Omeclamox®-Pak consists of a pack of ten individual daily administration cards, each card containing two omeprazole delayed-release 20 mg capsules, USP, two clarithromycin 500 mg tablets, USP, and four amoxicillin 500 mg capsules, USP, for oral administration.
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.
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 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.
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].
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].
DOSAGE AND ADMINISTRATION
The recommended adult oral regimen is omeprazole delayed-release capsules 20 mg plus clarithromycin 500 mg plus amoxicillin 1000 mg, each given twice daily, for 10 days, in the morning and evening before eating a meal. Inform patients that omeprazole, clarithromycin, and amoxicillin should not be crushed or chewed, and should be swallowed whole.
In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief.
Dosage Forms And Strengths
Omeclamox®-Pak is supplied in a carton containing ten individual daily administration cards. Each card contains:
Omeprazole Delayed-Release Capsules, USP, 20 mg
Two opaque, hard gelatin lavender and grey capsules, with 'R 158' and 'OMEPRAZOLE 20 mg' imprinted on the capsules in black ink, containing off-white to pale-yellow, elliptical spherical pellets.
Clarithromycin Tablets, USP, 500 mg
Two white, biconvex beveled-edge capsule-shaped coated tablets debossed with '54 312' on one side and plain on the other side. Amoxicillin Capsules, USP, 500 mg
Four opaque hard gelatin peach and orange capsules, marked 'WC 731'. Each capsule contains amoxicillin trihydrate, equivalent to 500 mg amoxicillin.
Storage And Handling
Omeclamox®-Pak is supplied in a carton containing ten individual daily administration cards. Each card contains the morning dose and the evening dose of the following three drugs:
Omeprazole Delayed-Release Capsules, USP, 20 mg
Two opaque hard gelatin lavender and grey capsules, with 'R 158' and 'OMEPRAZOLE 20 mg' imprinted on the capsules in black ink, containing off-white to pale-yellow, elliptical spherical pellets.
Clarithromycin Tablets, USP, 500 mg
- Two white, biconvex beveled-edge capsule-shaped coated tablets debossed with '54 312' on one side and plain on the other side.
Amoxicillin Capsules, USP, 500 mg
- Four opaque hard gelatin peach and orange capsules, marked 'WC 731'. Each capsule contains amoxicillin trihydrate equivalent to 500 mg amoxicillin.
NDC 65224-707-11 Carton containing 10 daily
NDC 65224-707-00 Daily administration card
Store at controlled room temperature between 20°C and 25°C (68°F and 77°F). Protect from light and moisture.
Omeclamox®-Pak is distributed by CUMBERLAND PHARMACEUTICALS INC, Nashville, TN 37203. Omeprazole Delayed-Release Capsules, USP, 20 mg. Manufactured by Dr. Reddy's Laboratories, Limited, Bachepalli, 502 325, INDIA, Clarithromycin Tablets, USP, 500 mg. Manufactured by Roxane Laboratories, Inc., a division of Boehringer Ingelheim, Columbus, OH 43228, U.S.A., Amoxicillin Capsules, USP, 500 mg. Manufactured by Suir Pharma Ireland Ltd., Clonmel, IRELAND. Promoted by: For inquiries contact Cumberland Pharmaceuticals Inc. 1-877-484-2700. Revised: Dec 2014
Included as part of the PRECAUTIONS section.
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].
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].
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.
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]. 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.
Concomitant Gastric Malignancy
Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy.
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].
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.
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.
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.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.7 to 57 times a human dose of 20 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both males and females; the incidence of this effect was markedly higher in female rats, which had higher blood concentrations of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 6 times a human dose of 20 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret.
In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.2 to 6.5 times the human dose on a body surface area basis). No astrocytomas were observed in female rats in this study or in males or females from a 2-year carcinogenicity study in Sprague-Dawley rats at the high dose of 140.8 mg/kg/day (about 57 times the human dose on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/–) transgenic mouse carcinogenicity study was not positive.
Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay.
Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance.
Use In Specific Populations
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].
Multiple cohort studies in pregnant women exposed to omeprazole during the first trimester do not show an increased risk of congenital malformations. The majority of experience with omeprazole use during human pregnancy includes first trimester exposure and the duration of use is rarely specified. Three epidemiological studies compared the frequency of congenital malformations among infants born to women who used omeprazole during pregnancy with the frequency of malformations among infants of women exposed to H2-receptor antagonists or controls. One population-based prospective cohort study from the Swedish Medical Birth Registry, reported 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester), whose mothers used omeprazole during pregnancy. In utero exposure to omeprazole was not associated with an increased risk of malformations (odds ratio 0.82, 95% CI 0.50-1.34), low birth weight or low Apgar score. While the number of stillbirths and infants born with ventricular septal defects were slightly higher in the omeprazole-exposed group, these findings may have been due to chance and do not establish a causal relationship to omeprazole exposure.
A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole). The overall malformation rate was 4.4% (95% CI 3.6-5.3) and the malformation rate for first trimester exposure to omeprazole was 3.6% (95% CI 1.5-8.1). The relative risk of malformations associated with first trimester exposure to omeprazole compared with non-exposed women was 0.9 (95% CI 0.3-2.2). The study could effectively rule out a relative risk greater than 2.5 for all malformations. Rates of preterm delivery or growth retardation did not differ between the groups.
A controlled prospective observational study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rates of major congenital malformations was 4% for the omeprazole group, 2% for controls exposed to nonteratogens, and 2.8% in disease-paired controls (background incidence of major malformations 1-5%). Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight did not differ among the groups. The sample size in this study had 80% power to detect a 5-fold increase in the rate of major malformations.
Reproductive and developmental toxicology studies conducted in rats and rabbits during organogenesis at oral omeprazole doses up to 28 times the human dose of 40 mg/day did not show any evidence of fetal structural abnormalities. However, dose-related increases in embryo-lethality, fetal resorptions, and pregnancy loss occurred when pregnant rabbits received omeprazole at doses about 2.8 to 28 times the human dose of 40 mg/day. In a peri- and post-natal development study, when pregnant rats received omeprazole at doses about 2.8 to 28 times the human dose of 40 mg/day, dose-related embryo/fetal toxicity and postnatal developmental toxicity occurred in offspring.
When pregnant monkeys received 70 mg/kg/day oral clarithromycin (approximately equivalent to the maximum recommended human dose (MRHD) on a mg/m² basis) fetal growth retardation occurred at plasma concentrations that were 2 times the human serum concentrations achieved at the MRHD.
A low incidence of cardiovascular anomalies were observed in fetuses in two rat embryo-fetal studies of clarithromycin administered orally to dams on gestation days 6 to 15 at doses of 150 mg/kg/day, which resulted in plasma concentrations approximately 2 times the human serum concentrations achieved at the MRHD.
Four embryo-fetal studies in mice revealed a variable incidence of cleft palate following oral doses of 500 mg/kg/day and 1000 mg/kg/day (2 and 4 times the MRHD on a mg/m² basis, respectively) during organogenesis (gestation days 6 to 15). The 1000 mg/kg/day exposure resulted in plasma concentrations 17 times the human serum concentrations achieved at the MRHD. No teratogenic effects occurred in offspring from two studies in pregnant rabbits that received oral clarithromycin doses up to 125 mg/kg/day (approximately 2 times the maximum recommended human dose on a mg/m² basis) or intravenous doses of 30 mg/kg/day during the period of major organogenesis.
Reproduction studies have been performed in mice and rats at doses up to 10 times the human dose and revealed no evidence of impaired fertility or harm to the fetus due to amoxicillin.
Labor And Delivery
Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia.
Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions, but moderately increased the height and duration of contractions. However, it is not known whether amoxicillin affects labor or delivery in humans.
