AA-Lansoprazole-Amoxicillin-Clarithromycin Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ................................................................................................ 2

TABLE OF CONTENTS................................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION ......................................................................... 4

1 INDICATIONS ........................................................................................................................ 4

1.1 Pediatrics ...................................................................................................................... 5

1.2 Geriatrics ...................................................................................................................... 5

2 CONTRAINDICATIONS .......................................................................................................... 5

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ..................................................................... 7

4 DOSAGE AND ADMINISTRATION ......................................................................................... 8

4.1 Dosing Considerations .................................................................................................. 8

4.2 Recommended Dose and Dosage Adjustment .............................................................. 8

4.4 Administration .............................................................................................................. 9

4.5 Missed Dose .................................................................................................................. 9

5 OVERDOSAGE ...................................................................................................................... 9

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ....................................... 10

7 WARNINGS AND PRECAUTIONS ......................................................................................... 11

7.1 Special Populations ..................................................................................................... 22

7.1.1 Pregnant Women ............................................................................................... 22

7.1.2 Breast-feeding .................................................................................................... 23

7.1.3 Pediatrics ........................................................................................................... 24

7.1.4 Geriatrics ............................................................................................................ 24

8 ADVERSE REACTIONS ......................................................................................................... 25

8.1 Adverse Reaction Overview ........................................................................................ 25

8.2 Clinical Trial Adverse Reactions .................................................................................. 25

8.3 Less Common Clinical Trial Adverse Reactions ........................................................... 28

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ................................................................................................................. 34

8.5 Post-Market Adverse Reactions .................................................................................. 35

9 DRUG INTERACTIONS ......................................................................................................... 39

9.1 Serious Drug Interaction ............................................................................................. 39

9.2 Drug Interactions Overview ........................................................................................ 39

9.4 Drug-Drug Interactions ............................................................................................... 41

9.5 Drug-Food Interactions ............................................................................................... 60

9.6 Drug-Herb Interactions ............................................................................................... 60

9.7 Drug-Laboratory Test Interactions .............................................................................. 60

10 CLINICAL PHARMACOLOGY ................................................................................................ 60

10.1 Mechanism of Action .................................................................................................. 60

10.2 Pharmacodynamics ..................................................................................................... 61

10.3 Pharmacokinetics ........................................................................................................ 65

11 STORAGE, STABILITY AND DISPOSAL .................................................................................. 73

12 SPECIAL HANDLING INSTRUCTIONS ................................................................................... 74

PART II: SCIENTIFIC INFORMATION ........................................................................................... 75

13 PHARMACEUTICAL INFORMATION .................................................................................... 75

14 CLINICAL TRIALS ................................................................................................................. 77

14.1 Clinical Trials by Indication .......................................................................................... 77

14.2 Comparative Bioavailability Studies ............................................................................ 82

15 MICROBIOLOGY ................................................................................................................. 85

16 NON-CLINICAL TOXICOLOGY .............................................................................................. 86

17 SUPPORTING PRODUCT MONOGRAPHS .......................................................................... 106

PATIENT MEDICATION INFORMATION .................................................................................... 107

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

The components of the AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN [lansoprazole delayed-release capsules, in combination with clarithromycin tablets plus amoxicillin capsules as triple therapy], are indicated for:

• the treatment of patients with Helicobacter pylori (H. pylori) infection and active duodenal ulcer disease. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence (see 14.1 Clinical Trials by Indication and 4 DOSAGE AND ADMINISTRATION).

In patients with a recent history of duodenal ulcers who are H. pylori positive, eradication therapy may reduce the rate of recurrence of duodenal ulcers. The optimal timing for eradication therapy for such patients remains to be determined.

In patients who fail a therapy combination containing clarithromycin, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, an alternative therapy combination is recommended. Resistance to amoxicillin has not been demonstrated in clinical studies with lansoprazole delayed-release capsules and amoxicillin.

Table 1 summarizes the eradication rates for the H. pylori Triple Therapy treatment regimen.

Table 1 - Eradication Rates for the H. pylori Triple Therapy Treatment Regimens

To reduce the development of drug-resistant bacteria and maintain the effectiveness of clarithromycin tablets or amoxicillin capsules and other antibacterial drugs, clarithromycin tablets or amoxicillin capsules should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

1.1 Pediatrics

Pediatrics (1 to 17 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. See 7.1.3 Pediatrics.

1.2 Geriatrics

Geriatrics (≥ 65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. See 7.1.4 Geriatrics.

2 CONTRAINDICATIONS

Lansoprazole delayed-release capsules, in combination with clarithromycin tablets plus amoxicillin capsules are contraindicated in:

• Patients with known hypersensitivity to:

  • lansoprazole
  • clarithromycin or any macrolide antibiotic (e.g. erythromycin)
  • amoxicillin or other beta-lactam antibiotics (e.g. any penicillin or cephalosporin) or
  • any ingredient in the formulations of Lansoprazole Delayed-Release Capsules; Clarithromycin Tablets, or Amoxicillin Capsules, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

Clarithromycin is contraindicated:

• in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of clarithromycin.
• in patients who suffer from severe hepatic failure in combination with renal impairment. See 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and 7 WARNINGS AND PRECAUTIONS, Renal.
• in patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointes. See 7 WARNINGS AND PRECAUTIONS, Cardiovascular and 9.4 Drug-Drug Interactions, Table 8.
• in patients with electrolyte disturbances (hypokalaemia or hypomagnesaemia), due to the risk of prolongation of QT-interal and torsades de pointes.

• as concomitant therapy with:

  • astemizole,
  • cisapride,
  • domperidone,
  • pimozide,
  • terfenadine.

There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with the above, resulting in cardiac arrhytmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of hepatic metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported (see 9.4 Drug-Drug Interactions, Table 8)

• with concomitant administration of lomitapide (see 9 DRUG INTERACTIONS and 9.2 Drug Interactions Overview, Effects of Clarithromycin on Other Drugs.
• in concomitant use with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to an increased risk of myopathy, including rhabdomyolysis. See 9.4 Drug-Drug Interactions, Table 8.
• as concomitant therapy with ergot alkaloids (e.g., ergotamine or dihydroergotamine) as this may result in ergot toxicity. See 9.4 Drug-Drug Interactions, Table 8.
• as concomitant therapy with oral midazolam. See 9.4 Drug-Drug Interactions, Table 8.
• as concomitant therapy with colchicine due to the risk of life threatening and fatal colchicine toxicity. This risk may be further increased with concomitant medications metabolized by P-glycoprotein or strong CYP3A inhibitors. See 9.4 Drug-Drug Interactions, Table 8.

• as concomitant therapy with ticagrelor or ranolazine*.

  * Not marketed in Canada.

• as concomitant therapy with saquinavir/ritonavir. See 9.4 Drug-Drug Interactions, Table 8.

Amoxicillin is contraindicated:

• in cases where infectious mononucleosis is either suspected or confirmed.

Lansoprazole is contraindicated:

• in co-administration with rilpivirine. See 9.4 Drug-Drug Interactions, Table 7.

For information on the use of the individual components of the AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN when dispensed as individual medications outside the combined use for the treatment of Helicobacter pylori (H. pylori), the respective Product Monographs for these products should be consulted.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

Note: These products are intended only for use as described. The individual products contained in the AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN should not be used alone or in combination for other purposes. The information described in this product monograph concerns only the use of these products as indicated in this daily administration pack. For information on the use of the individual components when dispensed as individual medications outside this combined use for the eradication of helicobacter pylori (H. Pylori), the respective product monographs for these products should be consulted.

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

For the eradication of H. pylori, amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.

4.2 Recommended Dose and Dosage Adjustment

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

The recommended adult oral dose is 30 mg lansoprazole 500 mg clarithromycin, and 1000 mg amoxicillin, all given twice daily for 7, 10 or 14 days (see 1 INDICATIONS).

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Patients with Hepatic Impairment

Lansoprazole delayed-release capsules, USP: It is recommended that the initial dosing regimen need not be altered for patients with mild or moderate liver disease, but for patients with moderate impairment, doses higher than 30 mg lansoprazole / day should not be administered unless there are compelling clinical indications (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Clarithromycin tablets, USP: Clarithromycin may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function. See 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic.

Patients with Renal Impairment

Lansoprazole delayed-release capsules, USP: No dosage modification of lansoprazole is necessary (see 7 WARNINGS AND PRECAUTIONS, Renal).

Clarithromycin tablets, USP: Refer to 7 WARNINGS AND PRECAUTIONS, Renal.

Elderly Patients

The daily dose of lansoprazole should not exceed 30 mg (see 7.1.4 Geriatrics).

Concomitant Antacid Use

Simultaneous administration of lansoprazole with aluminum and magnesium hydroxide or magaldrate results in lower peak plasma levels, but does not significantly reduce bioavailability. Antacids may be used concomitantly if required. If sucralfate is to be given concomitantly, lansoprazole should be administered at least 30 minutes prior to sucralfate (see 10.3 Pharmacokinetics, Absorption, Absorption with Antacids). In clinical trials, antacids were administered concomitantly with lansoprazole capsules; this did not interfere with its effect.

4.4 Administration

Daily doses should be taken before meals.

Lansoprazole delayed-release capsules SHOULD NOT BE CRUSHED, CHEWED, BROKEN OR CUT.

4.5 Missed Dose

Patients should be instructed that if a dose of this medication has been 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.

5 OVERDOSAGE

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

In case of an overdose, patients should contact a physician, poison control center, or emergency room. There is neither a pharmacologic basis nor any data suggesting an increase in the toxicity of the AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN combination compared to its individual components.

Lansoprazole delayed-release capsules, USP

As in all cases where overdosing is suspected, treatment should be supportive and symptomatic. Any unabsorbed material should be removed from the gastrointestinal tract, and the patient should be carefully monitored. Lansoprazole is not removed from the circulation by hemodialysis. In one reported case of overdose, the patient consumed 600 mg of lansoprazole with no adverse reaction.

Oral doses up to 5000 mg/kg in rats (approximately 1300 times the recommended human dose based on body surface area) and mice (about 675.7 times the recommended human dose based on body surface area) did not produce deaths or any clinical signs.

Clarithromycin tablets, USP

Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. Clarithromycin is protein bound (70%). No data are available on the elimination of clarithromycin by hemodialysis or peritoneal dialysis.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Treatment of overdosage would likely be needed only in patients with severely impaired renal function, since patients with normal kidneys excrete penicillins at a fast rate. Hemodialysis would therefore represent the main form of treatment.

Activated charcoal may be administered to aid in the removal of unabsorbed drug. General supportive measures are recommended.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 2 - Dosage Forms, Strengths, Composition and Packaging

Composition

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN - H. pylori Individual Daily Administration Blister Pack

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN daily administration blister packs are available in boxes containing seven (7) days of therapy. Each triple therapy AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN daily administration blister pack contains:

Lansoprazole delayed-release capsules, USP:

• two hard gelatin capsules with black opaque body and pink opaque cap. Imprinted “APO L30” in white ink.

Clarithromycin tablets, USP:

• two light yellow, capsule shaped, biconvex, film-coated tablets, engraved “CLA500” on one side, “APO” on the other side.

Amoxicillin (amoxicillin trihydrate) capsules, USP:

• four hard gelatin capsules with gold opaque body, scarlet opaque cap and a loosely slugged powder fill. Printed “APO 500”.

7 WARNINGS AND PRECAUTIONS

See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

H. pylori Eradication and Compliance

To avoid failure of the eradication treatment with a potential for developing antimicrobial resistance and a risk of failure with subsequent therapy, patients should be instructed to follow closely the prescribed regimen.

For the eradication of H. pylori, amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.

The possibility of superinfections with fungal organisms or bacterial pathogens should be considered during therapy. In such cases, discontinue AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN and substitute appropriate treatment.

Lansoprazole delayed-release capsules, USP

Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy.

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. A temporary withdrawal of the PPI may be considered in some patients receiving treatments with high dose methotrexate (see 9.4 Drug-Drug Interactions, Methotrexate).

Drug Interactions with Antiretroviral Drugs

PPIs have been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. A change in gastric pH may change the absorption of the antiretroviral drug. Other possible mechanisms are via CYP 2Cl9.

Rilpivirine

Co-administration is contraindicated due to significant decrease in rilpivirine exposure and loss of therapeutic effect (see 2 CONTRAINDICATIONS).

Atazanavir and Nelfinavir

Co-administration with atazanavir or nelfinavir is not recommended due to decreased atazanavir and nelfinavir exposure (see the REYATAZ^® and VIRACEPT^® Product Monographs).

If the combination of AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN with atazanavir is judged unavoidable, close clinical monitoring is recommended in combination with the use of 400 mg atazanavir/100 mg ritonavir dose (see REYATAZ^® Product Monograph).

Saquinavir

If AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN is co-administered with saquinavir/ritonavir, caution and monitoring for potential saquinavir toxicities, including gastrointestinal symptoms, increased triglycerides, deep vein thrombosis and QT prolongation, are recommended. Dose reduction of saquinavir should be considered from the safety perspective for individual patients (see INVIRASE^® Product Monograph).

Clarithromycin tablets, USP

Caution should be exercised, particularly with patients at high risk of bleeding, when clarithromycin is co-administered with direct acting oral anticoagulants such as:

• dabigatran,
• rivaroxaban and
• apixaban

See 9.4 Drug-Drug Interactions.

Carcinogenesis and Mutagenesis

Lansoprazole delayed-release capsules, USP

Safety concerns of long-term treatment relate to hypergastrinemia, possible enterochromaffin-like (ECL) effect and carcinoid formation. ECL cell hyperplasia and gastric carcinoid tumours were observed in 4 animal studies. See 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity for further details.

Analysis of gastric biopsy specimens from patients after short-term treatment of proton pump inhibitors have not detected ECL cell effects similar to those seen in animal studies. Longer term studies in humans revealed a slight increase in the mean ECL-cell density, although there was no microscopic evidence of cell hyperplasia. Similar results were seen in the maintenance treatment studies, where patients received up to 15 months of lansoprazole therapy. Serum gastrin values increased significantly from their baseline values but reached a plateau after two months of therapy. By one month post-treatment, fasting serum gastrin values returned to lansoprazole therapy baseline. Moreover, results from gastric biopsies from short-term, long-term and maintenance treatment studies indicate that there are no clinically meaningful effects on gastric mucosa morphology among lansoprazole-treated patients. For further details, see information under 10.2 Pharmacodynamics and 16 NON-CLINICAL TOXICOLOGY, Carcinogenicity.

Clarithromycin tablets, USP

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.

The following in vitro mutagenicity tests have been conducted with clarithromycin: Salmonella/mammalian microsome test, bacterial induced mutation frequency test, in vitro chromosome aberration test, rat hepatocyte DNA synthesis assay, mouse lymphoma assay, mouse dominant lethal study, mouse micronucleus test. All tests had negative results except the in vitro chromosome aberration test which was weakly positive in one test and negative in another. In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin metabolites with negative results.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of amoxicillin. Studies to detect mutagenic potential of amoxicillin alone have not been conducted.

Cardiovascular

Clarithromycin tablets, USP

Clarithromycin must not be given to patients with electrolyte disturbances such as hypomagnesaemia or hypokalemia. See 2 CONTRAINDICATIONS.

Clarithromycin should be used with caution in patients with coronary artery disease, severe cardiac insufficiency, bradycardia (< 50 bpm), or when co-administered with other medicinal products associated with QT prolongation, due to the risk for QT prolongation and torsades de pointes. See 9 DRUG INTERACTIONS.

