lansoprazole, amoxicillin and clarithromycin
Dosage Form: kit - tablet, capsules
Prevpac®
(lansoprazole 30 mg capsules, amoxicillin 500 mg capsules, USP, and clarithromycin 500 mg tablets, USP)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Prevpac and other antibacterial drugs, Prevpac should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
THESE PRODUCTS ARE INTENDED ONLY FOR USE AS DESCRIBED. The individual products contained in this package should not be used alone or in combination for other purposes. The information described in this labeling concerns only the use of these products as indicated in this daily administration pack. For information on use of the individual components when dispensed as individual medications outside this combined use for treating Helicobacter pylori (H. pylori), please see the package inserts for each individual product.
Prevpac Description
Prevpac consists of a daily administration card containing two PREVACID 30 mg capsules, four amoxicillin 500-mg capsules, USP, and two clarithromycin 500 mg tablets, USP, for oral administration.
PREVACID® (lansoprazole) Delayed-Release Capsules
The active ingredient in PREVACID delayed release capsules is lansoprazole, a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C16H14F3N3O2S with a molecular weight of 369.37. PREVACID has the following structure:
Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.
Each delayed-release capsule contains enteric-coated granules consisting of 30 mg of lansoprazole (active ingredient) and the following inactive ingredients: sugar sphere, sucrose, methacrylic acid copolymer, low substituted hydroxypropyl cellulose, starch, magnesium carbonate, talc, polyethylene glycol, titanium dioxide, polysorbate 80, hydroxypropyl cellulose, colloidal silicon dioxide, D&C Red No. 28, FD&C Blue No. 1, and FD&C Red No. 40.
Amoxicillin Capsules, USP
Amoxicillin is a semi synthetic antibiotic, 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-azabicyclo[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 structure:
Amoxicillin capsules are intended for oral administration. Each yellow opaque capsule contains amoxicillin trihydrate equivalent to 500 mg of amoxicillin.
Inactive ingredients: Capsule shells - yellow ferric oxide, titanium dioxide, gelatin, black ferric oxide; Capsule contents – cellulose microcrystalline and magnesium stearate. Meets USP Dissolution Test 2.
BIAXIN® Filmtab® (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 structure:
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 yellow oval film-coated immediate-release tablet contains 500 mg of clarithromycin and the following inactive ingredients: hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium, D&C Yellow No. 10, magnesium stearate, microcrystalline cellulose, povidone, propylene glycol, sorbic acid, sorbitan monooleate, titanium dioxide, and vanillin.
Prevpac - Clinical Pharmacology
Pharmacokinetics
Pharmacokinetics when all three of the Prevpac components (PREVACID capsules, amoxicillin capsules, clarithromycin tablets) were coadministered has not been studied. Studies have shown no clinically significant interactions of PREVACID and amoxicillin or PREVACID and clarithromycin when administered together. There is no information about the gastric mucosal concentrations of PREVACID, 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.
PREVACID
PREVACID capsules contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. After a single-dose administration of 15 mg to 60 mg of oral lansoprazole, the peak plasma concentrations (Cmax) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to the administered dose. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.
Absorption
The absorption of lansoprazole is rapid, with the mean Cmax occurring approximately 1.7 hours after oral dosing, and the absolute bioavailability is over 80%. In healthy subjects, the mean (± SD) plasma half-life was 1.5 (± 1.0) hours. Both the Cmax and AUC are diminished by about 50 to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.
Distribution
Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is consistent over the concentration range of 0.05 to 5.0 mcg/mL.
Metabolism
Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by blocking the proton pump [(H+,K+)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of lansoprazole is less than 2 hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.
Elimination
Following single-dose oral administration of PREVACID, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the lansoprazole metabolites.
Amoxicillin
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 levels 1 to 2 hours after administration in the range of 5.5 mcg/mL to 7.5 mcg/mL.
Detectable serum levels 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.
Clarithromycin
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 decrease 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 mcg/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 mcg/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 also altered in subjects with impaired renal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Special Populations
Geriatric Use
The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly.
Renal Impairment
In patients with severe renal impairment, plasma protein binding decreased by 1.0% to 1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function.
Hepatic Impairment
In patients with various degrees of chronic hepatic impairment, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2 to 7.2 hours. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment.
Gender
In a study comparing 12 male and 6 female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results (see PRECAUTIONS, PREVACID, Use in Women).
Race
The pooled pharmacokinetic parameters of PREVACID from twelve U.S. Phase I studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of PREVACID in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.
Pharmacodynamics
Microbiology
Lansoprazole, clarithromycin and/or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Helicobacter pylori
Pretreatment Resistance
Clarithromycin pretreatment resistance rates (≥2.0 mcg/mL) were 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).