Omeclamox®-Pak contains omeprazole, clarithromycin, and amoxicillin. Information on use of each product during lactation is provided below.
Breast milk concentrations of omeprazole were measured in the breast milk of one woman following oral administration of 20 mg. The peak concentration was 20 mcg/L, less than 7% of the peak maternal serum concentration. Based on this information, the estimated infant daily dose in an exclusively human-milk fed infant is 3 mcg/kg/day. However, due to the potential for tumorigenicity shown for omeprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or express and discard milk during Omeclamox®-Pak treatment.
It is not known whether clarithromycin is excreted in human milk. However, other macrolide antibiotics are excreted in human milk. Clarithromycin is found in animal milk. Caution should be exercised when clarithromycin is administered to a nursing woman.
Penicillins are excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman.
The safety and effectiveness of Omeclamox®-Pak for pediatric patients with H. pylori have not been established.
Omeprazole was administered to over 2000 elderly individuals ( ≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. However, no dosage adjustment is necessary in the elderly [See CLINICAL PHARMACOLOGY].
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 serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. 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.
An analysis of clinical studies of amoxicillin was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 1811 subjects treated with amoxicillin, 85% were < 60 years old, 15% were ≥ 61 years old and 7% were ≥ 71 years old. This analysis and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
This drug 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.
In the presence of severe renal impairment with or without coexisting hepatic impairment, prolonged dosing intervals for the clarithromycin component may be appropriate.
It is recommended to avoid the use of Omeclamox®-Pak in patients with hepatic impairment [See CLINICAL PHARMACOLOGY].
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].
In case of an overdose, patients should contact a physician, poison control center, or emergency room. There is neither a pharmacologic basis nor data suggesting an increased toxicity of the combination compared to individual components.
As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, contact your local Poison Control Center at 1-800-222-1222.
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]. 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.
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.
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.
Omeclamox®-Pak is contraindicated in patients with a history of hypersensitivity to omeprazole, any macrolide antibiotic, or any penicillin.
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].
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].
1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988;30:66-67.
Mechanism Of Action
Omeprazole is an antisecretory drug whereas clarithromycin and amoxicillin are antibacterial drugs [See Microbiology].
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.
Omeprazole Delayed-Release Capsules, USP
Absorption And Distribution
Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acidlabile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma concentrations of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30-40% at doses of 20-40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500-600 mL/min.
The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules.
Omeprazole delayed-release capsules 40 mg was bioequivalent when administered with and without applesauce. However, omeprazole delayed-release capsules 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for omeprazole delayed-release capsules 20 mg. The clinical relevance of this finding is unknown. Protein binding is approximately 95%.
Metabolism And Excretion
Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma – the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity.
The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers.
In patients with chronic hepatic disease, the bioavailability of omeprazole increased to approximately 100% compared with an IV dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in normals of 0.5-1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500-600 mL/min in normal subjects. It is recommended to avoid the use of Omeclamox®-Pak in patients with hepatic impairment.
In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73m,2 the disposition of omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. No dose reduction is necessary in patients with renal impairment.
In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared with Caucasians. It is recommended to avoid the use of Omeclamox®-Pak in Asian patients unless it is deemed that the benefits outweigh the risks.
Clarithromycin Tablets, USP
Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly increase the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, clarithromycin tablets may be given without regard to food.
In nonfasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 3 to 4 μg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended dose of 500 mg administered every 8 to 12 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is up to 1 μg/mL, and its elimination half-life is about 7 to 9 hours. The steady-state concentration of this metabolite is generally attained within 3 to 4 days.
After a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is approximately 30%. The renal clearance of clarithromycin 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 a 500 mg tablet administered every 12 hours.
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 the subjects with impaired hepatic function when compared to healthy subjects.
The pharmacokinetics of clarithromycin was altered in subjects with impaired renal function. In the presence of severe renal impairment with or without coexisting hepatic impairment, prolonged dosing intervals for clarithromycin may be appropriate.