Clarithromycin is contraindicated in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia, including torsades de pointes. Clarithromycin is also contraindicated in patients with hypokalaemia due to the risk of QT prolongation and torsades de pointes. See 2 CONTRAINDICATIONS.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Kounis syndrome, a serious allergic reaction that can result in myocardial infarction, can occur as chest pain in association with an allergic reaction to amoxicillin.

Driving and Operating Machinery

Clarithromycin tablets, USP

There are no data on the effect of clarithromycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

Endocrine and Metabolism

Lansoprazole delayed-release capsules, USP

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically (see 8.5 Post-Market Adverse Reactions).

The chronic use of PPIs may lead to hypomagnesemia. Moreover, hypokalemia and hypocalcemia have been reported in the literature as accompanying electrolyte disorders.

Cyanocobalamin (Vitamin B₁₂) Deficiency

The prolonged use of proton pump inhibitors may impair the absorption of protein-bound Vitamin B₁₂ and may contribute to the development of cyanocobalamin (Vitamin B₁₂) deficiency.

Gastrointestinal

Lansoprazole delayed-release capsules, USP

When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with lansoprazole delayed-release capsules is instituted as treatment with this drug may alleviate symptoms and delay diagnosis.

Clostridium difficile-Associated Diarrhea

Decreased gastric acidity due to any means, including proton pump inhibitors (PPIs), increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors can lead to an increased risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile.

An increased risk for Clostridium difficile infection (CDI) and Clostridium difficile-associated diarrhea (CDAD) has been observed in association with PPI use in several observational studies. CDI/CDAD should be considered in the differential diagnosis for diarrhea that does not improve. Additional risk factors for CDI and CDAD include recent hospitalization, the use of antibiotics, old age and the presence of co-morbidities.

Patients should be prescribed PPIs at the lowest dose and for the shortest duration required for the condition being treated and be reassessed to ascertain whether continued PPI therapy remains beneficial.

Clarithromycin tablets, USP / Amoxicillin (amoxicillin trihydrate) capsules, USP

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including clarithromycin and amoxicillin. CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases. See 8.3 Less Common Clinical Trial Adverse Reactions.

Genitourinary

Lansoprazole delayed-release capsules, USP

In the 24-month toxicology study in rats, after 18 months of treatment, Leydig cell hyperplasia increased above the concurrent and historical control level at dosages of 15 mg/kg/day or higher (see 16 NON-CLINICAL TOXICOLOGY).

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 (see 16 NON-CLINICAL TOXICOLOGY).

These changes are associated with endocrine alterations which have not been, to date, observed in humans. For further details, see information under 10.2 Pharmacodynamics and 16 NON-CLINICAL TOXICOLOGY.

Hematologic

Amoxicillin (amoxicillin trihydrate) capsules, USP

Periodic assessment of hematopoietic function should be made during prolonged amoxicillin therapy.

Hepatic/Biliary/Pancreatic

Lansoprazole delayed-release capsules, USP

It is recommended that the initial dosing regimen need not be altered for patients with mild or moderate liver disease, but for patients with moderate impairment, doses higher than 30 mg / day should not be administered unless there are compelling clinical indications. Dose reduction in patients with severe hepatic disease should be considered.

Clarithromycin tablets, USP

Caution is advised in patients with impaired hepatic function.

Clarithromycin is principally excreted by the liver and kidney. In patients with a combination of hepatic (mild to moderate) and renal impairments, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate.

Clarithromycin is contraindicated in patients with severe hepatic failure in combination with renal impairment. See 2 CONTRAINDICATIONS.

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In some instances, hepatic failure with fatal outcomes has been reported and generally has been associated with serious underlying diseases and/or concomitant medications. Discontinue clarithromycin immediately if signs and symptoms of hepatitis occur, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Periodic assessment of hepatic function should be made during prolonged amoxicillin therapy.

Immune

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN in contraindicated in patients with a history of previous hypersensitivity to lansoprazole delayed-release capsules; clarithromycin, erythromycin, or any macrolide antibiotic; or amoxicillin or other beta-lactam antibiotics (e.g., any penicillin or cephalosporin) or any component of the formulations (including any non-medicinal ingredient, or component of the container). See 2 CONTRAINDICATIONS.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schonlein purpura, AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN should be discontinued immediately and appropriate treatment should be urgently initiated.

Lansoprazole delayed-release capsules, USP

Subacute cutaneous lupus erythematosus

Subacute cutaneous lupus erythematosus (SCLE) has been reported with the use of PPIs. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, the patient should seek medical help promptly and the healthcare professional should consider stopping AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN. The occurrence of SCLE with previous PPI treatment may increase the risk of SCLE with other PPIs (see 8.5 Post-Market Adverse Reactions).

Clarithromycin tablets, USP

Severe acute hypersensitivity reactions (including anaphylaxis) have been reported in patients receiving clarithromycin orally.

Clarithromycin should be administered with caution to any patient who has demonstrated some form of drug allergy, particularly to structurally- related drugs. If an allergic reaction to clarithromycin occurs, administration of the drug should be discontinued. Serious hypersensitivity reactions may require epinephrine, antihistamines, or corticosteroids.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, including amoxicillin. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

Severe cutaneous adverse reactions (SCAR) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported in association with beta-lactam treatment. When SCAR is suspected, AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN should be discontinued and appropriate therapy and/or measures should be taken.

Drug-induced enterocolitis syndrome, an allergic reaction with the leading symptom of protracted vomiting (1 to 4 hours after medicinal product administration), in the absence of allergic skin or respiratory symptoms, has been reported mainly in children receiving amoxicillin containing drug products. Further symptoms could comprise abdominal pain, lethargy, diarrhea, hypotension or leucocytosis with neutrophilia. In severe cases, drug-induced enterocolitis syndrome can progress to shock (see 8.5 Post-Market Adverse Reactions).

A morbilliform rash following the use of ampicillin in patients with infectious mononucleosis has been well documented and has also been reported to occur following the use of amoxicillin. Amoxicillin is contraindicated in cases where infectious mononucleosis is either suspected or confirmed. See 2 CONTRAINDICATIONS.

Monitoring and Laboratory Tests

Interference with Laboratory Tests

During treatment with antisecretory drugs, chromogranin A (CgA) increases due to decreased gastric acidity. Increased CgA levels may interfere with investigations for neuroendocrine tumours. To avoid this interference, AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN treatment should be stopped 14 days before CgA measurements (see 9.4 Drug-Drug Interactions).

Amoxicillin (amoxicillin trihydrate) capsules, USP

Periodic assessment of renal, hepatic and hematopoietic functions should be made during prolonged therapy with Amoxicillin (amoxicillin trihydrate).

Abnormal prolongation of prothrombin time (increased international normalized ratio (INR)) has been reported in patients receiving amoxicillin and oral anticoagulants (see 9.4 Drug-Drug Interactions, Table 9).

Musculoskeletal

Lansoprazole delayed-release capsules, USP

Bone Fracture

Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines (see 4.2 Recommended Dose and Dosage Adjustment and 8 ADVERSE REACTIONS).

Neurologic

Clarithromycin tablets, USP

Myasthenia Gravis

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.

Ophthalmologic

Lansoprazole delayed-release capsules, USP

Retinal atrophy

In animal studies, retinal atrophy was observed in rats dosed orally for 2 years with lansoprazole at doses of 15 mg/kg/day and above. These changes in rats are believed to be associated with the effects of taurine imbalance and phototoxicity in a susceptible animal model.

Clinical data available from long-term lansoprazole studies are not suggestive of any drug- induced eye toxicity in humans. In humans, there are presently no concerns for ocular safety with short-term lansoprazole treatment and the risks associated with long-term use for nearly 5 years appear to be negligible.

The finding of drug-induced retinal atrophy in the albino rat is considered to be species-specific with little relevance for humans. For further details, see information under 10.2 Pharmacodynamics and 16 NON-CLINICAL TOXICOLOGY, Special Toxicology.

Renal

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: Lansoprazole / clarithromycin / amoxicillin

For the eradication of H. pylori, amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.

Lansoprazole delayed-release capsules, USP

No dosage adjustment of lansoprazole is necessary in patients with renal impairment. See 4.2 Recommended Dose and Dosage Adjustment and 10 CLINICAL PHARMACOLOGY.

Clarithromycin tablets, USP

Caution is advised in patients with severe renal insufficiency.

Clarithromycin is principally excreted by the liver and kidney (see 4.2 Recommended Dose and Dosage Adjustment).

In patients with a combination of hepatic (mild to moderate) and renal impairments or in the presence of severe renal impairment, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate. For dosage adjustment recommendations, refer to the Clarithromycin Product Monograph.

Clarithromycin is contraindicated in patients with severe hepatic failure in combination with renal impairment. See 2 CONTRAINDICATIONS.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Periodic assessment of renal functions should be made during prolonged amoxicillin therapy.

Amoxicillin is excreted mostly by the kidney; the dosage for patients with renal impairment should be reduced in proportion to the degree of loss of renal function (see 4.2 Recommended Dose and Dosage Adjustment).

Reproductive Health: Female and Male Potential

• Fertility

  Lansoprazole delayed-release capsules, USP

  Reproductive studies conducted in pregnant rats at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on body surface area), and in rabbits at oral doses up to 30 mg/kg/day (16 times the recommended human dose based on body surface area), revealed no lansoprazole-related impairment of fertility, fetal malformations or developmental toxicity to fetuses or suckling neonates.

• Teratogenic Risk

  Lansoprazole delayed-release capsules, USP

  Lansoprazole is not considered to be teratogenic. Maternal toxicity and a significant increase in fetal mortality were observed in the rabbit study at doses above 10 mg/kg/day. In rats, maternal toxicity and a slight reduction in litter survival and weights were noted at doses above 100 mg/kg/day. See 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology.

  Clarithromycin tablets, USP

  Four teratogenicity studies in rats (3 with oral doses and 1 with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and 2 in rabbits (at oral doses up to 125 mg/kg/day or intravenous doses of 30 mg/kg/day administered during gestation days 6 to 18) failed to demonstrate any teratogenicity from clarithromycin. Two additional oral studies in a different rat strain at similar doses and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150 mg/kg/day administered during gestation days 6 to 15. Plasma levels after 150 mg/kg/day were 2 times the human serum levels.

  Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day during gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The 1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of 70 mg/kg/day produced fetal growth retardation at plasma levels that were 2 times the human serum levels.

  Embryonic loss has been seen in monkeys and rabbits (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).

Sensitivity/Resistance

Antibiotic Resistance in Relation to H. pylori Eradication

To avoid failure of the eradication treatment with a potential for developing antimicrobial resistance and a risk of failure with subsequent therapy, patients should be instructed to follow closely the prescribed regimen.

Development of Drug Resistant Bacteria

Prescribing clarithromycin tablets or amoxicillin capsules in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.

Clarithromycin tablets, USP

Use of any antimicrobial therapy, such as clarithromycin, to treat H. pylori infection may select for drug-resistant organisms.

Three patients [3/82 (3.7%)] who had isolates susceptible to clarithromycin pretreatment and were treated with the triple therapy regimen remained H. pylori positive post-treatment. None of the isolates from these 3 patients had susceptibility results available after treatment with triple therapy; therefore, it is unknown whether or not these patients developed resistance to clarithromycin. Sixteen percent of the patients treated with the dual therapy regimen developed clarithromycin resistance post-treatment. Therefore, development of clarithromycin resistance should be considered as a possible risk.

Amoxicillin (amoxicillin trihydrate) capsules, USP

If superinfections with mycotic or bacterial pathogens occur (usually involving Aerobacter, Pseudomonas or Candida) treatment with Amoxicillin should be discontinued and appropriate therapy instituted.

Use in Women

Over 4,000 women were treated with lansoprazole. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse events are also similar to those seen in males.

7.1 Special Populations

7.1.1 Pregnant Women

Lansoprazole delayed-release capsules, USP

There are no adequate or well-controlled studies in pregnant women. Therefore, lansoprazole should be used with caution during pregnancy, only if the potential benefit justifies the potential risk to the fetus.

Clarithromycin tablets, USP

Clarithromycin should not be used during pregnancy except where a physician has carefully weighed the benefits against risks and deemed no alternative therapy appropriate, particularly during the first 3 months of pregnancy. If pregnancy occurs while taking the drug, the patient should be apprised of the potential hazard to the fetus.

There are no adequate and well-controlled studies in pregnant women. Based on variable results obtained from animal studies and experience in humans, the possibility of adverse effects on embryofoetal development cannot be excluded. Some observational studies evaluating exposure to clarithromycin during the first and second trimester have reported an increased risk of miscarriage compared to no antibiotic use or other antibiotic use during the same period. The available epidemiological studies on the risk of major congenital malformations with use of macrolides including clarithromycin during pregnancy provide conflicting results. See 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

AMOXICILLIN (amoxicillin trihydrate) capsules, USP

The safety of amoxicillin in the treatment of infections during pregnancy has not been established. If the administration of amoxicillin to pregnant patients is considered to be necessary, its use requires that the potential benefits be weighed against the possible hazards to the fetus.

7.1.2 Breast-feeding

Lansoprazole delayed-release capsules, USP

Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. As many drugs are excreted in human milk, lansoprazole should not be given to breast-feeding mothers unless its use is considered essential. In this case breast-feeding should be avoided.

Clarithromycin tablets, USP

The safety of clarithromycin for use during breast-feeding of infants has not been established.

Clarithromycin is excreted in human breast milk. It has been estimated that an exclusively breastfed infant would receive about 1.7% of the maternal weight-adjusted dose of clarithromycin.

Preweaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma.

7.1.3 Pediatrics

Pediatrics (1 to 17 years of age)

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

The safety and effectiveness of lansoprazole / clarithromycin / amoxicillin in pediatric patients infected with H. pylori have not been established.

Lansoprazole delayed-release capsules

Developmental toxicity studies revealed that exposure to lansoprazole in juvenile rats starting at postnatal Days 7, 14, and 21 (approximately equivalent to neonatal, 1, and 2 year old human, respectively) resulted in development of heart valve thickening (see 16 NON-CLINICAL TOXICOLOGY, Juvenile Toxicity). However, the development of heart valve thickening has not been reported in pediatric clinical trials or in post-market reports.

7.1.4 Geriatrics

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

Elderly patients may suffer from asymptomatic renal and hepatic dysfunction. Care should be taken when administering AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN to this patient population (see 7 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic and 7 WARNINGS AND PRECAUTIONS, Renal).

Lansoprazole delayed-release capsules, USP

Benefits of use of PPIs should be weighed against the increased risk of fractures as patients in this category (> 71 years of age) may already be at high risk for osteoporosis-related fractures. If the use of PPIs is required, they should be managed carefully according to established treatment guidelines (see 4.2 Recommended Dose and Dosage Adjustment and 8 ADVERSE REACTIONS).

Ulcer healing rates in elderly patients are similar to those in younger age groups. The incidence rates of adverse events and laboratory test abnormalities are also similar to those seen in other age groups. The initial dosing regimen need not be altered for elderly patients, but subsequent doses higher than 30 mg / day should not be administered unless additional gastric acid suppression is necessary.

Clarithromycin tablets, USP

Dosage adjustment should be considered in elderly patients with severe renal impairment. In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg every 12 hours, the maximum concentrations of clarithromycin and 14-OH clarithromycin were increased. The AUC was also increased. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Amoxicillin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

The most frequently reported (≥3%) adverse events for patients who received triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%).

