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

OMECLAMOX-PAK (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)].

1.2 Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of OMECLAMOX-PAK and other antibacterial drugs OMECLAMOX-PAK should be used only to treat or prevent 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.

4.1 Hypersensitivity

OMECLAMOX-PAK is contraindicated in the following patients:

• Known history of hypersensitivity to omeprazole or benzimidazoles, any macrolide antibacterial drug, or any penicillin. Hypersensitivity reactions to omeprazole may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria. Hypersensitivity reactions to clarithromycin may include anaphylaxis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. 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 Warnings and Precautions (5.7), 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.

4.2 Serious Drug Interactions

• 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)].
• Coadministration of OMECLAMOX-PAK with lurasidone is contraindicated since it may result in an increase in lurasidone expose and the potential for serious adverse reactions [see Drug Interactions (7)].

5.1 Embryo-Fetal Toxicity

Clarithromycin, a component of OMECLAMOX-PAK, 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.

Based on findings in animal studies, OMECLAMOX-PAK is not recommended for use in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If OMECLAMOX-PAK is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5.2 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the components of OMECLAMOX-PAK: omeprazole, clarithromycin, and amoxicillin [see Adverse Reactions (6.3)].

Discontinue OMECLAMOX-PAK at the first signs or symptoms of SCAR or other signs of hypersensitivity and consider further evaluation.

5.3 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)].

5.4 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.

5.5 Clostridioides difficile-associated diarrhea

Clostridioides 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.

5.6 Concomitant Gastric Malignancy

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

5.7 AcuteTubulointerstitial Nephritis

Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs including omeprazole, a component of OMECLAMOX-PAK. TIN may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions, to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue OMECLAMOX-PAK and evaluate patients with suspected acute TIN [see Contraindications (4.1)].

5.8 Cutaneous and Systemic Lupus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE.

The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement.

Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported.

Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving OMECLAMOX-PAK, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g. ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.9 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.

5.10 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.

5.11 Development of Drug Resistant Bacteria

Prescribing OMECLAMOX-PAK (clarithromycin or amoxicillin component) 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, bromocriptine and lurasidone. OMECLAMOX_PAK is contraindicated in patients receiving lurasidone [see Contraindications (4.2)]. 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 (5.3)].

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

The effect of triazolobenzodiazepines/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 glucose tests based on the Benedict's copper reduction reaction that determines the amount of reducing substances like glucose in urine. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions 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

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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 emptying1.

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 proton pump inhibitor 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 antimicrobial. 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 penicillin class antibacterial, 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

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.

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 yellow 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)].

Embryo-Fetal Toxicity

Advise females of reproductive potential that that if pregnancy occurs while taking this OMECLAMOX-PAK, there is a potential hazard to the fetus [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

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
• Lurasidone
• 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)
• Triazolobenzodiazepines (e.g., triazolam and alprazolam) and related benzodiazepines (e.g., midazolam)
• Probenecid
• Drugs for which gastric pH can affect bioavailability

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)].

Acute Tubulointerstitial Nephritis

Advise the patient or caregiver to call the patient's healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Warnings and Precautions (5.7)].

Cutaneous or Systemic Lupus

Advise patients to report any symptoms associated with cutaneous or systemic lupus erythematosus [see Warnings and Precautions (5.8)].

Antibacterial Resistance

Patients should be counseled 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.

Severe Cutaneous Adverse Reactions

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking OMECLAMOX-PAK immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity [see WARNINGS AND PRECAUTIONS (5.2)].

OMECLAMOX-PAK is manufactured for CUMBERLAND PHARMACEUTICALS INC., Nashville, TN 37203.