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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 consists of a daily administration pack containing two PREVACID 30-mg capsules, four amoxicillin 500-mg capsules, USP, and two clarithromycin 500-mg tablets, for oral administration.
PREVACID ® (lansoprazole) Delayed-Release Capsules
The active ingredient in PREVACID capsules is 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 C 16 H 14 F 3 N 3 O 2 S with a molecular weight of 369.37. The structural formula is:
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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 lansoprazole (30 mg), hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, colloidal silicon dioxide, magnesium carbonate, methacrylic acid copolymer, starch, talc, sugar sphere, sucrose, polyethylene glycol, polysorbate 80, and titanium dioxide. Components of the gelatin capsule include gelatin, titanium dioxide, D&C Red No. 28, FD&C Blue No. 1, and FD&C Red No. 40.
TRIMOX ® (amoxicillin, USP)
Amoxicillin, USP, (2 S ,5 R ,6 R )-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, is a semisynthetic penicillin, an analogue of ampicillin. It has the following chemical structure:
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The empirical formula is C 16 H 18 N 3 O 5 S · 3H 2 O, and the molecular weight is 419.45.
The maroon and light-pink capsules contain amoxicillin trihydrate equivalent to 500 mg of amoxicillin. The inactive ingredient in the capsules is magnesium stearate.
BIAXIN ® Filmtab ® (clarithromycin tablets)
Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6- 0 -methylerythromycin. The molecular formula is C 38 H 69 NO 13 , and the molecular weight is 747.96. The structural formula is:
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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 tablet contains 500 mg of clarithromycin and the following inactive ingredients: cellulosic polymers, croscarmellose sodium, D&C Yellow No. 10, FD&C Blue No. 1, magnesium stearate, povidone, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide, and vanillin.
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. 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 mg to 60 mg after single-oral administration. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.
The absorption of lansoprazole is rapid, with mean C max occurring approximately 1.7 hours after oral dosing, and relatively complete with absolute bioavailability over 80%. In healthy subjects, the mean (± SD) plasma half-life was 1.5 (± 1.0) hours. Both C max and AUC are diminished by about 50% if the drug is given 30 minutes after food as opposed to the fasting condition. There is no significant food effect if the drug is given before meals.
Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is consistent over the concentration range of 0.05 to 5.0 mcg/mL.
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 (H + ,K + )-ATPase within the parietal cell canaliculus, but are not present in the systemic circulation. The plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion. Thus, the plasma elimination half-life is less than two hours while the acid inhibitory effect lasts more than 24 hours.
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 14 C-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 metabolites of lansoprazole.
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.
In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-1.5% after administration of 60 mg of lansoprazole. Patients with renal insufficiency had a shortened elimination half-life and decreased total AUC (free and bound). AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment, and C max and T max were not different from subjects with healthy kidneys.
In patients with various degrees of chronic hepatic disease, the mean plasma half-life of the drug was prolonged from 1.5 hours to 3.2-7.2 hours. An increase in mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Dose reduction in patients with severe hepatic disease should be considered.
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 are approximately twice that seen in pooled U.S. data; however, the inter-individual variability is high. The C max values are comparable.
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 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. Amoxicillin is not highly protein-bound. In blood 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 1 to 2 hours after administration in the range of 5.5 to 7.5 µg/mL.
Detectable serum levels are observed up to eight 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%. Food slightly delays both the onset of clarithromycin absorption and the formation of the antimicrobially active metabolite, 14-OH clarithromycin, but does not affect the extent of bioavailability. Therefore, clarithromycin tablets may be given without regard to food.
In fasting healthy human subjects, peak serum concentrations were attained within two hours after oral dosing. Steady-state peak serum clarithromycin concentrations were attained in two to three days and were approximately 2 to 3 µg/mL with a 500-mg dose administered every 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 12 hours. With a 500-mg dose every 8 to 12 hours, the peak steady-state concentration of 14-OH clarithromycin, the principal metabolite, is up to 1 µg/mL and its elimination half-life is about 7 to 9 hours. The steady-state concentration of this metabolite is generally attained within 2 to 3 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 .)
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 section.
