Hp-PAC (Lansoprazole Clarithromycin Amoxicillin)
Eradication of H. pylori : H. pylor i is considered to be a major factor in the etiology of duodenal ulcer disease. The presence of H. pylori may damage the mucosal integrity due to the production of enzymes (catalase, lipases, phospholipases, proteases, and urease), adhesins and toxins; the inflammatory response generated in this manner contributes to mucosal damage.
The concomitant administration of antimicrobials such as clarithromycin and amoxicillin, and an antisecretory agent such as lansoprazole, improves the eradication of H. pylori as compared to individual drug administration. The higher pH resulting from antisecretory treatment, optimizes the environment for the pharmacologic action of the antimicrobial agents against H. pylori.
Hp-PAC: Pharmacokinetics : The pharmacokinetics of the drugs when all 3components of the Hp-PAC (lansoprazole capsules, clarithromycin tablets and amoxicillin capsules) were coadministered, has not been studied. Studies have shown no clinically significant interactions between lansoprazole and amoxicillin or lansoprazole and clarithromycin when coadministered. There is no information about the gastric mucosal concentrations of lansoprazole, amoxicillin and clarithromycin after administration of these agents concomitantly. The systemic pharmacokinetic information presented below is based on studies in which each product was administered alone.
Lansoprazole: General: Lansoprazole inhibits the gastric H +,K +-ATPase (the proton pump) which catalyzes the exchange of H +andK +. It is effective in the inhibition of both basal acid secretion and stimulated acid secretion.
In healthy subjects, single and multiple doses of lansoprazole (15to 60 mg) have been shown to decrease significantly basal gastric acid output and to increase significantly mean gastric pH and percent of time at pH > 3 and 4. These doses have also been shown to reduce significantly meal-stimulated gastric acid output and gastric secretion volume. Single or multiple doses of lansoprazole (10to 60mg) reduced pentagastrin-stimulated acid output. In addition, lansoprazole has been demonstrated to reduce significantly basal and pentagastrin-stimulated gastric acid secretion among duodenal ulcers and hypersecretory patients, and basal gastric acid secretion among patients with gastric ulcer disease.
A dose-response effect was analyzed by considering the results from clinical pharmacology studies that evaluated more than 1dose of lansoprazole. The results indicated that, in general, as the dose was increased from 7.5 mg to 30 mg, there was a decrease in mean gastric acid secretion and an increase in the average time spent at higher pH values (pH > 4).
The results of pharmacodynamic studies with lansoprazole in normal subjects suggest that doses of 7.5 to 10 mg are substantially less effective in inhibiting gastric acid secretion than doses of 15mg or greater. In view of these results, the doses of lansoprazole evaluated in the principal clinical trials ranged from 15 to 60mg daily.
Pharmacokinetics : Prevacid contains an enteric-coated granule formulation of lansoprazole to ensure that absorption of lansoprazole begins only after the granules leave the stomach (lansoprazole is acid-labile). Peak plasma concentrations of lansoprazole (C max) and the area under the plasma concentration curve (AUC) of lansoprazole are approximately proportional in doses from 15 to 60 mg after single-oral administration. Lansoprazole pharmacokinetics are unaltered by multiple dosing and the drug does not accumulate.
Lansoprazole is highly bioavailable when administered orally. The absolute bioavailability was shown to be 86% for a 15 mg capsule and 80% for a 30 mg capsule. The apparent first pass effect is minimal.
Absorption: The absorption of lansoprazole is rapid, with mean peak plasma levels of lansoprazole occurring at approximately 1.7 hours. Peak plasma concentrations of lansoprazole (C max) and the area under the plasma concentration curve (AUC) are approximately proportional to dose throughout the range that has been studied (up to 60 mg).
Absorption with Food: Food reduces the peak concentration and the extent of absorption by about 50%. Moreover, the results of a pharmacokinetic study that compared the bioavailability of lansoprazole following a.m. dosing (fasting) vs p.m. dosing (3hours after a meal) indicated that both C max and AUC values were increased by approximately 2-fold or more with a.m. dosing. Therefore, it is recommended that lansoprazole be administered in the morning prior to breakfast.
Absorption with Antacids: Simultaneous administration of lansoprazole with Maalox (aluminum and magnesium hydroxide) or Riopan (magaldrate) resulted in lower peak serum levels, but did not significantly reduce the bioavailability of lansoprazole.
In a single-dose crossover study when 30 mg of lansoprazole was administered concomitantly with 1g of sucralfate in healthy volunteers, absorption of lansoprazole was delayed and its bioavailability was reduced. The value of lansoprazole AUC was reduced by 17% and that for C max was reduced by 21%.
In a similar study when 30 mg of lansoprazole was administered concomitantly with 2 g of sucralfate, lansoprazole AUC and C max were reduced by 32% and 55%, respectively. When lansoprazole dosing occurred 30 minutes prior to sucralfate administration, C max was reduced by only 28% and there was no statistically significant difference in lansoprazole AUC. Therefore, lansoprazole may be given concomitantly with antacids but should be administered at least 30minutes prior to sucralfate.
Distribution: Lansoprazole is 97% bound to plasma proteins. The mean total body clearance (Cl) of lansoprazole was calculated at 31 ± 8 L/h, and the volume of distribution (V ss) was calculated to be 29 ± 4L.
Elimination: Following single dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine. After a single dose of 14C-lansoprazole, approximately one-third of the dose was excreted in the urine and approximately two-thirds were recovered in the feces. This implies a significant biliary excretion of the metabolites of lansoprazole.
Metabolism: Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma: the hydroxylated sulfinyl and the sulfone derivatives of lansoprazole. These metabolites have very little or no antisecretory activity. Within the parietal cell canaliculus, lansoprazole is thought to be transformed into 2active metabolites that inhibit acid secretion by (H +,K +)-ATPase; these metabolites are not present in the systemic circulation. The plasma elimination half-life of lansoprazole does not reflect the duration of suppression of gastric acid secretion. Thus, the plasma elimination half-life is less than 2hours while the acid inhibitory effect lasts over 24 hours.
Special Populations: Hepatic Impairment: As would be expected with a drug that is primarily metabolized by the liver, in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) chronic hepatic disease, the plasma half-life of the drug increased to 5.2 hours compared to the 1.5 hours half-life in healthy subjects. An increase in AUC of 3.4-fold was observed in patients with hepatic impairment versus healthy subjects (7096 vs 2645ng.h/mL); this was due to slower elimination of lansoprazole; C max was not significantly affected.
Renal Impairment: In patients with mild (Cl cr 40 to 80 mL/min), moderate (Cl cr 20to 40mL/min) and severe (Cl cr <20mL/min) chronic renal impairment, the disposition of lansoprazole was very similar to that of healthy volunteers.
The impact of dialysis on lansoprazole was evaluated from a pharmacokinetic standpoint, and there were no significant differences in AUC, C max or t 1/2 between dialysis day and dialysis-free day. Dialysate contained no measurable lansoprazole or metabolite. Lansoprazole is not significantly dialyzed.
Geriatrics: The results from the studies that evaluated the pharmacokinetics of lansoprazole in an older population revealed that in comparison with younger subjects, older subjects exhibited significantly larger AUCs and longer t 1/2s. Lansoprazole did not accumulate in the older subjects upon multiple dosing since the longest mean t 1Ä2 in the studies was 2.9 hours, and lansoprazole is dosed once daily. C max in the elderly was comparable to that found in adult subjects.
