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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use PREVACID safely and effectively. See full prescribing information for Prevacid.
PREVACID (lansoprazole) delayed-release capsules, for oral use PREVACID SoluTab (lansoprazole) delayed-release orally disintegrating tablets, for oral use Initial U.S. Approval: 1995
---------------------------RECENT MAJOR CHANGES---------------------------
Indications and Usage, Gastroesophageal Reflux Disease
(GERD) (1.7) 12/
Dosage and Administration, Recommended Dose (2.1) 12/
Contraindications (4) 12/
Warnings and Precautions, Acute Interstitial Nephritis (5.2) 12/
Warnings and Precautions, Cyanocobalamin (vitamin B12)
Deficiency (5.3) 12/
----------------------------INDICATIONS AND USAGE----------------------------
PREVACID is a proton pump inhibitor (PPI) indicated for:
- Short-Term Treatment of Active Duodenal Ulcer (1.1)
- H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (1.2)
- Maintenance of Healed Duodenal Ulcers (1.3)
- Short-Term Treatment of Active Benign Gastric Ulcer (1.4)
- Healing of nonsteroidal anti-inflammatory drugs (NSAID)- Associated Gastric Ulcer (1.5)
- Risk Reduction of NSAID-Associated Gastric Ulcer (1.6)
- Gastroesophageal Reflux Disease (GERD) (1.7)
- Maintenance of Healing of Erosive Esophagitis (EE) (1.8)
- Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (ZES) (1.9)
-----------------------DOSAGE AND ADMINISTRATION------------------------ Indication Dose Frequency Duodenal Ulcers (1.1, 1.3) Short-Term Treatment 15 mg Once daily for 4 wks Maintenance of Healed 15 mg Once daily H. pylori Eradication to Reduce Recurrence of Duodenal Ulcer (1.2) Triple Therapy: PREVACID Amoxicillin Clarithromycin
30 mg 1 gram 500 mg
Twice daily for 10 or 14 days
Dual Therapy: PREVACID Amoxicillin
30 mg 1 gram
Three times daily for 14 days Benign Gastric Ulcer (1.4)
Short-Term Treatment 30 mg
Once daily up to 8 wks NSAID-associated Gastric Ulcer (1.6)
Healing 30 mg
Once daily for 8 wks
Risk Reduction 15 mg
Once daily up to 12 wks GERD (1.7) Short-Term Treatment of Symptomatic GERD 15 mg^
Once daily up to 8 wks
Short-Term Treatment of EE 30 mg
Once daily up to 8 wks Pediatric (8.4) (1 to 11 years of age) Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of EE
≤ 30 kg 15 mg Once daily up to 12 wks
30 kg (^) 30 mg Once daily up to 12 wks
(12 to 17 years of age) Short-Term Treatment of Symptomatic GERD Nonerosive GERD (^) 15 mg Once daily up to 8 wks EE 30 mg Once daily up to 8 wks Maintenance of Healing of EE (1.8)* 15 mg Once daily*
Pathological Hypersecretory Conditions (i.e., ZES) (1.9) 60 mg^ Once daily *Studied for 12 months
-------------------DOSAGE FORMS AND STRENGTHS------------------
Capsules and Tablets: 15 mg and 30 mg. (3)
----------------------------CONTRAINDICATIONS----------------------------- Contraindicated in patients with known severe hypersensitivity to any component of the PREVACID formulation. (4)
---------------------WARNINGS AND PRECAUTIONS--------------------
- Gastric Malignancy: Symptomatic response with PREVACID does not preclude the presence of gastric malignancy. (5.1)
- Acute Interstitial Nephritis: Acute interstitial nephritis has been observed in patients taking PPIs. (5.2)
- Cyanocobalamin (vitamin B12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. (5.3)
- Clostridium difficile Associated Diarrhea: PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.4)
- Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.5)
- Hypomagnesemia: Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. (5.6)
---------------------------ADVERSE REACTIONS----------------------------
Most commonly reported adverse reactions (≥1%): diarrhea, abdominal pain, nausea and constipation. (6)
**To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America Inc. at 1-877-TAKEDA-7 (1-877-825-
- or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.**
