gastrin increased to levels greater than those present prior to initiation of lansoprazole therapy.
Short-term Treatment of Active Duodenal Ulcer Lansoprazole is indicated for short-term treatment (up to 4 weeks) for healing and symptom relief active duodenal ulcer. H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy (Lansoprazole/Amoxicillin/Clarithromycin):
Lansoprazole delayed-release capsules, in combination with amoxicillin
plus clarithromycin as triple
therapy, are 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 CLINICAL
STUDIES and Dual Therapy (Lansoprazole/Amoxicillin): Lansoprazole delayed-release capsules, in combination with amoxicillin as dual therapy, are 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 Clarithromycin, Microbiology). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. (See CLINICAL STUDIES and DOSAGE AND ADMINISTRATION). Maintenance of Healed Duodenal Ulcers Lansoprazole delayed-release capsules are indicated to maintain healing of duodenal ulcers. Controlled studies do not extend beyond 12 months. Short-Term Treatment of Active Benign Gastric Ulcer Lansoprazole delayed-release capsules are indicated for short-term treatment (up to 8 weeks) for healing and symptom relief of active benign gastric ulcer. Gastroesophageal Reflux Disease (GERD) Short-term Treatment of Symptomatic GERD: Lansoprazole delayed-release capsules are indicated for the treatment of heartburn and other symptoms associated with GERD. Short-term Treatment of Erosive Esophagitis: Lansoprazole are indicated for short-term treatment (up to 8 weeks) for healing and symptom relief of all grades of erosive esophagitis. For patients who do not heal with lansoprazole for 8 weeks (5-10%) it may be helpful to give an additional 8 weeks of treatment. If there is a recurrence of erosive esophagitis an additional 8 week course of lansoprazole may be considered. Maintenance of Healing of Erosive Esophagitis Lansoprazole delayed-release capsules are indicated to maintain healing of erosive esophagitis. Controlled studies did not extend beyond 12 months. Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Lansoprazole are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
Short Term Treatment of Duodenal Ulcer The recommended adult oral
dose is 15 mg daily before eating
for 4 weeks. (See H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: Lansoprazole/amoxicillin/clarithromycin:
The recommended adult oral
dose is 30 mg lansoprazole, 1
gram amoxicillin, and 500 mg
clarithromycin, all given twice daily (q 12h) for 10 or 14 days. (See
Dual Therapy: Lansoprazole/amoxicillin: The recommended
adult oral dose
is 30 mg lansoprazole
and 1 gram amoxicillin, each
given three times daily (q 8h) for 14 days. (See Please refer to amoxicillin and clarithromycin
for CONTRA Maintenance of Healed Duodenal Ulcers The recommended adult oral dose is 15 mg once daily. (See CLINICAL STUDIES.) Short Term Treatment of Gastric Ulcer The recommended adult oral dose is 30 mg once daily for up to eight weeks. (See CLINICAL STUDIES.) Gastroesophageal Reflux Disease (GERD) Short Term Treatment of Symptomatic GERD: The recommended adult oral dose is 15 mg once daily for up to 8 weeks. Short Term Treatment of Erosive Esophagitis The recommended adult oral
dose is 30 mg once daily for
up to 8 weeks. For patients who do not heal
with lansoprazole for
8 weeks (5-10%) it may be helpful to give an additional 8 weeks of treatment.
(See If there is a recurrence of erosive esophagitis, an additional 8 week course of lansoprazole may be considered. Maintenance of Healing of Erosive Esophagitis The recommended adult oral dose is 15 mg once daily. (See CLINICAL STUDIES) Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome The dosage of lansoprazole in patients with pathologic hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose 60 mg once a day. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Dosages up to 90 mg bid have been administered. Daily dosages 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. No dosage adjustment is necessary in patients with renal insufficiency or the elderly. For patients with severe liver disease, dosage adjustment should be considered. Lansoprazole delayed-release capsules should be taken before eating. In the clinical trials, antacids were used concomitantly with lansoprazole. For patients who have difficulty swallowing capsules, lansoprazole delayed-release capsules can be opened, and the intact granules contained within can be sprinkled on one tablespoon of applesauce and swallowed immediately. The granules should not be chewed or crushed. The granules have also been shown in vitro to remain intact when exposed to apple, cranberry, grape, orange, pineapple, prune, tomato, and V-8® vegetable juice and stored up to 30 minutes. For patients who have a nasogastric tube in place, lansoprazole delayed-release capsules can be opened and the intact granules mixed in 40 ml of apple juice and injected through the nasogastric tube into the stomach. After administering the granules, the nasogastric tube should be flushed with additional apple juice to clear the tube. HOW SUPPLIED Prevacid delayed-release capsules, 15 mg, are opaque, hard gelatin, colored pink and green. The 30 mg are opaque, hard gelatin, pink and black colored capsules. Storage: Lansoprazole capsules should be stored in a tight container protected from moisture. Store between (15-30°C) 59-86°F PRODUCT LISTING
REFERENCES1. National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL, January 11-13, 1998.
Worldwide, over 6100 patients have been treated with lansoprazole in Phase 2-3 clinical trials involving various dosages and duration of treatment. In general, lansoprazole treatment has been well tolerated in both short-term and long-term trials. The following adverse events were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of lansoprazole treated patients and occurred at a greater rate in lansoprazole-treated patients than placebo-treated patients (see TABLE 17).
Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea is similar between patients who received placebo and patients who received lansoprazole 15 mg and 30 mg, but higher in the patients who received lansoprazole 60 mg patients (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. Additional Adverse Experiences Occurring in <1% of Patients or Subjects in Domestic and/or International Trials, or Occurring Since the Drug was Marked
Combination Therapy with Amoxicillin and Clarithromycin In clinical trials using combination therapy with lansoprazole plus amoxicillin and clarithromycin, and lansoprazole 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 lansoprazole, amoxicillin, or clarithromycin. Triple Therapy: Lansoprazole/amoxicillin/clarithromycin: The most frequently reported adverse events 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 events between the 10- and 14-day triple therapy regimens. No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen. Dual Therapy: Lansoprazole/amoxicillin: The most frequently reported adverse events for patients who received lansoprazole tid plus amoxicillin tid dual therapy were diarrhea (8%) and headache (7%). No treatment-emergent adverse events were observed at significantly higher rates with lansoprazole tid plus amoxicillin tid dual therapy than with lansoprazole alone. For more information, see amoxicillin, ADVERSE REACTIONS and clarithromycin, ADVERSE REACTIONS. Laboratory Values The following changes in laboratory parameters were reported as adverse events. 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, eosinophilia, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increase/decreased/abnormal platelets and increased gastrin levels. Additional isolated laboratory abnormalities were reported. In the placebo controlled studies, when SGOT (ALT) and SGPT (AST) were evaluated, 0.4% (1/250) placebo patients and 0.3% (2/795) lansoprazole patients had enzyme elevations greater than three times the upper limit of normal range at the first final treatment visit. None of these patients reported jaundice at any time during the study. In clinical trials using combination therapy with lansoprazole plus amoxicillin and clarithromycin, and lansoprazole plus amoxicillin, no increased laboratory abnormalities particular to these drug combinations were observed. For more information on laboratory value
changes, see amoxicillin,
Lansoprazole is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that lansoprazole 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, clarithromycin, or terfenadine in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. When lansoprazole was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be clinical concern. Nonetheless, individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood levels. Lansoprazole has also been shown to have no clinically significant interaction with amoxicillin. In a single-dose crossover study examining lansoprazole 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 lansoprazole delayed-release capsules; this did not interfere with its effect. Lansoprazole causes a profound and long lasting inhibition of gastric acid secretion; therefore, it is theoretically possible that lansoprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g. ketoconazole, ampicillin esters, iron salts, digoxin).
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL
CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY
OCCURS WHILE TAKING CLARITHROMYCIN, THE PATIENT SHOULD BE APPRISED OF
THE POTENTIAL HAZARD TO THE FETUS. (SEE Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”. After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. These reactions are more apt to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been well documented reports of individuals with a history of penicillin hypersensitivity reactions who have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
General Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy. Information for the Patient Lansoprazole should be taken before eating. For patients who have difficulty swallowing capsules, lansoprazole delayed-release capsules can be opened, and the intact granules contained within can be sprinkled on one tablespoon of applesauce and swallowed immediately. The granules should not be chewed or crushed. The granules have also been shown in vitro to remain intact when exposed to apple, cranberry, grape, orange, pineapple, prune, tomato, and V-8® vegetable juice and stored up to 30 minutes. For patients who have a nasogastric tube in place, lansoprazole delayed-release capsules can be opened and the intact granules mixed in 40 ml of apple juice and injected through the nasogastric tube into the stomach. After administering the granules, the nasogastric tube should be flushed with additional apple juice to clear the tube. Carcinogenesis, Mutagenesis, and Impairment of Fertility In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with doses of 5 to 150 mg/kg/day, about 1 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) given the recommended human dose of 30 mg/day (22.2 mg/m2). 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 (4 to 40 times the recommended human dose based on body surface area) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg/kg/day (13 times the recommended human dose based on body surface area) in a 1-year toxicity study. In a 24-month carcinogenicity study, CD-1 mice were treated orally with doses of 15 to 600 mg/kg/day, 2 to 80 times the recommended human dose based on body surface area. Lansoprazole produced as 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 body surface area) and female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on body surface area) 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 the body surface area). Lansoprazole was not genotoxic in the Ames test, 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. It was positive in in vitro human lymphocyte chromosomal aberration assays. Lansoprazole oral doses up to 150 mg/kg/day (40 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy, Teratogenic Effects, Pregnancy Category B Lansoprazole: Teratology studies have been performed in pregnant rats at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on body surface area) and pregnant rabbits at oral doses up to 30 mg/kg/day (16 times the recommended human dose based on body surface area) 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. Clarithromycin, Pregnancy Category C: See 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 the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established. Use in Women Over 800 women were treated with lansoprazole. Ulcer healing rates in females are similar to those in males. The incidence rates of adverse events are also similar to those seen in males. Use in Geriatric Patients Ulcer healing rates in elderly patients are similar to those in a younger age group. The incidence rates of adverse events and laboratory test abnormalities are also similar to those seen in younger patients. For elderly patients, dosage and administration of lansoprazole need not be altered for a particular indication.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||