Children: The pharmacokinetics of lansoprazole have not been investigated in patients <18years of age.
Gender: In a study comparing 12 male and 6female subjects, no gender differences were found in pharmacokinetics or intragastric pH results.
Race: The pooled pharmacokinetic parameters of lansoprazole from 12U.S. PhaseI studies (N=513) were compared to the mean pharmacokinetic parameters from 2Asian studies (N=20). The mean AUCs of lansoprazole in Asian subjects are approximately twice that seen in pooled U.S. data, however, the inter-individual variability is high. The C max values are comparable.
Clarithromycin: Pharmacokinetics : The absolute bioavailability of 250and 500 mg clarithromycin is approximately 50%. Food slightly delays the onset of clarithromycin absorption but does not affect the extent of bioavailability. Therefore, clarithromycin may be given without regard to meals.
In fasting healthy human subjects, peak serum concentrations are attained within 2 hours after oral dosing. Steady-state peak serum clarithromycin concentrations, which are attained within 2to 3 days, are approximately 1mg/L with a 250 mg dose twice daily and 2 to 3mg/L with a 500mg dose twice daily. The elimination half-life of clarithromycin is about 3 to 4 hours with 250mg twice daily dosing but increases to about 5 to 7 hours with 500mg administered twice daily.
The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 and 500 mg administered twice daily. With 250 mg twice daily, the principal metabolite, 14-OH clarithromycin attains a peak steady-state concentration of about 0.6 mg/L and has an elimination half-life of 5 to 6 hours. With a 500 mg twice daily dose, the peak steady-state of 14-OH concentrations of clarithromycin are slightly higher (up to 1 mg/L) and its elimination half-life is about 7 hours. With either dose, the steady-state concentration of this metabolite is generally attained within 2to 3 days.
Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin twice a day to adult patients with HIV infection were similar to those observed in healthy volunteers. However, at the higher clarithromycin doses which may be required to treat mycobacterial infections, clarithromycin concentrations can be much higher than those observed at 500 mg clarithromycin doses. In adult HIV-infected patients taking 2000mg/day in 2divided doses, steady-state clarithromycin C max values ranged from 5 to 10 mg/L. C max values as high as 27 mg/L have been observed in HIV-infected adult patients taking 4000 mg/day in 2divided doses of clarithromycin.
Elimination half-lives appeared to be lengthened at these higher doses as well. The higher clarithromycin concentrations and longer elimination half-lives observed at these doses are consistent with the known nonlinearity in clarithromycin pharmacokinetics.
Clarithromycin 500 mg t.i.d. and omeprazole 40 mg daily were studied in fasting healthy adult subjects. When clarithromycin was given alone at 500 mg q8h, the mean steady-state C max value was approximately 3.8µg/mL and the mean C min value was approximately 1.8µg/mL. The mean AUC 0-8 for clarithromycin was 22.9 µg.h/mL. The T max and half-life were 2.1 h and 5.3 h, respectively, when clarithromycin was dosed at 500 mg t.i.d.
When clarithromycin was administered with omeprazole, increases in omeprazole half-life and AUC 0-24 were observed. For all subjects combined, the mean omeprazole AUC 0-24 was 89% greater and the harmonic mean for omeprazole T 1/2 was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady state C max, C min, and AUC 0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively over values achieved when clarithromycin was administered with placebo.
Hepatic and Renal Impairment: The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in subjects with impaired hepatic function when compared to healthy subjects.
The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function.
Amoxicillin: Pharmacokinetics : Amoxicillin is stable in the presence of gastric acid and is well absorbed from the gastrointestinal tract and may be given with no regard to food. It diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when the meninges are inflamed. The half-life of amoxicillin is 61.3 min. Most of the amoxicillin is excreted unchanged in urine; its excretion can be delayed by concurrent administration of probenecid. Amoxicillin is not highly protein-bound. In serum, amoxicillin is approximately 20% protein-bound as compared to 60% for penicillin G.
Orally administered doses of 500 mg amoxicillin capsules result in average peak blood levels 1to 2 hours after administration in the range of 5.5 to 7.5 µg/mL.
Detectable serum levels are observed up to 8hours 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.
Eradication Of H. Pylori : H. pylor I Is Considered To Be A Major Factor In The Etiology Of Duodenal Ulcer Disease. The Presence Of H. Pylori May Damage The Mucosal Integrity Due To The Production Of Enzymes (catalase, Lipases, Phospholipases, Proteases, And Urease), Adhesins And Toxins; The Inflammatory Response Generated In This Manner Contributes To Mucosal Damage.
The Concomitant Administration Of Antimicrobials Such As Clarithromycin And Amoxicillin, And An Antisecretory Agent Such As Lansoprazole, Improves The Eradication Of H. Pylori As Compared To Individual Drug Administration. The Higher PH Resulting From Antisecretory Treatment, Optimizes The Environment For The Pharmacologic Action Of The Antimicrobial Agents Against H. Pylori.
Hp-PAC: Pharmacokinetics : The Pharmacokinetics Of The Drugs When All 3components Of The Hp-PAC (lansoprazole Capsules, Clarithromycin Tablets And Amoxicillin Capsules) Were Coadministered, Has Not Been Studied. Studies Have Shown No Clinically Significant Interactions Between Lansoprazole And Amoxicillin Or Lansoprazole And Clarithromycin When Coadministered. There Is No Information About The Gastric Mucosal Concentrations Of Lansoprazole, Amoxicillin And Clarithromycin After Administration Of These Agents Concomitantly. The Systemic Pharmacokinetic Information Presented Below Is Based On Studies In Which Each Product Was Administered Alone.
Lansoprazole: General: Lansoprazole Inhibits The Gastric H +,K +-ATPase (the Proton Pump) Which Catalyzes The Exchange Of H +andK +. It Is Effective In The Inhibition Of Both Basal Acid Secretion And Stimulated Acid Secretion.
In Healthy Subjects, Single And Multiple Doses Of Lansoprazole (15to 60 Mg) Have Been Shown To Decrease Significantly Basal Gastric Acid Output And To Increase Significantly Mean Gastric PH And Percent Of Time At PH > 3 And 4. These Doses Have Also Been Shown To Reduce Significantly Meal-stimulated Gastric Acid Output And Gastric Secretion Volume. Single Or Multiple Doses Of Lansoprazole (10to 60mg) Reduced Pentagastrin-stimulated Acid Output. In Addition, Lansoprazole Has Been Demonstrated To Reduce Significantly Basal And Pentagastrin-stimulated Gastric Acid Secretion Among Duodenal Ulcers And Hypersecretory Patients, And Basal Gastric Acid Secretion Among Patients With Gastric Ulcer Disease.
A Dose-response Effect Was Analyzed By Considering The Results From Clinical Pharmacology Studies That Evaluated More Than 1dose Of Lansoprazole. The Results Indicated That, In General, As The Dose Was Increased From 7.5 Mg To 30 Mg, There Was A Decrease In Mean Gastric Acid Secretion And An Increase In The Average Time Spent At Higher PH Values (pH > 4).