Amoxicillin Capsules, USP
Amoxicillin is stable in the presence of gastric acid and may be given without regard to meals. It is rapidly absorbed after oral administration. It diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approximately 20% proteinbound.
Orally administered doses of 500 mg amoxicillin capsules result in average peak blood concentrations 1 to 2 hours after administration in the range of 5.5 μg /mL to 7.5 μg /mL. Detectable serum concentrations are observed up to 8 hours after an orally administered dose of amoxicillin. Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours.
Combination Therapy Of Omeprazole with Antimicrobials
Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and T½ increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin.
The plasma concentrations of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.
Table 1 : Mean ± SD Clarithromycin Tissue
Concentrations 2 hours after Dose
|Tissue||Clarithromycin (μg/g)||Clarithromycin + Omeprazole (μg/g)|
|Antrum||10.48 ± 2.01 (n = 5)||19.96 ± 4.71 (n=5)|
|Fundus||20.81 ± 7.64 (n = 5)||24.25 ± 6.37 (n= 5)|
|Mucus||4.15 ± 7.74 (n = 4)||39.29 ± 32.79 (n=4)|
Antiretroviral Drugs and Omeprazole
The clinical importance and the mechanisms behind interactions between omeprazole and antiretroviral drugs are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via inhibition of CYP2C19.
Following multiple doses of nelfinavir (1250 mg twice daily) and omeprazole (40 mg once daily), AUC of nelfinavir and the M8 metabolite was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75%.
Following multiple doses of atazanavir (400 mg once daily) and omeprazole (40 mg once daily 2 hours before atazanavir), AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and atazanavir is not recommended.
Saquinavir serum AUC, Cmax and Cmin increased by 82%, 75% and 106%, respectively, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg once daily coadministered days 11 to 15 [See DRUG INTERACTIONS].
Cilostazol and Omeprazole
Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in crossover study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg b.i.d. to 50 mg b.i.d. should be considered [See DRUG INTERACTIONS].
Theophylline and Clarithromycin
Theophylline is metabolized by CYP1A2 and CYP3A4. Clarithromycin will increase theophylline plasma concentrations when it is administered concomitantly. In two studies in which theophylline was administered with clarithromycin (theophylline sustainedrelease formulation dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg every 12 hours clarithromycin), the steadystate Cmax, Cmin, and AUC of theophylline increased about 20%. 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 DRUG INTERACTIONS].
Voriconazole And Omeprazole
Voriconazole is an inhibitor of CYP2C19, CYP2C9, and CYP3A4. Coadministration of voriconazole and omeprazole will increase omeprazole plasma exposure. When voriconazole (400 mg every 12 hours x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole. Dose adjustment of omeprazole is not normally required.
Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of mycophenolate mofetil approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of mycophenolic acid.
Mechanism Of Action
Omeprazole, an antisecretory drug with the substituted benzimidazoles, suppresses 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 gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-dependent and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Omeprazole can also exhibit anti-bacterial activity depending on the culture conditions. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more.
Clarithromycin exerts its antibacterial activity by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.
Amoxicillin acts through the inhibition of biosynthesis of cell wall mucopeptide.
Activity In Vitro And In Vivo
Triple therapy with omeprazole, clarithromycin and amoxicillin has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as indicated [See INDICATIONS AND USAGE].
In vitro studies show that chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with bactericidal effects of penicillin; however, the clinical significance of this interaction is not well documented.
Helicobacter pylori Pretreatment Resistance
Clarithromycin pretreatment resistance rates were 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin triple therapy studies [See Clinical Studies].