Lansoprazole delayed-release capsules, USP

Worldwide, over 10,000 patients have been treated with lansoprazole delayed-release capsules during Phase II-III short-term and long-term clinical trials involving various dosages and duration of treatment. In general, lansoprazole treatment has been well tolerated.

Clarithromycin tablets, USP

The majority of side effects observed in clinical trials involving 3563 patients treated with clarithromycin were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections discontinued therapy because of drug-related side-effects. The most common drug-related adverse reactions in adults taking clarithromycin were nausea, diarrhea, abdominal pain, dyspepsia, headache, taste perversion and vomiting.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

Patients in the 7-day triple therapy regimen reported fewer adverse events than those in the 10- and/or 14-day triple therapy regimens. 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.

Combination Therapy with Clarithromycin and Amoxicillin

In clinical trials using combination therapy with lansoprazole plus clarithromycin and amoxicillin, no adverse reactions related to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that have been previously reported with lansoprazole, clarithromycin, or amoxicillin.

For more information on adverse reactions with lansoprazole, clarithromycin or amoxicillin, refer to their respective Product Monographs, under the 8 ADVERSE REACTIONS section.

Lansoprazole delayed-release capsules, USP

The following adverse events were reported to have a possible or probable relationship to drug as described by the treating physician in 1% or more of lansoprazole delayed-release capsules-treated patients who participated in placebo- and positive-controlled trials (Table 3 and Table 4, respectively). Numbers in parentheses indicate the percentage of the adverse events reported.

Table 3 - Incidence of Possibly or Probably Treatment-Related Adverse Events in Short-Term, Placebo-Controlled Studies in Takeda* Safety Database

In the Takeda Safety Database, all short-term, Phase II/III studies, 1 or more treatment-emergent adverse events were reported by 715/1359 (52.6%) lansoprazole-treated patients; of those considered to be possibly or probably treatment-related adverse events, 1 or more were reported by 276/1359 (20.3%) lansoprazole-treated patients. In all short-term, Phase II/III studies, 1 or more treatment-emergent adverse events were reported by 150/254 (59.1%) placebo-treated patients; of those considered to be possibly or probably treatment-related adverse events, 1 or more were reported by 56/254 (22.0%).

The most frequent adverse events reported in the European short-term studies were diarrhea (3.3%), laboratory test abnormal (2.3%), headache (1.5%), constipation (1.2%), asthenia (1.1%), dizziness (1.1%), and abdominal pain (1.0%). The most frequent adverse events reported in the Asian short-term studies were unspecified laboratory test abnormalities (7.3%), eosinophilia (1.0%), and increased SGPT (1.0%).

Table 4 - Incidence of Possibly or Probably Treatment-Related Adverse Events in Short-Term, Positive-Controlled Studies in Takeda* Safety Database

8.3 Less Common Clinical Trial Adverse Reactions

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

The additional adverse reactions which were reported as possibly or probably related to treatment (< 3%) in clinical trials when all 3 components of this therapy were given concomitantly are listed below and divided by body system:

Lansoprazole delayed-release capsules, USP

Additional adverse experiences occurring in < 1% of patients or subjects in domestic and/or international trials, or occurring since the drug was marketed, are shown below within each body system. Other adverse reactions have been observed during post-marketing surveillance; see 8.5 Post-Market Adverse Reactions.

* The majority of hematologic cases received were foreign-sourced and their relationship to lansoprazole was unclear.

Clarithromycin tablets, USP

The following adverse reactions from the Clarithromycin Product Monograph, reported during clinical trials and during post-marketing surveillance, are provided for information:

Amoxicillin (amoxicillin trihydrate) capsules, USP

As with other penicillins, it may be expected that untoward reactions will be related to sensitivity phenomena. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and cephalosporins and in those with a history of allergy, asthma, hay fever or urticaria.

The following adverse reactions have been reported as associated with the use of amoxicillin.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Lansoprazole delayed-release capsules, USP

In addition, 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 gamma globulins, increased GGTP,

increased/decreased/abnormal white blood cells (WBC), abnormal AG ratio, abnormal red blood cells (RBC), bilirubinemia, eosinophilia, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased lactate dehydrogenase (LDH), increased/decreased/abnormal platelets, and increased gastrin levels. 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 lansoprazole, respectively had enzyme elevations > 3 x upper limit of normal range at the final treatment visit. None of these lansoprazole patients reported jaundice at any time during the study.

For more information on laboratory value changes with amoxicillin, refer to the respective Product Monograph, under the 8 ADVERSE REACTIONS section.

Clarithromycin tablets, USP

Changes in laboratory values with possible clinical significance reported during clinical studies or during post-marketing surveillance are displayed in Table 5.

Table 5 - Abnormal Hematologic and Clinical Chemistry Findings in Patients with Respiratory Tract or Skin Infections Treated with Clarithromycin Tablets

8.5 Post-Market Adverse Reactions

Lansoprazole delayed-release capsules, USP

These events were reported during post-marketing surveillance. Estimates of frequency cannot be made since such events are reported voluntarily from a population of unknown size. Due to the uncontrolled nature of spontaneous reports, a clear causal relationship to lansoprazole cannot be established.

In an estimated exposure of 240 million patients worldwide (in both post-marketing surveillance and the clinical trials), the most commonly reported ophthalmic adverse events are amblyopia (13) and vision blurred (67) according to the MedDRA terminology. All the 13 cases of amblyopia had the reported term/verbatim “blurred or smeary vision”. Only 2 of these 13 reports were considered serious, and both are foreign-sourced reports with very little information provided. Among the 67 reports with the “vision blurred”, 10 were considered serious and might be related to optic neuritis/neuropathy, whether or not believed related to the drug. In 2 of these 10 cases, 1 of the examining ophthalmologists proposed a diagnosis of anterior-ischemic optic neuropathy (AION). Eight out of the 10 cases were foreign-sourced. Only 2 US-sourced serious cases involved the report of blurred vision. Both were consumer reports without any detailed information. No physician assessed any causality in either case.

Withdrawal of long term PPI therapy can lead to aggravation of acid related symptoms and may result in Rebound Acid Hyper-secretion.

There have been post-marketing reports of subacute cutaneous lupus erythematosus (SCLE) (See 7 WARNINGS AND PRECAUTIONS, Immune).

Clarithromycin tablets, USP

The following list of adverse events is a compilation of adverse reactions from Post-marketing Surveillance and Post-marketing Clinical Studies for all clarithromycin formulations.

Table 6 - Clarithromycin Post-Market Adverse Drug Reactions

Colchicine

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see 2 CONTRAINDICATIONS).

Amoxicillin (amoxicillin trihydrate) capsules, USP

Gastrointestinal: Drug-induced enterocolitis syndrome has been reported in patients receiving amoxicillin containing drug products (see 7 WARNINGS and PRECAUTIONS, Immune).

Neurological: Amoxicillin can lead to cases of aseptic meningitis of unknown frequency.

Other immune system disorders: Kounis syndrome.

Skin and subcutaneous tissue disorders: Linear IgA disease has also been reported in patients receiving amoxicillin containing drug products.

9 DRUG INTERACTIONS

9.1 Serious Drug Interaction

9.2 Drug Interactions Overview

Lansoprazole delayed-release capsules, USP

Lansoprazole is metabolized through the cytochrome P450 system, specifically through CYP3A and CYP2C19. 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, acetylsalicylic acid, ibuprofen, phenytoin, prednisone, diazepam, clarithromycin, propranolol, amoxicillin or terfenadine in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

Drugs that Inhibit or Induce CYP2C19

Inhibitors of CYP2C19 such as fluvoxamine would likely increase the systemic exposure of lansoprazole. Inducers of CYP2C19 may decrease the systemic exposure of lansoprazole.

Drugs with pH Dependent Absorption Pharmacokinetics

Lansoprazole causes a profound and long lasting inhibition of gastric acid secretion; therefore, 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 tablets, USP

Many categories of drugs are metabolized by CYP3A and/or transported by P-gp located in the liver and in the intestine. Some drugs inhibit and others induce the activities of CYP3A and/or P-gp. Administration of such inhibitors or inducers may impact upon the metabolism. In some cases serum concentration may be increased and in others decreased. Care must therefore be exercised when co-administering such drugs.

Clarithromycin is reported to be an inhibitor of CYP3A and P-gp. This may lead to increased or prolonged serum levels of those drugs also metabolized by CYP3A or transported by P-gp when co-administered with clarithromycin. For such drugs the monitoring of their serum concentrations may be necessary.

Clarithromycin should be used with caution in patients receiving treatment with other drugs known to be CYP3A and/or P-gp substrates, especially if the CYP3A/P-gp substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by CYP3A or transported by P-gp. Dosage adjustments may be considered, and when possible, serum concentrations of these drugs should be monitored closely in patients concurrently receiving clarithromycin.

With certain drugs, co-administration of clarithromycin is contraindicated or should be avoided (see Table 8).

Effects of Clarithromycin on Other Drugs:

The following drugs or drug classes are known or suspected to be metabolized by the same CYP3A isozyme: alprazolam, astemizole, carbamazepine, cilostazol, cisapride, cyclosporine, disopyramide, domperidone, ergot alkaloids, ibrutinib, lomitapide, lovastatin, methylprednisolone, midazolam, omeprazole, oral anticoagulants (e.g. warfarin, rivaroxaban, apixaban), atypical antipsychotics (e.g. quetiapine), pimozide, quinidine, rifabutin, sildenafil, simvastatin, tacrolimus, terfenadine, triazolam and vinblastine, but this list is not comprehensive. See 9.4 Drug-Drug Interactions.

Direct acting oral anticoagulants (DOACs): The DOAC dabigatran is a substrate for the efflux transporter P-gp. Rivaroxaban and apixaban are metabolised via CYP3A4 and are also substrates for P-gp. Caution should be exercised when clarithromycin is co-administered with these agents, particularly in patients at high risk of bleeding. See 7 WARNINGS AND PRECAUTIONS, General.

9.4 Drug-Drug Interactions

Lansoprazole delayed-release capsules, USP

Table 7 summarizes the established and potential drug interactions with lansoprazole.

Table 7 - Established or Potential Drug-Drug Interactions with Lansoprazole

Clarithromycin tablets, USP

Some of the drug-drug interactions which have been reported between clarithromycin-macrolides and other drugs or drug categories are listed in Table 8.

The drugs listed in Table 8 are based on drug interactions case reports, clinical trials, or potential interactions due to the expected mechanism of the interaction.

Table 8 - Established or Potential Drug-Drug Interactions with Clarithromycin

Amoxicillin (amoxicillin trihydrate) capsules, USP

Table 9 - Established or Potential Drug-Drug Interactions with Amoxicillin

Legend: T = Theoretical

9.5 Drug-Food Interactions

Lansoprazole delayed-release capsules, USP

Food reduces the peak concentration and the extent of absorption of lansoprazole. Therefore, it is recommended that lansoprazole be administered in the morning prior to breakfast.

Clarithromycin tablets, USP

Clarithromycin tablets may be given with or without meals.

9.6 Drug-Herb Interactions

Clarithromycin tablets, USP

St. John’s Wort (Hypericum perforatum) is an inducer of CYP3A and may induce the metabolism of clarithromycin. This may result in sub-therapeutic levels of clarithromycin leading to reduced efficacy.

9.7 Drug-Laboratory Test Interactions

Lansoprazole delayed-release capsules, USP

During treatment with antisecretory drugs, chromogranin A (CgA) increases due to decreased gastric acidity. Increased Chromogranin A (CgA) level may interfere with investigations for neuroendocrine tumours. To avoid this interference, AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN treatment should be stopped 14 days before CgA measurements (see 10.2 Pharmacodynamics, Pharmacodynamic Properties).

Amoxicillin (amoxicillin trihydrate) capsules, USP

Amoxicillin may:

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Lansoprazole delayed-release capsules, USP

Lansoprazole delayed-release capsules inhibits the gastric H⁺, K⁺-ATPase (the proton pump) which catalyzes the exchange of H⁺ and K⁺. It is effective in the inhibition of both basal acid secretion and stimulated acid secretion.

Humans

Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or histamine H₂ 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. The inhibition of gastric acid secretion persists for up to 36 hours after a single dose. Thus, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.

Clarithromycin tablets, USP

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria and suppressing protein synthesis.

10.2 Pharmacodynamics

Eradication of Helicobacter pylori

Helicobacter pylori is considered to be a major factor in the etiology of duodenal ulcer disease. The presence of H. pylori may damage the mucosal integrity due to the production of enzymes (catalase, lipases, phospholipases, proteases, and urease), adhesins and toxins; the inflammatory response generated in this manner contributes to mucosal damage.

The concomitant administration of an antimicrobial(s) such as clarithromycin and amoxicillin, and an antisecretory agent such as lansoprazole, improves the eradication of H. pylori as compared to individual drug administration. The higher pH resulting from antisecretory treatment, optimizes the environment for the pharmacologic action of the antimicrobial agent(s) against H. pylori.

Lansoprazole delayed-release capsules, USP

In healthy subjects, single and multiple doses of lansoprazole delayed-release capsules (15 mg to 60 mg) have been shown to decrease significantly basal gastric acid output and to increase significantly mean gastric pH and percent of time at pH > 3 and 4. These doses have also been shown to reduce significantly meal-stimulated gastric acid output and gastric secretion volume. Single or multiple doses of lansoprazole delayed-release capsules (10 mg to 60 mg) reduced pentagastrin-stimulated acid output. In addition, lansoprazole delayed-release capsules have been demonstrated to reduce significantly basal and pentagastrin-stimulated gastric acid secretion among Duodenal Ulcer and hypersecretory patients, and basal gastric acid secretion among patients with Gastric Ulcer disease.

A dose-response effect was analyzed by considering the results from clinical pharmacology studies that evaluated more than one dose of lansoprazole delayed-release capsules. The results indicated that, in general, as the dose was increased from 7.5 mg to 30 mg, there was a decrease in mean gastric acid secretion and an increase in the average time spent at higher pH values (pH > 4).

The results of pharmacodynamic studies with lansoprazole delayed-release capsules in normal subjects suggest that doses of 7.5 to 10 mg are substantially less effective in inhibiting gastric acid secretion than doses of 15 mg or greater. In view of these results, the doses of lansoprazole delayed-release capsules evaluated in the principal clinical trials ranged from 15 mg to 60 mg daily.

Pharmacodynamic Properties

During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours.

Available published evidence suggests that proton pump inhibitors should be discontinued 14 days prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, Interference with Laboratory Tests).

Humans

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. Lansoprazole also significantly reduced pentagastrin-stimulated acid output. In patients with hyper secretion 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 to omeprazole 20 mg for 5 days, the following effects of lansoprazole on intragastric pH were noted (Table 10).

Table 10 - Mean Antisecretory Effects of Lansoprazole After Multiple Daily Dosing

After the initial dose in this study, increased gastric pH was seen within 1 to 2 hours with lansoprazole 30 mg, 2 to 3 hours with lansoprazole 15 mg, and 3 to 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 to 2 hours postdosing with lansoprazole 15 mg and omeprazole 20 mg.

Higher levels of acid suppression have been predicted to potentiate the activity of antibiotics in eradicating H. pylori. The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of lansoprazole delayed-release capsules given once daily, twice daily and three times a day (Table 11).