-----------------------------DRUG INTERACTIONS---------------------------
- Atazanavir: Do not co-administer with atazanavir. (7.1)
- Drugs with pH-Dependent Absorption: May interfere with the absorption of drugs where gastric pH is important for bioavailability (e.g. ampicillin esters, digoxin, iron salts, erlotinib, ketoconazole, atazanavir, and mycophenolate mofetil). (7.1)
- Warfarin: Concomitant warfarin use may require monitoring for increases in INR and prothrombin time. (7.2)
- Tacrolimus: Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. (7.3)
- Theophylline: Titration of theophylline dosage may be required when concomitant PREVACID use is started or stopped. (7.4)
- Methotrexate: PREVACID may increase serum levels of methotrexate. (7.6)
----------------------USE IN SPECIFIC POPULATIONS-------------------
- Consider dose adjustment in patients with severe liver impairment. (8.7)
- PREVACID is not effective in patients with symptomatic GERD 1 month to less than 1 year of age. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
Revised: 12/
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Short-Term Treatment of Active Duodenal Ulcer 1.2 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence 1.3 Maintenance of Healed Duodenal Ulcers 1.4 Short-Term Treatment of Active Benign Gastric Ulcer 1.5 Healing of NSAID-Associated Gastric Ulcer 1.6 Risk Reduction of NSAID-Associated Gastric Ulcer 1.7 Gastroesophageal Reflux Disease (GERD) 1.8 Maintenance of Healing of Erosive Esophagitis (EE) 1.9 Pathological Hypersecretory Conditions Including Zollinger- Ellison Syndrome (ZES)
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose 2.2 Special Populations 2.3 Important Administration Information
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Gastric Malignancy 5.2 Acute Interstitial Nephritis 5.3 Cyanocobalamin (vitamin B12) Deficiency 5.4 Clostridium difficile Associated Diarrhea 5.5 Bone Fracture 5.6 Hypomagnesemia 5.7 Concomitant Use of PREVACID with Methotrexate
6 ADVERSE REACTIONS
6.1 Clinical 6.2 Postmarketing Experience 6.3 Combination Therapy with Amoxicillin and Clarithromycin 6.4 Laboratory Values
7 DRUG INTERACTIONS
7.1 Drugs with pH-Dependent Absorption Kinetics 7.2 Warfarin 7.3 Tacrolimus 7.4 Theophylline 7.5 Clopidogrel 7.6 Methotrexate 7.7 Combination Therapy with Clarithromycin 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 8.8 Gender 8.9 Race 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
2.1 Recommended Dose
Indication Recommended Dose Frequency Duodenal Ulcers Short-Term Treatment 15 mg Once daily for 4 weeks Maintenance of Healed 15 mg Once daily H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence* Triple Therapy: PREVACID 30 mg Twice daily (q12h) for 10 or 14 days Amoxicillin 1 gram Twice daily (q12h) for 10 or 14 days Clarithromycin 500 mg Twice daily (q12h) for 10 or 14 days Dual Therapy: PREVACID 30 mg Three times daily (q8h) for 14 days Amoxicillin 1 gram Three times daily (q8h) 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‡ Pediatric
(1 to 11 years of age) 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§
(12 to 17 years of age) Short-Term Treatment of Symptomatic GERD
Nonerosive GERD 15 mg Once daily for up to 8 weeks 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 amoxicillin and clarithromycin full prescribing information for CONTRAINDICATIONS and WARNINGS, 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 PREVACID for 8 weeks (5 to 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 PREVACID may be considered. §The PREVACID dose was increased (up to 30 mg twice daily) in some pediatric patients after 2 or more weeks of treatment if they remained symptomatic. For pediatric patients unable to swallow an intact capsule please see Administration Options. ¶ (^) 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 PREVACID for more than 4 years.
