1.1 Eradication of Helicobacter pylori in Patients with Active Duodenal Ulcer or History of Duodenal Ulcer Disease

Omeprazole delayed-release capsules, clarithromycin tablets, and amoxicillin capsules taken together are indicated for the treatment of patients with Helicobacter pylori infection and duodenal ulcer disease (active or one-year history) to eradicate H. pylori in adults. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [See Clinical Studies (14.1)].

In patients who fail therapy with Omeclamox-Pak™, perform susceptibility testing. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, institute alternative antimicrobial therapy [See Clinical Pharmacology, Microbiology (12.4)].

4.1 Hypersensitivity

Omeclamox-Pak™ is contraindicated in patients with a history of hypersensitivity to omeprazole, any macrolide antibiotic, or any penicillin.

Hypersensitivity reactions to omeprazole may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, and urticaria [See Adverse Reactions (6.3)].

Hypersensitivity reactions to clarithromycin may include anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis [See Adverse Reactions (6.3)].

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. 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. Before initiating therapy with amoxicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.

Hypersensitivity reactions to amoxicillin may include serum sickness like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria [See Adverse Reactions (6.3)].

4.2 Serious Drug Interactions (Cardiotoxicity, Ergotism)

Because of the clarithromycin component, Omeclamox-Pak™ is contraindicated in patients taking ergotamine or dihydroergotamine and pimozide. Cardiac arrhythmias, some fatal, have been reported with the use of clarithromycin and/or erythromycin and pimozide. Arrhythmias have included QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes, and are most likely due to inhibition of metabolism of these drugs by clarithromycin and/or erythromycin [See Drug Interactions (7.2, 7.3)].

5.1 Fetal Risk and Clarithromycin

Clarithromycin has demonstrated adverse effects on pregnancy outcomes and/or embryo-fetal development in monkeys, rats, mice, and rabbits at doses that produced plasma concentrations 2 to 17 times the serum concentrations achieved in humans at the maximum recommended human dose.

Clarithromycin should be used in pregnant women only in clinical circumstances where no alternative therapy is appropriate, and the potential benefit to the patient outweighs the potential risk to the fetus [See Use in Specific Populations (8.1)].

5.2 Colchicine Toxicity with Clarithromycin

There have been postmarketing reports of colchicine toxicity, some fatal, with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Monitor patients for clinical symptoms of colchicine toxicity [See Drug Interactions (7.1)].

5.3 Myasthenia Gravis

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

5.4 Clostridium difficile-associated diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with use of clarithromycin and amoxicillin, and may range in severity from mild diarrhea to fatal colitis [See Adverse Reactions (6.3)]. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.5 Concomitant Gastric Malignancy

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

5.6 Acute Interstitial Nephritis

Acute interstitial nephritis (AIN) has been observed in patients taking PPIs including omeprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue omeprazole if AIN develops. [See Contraindications (4.1)].

5.7 Development of Bacterial Superinfections

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy with Omeclamox-Pak™ due to the clarithromycin and amoxicillin components. If superinfections occur, Omeclamox-Pak™ should be discontinued and appropriate therapy instituted.

5.8 Mononucleosis and Ampicillin

A high percentage of patients with mononucleosis who receive ampicillin develop an erythematosus skin rash. Thus, administration of ampicillin-class antibiotics is not recommended in patients with mononucleosis.

5.9 Development of Drug Resistant Bacteria

Prescribing clarithromycin or amoxicillin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical trials using triple therapy with omeprazole, clarithromycin, and amoxicillin, no adverse reactions unique to triple therapy were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone. The most frequent adverse reactions observed in clinical trials using combination therapy with omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone.

6.2 Adverse Reactions from Labeling for the Individual Components of Omeclamox-Pak™

The safety data below reflect exposure to omeprazole delayed-release capsules and clarithromycin worldwide in clinical trials for various indications using doses and durations of therapy that may differ from how they are used as a component of Omeclamox-Pak™. For complete information on these reactions, see the full prescribing information for omeprazole delayed-release capsules and clarithromycin.

6.3 Post-Marketing Experience with the Individual Components of Omeclamox-Pak™

Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.

Effect of Omeprazole

Omeprazole is a substrate and an inhibitor of CYP2C19 in vivo, a substrate of CYP3A4 in vivo, and an inhibitor of CYP2C19 in vitro. Therefore, omeprazole may affect the metabolism and plasma concentrations of drugs that are metabolized by these CYP enzymes. Although in healthy subjects no interaction with theophylline or propranolol was reported, there have been reports of an interaction with other drugs metabolized via the CYP enzyme system (e.g., cyclosporine, disulfiram, benzodiazepines). Carefully monitor patients taking these drugs to determine if dosage adjustments of these drugs are necessary when taken concomitantly with omeprazole.