Amoxicillin pretreatment susceptible isolates (≤0.25 mcg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of 957 patients (2.2%) by E-test, and 2 of 100 patients (2.0%) by agar dilution, had amoxicillin pretreatment MICs of greater than 0.25 mcg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 mcg/mL by E-test and the patient was eradicated of H. pylori.
| Clarithromycin Pretreatment Results | Clarithromycin Post-treatment Results | |||||
|---|---|---|---|---|---|---|
| H. pylori negative - eradicated | H. pylori positive – not eradicated Post-treatment susceptibility results | |||||
| S† | I† | R† | No MIC | |||
| ||||||
| Triple Therapy 14-Day (lansoprazole 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) (M95-399, M93-131, M95-392) | ||||||
| Susceptible† | 112 | 105 | 7 | |||
| Intermediate† | 3 | 3 | ||||
| Resistant† | 17 | 6 | 7 | 4 | ||
| Triple Therapy 10-Day (lansoprazole 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) (M95-399) | ||||||
| Susceptible† | 42 | 40 | 1 | 1 | ||
| Intermediate† | ||||||
| Resistant† | 4 | 1 | 3 | |||
Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done if possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or other regimens which include clarithromycin as the sole antimicrobial agent.
Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes
In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (≤0.25 mcg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg three times daily per amoxicillin 1 g three times daily dual therapy and a total of 12.8% (22/172) of the patients failed the 10- and 14-day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.
Susceptibility Test for Helicobacter pylori
The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.1 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 × 107 – 1 × 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. 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:
| |
| Clarithromycin MIC (mcg/mL)* | Interpretation |
| ≤0.25 | Susceptible (S) |
| 0.5-1.0 | Intermediate (I) |
| ≥2.0 | Resistant (R) |
| Amoxicillin MIC (mcg/mL)*,† | Interpretation |
| ≤0.25 | Susceptible (S) |
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:
| Microorganisms | Antimicrobial Agent | MIC (mcg/mL)* |
|---|---|---|
| ||
| H. pylori ATCC 43504 | Clarithromycin | 0.015-0.12 |
| H. pylori ATCC 43504 | Amoxicillin | 0.015-0.12 |
After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than 3 and greater than 4. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.
The intragastric pH results of a five-day, pharmacodynamic, crossover study of 15 mg and 30 mg of once daily lansoprazole are presented in Table 2.
| PREVACID | |||||
|---|---|---|---|---|---|
| Parameter | Baseline Value | 15 mg | 30 mg | ||
| Day 1 | Day 5 | Day 1 | Day 5 | ||
| NOTE: An intragastric pH of greater than 4 reflects a reduction in gastric acid by 99%. | |||||
| |||||
| Mean 24 Hour pH | 2.1 | 2.7* | 4.0* | 3.6† | 4.9† |
| Mean Nighttime Hour pH | 1.9 | 2.4 | 3.0* | 2.6 | 3.8† |
| % Time Gastric pH>3 | 18 | 33* | 59* | 51† | 72† |
| % Time Gastric pH>4 | 12 | 22* | 49* | 41† | 66† |
After the initial dose in this study, increased gastric pH was seen within 1 to 2 hours with 30 mg of lansoprazole and 2 to 3 hours with 15 mg of lansoprazole. After multiple daily dosing, increased gastric pH was seen within the first hour post-dosing with 30 mg of lansoprazole and within 1 to 2 hours post-dosing with 15 mg of lansoprazole.
Acid suppression may enhance the effect of antimicrobials in eradicating Helicobacter pylori (H. pylori). The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of PREVACID given daily, twice daily and three times daily.
| PREVACID | ||||
|---|---|---|---|---|
| Parameter | 30 mg daily | 15 mg twice daily | 30 mg twice daily | 30 mgthree time daily |
| ||||
| % Time Gastric pH>5 | 43 | 47 | 59* | 77† |
| % Time Gastric pH>6 | 20 | 23 | 28 | 45† |
The inhibition of gastric acid secretion as measured by intragastric pH gradually returned to normal over two to four days after multiple doses. There was no indication of rebound gastric acidity.
Clinical Studies
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
Randomized, double-blind clinical studies performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of Prevpac as triple 14-day therapy for the eradication of H. pylori. The triple therapy regimen (PREVACID 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) produced statistically significantly higher eradication rates than PREVACID plus amoxicillin, PREVACID plus clarithromycin, and amoxicillin plus clarithromycin dual therapies.
H. pylori eradication was defined as two negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.
Triple therapy was shown to be more effective than all possible dual therapy combinations. The combination of PREVACID plus amoxicillin and clarithromycin as triple therapy was effective in eradicating H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.
