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 acid- labile), 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

Among those females aged 18 to 44 years of age, 22.4% were diagnosed with skin infections and 7.6% had pneumonia. 

Geriatric Patients

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. 

Hepatic Impairment

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. 

Renal Impairment

In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73m2, 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. 

Asian Patients

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% protein- bound. 

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 T1/2 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. 

Drug Interactions

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 (7.6)]. 

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 (7.7)]. 

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 sustained- release formulation dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg every 12 hours clarithromycin), the steady-state 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 (7.9)]. 

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. 

Mycophenolate mofetil

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.