The Results Of Pharmacodynamic Studies With Lansoprazole In Normal Subjects Suggest That Doses Of 7.5 To 10 Mg Are Substantially Less Effective In Inhibiting Gastric Acid Secretion Than Doses Of 15mg Or Greater. In View Of These Results, The Doses Of Lansoprazole Evaluated In The Principal Clinical Trials Ranged From 15 To 60mg Daily.
Pharmacokinetics : Prevacid Contains An Enteric-coated Granule Formulation Of Lansoprazole To Ensure That Absorption Of Lansoprazole Begins Only After The Granules Leave The Stomach (lansoprazole Is Acid-labile). Peak Plasma Concentrations Of Lansoprazole (C Max) And The Area Under The Plasma Concentration Curve (AUC) Of Lansoprazole Are Approximately Proportional In Doses From 15 To 60 Mg After Single-oral Administration. Lansoprazole Pharmacokinetics Are Unaltered By Multiple Dosing And The Drug Does Not Accumulate.
Lansoprazole Is Highly Bioavailable When Administered Orally. The Absolute Bioavailability Was Shown To Be 86% For A 15 Mg Capsule And 80% For A 30 Mg Capsule. The Apparent First Pass Effect Is Minimal.
Absorption: The Absorption Of Lansoprazole Is Rapid, With Mean Peak Plasma Levels Of Lansoprazole Occurring At Approximately 1.7 Hours. Peak Plasma Concentrations Of Lansoprazole (C Max) And The Area Under The Plasma Concentration Curve (AUC) Are Approximately Proportional To Dose Throughout The Range That Has Been Studied (up To 60 Mg).
Absorption With Food: Food Reduces The Peak Concentration And The Extent Of Absorption By About 50%. Moreover, The Results Of A Pharmacokinetic Study That Compared The Bioavailability Of Lansoprazole Following A.m. Dosing (fasting) Vs P.m. Dosing (3hours After A Meal) Indicated That Both C Max And AUC Values Were Increased By Approximately 2-fold Or More With A.m. Dosing. Therefore, It Is Recommended That Lansoprazole Be Administered In The Morning Prior To Breakfast.
Absorption With Antacids: Simultaneous Administration Of Lansoprazole With Maalox (aluminum And Magnesium Hydroxide) Or Riopan (magaldrate) Resulted In Lower Peak Serum Levels, But Did Not Significantly Reduce The Bioavailability Of Lansoprazole.
In A Single-dose Crossover Study When 30 Mg Of Lansoprazole Was Administered Concomitantly With 1g Of Sucralfate In Healthy Volunteers, Absorption Of Lansoprazole Was Delayed And Its Bioavailability Was Reduced. The Value Of Lansoprazole AUC Was Reduced By 17% And That For C Max Was Reduced By 21%.
In A Similar Study When 30 Mg Of Lansoprazole Was Administered Concomitantly With 2 G Of Sucralfate, Lansoprazole AUC And C Max Were Reduced By 32% And 55%, Respectively. When Lansoprazole Dosing Occurred 30 Minutes Prior To Sucralfate Administration, C Max Was Reduced By Only 28% And There Was No Statistically Significant Difference In Lansoprazole AUC. Therefore, Lansoprazole May Be Given Concomitantly With Antacids But Should Be Administered At Least 30minutes Prior To Sucralfate.
Distribution: Lansoprazole Is 97% Bound To Plasma Proteins. The Mean Total Body Clearance (Cl) Of Lansoprazole Was Calculated At 31 ± 8 L/h, And The Volume Of Distribution (V Ss) Was Calculated To Be 29 ± 4L.
Elimination: Following Single Dose Oral Administration Of Lansoprazole, Virtually No Unchanged Lansoprazole Was Excreted In The Urine. After A Single Dose Of 14C-lansoprazole, Approximately One-third Of The Dose Was Excreted In The Urine And Approximately Two-thirds Were Recovered In The Feces. This Implies A Significant Biliary Excretion Of The Metabolites Of Lansoprazole.
Metabolism: Lansoprazole Is Extensively Metabolized In The Liver. Two Metabolites Have Been Identified In Measurable Quantities In Plasma: The Hydroxylated Sulfinyl And The Sulfone Derivatives Of Lansoprazole. These Metabolites Have Very Little Or No Antisecretory Activity. Within The Parietal Cell Canaliculus, Lansoprazole Is Thought To Be Transformed Into 2active Metabolites That Inhibit Acid Secretion By (H +,K +)-ATPase; These Metabolites Are Not Present In The Systemic Circulation. The Plasma Elimination Half-life Of Lansoprazole Does Not Reflect The Duration Of Suppression Of Gastric Acid Secretion. Thus, The Plasma Elimination Half-life Is Less Than 2hours While The Acid Inhibitory Effect Lasts Over 24 Hours.
Special Populations: Hepatic Impairment: As Would Be Expected With A Drug That Is Primarily Metabolized By The Liver, In Patients With Mild (Child-Pugh Class A) Or Moderate (Child-Pugh Class B) Chronic Hepatic Disease, The Plasma Half-life Of The Drug Increased To 5.2 Hours Compared To The 1.5 Hours Half-life In Healthy Subjects. An Increase In AUC Of 3.4-fold Was Observed In Patients With Hepatic Impairment Versus Healthy Subjects (7096 Vs 2645ng.h/mL); This Was Due To Slower Elimination Of Lansoprazole; C Max Was Not Significantly Affected.
Renal Impairment: In Patients With Mild (Cl Cr 40 To 80 ML/min), Moderate (Cl Cr 20to 40mL/min) And Severe (Cl Cr <20mL/min) Chronic Renal Impairment, The Disposition Of Lansoprazole Was Very Similar To That Of Healthy Volunteers.
The Impact Of Dialysis On Lansoprazole Was Evaluated From A Pharmacokinetic Standpoint, And There Were No Significant Differences In AUC, C Max Or T 1/2 Between Dialysis Day And Dialysis-free Day. Dialysate Contained No Measurable Lansoprazole Or Metabolite. Lansoprazole Is Not Significantly Dialyzed.
Geriatrics: The Results From The Studies That Evaluated The Pharmacokinetics Of Lansoprazole In An Older Population Revealed That In Comparison With Younger Subjects, Older Subjects Exhibited Significantly Larger AUCs And Longer T 1/2s. Lansoprazole Did Not Accumulate In The Older Subjects Upon Multiple Dosing Since The Longest Mean T 1Ä2 In The Studies Was 2.9 Hours, And Lansoprazole Is Dosed Once Daily. C Max In The Elderly Was Comparable To That Found In Adult Subjects.
Children: The Pharmacokinetics Of Lansoprazole Have Not Been Investigated In Patients <18years Of Age.
Gender: In A Study Comparing 12 Male And 6female Subjects, No Gender Differences Were Found In Pharmacokinetics Or Intragastric PH Results.
Race: The Pooled Pharmacokinetic Parameters Of Lansoprazole From 12U.S. PhaseI Studies (N=513) Were Compared To The Mean Pharmacokinetic Parameters From 2Asian Studies (N=20). The Mean AUCs Of Lansoprazole In Asian Subjects Are Approximately Twice That Seen In Pooled U.S. Data, However, The Inter-individual Variability Is High. The C Max Values Are Comparable.
Clarithromycin: Pharmacokinetics : The Absolute Bioavailability Of 250and 500 Mg Clarithromycin Is Approximately 50%. Food Slightly Delays The Onset Of Clarithromycin Absorption But Does Not Affect The Extent Of Bioavailability. Therefore, Clarithromycin May Be Given Without Regard To Meals.