Table 11 - Mean Antisecretory Effects After 5 Days of Twice Daily and Three Times Daily Dosing of Lansoprazole

The inhibition of gastric acid secretion as measured by intragastric pH returns gradually to normal over 2 to 4 days after multiple doses. There is no indication of rebound gastric acidity.

Other gastric and esophageal effects

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 17% in blood flow in the antrum, pylorus and duodenal bulb was seen. Lansoprazole did not significantly affect gastric emptying of liquids, but significantly slowed the gastric emptying of digestible solids. Esophageal motility and lower esophageal sphincter tone were not modified by lansoprazole therapy. Lansoprazole increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. In patients with gastric ulcer, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice; however no significant increase in nitrosamine concentrations were observed.

Enterochromaffin-like cell effects / Carcinoid formation

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 rats. 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 one year toxicity study. Hypergastrinemia secondary to prolonged and sustained hypochlorhydria, such as that induced by high doses of ranitidine, omeprazole, and surgery, has been postulated to be the mechanism by which ECL cell hyperplasia and gastric carcinoid tumors develop.

Gastric biopsy specimens from the body of the stomach from over 300 patients treated continuously with lansoprazole for 8 weeks to 120 weeks have not shown evidence of ECL effects similar to those seen in rats. Longer term data are needed to rule out the possibility of an increased risk for the development of gastric carcinoid tumors in patients receiving long-term therapy with lansoprazole.

Serum gastrin effects

Fasting serum gastrin levels increased modestly during the first 2 to 4 weeks of therapy with 15 to 60 mg of lansoprazole. This increase was dose-dependent. Median serum gastrin values in over 2100 patients treated with lansoprazole 15 to 60 mg remained within normal range and generally increased 1.5 to 2 fold. Gastrin values returned to pretreatment levels within 4 weeks after discontinuation of therapy.

Clarithromycin tablets, USP

Helicobacter pylori

The presence of H. pylori may damage the mucosal integrity and defenses so that exposure to acid/pepsin, even in normal concentrations, produces ulceration.

H. pylori displays potent urease activity which may produce an alkaline environment around the organism. Excess ammonia produced by urea hydrolysis is toxic to mucosal cells and may lead to parietal cell failure and/or to a disturbance of the normal negative feedback of acid to the antral G-cells which secrete gastrin. In addition, H. pylori produces catalases, lipases, phospholipases, proteases, adhesins and toxins. These enzymes may further degrade the mucous layer and damage the epithelial cell membrane. Also, the presence of H. pylori stimulates an active inflammatory response which contributes to mucosal damage.

Gustavson et al. (1995) showed that concentrations of 39.3, 23.1 mcg/g and 25.2 mcg/g clarithromycin were achieved in the gastric mucosa 2, 4, and 6 hours respectively after administering 500 mg clarithromycin t.i.d. and that corresponding concentrations of the 14 hydroxy-metabolite were 3.2, 1.1, and 4.1 mcg/g respectively. Similar results were obtained whether or not clarithromycin was given alone or together with 40 mg omeprazole once daily (Logan et al., 1995). Although the activity of the hydroxy metabolite is about half of the parent drug and its concentrations are lower, it may still contribute antibacterial activity.

10.3 Pharmacokinetics

AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy:

Lansoprazole / clarithromycin / amoxicillin

The pharmacokinetics of the drugs when all three components of the AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN (lansoprazole capsules, clarithromycin tablets and amoxicillin capsules) were co-administered, has not been studied. Studies have shown no clinically significant interactions between lansoprazole and amoxicillin or lansoprazole and clarithromycin when co-administered. There is no information about the gastric mucosal concentrations of lansoprazole, amoxicillin and clarithromycin after administration of these agents concomitantly. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.

Lansoprazole delayed-release capsules, USP

Lansoprazole delayed-release capsules contain an enteric-coated granule formulation of lansoprazole to ensure that absorption of lansoprazole begins only after the granules leave the stomach (lansoprazole is acid-labile). Peak plasma concentrations of lansoprazole (C_max) and the area under the plasma concentration curve (AUC) of lansoprazole are approximately proportional in doses from 15 mg to 60 mg after single-oral administration. Lansoprazole pharmacokinetics are unaltered by multiple dosing and the drug does not accumulate.

Lansoprazole is highly bioavailable when administered orally. In a definitive absolute bioavailability study, the absolute bioavailability was shown to be 86% for a 15 mg capsule and 80% for a 30 mg capsule. First pass effect is apparently minimal.

Table 12 summarizes the pharmacokinetic parameters (T_max, T_½, AUC and C_max) of lansoprazole delayed-release capsules in healthy subjects.

Table 12 - Pharmacokinetic Parameters of Lansoprazole Delayed-Release Capsules Pooled Across Phase I Studies

Clarithromycin tablets, USP

A summary of clarithromycin pharmacokinetic parameters following the administration of clarithromycin film-coated tablets is provided in Table 13.

Table 13 - Clarithromycin Pharmacokinetic Parameters Following the Administration of Clarithromycin Film-Coated Tablets

Absorption

Lansoprazole delayed-release capsules, USP

The absorption of lansoprazole is rapid, with mean peak plasma levels of lansoprazole occurring at approximately 1.7 hours. Peak plasma concentrations of lansoprazole (C_max) and the area under the plasma concentration curve (AUC) are approximately proportional to dose throughout the range that has been studied (up to 60 mg).

Absorption with Food

Food reduces the peak concentration and the extent of absorption by about 50% to 70%. Moreover, the results of a pharmacokinetic study that compared the bioavailability of lansoprazole following a.m. dosing (fasting) versus p.m. dosing (3 hours after a meal) indicated that both C_max and AUC values were increased by approximately 2-fold or more with a.m. dosing. Therefore, it is recommended that lansoprazole delayed-release capsules be administered in the morning prior to breakfast.

Absorption with Antacids

Simultaneous administration of lansoprazole delayed-release capsules with aluminum and magnesium hydroxide or magaldrate resulted in lower peak serum levels, but did not significantly reduce the bioavailability of lansoprazole.

In a single-dose crossover study when 30 mg of lansoprazole was administered concomitantly with 1 gram of sucralfate in healthy volunteers, absorption of lansoprazole was delayed and its bioavailability was reduced. The value of lansoprazole AUC was reduced by 17% and that for C_max was reduced by 21%.

In a similar study when 30 mg of lansoprazole was administered concomitantly with 2 grams of sucralfate, lansoprazole AUC and C_max were reduced by 32% and 55%, respectively. When lansoprazole dosing occurred 30 minutes prior to sucralfate administration, C_max was reduced by only 28% and there was no statistically significant difference in lansoprazole AUC. Therefore, lansoprazole may be given concomitantly with antacids but should be administered at least 30 minutes prior to sucralfate.

Clarithromycin tablets, USP

The absolute bioavailability of 250 mg and 500 mg clarithromycin tablets is approximately 50%. Food slightly delays the onset of clarithromycin absorption but does not affect the extent of bioavailability. Therefore, clarithromycin tablets may be given without regard to meals.

In fasting healthy human subjects, peak serum concentrations are attained within 2 hours after oral dosing. Steady-state peak serum clarithromycin concentrations, which are attained within 2 to 3 days, are approximately 1 mg/L with a 250 mg dose twice daily and 2 to 3 mg/L with a 500 mg dose twice daily. The elimination half-life of clarithromycin is about 3 to 4 hours with 250 mg twice daily dosing but increases to about 5 to 7 hours with 500 mg administered twice daily.

Clarithromycin displays non-linear pharmacokinetics at clinically relevant doses, producing greater than proportional increases in AUC with increasing dose. The degree of non-linearity is reduced on chronic clarithromycin administration (i.e., at steady state). The non-linearity of the pharmacokinetics of the principle metabolite, 14-OH clarithromycin, is slight at the recommended doses of 250 mg and 500 mg administered twice daily. With 250 mg twice daily, 14-OH clarithromycin attains a peak steady state concentration of about 0.6 mg/L and has an elimination half-life of 5 to 6 hours. With a 500 mg twice daily dose, the peak steady-state of 14-OH concentrations of clarithromycin are slightly higher (up to 1 mg/L) and its elimination half-life is about 7 hours. With either dose, the steady-state concentration of this metabolite is generally attained within 2 to 3 days.

Adult Patients with HIV

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin twice a day to adult patients with HIV infection were similar to those observed in healthy volunteers. However, at the higher clarithromycin doses which may be required to treat mycobacterial infections, clarithromycin concentrations can be much higher than those observed at 500 mg clarithromycin doses. In adult HIV-infected patients taking 2000 mg/day in two divided doses, steady-state clarithromycin C_max values ranged from 5 to 10 mg/L. C_max values as high as 27 mg/L have been observed in HIV-infected adult patients taking 4000 mg/day in two divided doses of clarithromycin tablets.

Elimination half-lives appeared to be lengthened at these higher doses as well. The higher clarithromycin concentrations and longer elimination half-lives observed at these doses are consistent with the known non-linearity in clarithromycin pharmacokinetics.

Clarithromycin and omeprazole

Clarithromycin 500 mg three times daily and omeprazole 40 mg once daily were studied in fasting healthy adult subjects. When clarithromycin was given alone as 500 mg every 8 hours, the mean steady state C_max value was approximately 3.8 mcg/mL and the mean C_min value was approximately 1.8 mcg/mL. The mean AUC_0-8 for clarithromycin was 22.9 mcg∙hr/mL. The T_max and half life were 2.1 hrs and 5.3 hrs, respectively, when clarithromycin was dosed at 500 mg t.i.d. When clarithromycin was administered with omeprazole, increases in omeprazole half-life and AUC_0-24 were observed. For all subjects combined, the mean omeprazole AUC_0-24 was 89% greater and the harmonic mean for omeprazole t_½ was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state C_max, C_min, and AUC_0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively over values achieved when clarithromycin was administered with placebo.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Amoxicillin is stable in the presence of gastric acid and is well absorbed from the gastrointestinal tract and may be given with no regard to food. The half-life of amoxicillin is 61.3 minutes.

Orally administered doses of 500 mg amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 5.5 to 7.5 mcg/mL.

Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin.

Amoxicillin is stable in the presence of gastric acid. Amoxicillin is rapidly and well absorbed after oral administration to fasting subjects. It was found in a recent study that peak serum antibiotic levels were reduced by 50% in subjects receiving amoxicillin immediately following a standard meal. Reducing the dose–water volume given with amoxicillin from 250 to 25 mL in fasted subjects also caused a significant reduction in serum amoxicillin levels. This may be due to the low water solubility of amoxicillin trihydrate (1000 mg in 370 mL water). In addition, food ingestion immediately before dosing also reduced the urinary excretion.

Peak serum levels are attained between 1 and 2 hours after drug administration. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid. Amoxicillin is excreted largely unchanged in the urine while 10 to 25% of the administered dose is excreted in the form of penicilloic acid. The excretion of amoxicillin can be delayed by concurrent administration of probenecid. Amoxicillin is not highly protein bound. In blood serum, amoxicillin is approximately 17 to 18% protein bound compared to 59% for penicillin G.

The following amoxicillin mean serum levels were found following the administration of 250 mg capsules of Amoxicillin to 12 healthy adult volunteers:

Peak blood serum levels averaged 3.8 mcg/mL (range 2.35 to 6.38 mcg/mL) and the T_max was 1.50 hours. The mean biological half-life (t_½) was found to be 55.8 minutes with a mean elimination rate constant K_el of 0.7456 hour-1.

Twelve normal male subjects participated in a bioavailability study of Amoxicillin Granules for Suspension. Each subject was given 5 mL (250 mg) of reconstituted Amoxicillin Granules for Suspension in a single dose.

The following amoxicillin mean serum levels were found:

Peak plasma concentrations from 2.65 to 5.75 mcg/mL were obtained with a mean C_max of 4.24 ± 0.74 mcg/mL. The time required to reach peak concentrations ranged from 0.5 to 1.5 hours, with a T_max mean of 1.00 ± 0.21 hour.

The AUC's calculated for 0 to 7 hours ranged from 8.475 to 12.865 mcg∙h/mL. The mean AUC was 10.713 ± 1.443 mcg∙h/mL. The mean biological half-life for Amoxicillin Granules for Suspension was 26.4 minutes. The mean elimination rate constant (K_el) was 1.57 hour-1.

The administration of 500 mg amoxicillin to healthy fasting subjects has been reported to produce peak mean serum levels of 10.8 mcg/mL and 6.75 mcg/mL. Additional studies in healthy volunteers with normal renal function receiving 500 mg doses, indicated that peak serum levels could vary from 5.0 to 10.8 mcg/mL. Serum amoxicillin half-life values reported in the literature vary from 1 to 1.3 hours. About 60 to 80% of an oral dose of amoxicillin is excreted in the urine. In the presence of renal impairment the serum half-life increases (between 7 and 10 hours), necessitating a reduction in the dosage administered.

Distribution

Lansoprazole delayed-release capsules, USP

The apparent volume of distribution of lansoprazole is approximately 15.7 (± 1.9) L, distributing mainly in extracellular fluid. Lansoprazole is 97% bound to plasma proteins. The mean total body clearance (CL) of lansoprazole was calculated at 31 ± 8 L/h, and the volume of distribution (V_ss) was calculated to be 29 (± 4) L.

Clarithromycin tablets, USP

Clarithromycin distributes readily into body tissues and fluids, and provides tissue concentrations that are higher than serum concentrations. Examples from tissue and serum concentrations are presented in Table 14.

Table 14 - Representative Clarithromycin Tissue and Serum Concentrations Following the Administration of 250 mg b.i.d of Clarithromycin Film-Coated Tablets

Amoxicillin (amoxicillin trihydrate) capsules, USP

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when the meninges are inflamed. Amoxicillin is not highly protein-bound. In serum, amoxicillin is approximately 20% protein-bound as compared to 60% for penicillin G.

Metabolism

Lansoprazole delayed-release capsules, USP

Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma; the hydroxylated sulfinyl and the sulfone derivatives of lansoprazole. These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into 2 active species that inhibit acid secretion by blocking the proton pump (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. The 2 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 over 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect the duration of suppression of gastric acid secretion.

Clarithromycin tablets, USP

Clarithromycin is principally excreted by the liver and kidney. The major metabolite found in urine is 14-OH-clarithromycin.

Elimination

Lansoprazole delayed-release capsules, USP

Following single dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine. After a 30 mg single oral dose of ¹⁴C-lansoprazole, approximately one- third of the dose was excreted in the urine and approximately two-thirds were recovered in the feces. This implies a significant biliary excretion of the metabolites of lansoprazole.

Clarithromycin tablets, USP

At 250 mg twice daily, approximately 20% of an orally administered dose of clarithromycin film-coated tablet is excreted in the urine as the unchanged parent drug. The urinary excretion of unchanged clarithromycin is somewhat greater (approximately 30%) with 500 mg twice daily dosing. The renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH-clarithromycin which accounts for an additional 10 to 15% of the dose with twice daily dosing at either 250 mg or 500 mg. Most of the remainder of the dose is eliminated in the feces, primarily via the bile. About 5 to 10% of the parent drug is recovered from the feces. Fecal metabolites are largely products of N-demethylation, 14-hydroxylation or both.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Most of the amoxicillin is excreted unchanged in urine; its excretion can be delayed by concurrent administration of probenecid.

Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours.

Special Populations and Conditions

• Pediatrics

  AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN Triple Therapy: lansoprazole / clarithromycin / amoxicillin

  The safety and effectiveness of AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN in pediatric patients infected with H. pylori have not been established.