Effect of Clarithromycin

Clarithromycin is a substrate and inhibitor of CYP3A enzymes. Coadministration of clarithromycin with drugs metabolized by CYP3A may be associated with elevations in drug concentrations that could increase the therapeutic and adverse effects of the concomitant drug. There have been reports of CYP3A-based interactions of erythromycin and/or clarithromycin with cyclosporine, tacrolimus, alfentanil, rifabutin, methylprednisolone, cilostazol, and bromocriptine. In addition, there have been reports of interactions of erythromycin or clarithromycin with drugs not thought to be metabolized by CYP3A, including: hexobarbital, phenytoin, and valproate.

7.1 Colchicine

Concurrent use of colchicine and Omeclamox-Pak™ may increase plasma colchicine concentrations. Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). The clarithromycin component of Omeclamox-Pak™ is known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased plasma exposure to colchicine. Monitor patients for clinical symptoms of colchicine toxicity [See Warnings and Precautions (5.2)].

7.2 Ergotamine/Dihydroergotamine

Ergotamine/dihydroergotamine plasma concentrations may increase when administered concomitantly with Omeclamox-Pak™. Post-marketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Concomitant administration of clarithromycin with ergotamine or dihydroergotamine is contraindicated [See Contraindications (4.2)].

7.3 Pimozide

The coadministration of pimozide and Omeclamox-Pak™ may increase the pimozide plasma concentrations due to an interaction with the clarithromycin component of Omeclamox-Pak™. Post-marketing reports indicate that coadministration of clarithromycin with pimozide has been associated with cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes). Two sudden deaths have been reported when clarithromycin was added to ongoing pimozide therapy. Pimozide is metabolized partly by CYP3A4. When clarithromycin and pimozide are administered together, inhibition of CYP3A4 by clarithromycin may lead to increased plasma exposure to pimozide. Omeclamox-Pak™ is contraindicated in patients receiving pimozide [See Contraindications (4.2)].

7.4 Antiarrhythmics

Concurrent use of antiarrhythmic drugs and Omeclamox-Pak™ may potentiate the antiarrhythmic effects due to an interaction with the clarithromycin component of Omeclamox-Pak™. There have been post-marketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in post-marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitor electrocardiograms for QTc prolongation during coadministration of Omeclamox-Pak™ with antiarrhythmic drugs. Serum concentrations of antiarrhythmics, including digoxin, should also be monitored.

7.5 Anticoagulants

The simultaneous administration of anticoagulants and Omeclamox-Pak™ may alter the anticoagulant effects of warfarin and other oral anticoagulants due to an interaction with the omeprazole and clarithromycin components of Omeclamox-Pak™. Monitor prothrombin time and INR in patients receiving Omeclamox-Pak™ and oral anticoagulants simultaneously.

There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Spontaneous reports in the post-marketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants.

7.6 Antiretroviral Drugs

Concurrent use of antiretroviral agents and Omeclamox-Pak™ may alter the antiretroviral effects due to interactions with the omeprazole or clarithromycin components of Omeclamox-Pak™. Omeprazole has been reported to interact with some antiretroviral drugs such as atazanavir, nelfinavir, and saquinavir.

Concomitant use of atazanavir or nelfinavir with omeprazole is not recommended unless the benefits of taking atazanavir or nelfinavir with Omeclamox-Pak™ outweigh the risks. Coadministration of atazanavir or nelfinavir with proton pump inhibitors is expected to substantially decrease atazanavir or nelfinavir plasma concentrations and thereby reduce the therapeutic effect of either of these drugs [See Clinical Pharmacology (12.3)].

Coadministration of saquinavir with omeprazole may increase the serum concentrations of saquinavir. Dose reduction of saquinavir should be considered when coadministered with Omeclamox-Pak™ [See Clinical Pharmacology (12.3)].

7.7 Cilostazol

Concomitant administration of Omeclamox-Pak™ and cilostazol may increase systemic exposure of cilostazol due to an interaction with the omeprazole component of Omeclamox-Pak™. Therefore, a dose reduction of cilostazol by 50% should be considered when concomitantly administered with Omeclamox-Pak™ [See Clinical Pharmacology (12.3)].

7.8 Tacrolimus

Concomitant administration of Omeclamox-Pak™ and tacrolimus may increase the serum concentrations of tacrolimus due to an interaction with the omeprazole component of Omeclamox-Pak™. Frequent monitoring of whole blood trough concentrations of tacrolimus is recommended when concomitantly administered with Omeclamox-Pak™.

7.9 Theophylline

Omeclamox-Pak™ use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations due to an interaction with the clarithromycin component of Omeclamox-Pak™. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range [See Clinical Pharmacology (12.3)].