Amoxicillin pretreatment susceptible isolates ( ≤ 0.25 μg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 μg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 μg/mL by Etest.®
Table 2: Pre-treatment and post-treatment clarithromycin
susceptibility test results and clinical/bacteriological outcomes in patients treated
with triple therapy*
|Clarithromycin Pre-treatment Results||H. pylori negative - eradicated||Clarithromycin Post-treatment Results|
|H. pylori positive - not eradicated Post-treatment susceptibility results|
|aSusceptible (S) MIC ≤ 0.25 μg/mL,
Intermediate (I) MIC 0.5 μg/mL, Resistant (R) MIC ≥ 1 μg/mL.
*Treatment with omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice daily for 10 days (Studies 1, 2 and 3) followed by omeprazole 20 mg once daily for another 18 days (Studies 1 and 2).
Patients not eradicated of H. pylori following omeprazole/clarithromycin/amoxicillin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycinresistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/ amoxicillin triple therapy, or other regimens which include clarithromycin as the sole antimicrobial agent.
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]. One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107 – 1 x 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:
Table 3 : In vitro Susceptibility Interpretive
Criteria for Clarithromycin and Amoxicillin
|Clarithromvcin MIC (μg/mL)a||Interpretation|
|≤ 0.25||Susceptible (S)|
|≥ 1.0||Resistant (R)|
|Amoxicillin MIC (μg/mL)a,b||Interpretation|
|≤ 0.25||Susceptible (S)|
|aThese are breakpoints for the agar dilution
methodology and they should not be used to interpret results obtained using
bThere were not enough organisms with MICs > 0.25 μg/mL to determine a resistance breakpoint.
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:
Table 4 : Quality Control for Susceptibility Testing
|Microorganisma||Antimicrobial Agent||MIC (μg/mL)|
|H. pylori ATCC 43504||Clarithromycin||0.015-0.012|
|H. pylori ATCC 43504||Amoxicillin||0.015-0.012|
|aThese are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.|
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.
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.
Table 5: Per-Protocol and Intent-to-Treat H.
pylori Eradication Rates % of Patients Cured [95% Confidence Interval]
|omeprazole + clarithromycin + amozicillin||carithromycin + amoxicillin|
|Per - Protocol†||Intent-to-Treat‡||Per - Protocol†||Intent - to Treat‡|
|Study 1||*77 [64, 86]||*69 [57, 79]||43 [31, 56]||37 [27, 48]|
|(n = 64)||(n = 80)||(n = 67)||(n = 84)|
|Study 2||*78 [67, 88]||*73 [61, 82]||41 [29, 54]||36 [26, 47]|
|(n = 65)||(n = 77)||(n = 68)||(n = 83)|
|Study 3||*90 [80, 96]||*83 [74, 91]||33 [24, 44]||32 [23, 42]|
|(n = 69)||(n = 84)||(n = 93)||(n = 99)|
|†Patients were included in the analysis if they had confirmed
duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer within
5 years, study 3) and H. pylori infection at baseline defined as at
least two of three positive endoscopic tests from CLOtest,® histology, and/or
culture. Patients were included in the analysis if they completed the study.
Additionally, if patients dropped out of the study due to an adverse event
related to the study drug, they were included in the analysis as failures of
therapy. The impact of eradication on ulcer recurrence has not been assessed in
patients with a past history of ulcer.
‡Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy.
*(p < 0.05) versus clarithromycin plus amoxicillin.
1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988;30:66-67.
2. Clinical Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard- Eighth Edition. CLSI document M07-A8. Wayne, PA: Clinical and Laboratory Standards Institute; 2009.
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].
Patients should be advised to report to their doctor the use of any other medications while taking Omeclamox®-Pak [See DRUG INTERACTIONS].
The simultaneous administration of any of the following drugs with Omeclamox®-Pak may result in clinically significant adverse reactions or even death:
- Antiarrhythmic drugs (e.g., quinidine, disopyramide)
- Anticoagulants (e.g., warfarin)
- HMG-CoA reductase inhibitors (also known as statins)
- Triazolobenziodidiazepines (e.g., triazolam and alprazolam) and related benzodiazepines (e.g., midazolam)
- Drugs for which gastric pH can affect bioavailability
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].
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.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.