In Fasting Healthy Human Subjects, Peak Serum Concentrations Are Attained Within 2 Hours After Oral Dosing. Steady-state Peak Serum Clarithromycin Concentrations, Which Are Attained Within 2to 3 Days, Are Approximately 1mg/L With A 250 Mg Dose Twice Daily And 2 To 3mg/L With A 500mg Dose Twice Daily. The Elimination Half-life Of Clarithromycin Is About 3 To 4 Hours With 250mg Twice Daily Dosing But Increases To About 5 To 7 Hours With 500mg Administered Twice Daily.
The Nonlinearity Of Clarithromycin Pharmacokinetics Is Slight At The Recommended Doses Of 250 And 500 Mg Administered Twice Daily. With 250 Mg Twice Daily, The Principal Metabolite, 14-OH Clarithromycin Attains A Peak Steady-state Concentration Of About 0.6 Mg/L And Has An Elimination Half-life Of 5 To 6 Hours. With A 500 Mg Twice Daily Dose, The Peak Steady-state Of 14-OH Concentrations Of Clarithromycin Are Slightly Higher (up To 1 Mg/L) And Its Elimination Half-life Is About 7 Hours. With Either Dose, The Steady-state Concentration Of This Metabolite Is Generally Attained Within 2to 3 Days.
Steady-state Concentrations Of Clarithromycin And 14-OH Clarithromycin Observed Following Administration Of 500 Mg Doses Of Clarithromycin Twice A Day To Adult Patients With HIV Infection Were Similar To Those Observed In Healthy Volunteers. However, At The Higher Clarithromycin Doses Which May Be Required To Treat Mycobacterial Infections, Clarithromycin Concentrations Can Be Much Higher Than Those Observed At 500 Mg Clarithromycin Doses. In Adult HIV-infected Patients Taking 2000mg/day In 2divided Doses, Steady-state Clarithromycin C Max Values Ranged From 5 To 10 Mg/L. C Max Values As High As 27 Mg/L Have Been Observed In HIV-infected Adult Patients Taking 4000 Mg/day In 2divided Doses Of Clarithromycin.
Elimination Half-lives Appeared To Be Lengthened At These Higher Doses As Well. The Higher Clarithromycin Concentrations And Longer Elimination Half-lives Observed At These Doses Are Consistent With The Known Nonlinearity In Clarithromycin Pharmacokinetics.
Clarithromycin 500 Mg T.i.d. And Omeprazole 40 Mg Daily Were Studied In Fasting Healthy Adult Subjects. When Clarithromycin Was Given Alone At 500 Mg Q8h, The Mean Steady-state C Max Value Was Approximately 3.8µg/mL And The Mean C Min Value Was Approximately 1.8µg/mL. The Mean AUC 0-8 For Clarithromycin Was 22.9 µg.h/mL. The T Max And Half-life Were 2.1 H And 5.3 H, Respectively, When Clarithromycin Was Dosed At 500 Mg T.i.d.
When Clarithromycin Was Administered With Omeprazole, Increases In Omeprazole Half-life And AUC 0-24 Were Observed. For All Subjects Combined, The Mean Omeprazole AUC 0-24 Was 89% Greater And The Harmonic Mean For Omeprazole T 1/2 Was 34% Greater When Omeprazole Was Administered With Clarithromycin Than When Omeprazole Was Administered Alone. When Clarithromycin Was Administered With Omeprazole, The Steady State C Max, C Min, And AUC 0-8 Of Clarithromycin Were Increased By 10%, 27%, And 15%, Respectively Over Values Achieved When Clarithromycin Was Administered With Placebo.
Hepatic And Renal Impairment: The Steady-state Concentrations Of Clarithromycin In Subjects With Impaired Hepatic Function Did Not Differ From Those In Normal Subjects; However, The 14-OH Clarithromycin Concentrations Were Lower In The Hepatically Impaired Subjects. The Decreased Formation Of 14-OH Clarithromycin Was At Least Partially Offset By An Increase In Renal Clearance Of Clarithromycin In Subjects With Impaired Hepatic Function When Compared To Healthy Subjects.
The Pharmacokinetics Of Clarithromycin Was Also Altered In Subjects With Impaired Renal Function.
Amoxicillin: Pharmacokinetics : Amoxicillin Is Stable In The Presence Of Gastric Acid And Is Well Absorbed From The Gastrointestinal Tract And May Be Given With No Regard To Food. It Diffuses Readily Into Most Body Tissues And Fluids, With The Exception Of Brain And Spinal Fluid, Except When The Meninges Are Inflamed. The Half-life Of Amoxicillin Is 61.3 Min. Most Of The Amoxicillin Is Excreted Unchanged In Urine; Its Excretion Can Be Delayed By Concurrent Administration Of Probenecid. Amoxicillin Is Not Highly Protein-bound. In Serum, Amoxicillin Is Approximately 20% Protein-bound As Compared To 60% For Penicillin G.
Orally Administered Doses Of 500 Mg Amoxicillin Capsules Result In Average Peak Blood Levels 1to 2 Hours After Administration In The Range Of 5.5 To 7.5 µg/mL.
Detectable Serum Levels Are Observed Up To 8hours 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.
In patients with known hypersensitivity to any component of the formulation of Prevacid, any macrolide, antibiotic, or any penicillin.
Concomitant administration of the components of the Hp-PAC with astemizole, terfenadine, cisapride, or pimozide is contraindicated. There have been postmarketing reports of drug interactions when clarithromycin and/or erythromycin are coadministered with astemizole, terfenadine, cisapride, or pimozide resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of hepatic metabolism of these drugs by erythromycin and clarithromycin.
For information on the use of the individual components of the Hp-PAC when dispensed as individual medications outside the combined use for the treatment of H.pylori, the respective product monographs for these products should be consulted.
Clarithromycin: Pregnancy: Clarithromycin should not be used in pregnancy except where no alternative therapy is appropriate, particularly during the first 3 months of pregnancy. If pregnancy occurs while taking the drug, the patient should be apprised of the potential hazard to the fetus. Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryo-fetal development in monkeys, mice, rats and rabbits at doses that produced plasma levels 2 to 17 times the serum levels obtained in humans treated at the maximum recommended doses (see Warnings section in the clarithromycin product monograph).
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C. difficile is a primary cause of “antibiotic-associated colitis”.
After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile .
Allergic reactions (including anaphylaxis) have been reported in patients receiving clarithromycin orally.
Amoxicillin: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. These reactions are more apt to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.
There have been well-documented reports of individuals with a history of penicillin hypersensitivity reactions who have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted.
Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, corticosteroids, and airway management, including intubation, as indicated.
Lansoprazole: When gastric ulcer is suspected, the possibility of malignancy should be excluded before therapy with lansoprazole is instituted as treatment with this drug may alleviate symptoms and delay diagnosis.
Pregnancy : There are no adequate or well-controlled studies in pregnant women. Therefore, lansoprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Reproductive studies conducted in pregnant rats at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on body surface area), and in rabbits at oral doses up to 30mg/kg/day (16 times the recommended human dose based on body surface area), did not disclose any evidence of a teratogenic effect. Maternal toxicity and a significant increase in fetal mortality were observed in the rabbit study at doses above 10mg/kg/day. In rats, maternal toxicity and a slight reduction in litter survival and weights were noted at doses above 100mg/kg/day.