(^) Controlled studies did not extend beyond 12 months
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 2 doses at one time to make up for a missed dose.
2.2 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 Specific Populations (8.5, 8.6 and 8.7)].
2.3 Important Administration Information
Administration Options PREVACID Delayed-Release Capsules – Oral Administration
- PREVACID Delayed-Release Capsules should be swallowed whole.
- Alternatively, for patients who have difficulty swallowing capsules, PREVACID Delayed-Release Capsules can be opened and administered as follows: o Open capsule. o Sprinkle intact granules on one tablespoon of either applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears. o Swallow immediately.
- PREVACID Delayed-Release Capsules may also be emptied into a small volume of either apple juice, orange juice or tomato juice and administered as follows:
o Open capsule. o Sprinkle intact granules into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately 2 ounces). o Mix briefly. o Swallow immediately. o To ensure complete delivery of the dose, the glass should be rinsed with two or more volumes of juice and the contents swallowed immediately.
PREVACID Delayed-Release Capsules – Nasogastric Tube (≥16 French) Administration
- For patients who have a nasogastric tube in place, PREVACID Delayed-Release Capsules can be administered as follows: o Open capsule. o Mix intact granules into 40 mL of apple juice. DO NOT USE OTHER LIQUIDS. o Inject through the nasogastric tube into the stomach. o Flush with additional apple juice to clear the tube.
USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED.
PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets
- PREVACID SoluTab should not be broken or cut.
- PREVACID SoluTab should not be chewed. o Place the tablet on the tongue and allow it to disintegrate, with or without water, until the particles can be swallowed. o The tablet typically disintegrates in less than 1 minute. o Alternatively, for children or other patients who have difficulty swallowing tablets, PREVACID SoluTab can be delivered in two different ways.
PREVACID SoluTab – Oral Syringe For administration via oral syringe, PREVACID SoluTab 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 ofwater. 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.
PREVACID SoluTab – Nasogastric Tube (≥8 French) Administration For administration via a nasogastric tube, PREVACID SoluTab 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.
3 DOSAGE FORMS AND STRENGTHS
- 15 mg capsules are opaque, hard gelatin, colored pink and green with the TAP logo and “PREVACID 15” imprinted on the capsule.
- 30 mg capsules are opaque, hard gelatin, colored pink and black with the TAP logo and “PREVACID 30” imprinted on the capsule.
- 15 mg tablets are white to yellowish white, uncoated, colored orange to dark brown speckles with “15” debossed on one side of the tablet.
- 30 mg tablets are white to yellowish white, uncoated, colored orange to dark brown speckles with “30” debossed on one side of the tablet.
4 CONTRAINDICATIONS
PREVACID is contraindicated in patients with known severe hypersensitivity to any component of the formulation of PREVACID. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria [see Adverse Reactions (6)].
For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with PREVACID, refer to the CONTRAINDICATIONS section of their package inserts.
5 WARNINGS AND PRECAUTIONS
5.1 Gastric Malignancy
Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy.
5.2 Acute Interstitial Nephritis
Acute interstitial nephritis has been observed in patients taking PPIs including PREVACID. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue PREVACID if acute interstitial nephritis develops [see Contraindications (4)].
5.3 Cyanocobalamin (vitamin B12) Deficiency
Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B12) 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.
5.4 Clostridium difficile Associated Diarrhea
Published observational studies suggest that proton pump inhibitor (PPI) therapy like PREVACID 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 Adverse Reactions (6.2)].
Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
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.
6.2 Postmarketing Experience
Additional adverse experiences have been reported since PREVACID has been marketed. The majority of these cases are foreign-sourced and a relationship to PREVACID 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 below by COSTART body system.
Body as a Whole – anaphylactic/anaphylactoid reactions; 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); Special Senses – speech disorder; Urogenital System – interstitial nephritis, urinary retention.