• Geriatrics

  Lansoprazole delayed-release capsules, USP

  The results from the studies that evaluated the pharmacokinetics of lansoprazole following oral administration in an older population revealed that in comparison with younger subjects, older subjects exhibited significantly larger AUCs and longer t_½s. Lansoprazole did not accumulate in the older subjects upon multiple dosing since the longest mean t_½ in the studies was 2.9 hours, and lansoprazole is dosed once daily. C_max in the elderly was comparable to that found in adult subjects.

  Clarithromycin tablets, USP

  In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg of clarithromycin every 12 hours, the maximum concentrations of clarithromycin and 14-OH clarithromycin were increased. The AUC was also increased. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients (see 7 WARNINGS AND PRECAUTIONS, Renal).

• Sex

  In a study comparing 12 male and 6 female subjects, no gender differences were found in pharmacokinetics or intragastric pH results (see 7 WARNINGS AND PRECAUTIONS, Gastrointestinal, Use in Women).

• Ethnic Origin

  The pooled pharmacokinetic parameters of oral administered lansoprazole from 12 U.S. Phase I studies (N=513) were compared to the mean pharmacokinetic parameters from 2 Asian studies (N=20). The mean AUCs of lansoprazole in Asian subjects are approximately twice that seen in pooled U.S. data, however, the inter-individual variability is high. The C_max values are comparable.

• Hepatic Insufficiency

  Lansoprazole delayed-release capsules, USP

  As would be expected with a drug that is primarily metabolized by the liver, in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) chronic hepatic disease, the plasma half-life of the drug after oral administration increased to 5.2 hours compared to the 1.5 hours half-life in healthy subjects. An increase in AUC of 3.4 fold was observed in patients with hepatic impairment versus healthy subjects (7096 versus 2645 ng∙h/mL) which was due to slower elimination of lansoprazole; however, C_max was not significantly affected. Dose reduction in patients with severe hepatic disease should be considered.

  Clarithromycin tablets, USP

  The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in subjects with impaired hepatic function when compared to healthy subjects (see 7 WARNINGS AND PRECAUTIONS and 4.2 Recommended Dose and Dosage Adjustment).

• Renal Insufficiency

  Lansoprazole delayed-release capsules, USP

  In patients with mild (Clcr 40 to 80 mL/min), moderate (Clcr 20 to 40 mL/min) and severe (Clcr < 20 mL/min) chronic renal impairment, the disposition of lansoprazole after oral administration was very similar to that of healthy volunteers.

  The impact of dialysis on lansoprazole was evaluated from a pharmacokinetic standpoint, and there were no significant differences in AUC, C_max or t_½ between dialysis day and dialysis-free day. Dialysate contained no measurable lansoprazole or metabolite. Lansoprazole is not significantly dialysed.

  Clarithromycin tablets, USP

  The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function. The elimination of clarithromycin was impaired in patients with impaired renal function (see 7 WARNINGS AND PRECAUTIONS, Renal and 4.2 Recommended Dose and Dosage Adjustment).

  Amoxicillin (amoxicillin trihydrate) capsules, USP

  In the presence of renal impairment the serum half-life increases (between 7 and 10 hours), necessitating a reduction in the dosage administered. See 7 WARNINGS AND PRECAUTIONS, Renal.

11 STORAGE, STABILITY AND DISPOSAL

Store the AA-LANSOPRAZOLE-AMOXICILLIN-CLARITHROMYCIN blister cards between 15°C and 25°C.

Protect from light and moisture. Keep out of reach and sight of children.

12 SPECIAL HANDLING INSTRUCTIONS

None.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Lansoprazole delayed-release capsules, USP

Proper name:	Lansoprazole
Chemical name:	2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]- benzimidazole
Molecular formula and molecular mass:	C16H14F3N3O2S	369.36 g/mol
Structural formula:
Physicochemical properties:	Lansoprazole is a white to almost-white powder, which melts with decomposition at approximately 178°C-182°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. The rate of degradation of the compound in aqueous solution increases with decreasing pH. It has an octanol/water partition coefficient of 240 at pH 7.

Clarithromycin tablets, USP

Proper name:	Clarithromycin
Chemical name:	(3R*, 4S*, 5S*, 6R*, 7R*, 9R*, 11R*, 12R*, 13S*, 14R*)-4-[(2,6- dideoxy-3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyranosyl)oxy]- 14-ethyl-12,13-dihydroxy-7-methoxy-3,5,7,9,11,13-hexamethyl-6- [[3,4,6-trideoxy-3-(dimethylamino)-beta-D-xylo- hexopyranosyl]oxy]oxacyclotetradecane-2-10-dione.
Molecular formula and molecular mass:	C38H69NO13	747.96 g/mol
Structural formula:
Physicochemical properties:	Clarithromycin is a white to off-white crystalline powder. It is slightly soluble in methanol, ethanol and acetonitrile, and practically insoluble in water. The pKa of clarithromycin is 8.48; the pH of a 0.2% (Methanol: Water, 5:95) slurry is 8.8. The partition coefficient of clarithromycin is influenced by the pH of the water phase and polarity of the organic phase. For octanol (dipole moment = 0.25): water, the partition co-efficient varies from 5.63 to 46.0 for pH water increases from 2 to 8. The melting point of clarithromycin is approximately 225°C.

Amoxicillin (amoxicillin trihydrate) capsules, USP

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Helicobacter pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Randomized, double-blind clinical studies in patients with Helicobacter pylori (H. pylori) and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within 1 year) evaluated the efficacy of lansoprazole delayed-release capsules in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy, or lansoprazole delayed-release capsules in combination with amoxicillin as dual 14-day therapy for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of 2 different eradication regimens were established.

Triple therapy: Lansoprazole 30 mg twice daily / clarithromycin 500 mg twice daily / amoxicillin 1000 mg twice daily

All treatments were for 14 days. H. pylori eradication was defined as 2 negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.

Triple therapy was shown to be more effective than all possible dual therapy combinations (Table 15). 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 1 year) compared the efficacy of lansoprazole delayed-release capsules 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 (Table 15).

Table 15 - H. pylori Eradication Rates - Triple Therapy

(lansoprazole / clarithromycin / amoxicillin) Percent of Patients Cured [95% Confidence Interval] (Number of Patients)

^* Based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 positive endoscopic tests from CLOtest® (Delta West Ltd., Bentley, Australia), 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 1 year). All dropouts were included as failures of therapy.

^‡ (p < 0.05) versus lansoprazole / amoxicillin and lansoprazole / 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-days is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.

A randomized, open-label, parallel-group, multicenter clinical study performed in the U.K. in patients with H. pylori and duodenal ulcer disease and/or gastritis, compared the efficacy and safety of four 7-day triple therapy treatment regimens. The primary efficacy measure was eradication of H. pylori as defined by a negative ¹³C-urea breath test at least 28 days (Visit 3) after completing study medication. This study established that 7-day triple therapy with lansoprazole / clarithromycin / amoxicillin was as clinically effective in eradication H. pylori as the 10- or 14-day treatment regimens (Table 16).

Table 16 - Post-treatment Breath Test Results by Patient Population H. pylori Eradication Rates - Triple Therapy Regimen (lansoprazole / clarithromycin / amoxicillin)

* Based on evaluable patients with confirmed duodenal ulcer and/or gastritis and H. pylori infection at baseline defined as at least 2 of 3 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.

† “Worst case” assumed that missing Visit 3 breath test results were positive for H. pylori and “Best case” results assumed that missing Visit 3 results were negative for H. pylori.

# Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer.

A combination of lansoprazole plus clarithromycin and amoxicillin as triple therapy, was effective in eradicating H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

There were no statistically significant differences in H. pylori eradication rates between the levels of any potentially influential factors, including baseline duodenal ulcer status, baseline duodenal ulcer size, gender, age, race, or tobacco use for the evaluable, intent-to-treat (all available data), and modified intent-to-treat (worst case) analyses. H. pylori eradication rates at the Week 6 Visit for patients who received lansoprazole 30 mg twice daily, clarithromycin 500 mg twice daily, and amoxicillin 1000 mg twice daily are presented by concomitant factors in Table 17 and Table 18 for the 14-day and 10-day treatment studies, respectively.

A statistically significant difference in ulcer prevalence rates was observed between the levels for age in the evaluable, intent-to-treat (all available data), and modified intent-to-treat (worst case) analyses, with younger patients demonstrating a lower ulcer prevalence rate compared with older patients. No statistically significant differences in ulcer prevalence rates were observed between the levels of other potentially influential factors including baseline duodenal ulcer status, baseline duodenal ulcer size, gender, race, or tobacco use for the evaluable, intent-to-treat (all available data), and modified intent-to-treat (worst case) analyses.

A statistically significant difference in H. pylori eradication rates was observed between the levels of baseline duodenal ulcer size in the evaluable and intent-to-treat (all available data) analyses, with patients who had smaller ulcers (3 to 5 mm) demonstrating a lower H. pylori eradication rate compared with patients who had larger ulcers. Statistically significant differences in H. pylori eradication rates were also observed between the levels of age in the intent-to-treat (all available data) and modified intent-to-treat (worst case) analyses, with patients over 65 years of age demonstrating a higher H. pylori eradication rate compared with patients less than or equal to 65 years of age. No statistically significant differences in H. pylori eradication rates were observed between the levels of other potentially influential factors including baseline duodenal ulcer status, gender, race, or tobacco use for the evaluable, intent-to- treat (all available data), and modified intent-to-treat (worst case) analyses.

Table 17 - H. pylori Eradication Rates at the Week 6 Visit for Patients Who Received 14 days of Lansoprazole 30 mg Twice Daily, Clarithromycin 500 mg Twice Daily, and Amoxicillin 1000 mg Twice Daily by Concomitant Factors

No statistically significant differences were observed between the levels of any factor after stratification by study.

* Includes ex-tobacco users

Table 18 - H. pylori Eradication Rates at the Week 6 Visit for Patients Who Received 10 days of Lansoprazole 30 mg Twice Daily, Clarithromycin 500 mg Twice Daily, and Amoxicillin 1000 mg Twice Daily by Concomitant Factors

No statistically significant differences were observed among the levels of any factor.

* Includes only patients with active duodenal ulcer at baseline

† Includes ex-tobacco users

A statistically significant difference in ulcer prevalence rates was observed between baseline duodenal ulcer status (active or historical) in the evaluable, intent-to-treat (all available data), and modified intent-to-treat (worst case) analyses, with patients who had a historical duodenal ulcer at baseline demonstrating a lower ulcer prevalence rate compared with patients who had an active duodenal ulcer at baseline. No statistically significant differences in ulcer prevalence rates were observed among the levels of other potentially influential factors including baseline duodenal ulcer size, gender, age, race, or tobacco use for the evaluable, intent-to-treat (all available data), and modified intent-to-treat (worst case) analyses.

14.2 Comparative Bioavailability Studies

Lansoprazole delayed-release capsules

A single dose, fasting, 2-way crossover, comparative bioavailability study was conducted in 20 healthy adult volunteers (11 males and 9 females). The rate and extent of absorption of lansoprazole were measured and compared following a single oral 30 mg dose (1 x 30 mg) of Lansoprazole Delayed-Release Capsules, 30 mg or PREVACID^® Delayed-Release Capsules, 30 mg. The results from measured data are summarized in the table 19 below:

Table 19 - Summary Table of the Comparative Bioavailability Data – Lansoprazole

A single dose, low calorie, low fat (6% of calories from fat) fed, 2-way crossover, comparative bioavailability study was conducted in 43 healthy adult volunteers (27 males and 16 females). The rate and extent of absorption of lansoprazole were measured and compared following a single oral 30 mg dose (1 x 30 mg) of Lansoprazole Delayed-Release Capsules, 30 mg or PREVACID^® Delayed-Release Capsules, 30 mg. The results from measured data are summarized in the table 20 below:

Table 20 - Summary Table of the Comparative Bioavailability Data – Lansoprazole

A single dose, high calorie, high fat (50% of calories from fat) fed, 2-way crossover, comparative bioavailability study was conducted in 45 healthy adult male volunteers. The rate and extent of absorption of lansoprazole were measured and compared following a single oral 30 mg dose (1 x 30 mg) of Lansoprazole Delayed Release Capsules, 30 mg or PREVACID^® Delayed-Release Capsules, 30 mg. The results from measured data are summarized in the table 21 below:

Table 21 - Summary Table of the Comparative Bioavailability Data – Lansoprazole

Clarithromycin Tablets

A comparative bioavailability study was conducted in 21 healthy adult male volunteers. The rate and extent of absorption of clarithromycin was measured following oral administration of a single 500 mg dose (1 x 500 mg), under fasting conditions, of either Clarithromycin Tablets, 500 mg or BIAXIN BID^® (clarithromycin) Tablets, 500 mg and the two were compared. The results from measured data are summarized in the table 22 below.

Table 22 - Summary Table of the Comparative Bioavailability Data – Clarithromycin

Amoxicillin Capsules

A randomized, single dose, double-blind, 2-way crossover comparative bioavailability study was conducted in healthy adult volunteers under fasting conditions. The results obtained from 30 volunteers (17 males and 13 females) who completed the study are summarized in the table 23 below. The rate and extent of absorption of amoxicillin was measured and compared following a single oral dose (1 x 500 mg capsule) of Amoxicillin trihydrate Capsule, 500 mg (AA Pharma Inc.) and Amoxicillin ( amoxicillin trihydrate) Capsules, 500 mg taken from Hp-PAC^® (Takeda Pharmaceuticals America, Inc.).

Table 23 - Summary Table of the Comparative Bioavailability Data – Amoxicillin

15 MICROBIOLOGY

Clarithromycin tablets, USP

Clarithromycin exerts its antimicrobial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.

Clarithromycin is active in vitro against various aerobic and anaerobic gram-positive and gram- negative organisms. Additionally, the 14-OH clarithromycin metabolite also has significant antimicrobial activity which may be additive to the activity of the parent compound.

Clarithromycin is bactericidal to Helicobacter pylori; this activity is greater at neutral pH than at acid pH.

In vitro Activity of Clarithromycin against Helicobacter pylori

Clarithromycin has demonstrated in vitro activity against H. pylori isolated from patients with duodenal ulcers. In vitro susceptibility testing methods (broth microdilution, agar dilution, E-test, and disk diffusion) and diagnostic products currently available for determining MICs and zone sizes have not been standardized, validated, or approved for testing H. pylori. The clarithromycin MIC values and zone sizes will vary depending on the susceptibility testing methodology employed, media, growth additives, pH, inoculum concentration tested, growth phase, incubation atmosphere, and time.

Susceptibility Test for Helicobacter pylori

In vitro susceptibility testing methods and diagnostic products currently available for determining MICs and zone sizes have not been standardized, validated, or approved for testing H. pylori microorganisms. MIC values for H. pylori isolates collected during 2 U.S. clinical trials evaluating clarithromycin plus omeprazole, were determined by broth microdilution MIC methodology (Hachem CY et al., 1996). Results obtained during the clarithromycin plus omeprazole clinical trials fell into a distinct bimodal distribution of susceptible and resistant clarithromycin MICs.

If the broth microdilution MIC methodology published in Hachem CY et al., 1996 is used and the following tentative breakpoints are employed, there should be reasonable correlation between MIC results and clinical and microbiological outcomes for patients treated with clarithromycin plus omeprazole (see Table 24).

Table 24 - Susceptibility Testing for H. pylori in Patients Treated With Clarithromycin and Omeprazole

These breakpoints should not be used to interpret results obtained using alternative methods.