7.10 Carbamazepine

The simultaneous administration of carbamazepine and Omeclamox-Pak™ may alter the effect of carbamazepine due to an interaction with the clarithromycin component of Omeclamox-Pak™. Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine should be considered when administered concomitantly with Omeclamox-Pak™.

7.11 Sildenafil

The systemic exposure of sildenafil may increase when it is administered concomitantly with Omeclamox-Pak™ due to an interaction with the clarithromycin component of Omeclamox-Pak™; consider a reduction in sildenafil dosage (see sildenafil full prescribing information).

7.12 HMG-CoA Reductase Inhibitors (Statins)

Concurrent use of HMG-CoA reductase inhibitors (statins) and Omeclamox-Pak™ may alter the effect of HMG-CoA due to an interaction with the clarithromycin component of Omeclamox-Pak™. As with other macrolides, clarithromycin has been reported to increase concentrations of statins (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

7.13 Triazolobenziodidiazepines (e.g., triazolam and alprazolam) and related Benzodiazepines (e.g., midazolam)

The effect of triazolobenziodidiazepines/related benzodiazepines may be altered when administered concomitantly with Omeclamox-Pak™ due to an interaction with the clarithromycin component. There have been postmarketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam.

7.14 Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of Omeclamox-Pak™ and probenecid may result in increased and prolonged blood concentrations of the amoxicillin component of Omeclamox-Pak™.

7.15 Drugs for which Gastric pH can affect Bioavailability

Due to its effects on gastric acid secretion, omeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. As with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole.

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Coadministration of digoxin with omeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with omeprazole.

Coadministration of omeprazole in healthy subjects and in transplant patients receiving mycophenolate mofetil has been reported to reduce the exposure to mycophenolic acid (MPA), the active moiety, possibly due to a decrease in MPA solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving proton pump inhibitors (PPIs) and mycophenolate mofetil. Use omeprazole with caution in transplant patients receiving mycophenolate mofetil [See Clinical Pharmacology (12.3)].

7.16 Drug-Laboratory Test Interactions

High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using Clinitest®, Benedict's Solution or Fehling's Solution. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix®) be used.

Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estradiol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with amoxicillin.

8.1 Pregnancy

Pregnancy Category C (based on animal studies of omeprazole and clarithromycin)

There are no adequate and well controlled studies of omeprazole, clarithromycin, or amoxicillin (used separately or together) in pregnant women. Clarithromycin demonstrated adverse developmental effects in four animal species at clinically relevant doses. Omeprazole increased embryo-fetal loss in rabbits, but animal studies and multiple human studies do not show an increased risk for major malformations. Omeclamox-Pak™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus and there is no appropriate alternative therapy [See Warnings and Precautions (5.1)].

8.2 Labor and Delivery

8.3 Nursing Mothers

Omeclamox-Pak™ contains omeprazole, clarithromycin, and amoxicillin. Information on use of each product during lactation is provided below.

8.4 Pediatric Use

The safety and effectiveness of Omeclamox-Pak™ for pediatric patients with H. pylori have not been established.

8.5 Geriatric Use

8.6 Renal Impairment

In the presence of severe renal impairment with or without coexisting hepatic impairment, prolonged dosing intervals for the clarithromycin component may be appropriate.

8.7 Hepatic Impairment

It is recommended to avoid the use of Omeclamox-Pak™ in patients with hepatic impairment [See Clinical Pharmacology (12.3)].

8.8 Asian Patients

It is recommended to avoid the use of Omeclamox-Pak™ in Asian patients unless it is deemed that the benefits outweigh the risks [See Clinical Pharmacology (12.3)].

Omeprazole:

Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience [See Adverse Reactions (6.3)]. Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive.

Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs, respectively. Animals given these doses showed sedation, ptosis, tremors, convulsions, and decreased activity, body temperature, and respiratory rate and increased depth of respiration.

Clarithromycin:

Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea.

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

Amoxicillin:

In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.1

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria. Renal impairment appears to be reversible with cessation of drug administration. High blood concentrations may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin. Amoxicillin can be removed from circulation by hemodialysis.

Omeprazole Delayed-Release Capsules, USP:

The active ingredient in omeprazole delayed-release capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C17H19N3O3S, with a molecular weight of 345.42. The structural formula is:

Omeprazole is a white to off-white crystalline powder that melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol, and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.

Each omeprazole delayed-release capsule contains 20 mg of omeprazole in the form of enteric-coated granules with the following inactive ingredients: crospovidone, hypromellose, lactose, magnesium stearate, mannitol, meglumine, methacrylic acid copolymer, poloxamer, povidone and triethyl acetate. The capsule shells contain: D&C Red #28, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, yellow iron oxide, gelatin, silicon dioxide, sodium lauryl sulfate and titanium dioxide. Imprinting ink contains: D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, n-butyl alcohol, pharmaceutical glaze, propylene glycol, SDA-3A alcohol and synthetic black iron oxide.