6.3 Combination Therapy with Amoxicillin and Clarithromycin
In clinical trials using combination therapy with PREVACID plus amoxicillin and clarithromycin, and PREVACID 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 PREVACID, amoxicillin, or clarithromycin.
Triple Therapy: PREVACID/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 with any dual therapy regimen.
Dual Therapy: PREVACID/amoxicillin The most frequently reported adverse reactions for patients who received PREVACID 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 PREVACID three times daily plus amoxicillin three times daily dual therapy than with PREVACID alone.
For information about adverse reactions with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with PREVACID, refer to the ADVERSE REACTIONS section of their package inserts.
6.4 Laboratory Values
The following changes in laboratory parameters in patients who received PREVACID 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 PREVACID, 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 PREVACID reported jaundice at any time during the study.
In clinical trials using combination therapy with PREVACID plus amoxicillin and clarithromycin, and PREVACID 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 PREVACID, refer to the ADVERSE REACTIONS section of their package inserts.
7 DRUG INTERACTIONS
7.1 Drugs with pH-Dependent Absorption Kinetics
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. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ampicillin esters, ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with PREVACID [see Clinical Pharmacology (12.3)].
PREVACID is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, PREVACID should not be co-administered with atazanavir [see Clinical Pharmacology (12.3)].
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 PREVACID with caution in transplant patients receiving MMF.
7.2 Warfarin
In a study of healthy subjects, co-administration of single or multiple 60 mg doses of PREVACID and warfarin did not affect the pharmacokinetics of warfarin nor prothrombin time [see Clinical Pharmacology (12.3)]. 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 Clinical Pharmacology (12.3)].
7.3 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.
7.4 Theophylline
A minor increase (10%) in the clearance of theophylline was observed following the administration of PREVACID 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 PREVACID is started or stopped to ensure clinically effective blood levels [see Clinical Pharmacology (12.3)].
7.5 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 Clinical Pharmacology (12.3)]. No dose adjustment of clopidogrel is necessary when administered with an approved dose of PREVACID.
7.6 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 Warnings and Precautions (5.7)].
In a study of rheumatoid arthritis patients receiving low-dose methotrexate, PREVACID and naproxen, no effect on pharmacokinetics of methotrexate was observed [see Clinical Pharmacology (12.3)].
7.7 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 co-administration 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 PREVACID, refer to the DRUG INTERACTIONS section of their package inserts.
8. USE IN SPECIFIC POPULATIONS
8.1 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 Nonclinical Toxicology (13.2)].
See full prescribing information for clarithromycin before using in pregnant women.
8.3 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.
8.4 Pediatric Use
The safety and effectiveness of PREVACID have been established in pediatric patients 1 to 17 years of age for short-term treatment of symptomatic GERD and erosive esophagitis, however, PREVACID was not effective in patients with symptomatic GERD 1 month to less than 1 year of age in a multicenter, double-blind, placebo controlled study.
Neonate to less than 1 year of age
The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged less than 28 days and 1 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. 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 4 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 7 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 4 weeks of double-blind treatment.
necessary). †No data available for 5 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 44 to 88 pg/mL] at the final visit. (Normal serum gastrin levels are 25 to 111 pg/mL.)
The safety of PREVACID Delayed-Release Capsules has been assessed in these 87 adolescent patients. Of the 87 adolescent patients with GERD, 6% (5/87) took PREVACID for less than 6 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 package insert as occurring in less than 1% of adult patients, was reported in this study by 3 adolescent patients with nonerosive GERD, who had dizziness concurrently with other reactions (such as migraine, dyspnea, and vomiting).
8.5 Geriatric Use
No dosage adjustment of PREVACID is necessary in geriatric patients. The incidence rates of PREVACID-associated adverse reactions and laboratory test abnormalities are similar to those seen in younger patients [see Clinical Pharmacology (12.3)].
8.6 Renal Impairment
No dosage adjustment of PREVACID 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 Clinical Pharmacology (12.3)].