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Lansoprazole delayed-release capsules, USP

Acute Toxicity

Mouse and Rat

In an acute toxicity study, lansoprazole administered via the oral, subcutaneous and intraperitoneal routes was studied in groups of 5M, 5F Wistar rats and 5M, 5F ICR mice. Lansoprazole was suspended in 5% gum arabic adjusted to pH 7 for administration by all

3 routes. The LD₅₀ by the oral route in both rats and mice was greater than 5000 mg/kg, the highest dose tested. There were no deaths in either study. The only clinical sign noted was dark brown urine in mice.

By the subcutaneous route, the LD₅₀ was again greater than 5000 mg/kg, the highest dose tested. Again, there were no deaths in either species. Scratching at the injection site and abdominal stretching were observed in mice. There were no clinical signs in rats. Drug remnants were seen at the injection sites in both species.

Finally, when lansoprazole was administered via the intraperitoneal route, there were no deaths in mice at 5000 mg, but several rats of both sexes died within 2 days after dosing. Surviving rats were normal by the second day after dosing. The LD₅₀ in rats was approximately 5000 mg. Abdominal stretching, decreases in activity, respiratory depression, and hypotonia of abdominal muscles were seen in rats and mice. Dark purple urine was also seen in mice. At autopsy, drug remnants were seen in the peritoneal cavity in animals of both species. Discoloration of the liver was also seen in rats that died at 5000 mg. These studies demonstrated that lansoprazole has a very low degree of toxicity when given as a single dose by either the oral, subcutaneous, or intraperitoneal routes.

In an acute toxicity study of several metabolites, a contaminant, and partially degraded lansoprazole (40°C and 75% relative humidity for 6 months) were determined in ICR mice. The compounds and the routes tested were pyridyl-oxide derivative (oral), sulfonyl derivative or metabolite VII (oral and intraperitoneal), thio derivative or metabolite I (oral and intraperitoneal), 5-hydroxy derivative or metabolite VI (intraperitoneal), and partially degraded lansoprazole (oral). There were no deaths, and the LD₅₀ values in all cases were therefore greater than 5 g/kg, the limit dose. With oral administration, clinical signs were seen only with partially degraded lansoprazole. These included decreased activity, respiratory depression, hypo-irritability (decreased responsiveness), ataxia, and flattened posture (prostration). With intraperitoneal administration, decreased activity, hypo-irritability, and respiratory depression were seen with metabolites VI and VII. In addition, with metabolite VII, chromaturia (dark purple urine) and soft feces or diarrhea were seen. These findings are all similar to the results of previous acute toxicity studies with lansoprazole. Therefore, none of the tested compounds were more toxic than lansoprazole itself.

Dog

In a single-dose study, 2 male beagle dogs per group (fasted for 18 hours) were given lansoprazole orally by gavage at doses of 500, 1000, and 2000 mg/kg. The drug was suspended in 5% gum arabic, pH 7. The dogs were observed for 15 days after dosing and subjected to necropsy. Organ weights and histopathologic assessments of selected organs were obtained. There were no deaths, no treatment- related clinical signs, no effects on body weight or food consumption, no effects on weights of major organs, and no treatment-related gross or histopathologic changes. Therefore, a single dose of 2000 mg/kg was non-toxic. Higher dosing was not justified for humane reasons.

Long-Term Toxicity

Mouse

In a 3-month study, lansoprazole was given by oral gavage to groups of 10 male and 10 female CD-1 mice at dosages of 0, 15, 50, and 150 mg/kg/day. The vehicle was 5% gum arabic. Clinical signs, body weight, and food consumption were monitored. At the end of the study, blood was collected for hematology and biochemistry measurements. All animals were necropsied. Histologic evaluations were conducted on high-dosage and control animals, and stomachs were evaluated histologically in all animals.

There were no treatment-related deaths and no effects on clinical signs, body weight, food consumption, hematology, or serum chemistry variables. There were no treatment-related gross pathologic changes. Stomach weights were increased, and hyperplasia/hypertrophy of the glandular stomach was seen histologically at 50 and 150 mg/kg/day. These changes were secondary to the pharmacologic activity of the compound.

In a 13-week study, lansoprazole was given by oral gavage to groups of 10 male and 10 female CD-1 mice at dosages of 0, 150, 300, 600, 1200, and 2400 mg/kg/day. The drug was suspended in 5% gum arabic, pH 7. There were 3 possibly drug-related deaths at 2400 mg/kg/day. The only clinical sign observed was purple urine seen in all drug-treated groups. There were slight decreases (approximately 10 to 13% relative to controls) in hematocrit, hemoglobin, and erythrocyte counts in all drug-treated groups. Neutrophils were slightly decreased in drug-treated females. Total serum protein was decreased at 300 mg/kg/day or more. Stomach weights were increased in all drug-treated groups. Liver weights were increased at 300 mg/kg/day or more. Testis weights were decreased at 1200 and 2400 mg/kg/day. At necropsy, the glandular stomach appeared thickened, and erosions of the mucosa were evident at all dosages. The testes appeared small at 1200 and 2400 mg/kg/day. Histologically, hyperplasia and vacuolation were seen in the gastric fundic mucosa in all drug-treated groups. A mild, chronic gastritis was seen at 300 mg/kg/day or more. Hepatocellular hypertrophy and vacuolation were seen at 150 mg/kg/day or more, and a brown pigment was seen in the liver mainly at 2400 mg/kg/day. Seminiferous tubular atrophy and aspermatogenesis were seen with increased incidence at 1200 and 2400 mg/kg/day. Reduced amount of sperm was seen in the epididymides at 1200 mg/kg/day or more. A no-toxic-effect dosage was not determined in this study. The maximum therapeutic dose was judged to be in the range of 300 to 600 mg/kg/day.

Rat

In a 3-month study, lansoprazole was administered by gavage to groups of 15 Sprague-Dawley rats/sex at dosages of 0, 5, 15, 50, and 150 mg/kg/day 7 days per week. The drug was suspended in 5% gum arabic, pH 7.

There were no deaths and no behavioural signs of toxicity. Body weight was decreased in males at 150 mg/kg/day. There was no effect on food consumption. Hemoglobin and mean cell hemoglobin were decreased in females at 50 mg/kg/day or more, and in males at

150 mg/kg/day. Hematocrit was also decreased in males and females, and mean erythrocyte volume was decreased in males at 150 mg/kg/day. Total leukocyte counts were increased in females at 50 mg/kg/day or more. Serum total protein and globulin were decreased and A/G ratio increased in males at 150 mg/kg/day. There were no gross lesions noted at necropsy. Stomach weight was increased at 15 mg/kg/day or more. Liver weights were increased in females at 15 mg/kg/day or more. Thyroid and uterus weights were increased at 150 mg/kg/day. Thymus weights were decreased at 50 mg/kg/day or more. Histologically, thymic atrophy was observed at 15 mg/kg/day or more. In the stomach, increased chief cell hypertrophy, eosinophilia and single cell necrosis, eosinophilic material in gastric glands, and increased squamous cell hyperplasia and hyperkeratosis at the junction of the glandular and non-glandular mucosa were observed at 50 mg/kg/day or more.

Toxicity was demonstrated by decreased body weight in males, hematologic changes, decreases in serum protein, thymic atrophy, and chief cell necrosis. Hematologic changes and chief cell necrosis occurred at 50 mg/kg/day or more. Thymic atrophy was observed at 15 mg/kg/day or more. Therefore, the no-toxic-effect dosage was 5 mg/kg/day.

In a 4-week study, lansoprazole was administered orally by gavage to 10 Wistar rats/sex/group at dosages of 0, 15, 50, and 150 mg/kg/day (7 days/week). The drug was suspended in 5% gum arabic for administration.

There were no deaths and no behavioural signs of toxicity. Body weight gain was suppressed in males by 7% at 50 mg/kg/day and by 15% at 150 mg/kg/day. Food consumption was decreased in both sexes at 150 mg/kg/day and in males at 50 mg/kg/day. Hepatic drug-metabolizing enzymes, aminopyrine-N-demethylase and aniline hydroxylase activities, were increased at 150 mg/kg/day. Thymic atrophy was noted at necropsy at 150 mg/kg/day. Thymic weights were decreased 21 to 27% at 50 mg/kg/day and 48 to 49% at 150 mg/kg/day. Liver weights were increased at 50 and 150 mg/kg/day. Adrenal weights were increased in females at 150 mg/kg/day. Histologically, centrilobular hepatocellular hypertrophy was seen in the liver at 150 mg/kg/day. An increase in smooth endoplasmic reticulum in the liver was seen by electron microscopy. In the stomach, vacuolation of parietal cells and apical eosinophilia of chief cells were seen histologically, while dilation of parietal cell tubulovesicles was seen by electron microscopy at 150 mg/kg/day.

Toxicity was demonstrated by decreases in body weight gain and food consumption, and thymic atrophy at 50 mg/kg/day or more. The no-toxic-effect dosage was 15 mg/kg/day.

In a 13-week study, lansoprazole was administered to Wistar rats (10/sex/group) at dosages of 0, 5, 15, and 50 mg/kg/day, 7 days/week. The drug was suspended in 5% gum arabic adjusted to pH 7.

There were no deaths and no behavioral signs of toxicity. Body weight was decreased 5 to 6% in both sexes by the end of the study at 50 mg/kg/day. There were no treatment-related effects on hematology, serum chemistry, or urinalysis variables. Measurements of plasma T₃, T₄, and

TSH in the high-dosage and control animals revealed no differences between the 2 groups. Statistically significant elevations in serum gastrin, determined 20 hours post-dosing at the end of the study, were obtained in females at 15 mg/kg/day or more and in males at 50 mg/kg/day. At necropsy, the stomach glandular mucosa was observed to be thickened in both sexes at 50 mg/kg/day and in females at 15 mg/kg/day. Stomach weights were increased at all dosages.

Thymus and submaxillary weights were decreased at 50 mg/kg/day. Histologically, centrilobular hepatocellular hypertrophy was seen in the liver at 50 mg/kg/day. In the stomach, increased argyrophil cell density, hypertrophy of parietal cells, and sporadic necrosis of chief cells were seen at 50 mg/kg/day. Chief cell eosinophilia, hypertrophy, and hyperplasia were seen at all dosages. Dilation of tubulovesicles in parietal cells and small, dense granules in chief cells were seen by electron microscopy at 50 mg/kg/day.

Toxicity was demonstrated by decreased body and thymus weights and chief cell necrosis at 50 mg/kg/day. The no-toxic-effect dosage was 15 mg/kg/day.

In a 13-week study, male Wistar rats were given daily dosages of 50 mg/kg/day lansoprazole orally by gavage, and were then allowed to recover without treatment for periods of 4, 13, or 26 weeks. A control group was given vehicle (5% gum arabic, pH 7). There were 10 rats for each of the necropsy intervals (13 weeks treatment, 4 weeks recovery, 13 weeks recovery, and 26 weeks recovery).

The changes observed at the end of 13 weeks of treatment were similar to those seen at 50 mg/kg/day in the previous 13-week study. In this study, gastrin-secreting cells (G cells) were determined in the stomach pylorus by immunohistochemical staining. The volume density of G cells was found to be increased after 13 weeks of treatment. All of the changes were found to be reversible after 4 weeks recovery without treatment except stomach weight, changes in chief cells, and the increase in argyrophil cells. The increase in argyrophil cells was reversible after 13 weeks of recovery. Necrosis, eosinophilia, hypertrophy, and hyperplasia of chief cells showed partial reversal after 4 and 13 weeks recovery and complete reversal after 26 weeks, recovery. Stomach weight in the treated group was comparable to controls after 26 weeks of recovery.

In a 6-month study, lansoprazole was given to Sprague-Dawley rats (12/sex/group) at dosages of 0, 2, 10, and 50 mg/kg/day, 7 days/week. The drug was suspended in 5% gum arabic, pH 7, and administered orally by gavage.

There were no treatment-related deaths, no behavioral signs of toxicity, no effects on body weight or food consumption, and no treatment-related changes in serum chemistry or urinalysis variables. There was a transient decrease in hematocrit, mean erythrocyte cell volume, and mean erythrocyte cell hemoglobin at 50 mg/kg/day after 3 months of treatment. This was not seen at the end of the study. Stomach weight was increased in females at all dosages and in males at 10 mg/kg/day or more. Thymus weights were decreased at 50 mg/kg/day. Histologically, thymic atrophy was seen at 10 mg/kg/day or more. In the stomach, increased hypertrophy, eosinophilia, and single cell necrosis of chief cells and an increase in argyrophil cells were seen at 10 mg/kg/day or more. At 50 mg/kg/day, dilation of gastric glands and increased severity of inflammatory cell accumulation, squamous cell hyperplasia, and hyperkeratosis at the junction of the glandular and nonglandular mucosa were seen.

Toxicity was demonstrated by the hematologic changes at 50 mg/kg/day, thymic atrophy at 10 mg/kg/day or more and chief cell necrosis at 10 mg/kg/day or more. The no-toxic-effect dosage was 2 mg/kg/day.

In a 1-year study, lansoprazole was administered by oral gavage to Sprague-Dawley rats (30/sex/group) at dosages of 0, 1.5, 5, 15, and 50 mg/kg/day, 7 days per week. The vehicle was 5% gum arabic adjusted to pH 7.

There were no treatment-related deaths and no behavioral signs of toxicity. Body weight gain was decreased in males at 50 mg/kg/day, but there was no effect on food consumption. Hematocrit and hemoglobin were decreased at 50 mg/kg/day. There were no treatment-induced changes in serum chemistry or urinalysis variables. Stomach weight was increased at 5 mg/kg/day or higher. Liver weight was increased in females, while thymus weight was decreased in males at 50 mg/kg/day. Histologic evidence of thymic atrophy was also seen at 50 mg/kg/day. In the stomach, hypertrophy, eosinophilia and necrosis of chief cells was seen at 5 mg/kg/day or more. Dilated gastric glands and increased incidence of argyrophil cells were seen at 15 mg/kg/day or more. Increased severity of inflammatory cells, squamous hyperplasia, and hyperkeratosis at the junction of the glandular and nonglandular mucosa was seen at 50 mg/kg/day. In the testis at 50 mg/kg/day, an increased incidence of Leydig (interstitial) cell hyperplasia was observed, and a single, benign Leydig cell tumor was found.

Toxicity was characterized by decreased body weight gain in males, decreases in hematocrit and hemoglobin, thymic atrophy, and Leydig cell hyperplasia at 50 mg/kg/day and by chief cell necrosis at 5 mg/kg/day or more. The no-toxic- effect dosage was 1.5 mg/kg/day.

Dog

In a 6-month study, lansoprazole was given to 4 beagle dogs/sex/group in hard gelatin capsules at dosages of 0, 2, 10, and 50 mg/kg/day 7 days per week.

There were no deaths or behavioral signs of toxicity. There were no treatment- related effects on body weight, food consumption, urinalysis, or ophthalmologic, electrocardiographic, or serum chemistry variables. One dog in the high-dosage group had a few atrioventricular (A-V) nodal escape beats; however, this sometimes occurs spontaneously in dogs and was not considered treatment related either by the sponsor or a consulting veterinary cardiologist. There were transient (present at at 3 months but not at six months) decreases in hematocrit, hemoglobin, and erythrocyte counts in males at 2 and 10 mg/kg/day. Hematocrit, hemoglobin, mean cell hemoglobin, and mean erythrocyte volume were persistently decreased at both

3 and 6 months at 50 mg/kg/day in males. Total leukocyte count was increased in females at 50 mg/kg/day. There were no treatment-related findings at necropsy. Thymus weight was decreased in males at 50 mg/kg/day. Histologically, increased vacuolation of parietal cells in the gastric mucosa was seen at 10 mg/kg/day or more.