Lactation : It is not known whether lansoprazole is excreted in human milk. Because drugs are excreted in human milk, lansoprazole should not be given to nursing mothers unless its use is considered essential.
Children: Safety and effectiveness in children have not been established.
Hepatic Impairment: It is recommended that the initial dosing regimen need not be altered for patients with mild or moderate liver disease, but for patients with moderate impairment, doses higher than 30mg/day should not be administered unless there are compelling clinical indications.
General: Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy.
H. pylori Eradication and Compliance: To avoid failure of the eradication treatment with a potential for developing antimicrobial resistance and a risk of failure with subsequent therapy, patients should be instructed to follow closely the prescribed regimen.
For the eradication of H. pylori , amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.
The possibility of superinfections with fungal organisms or bacterial pathogens should be kept in mind during therapy. In such cases, discontinue Hp-PAC and substitute appropriate treatment.
Carcinogenicity: Safety concerns of long-term treatment relate to hypergastrinemia, possible ECL effect and carcinoid formation. ECL cell hyperplasia and gastric carcinoid tumors were observed in 4animal studies.
In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with doses of 5 to 150 mg/kg/day about 1 to 40 times the exposure on a body surface (mg/m 2) basis, of a 50-kg person of average height (1.46 m 2 body surface area (BSA)) given the recommended human dose of 30mg/day (22.2 mg/m 2). Lansoprazole produced dose-related gastric entero-chromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. It also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15to 150mg/kg/day (4 to 40 times the recommended human dose based on BSA) exceeded the low background incidence (range=1.4 to 10%) for this strain of rats. Testicular interstitial cell adenoma also occurred in 1of 30 rats treated with 50 mg/kg/day (13 times the recommended human dose based on BSA) in a 1-year toxicity study.
In a 24-month carcinogenicity study, CD-1 mice were treated orally with doses of 15 to 600mg/kg/day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. Lansoprazole also induced a low, non-dose-related incidence of carcinoid tumors in the gastric mucosa in several dose groups (1female mouse in the 15mg/kg/day group, 1male mouse in the 150 mg/kg/day group, and 2 males and 1 female in the 300mg/kg/day group). It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg/kg/day (40 to 80 times the recommended human dose based on BSA) and female mice treated with 150 to 600mg/kg/day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600mg/kg/day (10 to 80 times the recommended human dose based on BSA).
Analysis of gastric biopsy specimens from patients after short-term treatment of proton pump inhibitors have not detected ECL cell effects similar to those seen in animal studies. Longer term studies in humans revealed a slight increase in the mean ECL-cell density, although there was no microscopic evidence of cell hyperplasia. Similar results were seen in the maintenance treatment studies, where patients received up to 15 months of lansoprazole therapy. Serum gastrin values increased significantly from their baseline values but reached a plateau after 2months of therapy. By 1month post-treatment, fasting serum gastrin values returned to lansoprazole therapy baseline. Moreover, results from gastric biopsies from short-term, long-term and maintenance treatment studies indicate that there are no clinically meaningful effects on gastric mucosa morphology among lansoprazole-treated patients.
Retinal Atrophy: In animal studies, retinal atrophy was observed in rats dosed orally for 2 years with lansoprazole at doses of 15 mg/kg/day and above. These changes in rats are believed to be associated with the effects of taurine imbalance and phototoxicity in a susceptible animal model. Clinical data available from long-term lansoprazole studies are not suggestive of any drug-induced eye toxicity in humans. In humans, there are presently no concerns for ocular safety with short-term lansoprazole treatment and the risks associated with long-term use for nearly 5years appear to be negligible. The finding of drug-induced retinal atrophy in the albino rat is considered to be species-specific with little relevance for humans.
Leydig Cell Hyperplasia/Leydig Cell Tumors: In the 24-month toxicology study in rats, after 18 months of treatment, Leydig cell hyperplasia increased above the concurrent and historical control level at dosages of 15mg/kg/day or higher.
Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50mg/kg/day (13times the recommended human dose based on BSA) in a 1-year toxicity study.
These changes are associated with endocrine alterations which have not been, to date, observed in humans.
Drug Interactions : Lansoprazole: Lansoprazole is metabolized through the cytochrome P450 system, specifically through CYP3A and CYP2C19. Studies have shown that lansoprazole does not have clinically significant interactions with warfarin, antipyrine, indomethacin, ASA, ibuprofen, phenytoin, prednisone, antacids (Maalox and Riopan), diazepam, clarithromycin, propranolol, amoxicillin or terfenadine in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C19, CYP2D6, and CYP3A. When lansoprazole was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen, which is unlikely to be of clinical concern. Nonetheless, individual patients may require adjustment of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood levels.
In a single-dose crossover study when 30 mg of lansoprazole was administered concomitantly with 1g of sucralfate in healthy volunteers, absorption of lansoprazole was delayed and its bioavailability was reduced. The value of lansoprazole AUC was reduced by 17% and that for C max was reduced by 21%.
In a similar study when 30 mg of lansoprazole was administered concomitantly with 2 g of sucralfate, lansoprazole AUC and C max were reduced by 32% and 55%, respectively. When lansoprazole dosing occurred 30 minutes prior to sucralfate administration, C max was reduced by only 28% and there was no statistically significant difference in lansoprazole AUC. Therefore, lansoprazole may be given concomitantly with antacids but should be administered at least 30minutes prior to sucralfate.
Lansoprazole causes a profound and long-lasting inhibition of gastric acid secretion; therefore, it is theoretically possible that lansoprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, digoxin).
Clarithromycin: Many categories of drugs are metabolized by the cytochrome P450 3A4 enzyme located in the liver and in the intestine. Some drugs inhibit and others induce this enzyme. Coadministration of such drugs may impact upon each other's metabolism. In some cases serum concentration may be increased and in others decreased. Care must therefore be exercised when coadministering such drugs.
Clarithromycin is reported to be an inhibitor of the enzyme P450 3A4. This may lead to increased or prolonged serum levels of those drugs also metabolized by the enzyme when coadministered with clarithromycin. For such drugs the monitoring of their serum concentrations may be necessary.
The following lists some of the drug-drug interactions which have been reported between clarithromycin-macrolides and other drugs or drug categories. Like clarithromycin and omeprazole, most of the following drugs are metabolized by the P450 3A4 enzyme system.
Additional mechanisms, such as effects upon absorption, may also be responsible for interaction between drugs, including digoxin and clarithromycin.
Astemizole/Terfenadine: Macrolides have been reported to alter the metabolism of terfenadine resulting in increased serum levels of terfenadine which has occasionally been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications).
In a study involving 14 healthy volunteers, the concomitant administration of clarithromycin and terfenadine resulted in a 2-to 3-fold increase in the serum level of the acid metabolite of terfenadine, MDL 16 455, and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.
Carbamazepine: Clarithromycin administration in patients receiving carbamazepine has been reported to cause increased levels of carbamazepine. Blood level monitoring of carbamazepine may be considered.
Cisapride/Pimozide: Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see Contraindications).
Cyclosporine: There have been reports of elevated cyclosporine serum concentrations when clarithromycin and cyclosporine are used concurrently. Cyclosporine levels should be monitored and the dosage should be adjusted as necessary. Patients should also be monitored for increased cyclosporine toxicity.