8.7 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 Clinical Pharmacology (12.3)].
8.8 Gender
Over 4,000 women were treated with PREVACID. 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 Clinical Pharmacology (12.3)].
8.9 Race
The pooled mean pharmacokinetic parameters of PREVACID 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 PREVACID 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.
10 OVERDOSAGE
PREVACID is not removed from the circulation by hemodialysis. In one reported overdose, a patient consumed 600 mg of PREVACID with no adverse reaction. Oral PREVACID 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.
11 DESCRIPTION
The active ingredient in PREVACID Delayed-Release Capsules and PREVACID SoluTab Delayed-Release Orally Disintegrating 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 C 16 H 14 F 3 N 3 O 2 S with a molecular weight of 369.37. PREVACID has the following structure:
N
H
N S CH 2
O
N
H 3 C
OCH 2 CF 3
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.
PREVACID is supplied in delayed-release capsules and in delayed-release orally disintegrating tablets 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: sugar sphere, sucrose, methacrylic acid copolymer, low substituted hydroxypropyl cellulose, starch, magnesium carbonate, talc, polyethylene glycol, titanium dioxide, polysorbate 80, hydroxypropyl cellulose, colloidal silicon dioxide, D&C Red No. 28, FD&C Blue No. 1, FD&C Green No. 3^1 , and FD&C Red No. 40.
PREVACID SoluTab Delayed-Release Orally Disintegrating Tablets are available in two dosage strengths: 15 mg and 30 mg of lansoprazole per tablet. Each delayed-release orally disintegrating tablet contains enteric-coated microgranules consisting of 15 mg or 30 mg of lansoprazole (active ingredient)
and the following inactive ingredients: mannitol, methacrylic acid, hydroxypropyl cellulose, lactose monohydrate-microcrystalline cellulose sphere, triethyl citrate, crospovidone, polyacrylate, magnesium carbonate, aspartame^2 , glyceryl monostearate, hypromellose, magnesium stearate, citric acid, titanium dioxide, talc, artificial strawberry flavor, polyethylene glycol, polysorbate 80 and ferric oxide.
(^1) PREVACID 15-mg capsules only.
(^2) Phenylketonurics: Contains Phenylalanine 2.5 mg per 15 mg Tablet and 5.1 mg per 30 mg Tablet.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
PREVACID (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
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 3 and greater than 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.
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 4:
Table 4: Mean Antisecretory Effects After Single and Multiple Daily PREVACID Dosing PREVACID
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 1 to 2 hours with 30 mg of lansoprazole and 2 to 3 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 1 to 2 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 5 and 6 was evaluated in a crossover study of PREVACID given daily, twice daily and three times daily (Table 5).
Table 5: Mean Antisecretory Effects After 5 Days of Twice Daily and Three Times Daily Dosing
PREVACID
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 PREVACID 30 mg daily †(p<0.05) versus PREVACID 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 [see Nonclinical Toxicology (13.1)].
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
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.
12.3 Pharmacokinetics
PREVACID Delayed-Release Capsules and PREVACID SoluTab Delayed-Release Orally Disintegrating 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 (Cmax ) 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.
Absorption: The absorption of lansoprazole is rapid, with the mean Cmax 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 Cmax 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 2 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 PREVACID, 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.
Specific Populations
Pediatric Use:
One to 17 years of age
The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged 1 to 11 years and 12 to 17 years in two separate clinical studies. In children aged 1 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 Cmax 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 Cmax and AUC values of lansoprazole were not affected by body weight or age; and nearly dose- proportional increases in mean Cmax 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 Section 8.4 for the pharmacokinetics of lansoprazole in pediatric patients with GERD aged less than 28 days and 1 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 Use in Specific Populations (8.5)].
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 Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function. No dosage adjustment is necessary in patients with renal impairment [see Use in Specific Populations (8.6)].