Toxicity was characterized by hematologic changes and by decreased thymus weights at 50 mg/kg/day. The no-toxic effect dosage was 10 mg/kg/day.

In a 12-month study, Beagle dogs were given lansoprazole in hard gelatin capsules at dosages of 0, 1.5, 5, 15, and 50 mg/kg/day, 7 days per week. There were 4 dogs/sex/group. There were 2 deaths, 1 male each at 15 and 50 mg/kg/day.

In surviving dogs, there were no behavioral signs of toxicity, no effects on body weight or food consumption, no treatment-related ophthalmoscopic findings, and no effects on serum chemistry or urinalysis variables. There were no electrocardiogram (ECG) abnormalities in any of the dogs in the study. Total leukocyte counts were increased at 15 and 50 mg/kg/day; the increase at 15 mg/kg/day was transient (present at 3 months but not at later intervals) and in males only. Prostate weight was decreased at 5 mg/kg/day or more. Histologically, increased parietal cell vacuolization was seen at all dosages.

The cause of death or moribundity could not be determined for the 2 dogs that died. There were no indications from the other dogs in the study of any toxicity that could account for these deaths. Nevertheless, a conservative approach suggests that these 2 deaths be considered the result of toxicity due to drug treatment. Therefore, the no-toxic-effect dosage for this study was 5 mg/kg/day.

Pediatric Rat and Dog Studies

Two studies were conducted to evaluate the toxicity and toxicokinetics of lansoprazole in preadolescent rats and dogs. Selected dosages for the 2 species were identical to those used in adult animals in 4-week (Wistar strain) and 13-week (Sprague Dawley strain) studies in rats (Atkinson and Daly, 1986; Miyajima, 1986) and in a 13-week study in dogs (Chiba, 1989; Miyajima, 1989). Dosing of rats continued between weaning throughout adolescence (i.e., reproductive maturity). This age-range simulated the children age group of 2- to 12-year-olds. In dogs, dosing started 2 weeks after birth and continued for 4 weeks prior to weaning, followed by 7 weeks post-weaning for a total of 13 weeks. Evaluation of the stomach was emphasized, since part of the rationale for these studies was to evaluate the threshold for toxicity in target organ(s), particularly the stomach in younger premature animals and compare it to that of adult animals.

These studies also aimed at verifying any additional effects on developmental milestones due to dosing at these young ages.

The toxicity profile in preadolescent animals was not different from adult animals, and the no observable effect level (NOEL) doses were comparable between the 2 age groups. In the pediatric population the mean total initial lansoprazole dose is 0.87 mg/kg. Accordingly, the safety margin based on the NOEL of 5 mg/kg/day in 2 species was approximately 1 to 1.5-fold, based on plasma levels for lansoprazole only (excluding its metabolites); was approximately 1 to 3.5-fold based on surface area and was about 5.7 fold relative to this clinical dose.

Clarithromycin tablets, USP

Acute Toxicity

The acute toxicity of clarithromycin administered by a variety of routes, was studied in mice and rats. The median lethal dose by the oral route ranged from 2.7 to > 5.0 g/kg. Acute toxicity did not differ markedly between sexes (see Table 25).

Table 25 - Acute LD₅₀ values of Clarithromycin

The primary signs of toxicity included reduction in activities, behaviours, weight gains, respiration rates and sedation. The emetic activity of clarithromycin prevented the determination of the lethal dose in dog.

The acute oral toxicity of clarithromycin in very young mice and rats was determined. The median lethal dose (1.2 g/kg) was about 2 fold that seen in the older rodents.

Subchronic Toxicity

Studies were conducted in rats, dogs and monkeys with clarithromycin administered orally. The duration of administration ranged from 14 days to 42 days.

Rats

One study in rats (with oral doses up to 800 mg/kg/day) failed to show adverse effects in rats exposed to 50 mg/kg/day for 4 weeks. The clinical signs observed at toxic doses were reduced motility, piloerection, hypothermia and perineal urine staining. Changes occurred in biochemical parameters at 200 and 800 mg/kg/day indicative of hepatotoxicity which was confirmed by histopathologic findings of hepatocyte necrosis.

Other pathologic findings at the top 2 dose levels included swelling of the renal cortical tubular epithelia and atrophic changes to the lymphatic and genital systems. The same toxicity profile was observed in immature rats following the daily administration of oral doses up to 150 mg/kg/day of clarithromycin for 6 weeks. At 150 mg/kg/day, there was an increase in relative weights of liver and kidneys.

Dogs

Dogs were dosed orally with 0, 6.25, 25, 100 or 400 mg/kg/day of clarithromycin daily for 28 days. Emesis occurred sporadically in the treated dogs. No other adverse effects were seen in dogs exposed to 6.25 mg/kg/day. The clinical signs at higher dosages included loose stools, lacrimation and conjunctivitis.

Slight anorexia was noted in dogs receiving 100 mg/kg/day or more. Dogs at 400 mg/kg/day exhibited reduced red blood cell count, hematocrit, hemoglobin concentration, serum albumin, and mean urine pH and specific gravity. Increases were seen in serum transaminase, alkaline phosphatase, and total bilirubin concentrations.

Bilirubin was detected in the urine. Other pathologic changes at 400 mg/kg/day included biliary hyperplasia, gastric glandular atrophy, renal tubule epithelial atrophy, edema of the iris, ciliary body and choroid, capillary proliferation in the cornea, suppression of spermatogenesis, and adrenal medullary degeneration.

Monkeys

Monkeys were treated daily for 1 month with oral doses of 0, 25, 100 or 400 mg/kg/day. Two animals out of 10 receiving 400 mg/kg/day died. Salivation was recorded at all dosage levels. No other adverse effects were seen in animals treated daily with 25 mg/kg/day.

The clinical signs observed at higher doses and most frequently at 400 mg/kg/day were vomiting, emesis, sunken eyes, dehydration, emaciation, low rectal temperature, body weight loss, reduced food consumption, cloudiness of the cornea and reduction in intra-ocular pressure. Yellow discoloured feces were passed on a few isolated occasions by some animals given a dose of 400 mg/kg/day. As with the other species, the liver was the primary target at toxic doses as shown by early elevation of serum concentration of glucose, BUN, creatinine, ALT, AST, LDH, amylase and/or triglyceride; an electrolyte imbalance and low levels of protein, cholesterol, phospholipid; elevated leucine aminopeptidase (LAP).

Principal histopathologic changes were seen mainly in high dose monkeys, but some mid-dose monkeys exhibited similar alterations. Changes included necrosis and vacuolation of hepatocytes, vacuolation of renal cortical tubules, no spermatogenesis, thymic regression and single cell necrosis of the stomach. In man the recommended dose is 500 to 1000 mg/day or 7.1 to 14.3 mg/kg/day (70 kg person).

Chronic Toxicity

Rats

Rats (20/sex/group) were treated daily with oral doses of 0, 15, 37.5, 75 or 150 mg/kg/day for 3 months. There were 8 incidental deaths, but none of them were considered treatment related. Clinical signs included increased salivation, dehydration, hyperactivity and were observed in a dose-related manner. The only toxic effect noted, was some variation in body weight gain. No toxicologically significant changes occurred in hematology, biochemistry or urinalysis results.

Post mortem, there was an increase in mean relative liver and kidney weights at the top dose level. No microscopic changes were detected in the kidneys, but in the liver, there was a sex/dose-related increase in multinucleated hepatocytes. Effects were only seen in females at 150 mg/kg/day but in males occurred as low as 37.5 mg/kg/day.

A 6-month oral study was performed in rats (20 to 27/sex/group) at dosages of 0, 1, 6, 8, 40 or 200 mg/kg/day. Seven male and female rats from the control group and the 40 and 200 mg/kg/day groups were allowed a 63-day non-dosed recovery period. No mortalities occurred. Body weight and food intake were reduced at high doses during the dosing phase but normalized during recovery.

Water intake and urine volume increased in males and females of the 40 and 200 mg/kg/day groups. Dose-related hematological changes included reduced erythrocytes and HCT with increased MCV, MCH and MCHC and relative eosinophil counts. Biochemical changes were mainly restricted to the high dose group and included increased ALP and decreased phospholipids; decreased total cholesterol and triglycerides, and increased AST and ALT in males only and decreased albumin in females only.

Organ weight increases were found to include cecum, adrenals, liver, and spleen. Histopathological examinations showed drug-related, recovery-reversible, increases in multinucleated hepatocytes associated with minimal and focal necrosis in livers of both sexes at the top 2 dose levels. No relevant pathology was found in the cecum, adrenals or spleen to account for the increased weights. After recovery only the 200 mg/kg/day group had increased multinucleated hepatocytes.

Dogs

Dogs (7/sex/group) were administered daily with oral doses of 0, 10, 30, or 100 mg/kg/day of clarithromycin for 3 months. Emesis occurred at levels of 30 mg/kg and above. One male high dose dog was killed in extremis on day 69. Drug-related lesions were seen in the liver, gall bladder, thymus and stomach.

Hematological and biochemical changes at the high dose level included, decreased RBC and HCT, increased ALT, ALP, GGT, and decreased total protein and albumin. No significant organ weight changes were recorded, but treatment-related microscopic alterations in the liver and stomach of mild and high dose dogs were seen, as well as changes in gall bladder, spleen and thymus of high dose animals.

A 6 month oral study was also performed in dogs (4 to 5/sex/group) at dosages of 0, 0.8, 4, 20 or 100 mg/kg/day. At the 0 and 100 mg/kg levels, 1 male and 1 female dog were allowed a 1-month, non-dosed, recovery period. One male high dose dog died on day 174. This death was considered to be as a direct result of clarithromycin administration. Histopathologic examination revealed hepatic parenchymal damage, identifying the cause of clinical jaundice. Clinical signs during the dosing phase of the study were restricted to the top 2 dose levels and included emesis and ocular signs. Food consumption and water intake were reduced at 20 and 100 mg/kg/day.

Hematologic changes at 100 mg/kg were indicative of subclinical anemia. Biochemical alterations at the same level were associated with liver damage. Ocular changes were only apparent at the top dose level.

Increase in the weights of lung, liver, spleen, adrenals and kidneys were found at 100 mg/kg/day. Histopathologic examination of these organs showed degeneration of liver parenchyma, and toxic effects in adrenals. The thymus weight was reduced at 100 mg/kg/day. At the end of the recovery period all findings had regressed or reduced.

Monkeys

Monkeys (5 to 6/sex/group) were similarly administered clarithromycin at levels of 0, 25, 50 or 100 mg/kg/day for 6 months. At the 0 and 100 mg/kg levels, 1 male and 1 female monkey were allowed a 1-month recovery period. One high dose female died in week 25. Inhalation of vomit was considered to be the cause of death. Clinical signs were restricted to a dose-related incidence of emesis and salivation. No treatment-related effects were found in food consumption, ophthalmoscopy or hematology. Weight loss was restricted to 1 high dose female. Minor serum chemistry changes were seen at the 100 mg/kg level, particularly in plasma proteins. Urinalysis revealed a dose-related lowering of pH and SG at 13 weeks only. Organ weight increases in liver, adrenal and kidneys were seen at high doses, but pathology was restricted to minimal liver changes consisting of cytoplasmic rarefaction of centrilobular hepatocytes. All changes were reversed during the recovery period.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Acute Toxicity

The following LD₅₀ values for amoxicillin expressed in mg/kg of body weight have been reported.

Table 26 - Acute LD₅₀ Values for Amoxicllin (mg/kg)

Subacute Toxicity

Rats

In one study, male and female rats were orally administered 500 mg/kg amoxicillin daily for 21 days. With the exception of significantly greater (p < 0.01) BUN values in the female test group compared with controls, there were no toxic effects on the organs, tissues or fluids of the body, nor any adverse effects on food consumption, weight gain, or efficiency of food utilization reported in the study.

Histopathologic evaluation of tissues revealed a minimal degree of fatty change in livers of treated females. However, this finding was not considered a toxic change but related to a possible alteration in the intestinal flora.

Dogs

One male and 1 female dog were dosed orally with 250 mg/kg amoxicillin daily for 14 days. During the period of observation, no deaths occurred, no adverse changes in body weight and no effect on food consumption was found. Laboratory values were found within normal limits. At post-mortem, no gross or microscopic abnormalities were reported and organ weights were within normal limits.

Chronic Toxicity

Rats

In one study, male and female rats were given oral doses of 200, 500 and 2000 mg/kg/day amoxicillin, 6 days a week for 26 weeks. No apparent disturbances in absolute organ weights of either treated male or female animals were noted nor was any histologic evidence of response to treatment observed.

In another study, 3 groups of Sprague-Dawley rats were given oral doses of 200, 500 and

2000 mg/kg of amoxicillin for a test period of 13 to 15 weeks. There were no gross or histologic changes observed in the treated rats that were considered related to the administration of amoxicillin. Some of the intermediate and low-dose groups were shown to exhibit body weight gains lower (males) or slightly higher (females) than those of the control animals.

Dogs

It has been reported that amoxicillin was administered orally at doses of 200, 500 and 2000 mg/kg/day to male and female dogs for a period of 6 months. (Groups consisted of 6 male and 6 female dogs initially, but after 3 months dosing, each group was reduced to 3 dogs).

During the first 6 weeks of treatment, occasional bouts of vomiting, 1 to 4 hours after dosing, were reported in dogs receiving 2000 mg/kg/day and 4 bouts of vomiting were recorded in dogs receiving the intermediate dose of 500 mg/kg/day. Grey coloured feces were seen on very isolated occasions in dogs treated at high and intermediate dose levels only. On 7 occasions it involved dogs receiving the highest dose level (2000 mg/kg/day) and on 3 occasions dogs receiving the intermediate dose level (500 mg/kg/day).

Body weight gains of treated males were reported to be not significantly different from those of controls, but all dosed females increased in weight at a significantly slower rate than did the controls. This factor was reported to be attributable to excessive weight gain in the control animals. Food and water consumption was not affected. No abnormalities of the eyes were observed attributable to amoxicillin.

In a second study 2 groups of Beagle dogs were given oral doses of 500 mg/kg and 200 mg/kg of amoxicillin for 13 weeks. There were no gross or histologic changes reported in the treated dogs that were considered related to the administration of amoxicillin.

Carcinogenicity

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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. Testicular Leydig cell hyperplasia and tumors were also observed. The Leydig cell changes were shown through mechanistic studies to be rat-specific and not biologically relevant to humans.

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 a dose-related increased incidence of gastric ECL cell hyperplasia. Lansoprazole also induced a low, non-dose-related incidence of carcinoid tumours in the gastric mucosa in several dose groups (1 female mouse in the 15 mg/kg/day group, 1 male mouse in the 150 mg/kg/day group, and 2 males and 1 female in the 300 mg/kg/day group). It also produced an increased incidence of liver tumours (hepatocellular adenoma plus carcinoma). The tumour 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 body surface area).

No carcinogenic effect occurred in P53 knockout mice, which are known to be susceptible to carcinogenesis by genotoxic agents.