Clarithromycin Tablets, USP:

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6-0-methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96. Clarithromycin has the following structural formula:

Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water. Each tablet for oral administration contains 500 mg of clarithromycin and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose. Opadry II (White), povidone, stearic acid, and talc. Opadry II (White) contains hypromellose, polyethylene glycol, polydextrose, titanium dioxide and triacetin.

Amoxicillin Capsules, USP:

Amoxicillin, a semisynthetic antibiotic, is an analogue of ampicillin, with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Chemically it is (2S, 5R, 6R)-6-[(R)-(-)-2-amino-2-(p-hydroxyphenyl)acetamido]- 3,3-dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0] heptane-2-carboxylic acid trihydrate. Its empirical formula is C16H19N3O5S •3H2O with a molecular weight of 419.45. Amoxicillin has the following structural formula:

Amoxicillin capsules contain amoxicillin trihydrate equivalent to 500 mg of amoxicillin. Amoxicillin capsules USP also contain magnesium stearate and sodium lauryl sulfate. The capsule shell contains D&C Red No. 33, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, gelatin, sodium lauryl sulfate and titanium dioxide. Each 500 mg capsule contains up to 0.0052 mEq (0.119 mg) of sodium.

12.1 Mechanism of Action

Omeprazole is an antisecretory drug whereas clarithromycin and amoxicillin are antibacterial drugs [See Clinical Pharmacology (12.4)].

12.3 Pharmacokinetics

Pharmacokinetics when all three of the Omeclamox-Pak™ components were coadministered has not been studied. Studies have shown the low risk of clinically significant interactions of omeprazole and amoxicillin or omeprazole and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of omeprazole, clarithromycin and amoxicillin after administration of these drugs concomitantly. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone, or in combination of two components.

12.4 Microbiology

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the triple therapy clinical trials, 84.9% (157/185) of the patients in the omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 µg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.

Susceptibility Test for Helicobacter pylori:

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs [See References (15)]. One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 × 107 – 1 × 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for campylobacters. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

Effects on Gastrointestinal Microbial Ecology:

Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 H. pylori associated Duodenal Ulcer Disease

Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared omeprazole plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients with a history of a duodenal ulcer in the past 5 years but without an ulcer present at the time of enrollment. The dose regimen in the studies was omeprazole 20 mg twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg once daily. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 only). H. pylori status was determined by CLOtest®, histology and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative and none was positive.

The combination of omeprazole plus clarithromycin plus amoxicillin, was effective in eradicating H. pylori.

Store at controlled room temperature between 20°C and 25°C (68°F and 77°F). Protect from light and moisture.

17.1 Administration

Inform patients that each dose of Omeclamox-Pak™ contains four pills: one opaque lavender/grey capsule (omeprazole), one white tablet (clarithromycin) and two opaque, peach/orange capsules (amoxicillin).

Take each dose of four pills in the morning and four pills in the evening before eating a meal, for 10 days. Capsules and tablets should not be crushed or chewed, and should be swallowed whole [See Dosage and Administration (2)].

17.3 Drug Interactions

Patients should be advised to report to their doctor the use of any other medications while taking Omeclamox-Pak™ [See Drug Interactions (7)].

The simultaneous administration of any of the following drugs with Omeclamox-Pak™ may result in clinically significant adverse reactions or even death:

• Colchicine
• Ergotamine/dihydroergotamine
• Pimozide
• Antiarrhythmic drugs (e.g., quinidine, disopyramide)
• Digoxin
• Anticoagulants (e.g., warfarin)
• Atazanavir
• Nelfinavir
• Saquinavir
• Cilostazol
• Tacrolimus
• Theophylline
• Carbamazepine
• Sildenafil
• HMG-CoA reductase inhibitors (also known as statins)
• Triazolobenziodidiazepines (e.g., triazolam and alprazolam) and related benzodiazepines (e.g., midazolam)
• Probenecid
• Drugs for which gastric pH can affect bioavailability

17.4 Clostridium difficile-associated Diarrhea

Advise patients that diarrhea is a common problem caused by omeprazole and antibiotics that usually ends when the drug is discontinued. Sometimes after starting treatment, patients can develop severe diarrhea with watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the drug. If this occurs, patients should contact a physician as soon as possible [See Warnings and Precautions (5.4)].

17.5 Antibacterial Resistance

Counsel patients that antibacterial drugs including Omeclamox-Pak™ should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Omeclamox-Pak™ is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Omeclamox-Pak™ or other antibacterial drugs in the future.