Hepatic Impairment: In patients with various degrees of chronic hepatic impairment, the mean plasma half-life of lansoprazole was prolonged from 1. 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 Use in Specific Populations (8.7)].
Gender: In a study comparing 12 male and 6 female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results [see Use in Specific Populations (8.8)].
Drug-Drug Interactions
PREVACID 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).
PREVACID is metabolized through the cytochrome P 450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that PREVACID does not have clinically significant interactions with other drugs metabolized by the cytochrome P 450 system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P 450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.
Atazanavir: PREVACID causes long-lasting inhibition of gastric acid secretion. PREVACID substantially decreases the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of
atazanavir and the development of HIV resistance. Therefore, PREVACID, or other proton pump inhibitors, should not be co-administered with atazanavir.
Theophylline: When PREVACID 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 PREVACID 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 PREVACID, 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 7 days of naproxen 500 mg twice daily and PREVACID 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: PREVACID has also been shown to have no clinically significant interaction with amoxicillin.
Sucralfate : In a single-dose crossover study examining PREVACID 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 PREVACID and there was no evidence of a change in the efficacy of PREVACID.
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 PREVACID 30 mg (n=40), for 9 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 80to 92%) when PREVACID 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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated with oral lansoprazole doses of 5 to 150 mg/kg/day, about 1 to 40 times the exposure on a body surface (mg/m 2 ) basis of a 50 kg person of average height [1.46 m 2 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 (4 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, 2 to 80 times the recommended 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 genotoxic in 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 on fertility and reproductive performance of male and female rats.
13.2 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.
14 CLINICAL STUDIES
Duodenal Ulcer In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15, 30, and 60 mg of PREVACID once daily) study of 284 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after two and four weeks was significantly higher with all doses of PREVACID than with placebo. There was no evidence of a greater or earlier response with the two higher doses compared with PREVACID 15 mg. Based on this study and the second study described below, the recommended dose of PREVACID in duodenal ulcer is 15 mg per day (Table 7).
Table 9 H. pylori Eradication Rates – Triple Therapy (PREVACID/amoxicillin/clarithromycin) Percent of Patients Cured [95% Confidence Interval] (Number of patients)
Study Duration Triple Therapy Evaluable Analysis*
Triple Therapy Intent-to-Treat Analysis † M93-131 14 days 92 ‡ [80.0-97.7] (N=48)
[73.3-93.5]
(N=55)
M95-392 14 days 86 § [75.7-93.6] (N=66)
[72.0-90.8]
(N=70)
M95-399¶^ 14 days 85 [77.0-91.0] (N=113)
[73.9-88.1]
(N=126)
10 days 84 [76.0-89.8] (N=123)
[73.9-87.6]
(N=135)
*Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy. †Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy. ‡(p<0.05) versus PREVACID/amoxicillin and PREVACID/clarithromycin dual therapy. §(p<0.05) versus clarithromycin/amoxicillin dual therapy. ¶The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.
Table 10 H. pylori Eradication Rates – 14-Day Dual Therapy (PREVACID/amoxicillin) Percent of Patients Cured [95% Confidence Interval] (Number of patients)
Study Dual Therapy Evaluable Analysis*
Dual Therapy Intent-to-Treat Analysis † M93-131 77
‡ [62.5-87.2] (N=51)
[56.8-81.2]
(N=60)
M93-125 66
§ [51.9-77.5] (N=58)
[48.5-72.9]
(N=67)
*Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. †Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy. ‡ (^) (p<0.05) versus PREVACID alone. § (^) (p<0.05) versus PREVACID alone or amoxicillin alone.
Long-Term Maintenance Treatment of Duodenal Ulcers
PREVACID has been shown to prevent the recurrence of duodenal ulcers. Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed duodenal ulcers. Patients remained healed significantly longer and the number of recurrences of duodenal ulcers was significantly less in patients treated with PREVACID than in patients treated with placebo over a 12-month period (Table 11) [see Indications and Usage (1.3)].