Didanosine: Simultaneous administration of clarithromycin and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.
Digoxin: Elevated digoxin serum concentrations have been reported in patients receiving clarithromycin and digoxin concomitantly. In postmarketing surveillance some patients have shown clinical signs consistent with digoxin toxicity, including arrhythmias. Serum digoxin levels should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.
Disopyramide: Increased disopyramide plasma levels, resulting in ventricular fibrillation and QT prolongation, coincident with the coadministration of disopyramide and clarithromycin has rarely been reported.
Ergotamine/Dihydroergotamine: There are reports that ischemic reactions may occur when clarithromycin is given concurrently with ergotamine-containing drugs.
Concurrent use of clarithromycin and ergot alkaloids has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
Fluconazole: Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state clarithromycin C min and AUC of 33% and 18%, respectively. Steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole.
Lansoprazole/Omeprazole: One study demonstrated that concomitant administration of clarithromycin and lansoprazole resulted in increased serum levels of these drugs. However, no dosage adjustment was necessary.
Clarithromycin 500 mg t.i.d. was given in combination with omeprazole 40 mg q.d. to healthy subjects. The steady-state plasma concentrations of omeprazole were increased (i.e., C max, AUC 0-24, and T 1/2 increased by 30%, 89%, and 34%, respectively), by concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin.
To a lesser extent, omeprazole administration increases the serum concentrations of clarithromycin. Omeprazole administration also increases tissue and mucus concentrations of clarithromycin.
Lovastatin/Simvastatin: Rhabdomyolysis coincident with the coadministration of clarithromycin and the HMG-CoA reductase inhibitors, lovastatin and simvastatin, has rarely been reported.
Midazolam/Triazolam: Clarithromycin has been reported to decrease the clearance of midazolam and triazolam and thus may increase the pharmacologic effect of these drugs.
Rifabutin/Rifampin: Coadministration of rifabutin or rifampin and clarithromycin has resulted in decreased clarithromycin concentrations.
Clarithromycin has been reported to increase serum and tissue concentration of rifabutin and thus may increase the risk of toxicity.
Ritonavir/Indinavir: A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg q8h and clarithromycin 500mg q12h resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin C max increased by 31%, C min increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-[R]-hydroxy-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. However, for patients with renal impairment, the following dosage adjustments should be considered: For patients with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. Doses of clarithromycin greater than 1g/day should not be coadministered with ritonavir.
One study demonstrated that the concomitant administration of clarithromycin and indinavir resulted in a metabolic interaction; the clarithromycin AUC increased by 53% and the indinavir AUC was increased by 20%, but the individual variation was large. No dosage adjustment is necessary with normal renal function.
Tacrolimus: Concomitant administration of tacrolimus and clarithromycin may result in increased plasma levels of tacrolimus and increased risk of toxicity.
Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Warfarin/Acenocoumarol: There have been reports of increased anticoagulant effect when clarithromycin and oral anticoagulants are used concurrently. Anticoagulant parameters should be closely monitored. Adjustment of the anticoagulant dose may be necessary.
Clarithromycin has also been reported to increase the anticoagulant effect of acenocoumarol.
Zidovudine: Simultaneous oral administration of clarithromycin and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, therefore this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine.
Others: Interactions with erythromycin and/or clarithromycin have been reported with a number of other drugs metabolized by the cytochrome P 450 system, such as hexobarbital, alfentanil, bromocriptine, phenytoin or valproate. Serum concentrations of drugs metabolized by the cytochrome P 450 system should be monitored closely in patients concurrently receiving erythromycin or clarithromycin.
Pregnancy : There are no adequate and well-controlled studies in pregnant women. The benefits against risk, particularly during the first 3 months of pregnancy should be carefully weighed by a physician (see Warnings). Four teratogenicity studies in rats (3with oral doses and 1with i.v. doses up to 160mg/kg/day administered during the period of major organogenesis) and 2 in rabbits (at oral doses up to 125mg/kg/day or i.v. doses of 30mg/kg/day administered during gestation days 6 to 18) failed to demonstrate any teratogenicity from clarithromycin. Two additional oral studies in a different rat strain at similar doses and similar conditions demonstrated a low incidence of cardiovascular anomalies at doses of 150mg/kg/day administered during gestation days 6 to 15. Plasma levels after 150 mg/kg/day were 2 times the human serum levels.
Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000mg/kg/day during gestation days 6 to 15. Cleft palate was also seen at 500mg/kg/day. The 1000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of 70 mg/kg/day produced fetal growth retardation at plasma levels that were 2 times the human serum levels.
Embryonic loss has been seen in monkeys and rabbits.
Lactation : The safety of clarithromycin for use during breast-feeding of infants has not been established. Clarithromycin is excreted in human milk.
Preweaned rats, exposed indirectly via consumption of milk from dams treated with 150mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma.
Children: Use of clarithromycin tablets in children under 12 years of age has not been studied.
Use of clarithromycin granules for suspension in children under 6 months has not been studied. In pneumonia, clarithromycin granules were not studied in children younger than 3 years.
The safety of clarithromycin has not been studied in MAC patients under the age of 20 months. Neonatal and juvenile animals tolerated clarithromycin in a manner similar to adult animals. Young animals were slightly more intolerant to acute overdosage and to subtle reductions in erythrocytes, platelets and leukocytes, but were less sensitive to toxicity in the liver, kidney, thymus and genitalia.
Increased valproate and phenobarbital concentrations and extreme sedation were noted in a 3-year-old patient coincident with clarithromycin therapy. Cause and effect relationship cannot be established. However, monitoring of valproate and phenobarbital concentrations may be considered.
Geriatrics: Dosage adjustment should be considered in elderly patients with severe renal impairment. In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500mg q12h, the maximum concentrations of clarithromycin and 14-OH clarithromycin were increased. The AUC was also increased. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients.
Amoxicillin: Periodic assessment of renal, hepatic and hematopoietic functions should be made during prolonged therapy with amoxicillin.
If superinfections with mycotic or bacterial pathogens occur (usually involving Aerobacter, Pseudomonas or Candida) treatment with Amoxicillin should be discontinued and appropriate therapy instituted.
Renal Impairment: Because amoxicillin is excreted mostly by the kidney, the dosage for patients with renal impairment should be reduced in proportion to the degree of loss of renal function.
Geriatrics: There are no known specific precautions for the use of amoxicillin in the elderly.
Pregnancy : The safety of amoxicillin in the treatment of infections during pregnancy has not been established. If the administration of amoxicillin to pregnant patients is considered to be necessary, its use requires that the potential benefits be weighed against the possible hazards to the fetus.
A morbilliform rash following the use of ampicillin in patients with infectious mononucleosis has been well documented and has also been reported to occur following the use of amoxicillin.
Antibiotic Resistance in Relation to H. pylori Eradication: Three patients 3/82 (3.7%) who had isolates susceptible to clarithromycin pretreatment and were treated with the triple therapy regimen remained H. pylori positive post-treatment. None of the isolates from these 3patients had susceptibility results available after treatment with triple therapy; therefore, it is unknown whether or not these patients developed resistance to clarithromycin. Therefore, development of clarithromycin resistance should be considered as a possible risk.
Renal Impairment: Patients with renal insufficiency do not require dosage modification of lansoprazole.