Analysis of gastric biopsy specimens from patients after short-term treatment of proton pump inhibitors have not detected ECL cell effects similar to those seen in animal studies. Longer term studies in humans revealed a slight increase in the mean ECL-cell density, although there was no microscopic evidence of cell hyperplasia. Similar results were seen in the maintenance treatment studies, where patients received up to 15 months of lansoprazole therapy. Serum gastrin values increased significantly from their baseline values but reached a plateau after 2 months of therapy. By 1 month post-treatment, fasting serum gastrin values returned to lansoprazole therapy baseline. Moreover, results from gastric biopsies from short-term, long-term and maintenance treatment studies indicate that there are no clinically meaningful effects on gastric mucosa morphology among lansoprazole-treated patients.

In a 2-year study, lansoprazole was administered by oral gavage to Sprague-Dawley rats (60 males and 60 females per group) at dosages of 0, 1.5, 5, 15, and 50 mg/kg/day 5 days per week. Drug was suspended in 5% gum arabic (adjusted to pH 7.0 to 7.4).

Survival rates were 27 to 33% in males and 30 to 45% in females. The median survival time was 650 days in males and 683 days in females. Body weight gain was decreased at 50 mg/kg/day in both sexes and at all dosages in females. At the end of the study, body weight gains for high-dose males and females were both decreased 20% compared to controls. There were no other clinical signs of toxicity.

The incidence of interstitial (Leydig) cell hyperplasia was increased above concurrent and historical control levels at dosages of 15 and 50 mg/kg/day. The incidence of Leydig cell tumors was increased above concurrent control levels at 15 mg/kg/day and was at the high end of the historical control range at 50 mg/kg/day. The increases in incidence of Leydig cell hyperplasia and tumors were statistically significant at 15 and 50 mg/kg/day when compared to concurrent controls. Histologically, the Leydig cell tumors appeared similar to those that occur spontaneously in Sprague-Dawley rats and in aging Fischer 344 rats.

There were numerous changes in the gastric mucosa indicative of the pharmacologic effect of lansoprazole that were similar to those seen in previous toxicity studies. This included necrosis of chief cells which was seen at 5 mg/kg/day or more. A small increase in incidence of intestinal metaplasia was seen in both sexes at 50 mg/kg/day. Detailed examination of the intestinal metaplasia foci revealed the presence of Paneth cells, indicating complete type intestinal metaplasia in virtually every case. A single, carcinoid tumor was seen in the gastric fundic mucosa in a female at 50 mg/kg/day.

The decreases in body weight gain, necrosis of chief cells, and increased incidence of Leydig cell hyperplasia and tumors demonstrated that a MTD was administered.

The results suggest that oral administration of lansoprazole at dosages of 15 and 50 mg/kg/day for 2 years leads to higher levels of interstitial (Leydig) cell hyperplasia and tumors than found in control rats. There was no evidence for any other tumorigenic response due to drug administration.

Clarithromycin tablets, USP

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of amoxicillin. Studies to detect mutagenic potential of amoxicillin alone have not been conducted.

Genotoxicity

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Lansoprazole was positive in the Ames assay for bacterial mutagenicity and in the chromosomal aberration studies in human lymphocytes, but it was negative in 3 in vivo studies for genotoxicity. 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. Also, a mammalian cell mutagenesis assay was negative.

In vitro cytogenetics studies showed increased levels of aberrations consisting mainly of chromatid breaks which occurred only at cytotoxic concentrations. These cytotoxic concentrations were at least 50 to 60 times expected clinical blood levels of parent drug. Therefore, such concentrations will not be used in humans.

Clarithromycin tablets, USP

The following in vitro mutagenicity tests have been conducted with clarithromycin: Salmonella/mammalian microsome test, bacterial induced mutation frequency test, in vitro chromosome aberration test, rat hepatocyte DNA synthesis assay, mouse lymphoma assay, mouse dominant lethal study, mouse micronucleus test.

All tests had negative results except the in vitro chromosome aberration test which was weakly positive in 1 test and negative in another. In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin metabolites with negative results.

Amoxicillin (amoxicillin trihydrate) capsules, USP

Long-term studies in animals have not been performed with amoxicillin.

Reproductive and Developmental Toxicology

Lansoprazole delayed-release capsules, USP

Six separate studies covering all phases of the reproductive process have been conducted. Treatment with lansoprazole caused a dose related reduction of implantations, viable fetuses and live births, and caused delayed parturition at 150 mg/kg/day.

However, lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.

In 2 teratology studies, lansoprazole at dosages up to 300 mg/kg/day (approximately 600 times the human dose) was administered to rats on Days 6 to 17 of pregnancy. At higher dosages (150 to 300 mg/kg/day), only decreased fetal body weights were observed. Also at higher dosages, reduced ossification of vertebrae was indicative of fetal toxicity.

In rabbits, doses of lansoprazole up to 30 mg/kg/day (approximately 60 times the human dose) were administered on Days 6 to 18 of pregnancy. A treatment-related effect on fetal mortality at 30 mg/kg/day was noted, but there were no treatment related external, skeletal, or visceral abnormalities.

Reproductive studies in pregnant rats and rabbits revealed no lansoprazole-related impairment of fertility, fetal malformations or developmental toxicity to fetuses or suckling neonates.

Lansoprazole is not considered to be teratogenic.

Clarithromycin tablets, USP

Fertility and reproduction studies have shown that daily doses of 150 to160 mg/kg/day to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were 2 times the human serum levels.

In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum levels. When given orally after 150 mg/kg/day, clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.

In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m², which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m².

Amoxicillin (amoxicillin trihydrate) capsules, USP

Rats

Daily doses of 200 and 500 mg/kg amoxicillin were administered orally in 1 reported study. Male rats that had attained a minimum age of 40 days were treated for 63 days and sexually mature females for 14 days prior to mating. Dosing continued throughout the remainder of the investigation. The duration of gestation was unaffected by treatment at either dosage. It was noted that pregnancy rate at 500 mg/kg was slightly lower than that of controls at the first and second matings. At 200 mg/kg, the pregnancy rate was essentially comparable to control values at both matings. The chronologic sequence of mating was comparable for all groups; at 500 mg/kg the total number of animals showing evidence of mating was slightly lower than that of controls at both pairings. Pre-and post-implantation losses were comparable for all groups at the first and second pregnancies.

Among the rats allowed to rear their young, litter sizes, litter weights, mean pup weights and the pup mortality rates for the group dosed at 500 mg/kg amoxicillin were comparable to control values at birth, 4 and 21 days postpartum. Mean pup weights and pup mortality rates were similarly unaffected by 200 mg/kg amoxicillin; but litter sizes and litter weights were lower than control values from birth through lactation. These differences were considered to be unrelated to treatment. No abnormal young were observed.

Effects on Pregnancy

Amoxicillin was administered at doses of 200 mg/kg, 500 mg/kg and 1000 mg/kg orally during gestation from day 6 through 15. Amoxicillin did not modify pregnancy, percentage of resorption and did not produce fetal abnormalities as compared with negative control rats.

Effects on Peri- and Post-Natal Development of the Rat

Amoxicillin was administered orally at 200 and 500 mg/kg/day from day 15 of gestation through lactation to 21 days postpartum. Body weight gain, pregnancy rate, and the duration of gestation of parent animals were unaffected by treatment at any dosage. There was a significant dose-related trend to lower litter size and weight at birth. This persisted through lactation to weaning despite reduced pup mortality and increased mean pup weight in the test groups compared with controls. No abnormal young were observed.

Mice

It has been reported that amoxicillin administered at doses of 200, 500 and 2000 mg/kg/day orally during days 6 to 15 of pregnancy produced no obvious signs of reaction to treatment or deaths among parent animals. Body weight changes of pregnant dams were comparable for all groups, as was the pregnancy rate.

Fetal loss was significantly higher among all test groups than among controls. However, as implantation rates also tended to be higher at the 500 and 2000 mg/kg doses, litter sizes were only marginally, and not significantly, lower than the control value. Litter sizes and implantation rate also tended to lie at or above the upper limit of the laboratory range. Due to the latter factors, the biologic importance of the increased fetal loss was uncertain.

It was noted that mean pup weights were comparable for all groups. The distribution of skeletal variants was considered to be unaffected by treatment at any dosage. A significantly higher proportion of pups with cervical ribs was found in the 200 mg/kg dose group. Cervical rib and 14^th rib are the prolongations of the transverse processes of the cervical or lumbar vertebrae. Supernumerary ribs have an incidence which depends on the strain of animals. Cervical ribs are not abnormalities and have no pathologic significance.

In this experiment the incidence of cervical ribs was 12% in control rats and 16% in the drug-treated groups if the 3 groups are calculated together. If the groups are considered individually, then in the lowest dose group (200 mg/kg) the incidence of cervical ribs was 24%, which is, statistically, significantly higher than in the controls. This finding was not considered to be drug related since at the 500 mg/kg dose level the incidence of cervical ribs was significantly lower than in controls. At the highest dose level (2000 mg/kg) the incidence of cervical ribs was 17%, similar to the controls. The incidence of visceral abnormalities was not significantly affected at any dose level.

Special Toxicology

Lansoprazole delayed-release capsules, USP

Retinal Atrophy

In two 24-month toxicology studies in albino rats, drug-related retinal changes were seen at dosages of 15 mg/kg/day or higher in females and 50 mg/kg/day or higher in males. These retinal changes were similar to the spontaneous age-related and/or light induced retinal changes normally seen in rats. However, at the higher dosages, higher incidence of diffuse atrophy involving central as well as peripheral retina and a higher incidence of bilateral retinal atrophy occurred.

Retinal atrophy was only observed in albino rats treated continuously for 2 years. These changes in rats are believed to be associated with the effects of taurine imbalance and phototoxicity in a susceptible animal model. This lesion was not seen in other species including mice dogs and monkeys.

Clarithromycin tablets, USP

Acute Renal Toxicity

There was no evidence of nephrotoxicity of clarithromycin in the rat at doses up to 500 mg/kg/day.

Hepatotoxicity

In the in vitro and in vivo hepatotoxicity studies comparing clarithromycin with erythromycin, it was found that clarithromycin caused no greater cytotoxicity than erythromycin stearate and much less toxicity than erythromycin estolate. Hepatic enzyme induction was not found in doses below 500 mg/kg/day. In cynomolgus monkeys, the closest metabolic model for humans, elevations of ALT and LDH were identified at 200 mg/kg/day.

In dogs, a rise of ALT has been seen at 100 mg/kg/day, and in Wistar rats, a similar elevation of enzymes was seen at 200 mg/kg/day. Morphologic lesions related to prolonged exposure to clarithromycin (up to 6 months) have been consistent with reportedly reversible changes in rat, dog, and monkey studies. Such doses are many times beyond the therapeutic range in humans, which is within 8 to 10 mg/kg/day.

Ocular Toxicity

Ocular lesions appear confined to dogs and monkeys receiving lethal doses, which were large multiples of the human therapeutic dose. Radiolabelled clarithromycin studies indicate the eye is not selectively burdened by drug deposits and that clearance from this tissue follows that seen in other tissues. Opacities occur in the cornea following widespread extraocular tissue changes which are detectable via numerous diagnostic methods. Reduced intraocular pressure precedes corneal opacity in a relatively predictive manner. Some evidence for transient opacity and at least partial resolution was noted in animal studies, but most animals succumbed to other organ dysfunctions shortly after opacities were observed.

Animals given doses close to the therapeutic dose had no ocular changes. No ophthalmologic effects were noted in rabbits treated at doses of 40 and 160 mg/kg/day for 28 days.

Ototoxicity

No effects on pinna reflex were seen in guinea pigs at a dose of 400 mg/kg/day but inner and outer hair cells disappeared suggesting toxic damage. No evidence of damage was reported at 200 mg/kg/day.

Juvenile Toxicity

Lansoprazole delayed-release capsules, USP

In a juvenile rat study, adverse effects on bone growth and development and heart valves were observed at lansoprazole doses higher than the maximum recommended equivalent human dose.

An eight-week oral toxicity study with a four-week recovery phase was conducted in juvenile rats with lansoprazole administered from postnatal Day 7 (age equivalent to neonatal humans) through 62 (age equivalent to approximately 14 years in humans) at doses of 40 to 500 mg/kg/day (about 1.2 to 12 times the daily pediatric dose of 15 mg in children age one to 11 years weighing 30 kg or less, based on AUC).

Heart valve thickening occurred at a lansoprazole dose of 500 mg/kg/day (approximately 12 times the daily dose of 15 mg in pediatric patients based on AUC, age one to 11 years weighing 30 kg or less). Heart valve thickening was not observed at the next lower dose (250 mg/kg/day) and below. The findings trended towards reversibility after a four-week drug-free recovery period.

No effects on heart valves were observed in a 13-week intravenous toxicity study of lansoprazole in adolescent rats (approximately 12 years human age equivalence) at systemic exposures similar to those achieved in the eight-week oral toxicity study in juvenile (neonatal) rats.

In the eight-week oral toxicity study of lansoprazole, doses equal to or greater than 100 mg/kg/day produced delayed growth, with impairment of weight gain observed as early as postnatal Day 10 (age equivalent to neonatal humans). At the end of treatment, the signs of impaired growth at 100 mg/kg/day and higher included reductions in body weight (14% to 44% compared to controls), absolute weight of multiple organs, femur weight, femur length and crown-rump length. Femoral growth plate thickness was reduced only in males and only at the 500 mg/kg/day dose. The effects related to delayed growth persisted through the end of the 4- week recovery period. Longer term data were not collected.

In a follow-up developmental sensitivity toxicity study, juvenile rats (12 rats per treatment group) were orally administered 250 and/or 500 mg/kg/day lansoprazole for four or eight weeks starting on postnatal Day (PND) 7 (age equivalent to neonatal humans), PND 14 (age equivalent to approximately one year in humans), or PND 21 (age equivalent to approximately two years in humans).

Signs of toxicity (lower mean body weight gain and/or heart valve thickening) were observed in all dose groups of juvenile rats. Incidences of heart valve thickening were 2/12, 5/12 and 0/12, respectively, in juvenile rats in those groups dosed starting at ages 7, 14, and 21 day with 500 mg/kg/day lansoprazole for 4 weeks. Heart valve thickening in animals in those groups dosed with 500 mg/kg/day lansoprazole for eight weeks starting at PND 7, 14, and 21 were 2/12, 7/12, and 1/12, respectively.

Due to the high incidence of mortality (9 of 24 males were found dead and 15 of 24 males were euthanized between PND 18 and PND 21) in the 500 mg/kg/day dose group starting at PND 14, the 500 mg/kg/day dose groups were terminated and replaced with 250 mg/kg/day dose groups.

Incidences of heart valve thickening in juvenile rats dosed with 250 mg/kg/day (approximately four times the expected lansoprazole exposure based on AUC in pediatric patients 1 to 11 years of age) starting at PND 14 were two (2/12) and one (1/12) in the four week and eight week dose groups, respectively. Incidences of the heart valve thickening were observed in almost all dose groups. Juvenile rats younger than PND 21 (age equivalent to approximately two years in humans) were more sensitive to the development of heart valve thickening.

The relevance of these findings to pediatric patients less than 12 years of age is unknown. The findings in this study are not relevant for patients 12 years of age and above.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. Hp-PAC^® (lansoprazole delayed-release capsules (manufacturer’s standard), 30 mg, clarithromycin tablets, USP, film-coated, 500 mg, amoxicillin capsules, 500 mg), submission control 235886, Product Monograph, Takeda Pharmaceuticals America, Inc. (MAY 21, 2020)