Table 11: Endoscopic Remission Rates
Trial Drug No. of Pts.
Percent in Endoscopic Remission
0-3 mo. 0-6 mo. 0-12 mo.
PREVACID 15 mg daily 86 90% *****^ 87% *****^ 84% *****
Placebo 83 49% 41% 39%
PREVACID 30 mg daily 18 94% *****^ 94% *****^ 85% *****
PREVACID 15 mg daily 15 87% *****^ 79% *****^ 70% *****
Placebo 15 33% 0% 0%
%=Life Table Estimate ***** (p≤0.001) versus placebo.
In trial #2, no significant difference was noted between PREVACID 15 mg and 30 mg in maintaining remission.
Gastric Ulcer
In a U.S. multicenter, double-blind, placebo-controlled study of 253 patients with endoscopically documented gastric ulcer, the percentage of patients healed at four and eight weeks was significantly higher with PREVACID 15 mg and 30 mg once a day than with placebo (Table 12) [see Indications and Usage (1.4)].
Table 12: Gastric Ulcer Healing Rates PREVACID Placebo (N=64)
Week
15 mg daily (N=65)
30 mg daily (N=63)
60 mg daily (N=61) 4 64.6% *^ 58.1% *^ 53.3% *^ 37.5% 8 92.2% *^ 96.8% *^ 93.2% *^ 76.7% *(p≤0.05) versus placebo.
Patients treated with any PREVACID dose reported significantly less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets used per day than the placebo group.
Independent substantiation of the effectiveness of PREVACID 30 mg was provided by a meta-analysis of published and unpublished data.
Healing of NSAID-Associated Gastric Ulcer
In two U.S. and Canadian multicenter, double-blind, active-controlled studies in patients with endoscopically confirmed NSAID-associated gastric ulcer who continued their NSAID use, the percentage of patients healed after 8 weeks was statistically significantly higher with 30 mg of PREVACID than with the active control. A total of 711 patients were enrolled in the study, and 701 patients were treated. Patients ranged in age from 18 to 88 years (median age 59 years), with 67% female patients and 33% male patients. Race was distributed as follows: 87% Caucasian, 8% Black, 5% Other. There was no statistically significant difference between PREVACID 30 mg daily and the active control on symptom relief (i.e., abdominal pain) (Table 13) [see Indications and Usage (1.5)].
Table 13 : NSAID-Associated Gastric Ulcer Healing Rates* Study #
PREVACID 30 mg daily
Active Control†
Week 4 60% (53/88) ‡^ 28% (23/83)
Week 8 79% (62/79) ‡^ 55% (41/74)
Study #
PREVACID 30 mg daily
Active Control†
Week 4 53% (40/75) 38% (31/82)
Week 8 77% (47/61) ‡^ 50% (33/66) *Actual observed ulcer(s) healed at time points ±2 days †Dose for healing of gastric ulcer ‡ (^) (p≤0.05) versus the active control
Figure 1
Figure 2
In two U.S., multicenter double-blind, ranitidine-controlled studies of 925 total patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, lansoprazole 15 mg was superior to ranitidine 150 mg (twice daily) in decreasing the frequency and severity of day and night heartburn associated with GERD for the 8-week treatment period. No significant additional benefit from lansoprazole 30 mg once daily was observed [see Indications and Usage (1.7)].
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 presented in Table 16:
Table 16 : Erosive Esophagitis Healing Rates
PREVACID
15 mg daily 30 mg daily 60 mg daily Placebo Week (N=69) (N=65) (N=72) (N=63)
4 67.6% *^ 81.3% *†^ 80.6% *†^ 32.8%
6 87.7% *^ 95.4% *^ 94.3% *^ 52.5%
8 90.9% *^ 95.4% *^ 94.4% *^ 52.5%
*(p≤0.001) versus placebo. †(p≤0.05) versus PREVACID 15 mg.