Geriatrics: Ulcer healing rates in elderly patients are similar to those in younger age groups. The incidence rates of adverse events and laboratory test abnormalities are also similar to those seen in other age groups. The initial dosing regimen need not be changed for elderly patients, but subsequent doses higher than 30 mg/day should not be administered unless additional gastric acid suppression is necessary.
Women: Over 800 women were treated with lansoprazole. Ulcer healing rates in females are similar to those in males. The incidence rates of adverse events are also similar to those seen in males.
Hp-PAC-Triple Therapy: The most frequently reported (³3%) adverse events for patients who received triple therapy were diarrhea (7%), headache (6%), and taste perversion (5%). Patients in the 7-day triple therapy regimen reported fewer adverse events than those in the 10- and/or 14-day triple therapy regimens. There were no statistically significant differences in the frequency of reported adverse events between the 10- and 14-day triple therapy regimens. No treatment-emergent adverse events were observed at significantly higher rates with triple therapy than with any dual therapy regimen.
The additional adverse reactions which were reported as possibly or probably related to treatment (<3%) in clinical trials when all three components of this therapy were given concomitantly are listed below and divided by body system:
Body as a Whole: abdominal pain.
Digestive: dark stools, dry mouth/thirst, glossitis, rectal itching, nausea, oral moniliasis, stomatitis, tongue discoloration, tongue disorder, vomiting.
Musculoskeletal: myalgia.
Nervous System: confusion, dizziness.
Respiratory: respiratory disorders.
Skin and Appendages: skin reactions.
Urogenital: vaginitis, vaginal moniliasis.
Lansoprazole: Worldwide, over 7000 patients have been treated with lansoprazole delayed-release capsules during Phase II-III short-term and long-term clinical trials involving various dosages and duration of treatment. In general, lansoprazole treatment has been well tolerated.
Short-term Studies: The following adverse events were reported to have a possible or probable relationship to drug as described by the treating physician in 1% or more of lansoprazole-treated patients who participated in placebo- and positive-controlled trials (see Tables III and IV, respectively). Numbers in parentheses indicate the percentage of the adverse events reported.
In the TAP Safety Database, all short-term, Phase II/III studies, one or more treatment-emergent AEs were reported by 715/1359 (52.6%) lansoprazole-treated patients; of those considered to be possibly or probably treatment-related AEs, one or more were reported by 276/1359 (20.3%) lansoprazole-treated patients. In all short-term, Phase II/III studies, one or more treatment-emergent AEs were reported by 150/254 (59.1%) placebo-treated patients; of those considered to be possibly or probably treatment-related AEs, one or more were reported by 56/254 (22%).
The most frequent AEs reported in the European short-term studies were diarrhea (3.3%), laboratory test abnormal (2.3%), headache (1.5%), constipation (1.2%), asthenia (1.1%), dizziness (1.1%), and abdominal pain (1%). The most frequent AEs reported in the Asian short-term studies were unspecified laboratory test abnormalities (7.3%), eosinophilia (1%), and increased ALT (1%).
Body as a Whole: asthenia, candidiasis, chest pain (not otherwise specified), edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, carcinoma, general pain.
Cardiovascular: angina, cerebrovascular accident, hypertension/hypotension, myocardial infarction, palpitations, shock (circulatory failure), vasodilation.
Digestive: melena, cholelithiasis, abnormal stools/melena, bezoar, constipation, dry mouth/thirst, flatulence, gastroenteritis, gastrointestinal hemorrhage, hematemesis, anorexia, increased appetite, increased salivation, rectal hemorrhage, cardiospasm, dyspepsia, dysphagia, eructation, esophageal stenosis, esophageal ulcer, esophagitis, stomatitis, fecal discoloration, tenesmus, ulcerative colitis, gastric nodules/fundic gland polyps, carcinoid.
Endocrine: diabetes mellitus, goiter, hyperglycemia/hypoglycemia.
Hematologic and Lymphatic Systems*: agranulocytosis, anemia, aplastic anemia, hemolysis, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura.
Metabolic and Nutritional Disorders: gout, weight gain/loss, edema.
Musculoskeletal: arthritis/arthralgia, musculoskeletal pain, myalgia.
Nervous System: agitation, amnesia, apathy, confusion, dizziness, syncope, hallucinations, hostility aggravated, libido decreased, depression, hemiplegia, insomnia, somnolence, thinking abnormality, anxiety, nervousness, paresthesia.
Respiratory: asthma, bronchitis, cough increased, dyspnea, hemoptysis, hiccup, upper respiratory inflammation/infection, pneumonia, epistaxis.
Skin and Appendages: acne, pruritus, rash, urticaria, alopecia.
Special Senses: blurred vision, eye pain, visual field defect, tinnitus, ophthalmologic disorders, ear disorder, deafness, otitis media, taste perversion.
Urogenital: abnormal menses, albuminuria, breast enlargement/gynecomastia, breast tenderness, glycosuria, impotence, kidney calculus, hematuria, urinary urgency.
*The majority of hematologic cases received were foreign-sourced and their relationship to lansoprazole was unclear.
Combination Therapy with Clarithromycin and Amoxicillin: In clinical trials using combination therapy with lansoprazole plus clarithromycin and amoxicillin, no adverse reactions related to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that have been previously reported with lansoprazole, clarithromycin or amoxicillin.
For more information on adverse reactions with lansoprazole, clarithromycin or amoxicillin, refer to their respective product monographs, under the Adverse Effects section.
Laboratory Values: In addition, the following changes in laboratory parameters were reported as adverse events. Abnormal liver function tests, increased AST, increased ALT, increased creatinine, increased alkaline phosphatase, increased gamma globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, eosinophilia, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, and increased gastrin levels. Additional isolated laboratory abnormalities were reported.
In the placebo-controlled studies, when AST and ALT were evaluated, 0.4% (1/250) placebo patients and 0.3% (2/795) lansoprazole patients had enzyme elevations greater than 3times the upper limit of normal range at the final treatment visit. None of these patients reported jaundice at any time during the study.
Clarithromycin: The following adverse reactions from the clarithromycin Product Monograph are provided for information: The majority of side effects observed in clinical trials involving 3563patients treated with clarithromycin were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections discontinued therapy because of drug-related side effects.
The following adverse reactions were reported during these clinical studies or during postmarketing surveillance:
Body as a Whole: headache (2%), asthenia, infection, back pain, pain and chest pain.
Cardiovascular: As with other macrolides, QT prolongation, ventricular tachycardia, and torsades de pointes have rarely been reported with clarithromycin.
Digestive: nausea (4%), diarrhea (3%), abdominal pain (2%), dyspepsia (2%), vomiting (1%), constipation, flatulence, dry mouth, glossitis, stomatitis, gastrointestinal disorder, anorexia, oral moniliasis, tongue discoloration, hepatomegaly and pseudomembranous colitis. There have been reports of tooth discoloration in patients treated with clarithromycin. Tooth discoloration is usually reversible with professional dental cleaning.
As with other macrolides, hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.
Metabolic: There have been rare reports of hypoglycemia, some of which have occurred in patients on concomitant oral hypoglycemic agents or insulin.
Nervous System: dizziness, vertigo, tinnitus, nervousness, anxiety, insomnia, nightmares, somnolence, depression, confusion, disorientation, depersonalization, hallucinations and psychosis.