A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of PREVACID triple therapy for 10 and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori.
| (PREVACID/amoxicillin/clarithromycin) Percent of Patients Cured [95% Confidence Interval] (Number of patients) | |||
|---|---|---|---|
| Study | Duration | Triple Therapy Evaluable Analysis* | Triple Therapy Intent-to-Treat Analysis† |
| |||
| M93-131 | 14 days | 92‡ [80.0-97.7] (N=48) | 86‡ [73.3-93.5] (N=55) |
| M95-392 | 14 days | 86§ [75.7-93.6] (N=66) | 83§ [72.0-90.8] (N=70) |
| M95-399¶ | 14 days | 85 [77.0-91.0] (N=113) | 82 [73.9-88.1] (N=126) |
| 10 days | 84 [76.0-89.8] (N=123) | 81 [73.9-87.6] (N=135) | |
Indications and Usage for Prevpac
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
The components in Prevpac (PREVACID, amoxicillin, and clarithromycin) are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one-year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence (see CLINICAL STUDIES and DOSAGE AND ADMINISTRATION).
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Prevpac and other antibacterial drugs, Prevpac should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Please refer to the full prescribing information for amoxicillin and clarithromycin.
Contraindications
Prevpac is contraindicated in patients with known severe hypersensitivity to any component of the formulation of PREVACID.
A history of allergic reaction to any of the penicillins is a contraindication.
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics.
Concomitant administration of Prevpac and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, ergotamine or dihydroergotamine (see Drug Interactions). There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported.
For information about contraindications of other drugs that may be used in combination with amoxicillin or clarithromycin, refer to the CONTRAINDICATIONS section of their package inserts.
Warnings
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. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH AMOXICILLIN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN SHOULD BE DISCONTINUED AND APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING CLARITHROMYCIN, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES (see PRECAUTIONS - Pregnancy).
There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients (see PRECAUTIONS).
For information about warnings of other drugs that may be used in combination with amoxicillin or clarithromycin, refer to the WARNINGS section of their package inserts.
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clarithromycin and/or amoxicillin, and may range in severity from mild diarrhea to fatal colitis. 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.
Precautions
Symptomatic response to therapy with Prevpac does not preclude the presence of gastric malignancy.
The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur, Prevpac should be discontinued and appropriate therapy instituted.
Prescribing Prevpac 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.
Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be administered without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate.
Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.
For information about precautions of other drugs that may be used in combination with Prevpac, refer to the PRECAUTIONS section of their package inserts.
Information for Patients
Each dose of Prevpac contains four pills: one pink and black capsule (PREVACID), two opaque, yellow capsules (amoxicillin) and one yellow tablet (clarithromycin). Each dose should be taken twice per day before eating. Patients should be instructed to swallow each pill whole.
Prevpac may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications.
Patients should be counseled that antibacterial drugs including Prevpac should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Prevpac 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 Prevpac or other antibacterial drugs in the future.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop 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 antibiotic. If this occurs, patients should contact their physician as soon as possible.
Laboratory Tests
Amoxicillin
As with any potent drug, periodic assessment of renal, hepatic, and hematopoietic function should be made during prolonged therapy.
Drug Interactions
No drug interaction studies have been conducted specifically with Prevpac. The following drug interactions are for the individual drug components: PREVACID (lansoprazole), amoxicillin, and clarithromycin. Therefore, the decision to adjust dosage should depend on the clinician's assessment of among other things, the cumulative or net effect of the drug components of Prevpac.
PREVACID
PREVACID causes long-lasting inhibition of gastric acid secretion. PREVACID substantially decreases the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, PREVACID, or other proton pump inhibitors, should not be co-administered with atazanavir.
It is theoretically possible that PREVACID may also interfere with the absorption of other drugs where gastric pH is an important determinant of bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).
PREVACID is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that PREVACID does not have clinically significant interactions with other drugs metabolized by the cytochrome P450 system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.
Theophylline
When PREVACID was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be of clinical concern. Nonetheless, individual patients may require additional titration of their theophylline dosage when PREVACID is started or stopped to ensure clinically effective blood levels.
Tacrolimus
Concomitant administration of lansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Warfarin
In a study of healthy subjects, neither the pharmacokinetics of warfarin enantiomers nor prothrombin time were affected following single or multiple 60 mg doses of lansoprazole. However, there have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving proton pump inhibitors, including PREVACID, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
Sucralfate
In a single-dose crossover study examining PREVACID 30 mg and omeprazole 20 mg each administered alone and concomitantly with sucralfate 1 gram, absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17% and 16%, respectively, when administered concomitantly with sucralfate. Therefore, proton pump inhibitors should be taken at least 30 minutes prior to sucralfate. In clinical trials, antacids were administered concomitantly with PREVACID and there was no evidence of a change in the efficacy of PREVACID.
Amoxicillin
Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin.
Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.
Clarithromycin
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. In two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h clarithromycin), the steady-state levels of Cmax, Cmin, and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.
Concomitant administration of single doses of clarithr
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