In this study, all PREVACID groups reported significantly greater relief of heartburn and less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets taken per day than the placebo group. Although all doses were effective, the earlier healing in the higher two doses suggests 30 mg daily as the recommended dose.
PREVACID was also compared in a U.S. multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis. PREVACID at a dose of 30 mg was significantly more effective than ranitidine 150 mg twice daily as shown below (Table 17).
Table 17 : Erosive Esophagitis Healing Rates
Week
PREVACID
30 mg daily (N=115)
Ranitidine 150 mg twice daily (N=127) 2 66.7% *^ 38.7%
4 82.5% *^ 52.0%
6 93.0% *^ 67.8%
8 92.1% *^ 69.9% *(p≤0.001) versus ranitidine.
In addition, patients treated with PREVACID reported less day and nighttime heartburn and took less antacid tablets for fewer days than patients taking ranitidine 150 mg twice daily.
Although this study demonstrates effectiveness of PREVACID in healing erosive esophagitis, it does not represent an adequate comparison with ranitidine because the recommended ranitidine dose for esophagitis is 150 mg four times daily, twice the dose used in this study.
In the two trials described and in several smaller studies involving patients with moderate to severe erosive esophagitis, PREVACID produced healing rates similar to those shown above.
In a U.S. multicenter, double-blind, active-controlled study, 30 mg of PREVACID was compared with ranitidine 150 mg twice daily in 151 patients with erosive reflux esophagitis that was poorly responsive to a minimum of 12 weeks of treatment with at least one H 2 -receptor antagonist given at the dose indicated for symptom relief or greater, namely, cimetidine 800 mg/day, ranitidine 300 mg/day, famotidine 40 mg/day or nizatidine 300 mg/day. PREVACID 30 mg was more effective than ranitidine 150 mg twice daily in healing reflux esophagitis, and the percentage of patients with healing were as follows. This study does not constitute a comparison of the effectiveness of histamine H 2 -receptor antagonists with PREVACID, as all patients had demonstrated unresponsiveness to the histamine H 2 -receptor antagonist mode of treatment. It does indicate, however, that PREVACID may be useful in patients failing on a histamine H 2 -receptor antagonist (Table 18) [see Indications and Usage (1.7)].
Table 18 : Reflux Esophagitis Healing Rates in Patients Poorly Responsive to Histamine H 2 - Receptor Antagonist Therapy
Week
PREVACID
30 mg daily (N=100)
Ranitidine 150 mg twice daily (N=51) 4 74.7% *^ 42.6%
8 83.7% *^ 32.0%
*(p≤0.001) versus ranitidine.
Long-Term Maintenance Treatment of Erosive Esophagitis
Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed esophagitis. Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with PREVACID than in patients treated with placebo over a 12-month period (Table 19).
Table 19 : Endoscopic Remission Rates
Percent in Endoscopic Remission
Trial Drug No. of Pts. 0-3 mo. 0-6 mo. 0-12 mo.
#1 PREVACID 15 mg daily^59 83%^
PREVACID 30 mg daily 56 93% *^ 93% *^ 90% *
Placebo 55 31% 27% 24%
#2 PREVACID 15 mg daily^50 74%^
PREVACID 30 mg daily 49 75% *^ 72% *^ 55% *
Placebo 47 16% 13% 13%
%=Life Table Estimate *(p≤0.001) versus placebo.
Regardless of initial grade of erosive esophagitis, PREVACID 15 mg and 30 mg were similar in maintaining remission.
In a U.S., randomized, double-blind, study, PREVACID 15 mg daily (n = 100) was compared with ranitidine 150 mg twice daily (n = 106), at the recommended dosage, in patients with endoscopically-proven healed erosive esophagitis over a 12-month period. Treatment with PREVACID resulted in patients remaining healed (Grade 0 lesions) of erosive esophagitis for significantly longer periods of time than those treated with ranitidine (p<0.001). In addition, PREVACID was significantly more effective than ranitidine in providing complete relief of both daytime and nighttime heartburn. Patients