Respiratory: rhinitis, cough increased, dyspnea, pharyngitis and asthma.
Skin and Appendages: pruritus, rash, sweating; allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis and Stevens-Johnson syndrome have occurred with orally administered clarithromycin.
Special Senses: taste perversion (2%), ear disorder, abnormal vision and conjunctivitis. There have been reports of hearing loss with clarithromycin which is usually reversible upon withdrawal of therapy. Reports of alteration of the sense of smell, usually in conjunction with taste perversion or taste loss have also been reported.
Urogenital: hematuria, vaginal moniliasis, vaginitis and dysmenorrhea.
Hemic and Lymphatic: eosinophilia, anemia, leukopenia and thrombocythemia. Isolated cases of thrombocytopenia have been reported.
Changes in Laboratory Values: Changes in laboratory values with possible clinical significance were as follows: Hepatic: elevated ALT <1%, AST <1%, GGT <1%, alkaline phosphatase <1%, LDH <1% and total bilirubin <1%. Hematologic: decreased WBC <1% and elevated prothrombin time (1%). Renal: elevated BUN (4%) and elevated serum creatinine <1%.
Others: CNS side effects (including seizures) have been occasionally reported with erythromycin, another macrolide.
In studies of adults with pneumonia comparing clarithromycin to erythromycin base or erythromycin stearate, there were significantly fewer adverse events involving the digestive system in patients treated with clarithromycin.
Postmarketing Experience: Hypersensitivity reactions have been reported, including anaphylaxis.
Amoxicillin: As with other penicillins, it may be expected that untoward reactions will be related to sensitivity phenomena. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and cephalosporins and in those with a history of allergy, asthma, hay fever or urticaria.
The following adverse reactions have been reported as associated with the use of amoxicillin.
Gastrointestinal: nausea, vomiting and diarrhea;
Hypersensitivity Reactions: skin rashes and urticaria have been reported frequently. A few cases of exfoliative dermatitis and erythema multiforme have been reported. Anaphylaxis is the most serious reaction experienced and has usually been associated with the parenteral dosage form.
Note: Urticaria, other skin rashes, and serum sickness-like reactions may be controlled with antihistamines and if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy. Serious anaphylactic reactions require the immediate use of epinephrine, oxygen and i.v. steroids.
Liver: A moderate rise in AST has been noted, particularly in infants, but the significance of this finding is not known. Transient increases in serum alkaline phosphatase and lactic dehydrogenase levels have also been observed but they returned to normal on discontinuation of amoxicillin.
Hematologic and Lymphatic: anemia thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, neutropenia and agranulocytosis have been reported during therapy with the penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be a hypersensitivity phenomena.
Digestive: glossitis, black “hairy” tongue and stomatitis.
Nervous System: As with other penicillins, acute and chronic toxicity is not a clinical problem. At extremely high doses, convulsions can occur. When penicillin reaches a high concentration in the cerebrospinal fluid, neurotoxic symptoms consisting of myoclonia, convulsive seizures and depressed consciousness may occur. Unless administration of the drug is stopped or its dosage reduced, the syndrome may progress to coma and death. Although penicillins do not normally cross the blood-brain barrier to any substantial extent, if massive doses are given (several g/day) to elderly patients, patients with inflamed meninges or patients with impaired renal function, the above toxic reactions are likely to occur.
Symptoms and Treatment: Hp-PAC: In case of an overdose, patients should contact a physician, Poison Control Centre, or emergency room. There is neither a pharmacologic basis nor any data suggesting an increase in the toxicity of the Hp-PAC combination compared to its individual components.
Lansoprazole: As in all cases where overdosing is suspected, treatment should be supportive and symptomatic. Any unabsorbed material should be removed from the gastrointestinal tract, and the patient should be carefully monitored. Lansoprazole is not removed from the circulation by hemodialysis. In one reported case of overdose, the patient consumed 600 mg of lansoprazole with no adverse reaction.
Oral doses up to 5000 mg/kg in rats (approximately 1300 times the recommended human dose based on BSA) and mice (about 675.7 times the recommended human dose based on BSA) did not produce deaths or any clinical signs.
Clarithromycin: Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures.
Clarithromycin is protein bound (70%). No data are available on the elimination of clarithromycin by hemodialysis or peritoneal dialysis.
Amoxicillin: Treatment of overdosage would likely be needed only in patients with severely impaired renal function, since patients with normal kidneys excrete penicillins at a fast rate. Hemodialysis would therefore represent the main form of treatment.
H.pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence: Triple Therapy: lansoprazole/clarithromycin/amoxicillin: The recommended adult oral dose is 30 mg lansoprazole, 500 mg clarithromycin, and 1 g amoxicillin, all given twice daily for 7, 10, or 14 days (see Indications). Daily doses should be taken before meals.
Optimal therapeutic regimens consisting of a shorter treatment duration for the eradication of H. pylori are currently under investigation.
For the eradication of H. pylori , amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.
Hepatic Impairment: The daily dose of lansoprazole should not exceed 30 mg (see Warnings).
Renal Impairment: No dosage modification of lansoprazole is necessary (see Precautions).
Geriatrics: The daily dose should not exceed 30 mg (see Precautions).
Concomitant Antacid Use: Simultaneous administration of lansoprazole with Maalox (aluminum and magnesium hydroxide) or Riopan (magaldrate) results in lower peak plasma levels, but does not significantly reduce bioavailability. Antacids may be used concomitantly if required. If sucralfate is to be given concomitantly, lansoprazole should be administered at least 30 minutes prior to sucralfate (see Pharmacology, Absorption with Antacids). In clinical trials, antacids were administered concomitantly with lansoprazole delayed-release capsules; this did not interfere with its effect.
Hp-PAC--Individual Daily Administration Blister Pack: Each triple therapy Hp-PAC (lansoprazole • amoxicillin • clarithromycin) daily administration blister pack contains:
Prevacid 30 mg (Lansoprazole Delayed-release Capsules): 2opaque, hard gelatin, pink and black capsules, with the TAP logo and “PREVACID 30” imprinted on the capsule, contains: lansoprazole 30 mg each. Nonmedicinal ingredients: cellulosic polymers, colloidal silicon dioxide, D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, gelatin, magnesium carbonate, methacrylic acid copolymer, polyethylene glycol, polysorbate 80, starch, sucrose, sugar spheres, talc and titanium dioxide.
Biaxin 500 mg (Clarithromycin Film-coated Tablets): 2pale yellow, oval, film-coated tablets, with the Abbott logo engraved on one side, contains: clarithromycin 500mg each. Nonmedicinal ingredients: cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide and vanillin. Tartrazine-free.
Amoxicillin 500 mg (Amoxicillin Trihydrate Capsules): 4opaque, scarlet and yellow capsules, with the Abbott logo and “500” imprinted on the capsule, contains: amoxicillin trihydrate 500 mg each. Nonmedicinal ingredients: cornstarch, D&C Yellow#10, FD&C Blue #1, FD&C Red #3, FD&C Red #40, FD&C Yellow #6, gelatin, magnesium stearate, silicon dioxide, sodium lauryl sulfate and titanium dioxide.
Store the Hp-PAC blister cards between 15 and 25°C. Protect from light and moisture. Hp-PAC daily administration blister packs are available in boxes containing 7days of therapy.
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Hp-PAC
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H. Pylori Eradication Therapy