Helicobacter pylori
Pretreatment Resistance
Clarithromycin pretreatment resistance (>/= 2.0 µg/mL) was 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 µg/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 > 0.25 µg/mL. One patient on the 14-day triple therapy regimen had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 µg/mL by E-test and the patient was eradicated of H. pylori .
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Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori . Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or with regimens which include clarithromycin as the sole antimicrobial agent.
In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs (</= 0.25 µg/mL) were eradicated of H. pylori . Of those with pretreatment amoxicillin MICs of > 0.25 µg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg t.i.d./amoxicillin 1 gm t.i.d. 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.
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 × 10 7 - 1 × 10 8 CFU/mL for H. pylori ) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (>/= 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for campylobacters. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:
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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:
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1.National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL, January 11-13, 1998.
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 >3 and >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.
In a crossover study comparing lansoprazole 15 and 30 mg with omeprazole 20 mg for five days, the following effects on intragastric pH were noted:
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After the initial dose in this study, increased gastric pH was seen within 1-2 hours with lansoprazole 30 mg, 2-3 hours with lansoprazole 15 mg, and 3-4 hours with omeprazole 20 mg. After multiple daily dosing, increased gastric pH was seen within the first hour postdosing with lansoprazole 30 mg and within 1-2 hours postdosing with lansoprazole 15 mg and omeprazole 20 mg.
The percentage of time gastric pH was elevated above 5 and 6 was evaluated in a crossover study of PREVACID given q.d., b.i.d. and t.i.d.
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The inhibition of gastric acid secretion as measured by intragastric pH returns gradually to normal over two to four days after multiple doses. There is no indication of rebound gastric acidity.
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 BID plus amoxicillin 1 gm BID plus clarithromycin 500 mg BID) 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 .
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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 ).
PREVPAC is contraindicated in patients with known hypersensitivity to any component of the formulation of PREVACID, any macrolide antibiotic, or any penicillin.
Concomitant administration of PREVPAC with cisapride, pimozide, or terfenadine is contraindicated. There have been postmarketing reports of drug interactions when clarithromycin and/or erythromycin are co-administered with cisapride, pimozide, or terfenadine 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. Fatalities have been reported.
Serious and occasionally fatal hypersensitivity (anaphylactoid) 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 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 ANAPHYLACTOID REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
Clarithromycin:
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 .)
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin, 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 Clostridium 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 clinically effective against Clostridium difficile colitis
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.
The possibility of superinfections with mycotic organisms or bacterial pathogens should be kept in mind during therapy. In such cases, discontinue PREVPAC and substitute appropriate treatment.
Symptomatic response to therapy with PREVACID does not preclude the presence of gastric malignancy.
Information for Patients: Each dose of PREVPAC contains four pills: one pink and black capsule (PREVACID), two maroon and light-pink 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.
PREVACID:
PREVACID is metabolized through the cytochrome P 450 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 P 450 system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, clarithromycin, or terfenadine in healthy subjects. These compounds are metabolized through various cytochrome P 450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. 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.
PREVACID has also been shown to have no clinically significant interaction with amoxicillin.
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 Delayed-Release Capsules; this did not interfere with its effect.
PREVACID causes a profound and long-lasting inhibition of gastric acid secretion; therefore, it is theoretically possible that PREVACID may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg, ketoconazole, ampicillin esters, iron salts, digoxin).
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 C max , C min , and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.
Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered.
When clarithromycin and terfenadine were coadministered, plasma concentrations of the active acid metabolite of terfenadine were threefold higher, on average, than the values observed when terfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-hydroxy-clarithromycin were not significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions. Concomitant administration of clarithromycin with terfenadine is contraindicated. (See CONTRAINDICATIONS .)
Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously.
Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin levels should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.
For information on interactions between clarithromycin in combination with other drugs which may be administered to HIV-infected patients, see the BIAXIN package insert, Drug Interactions, under the PRECAUTIONS section.
The following drug interactions, other than increased serum concentrations of carbamazepine and active acid metabolite of terfenadine, have not been reported in clinical trials with clarithromycin; however, they have been observed with erythromycin products and/or with clarithromycin in postmarketing experience.
Concurrent use of erythromycin or clarithromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
Erythromycin has been reported to decrease the clearance of triazolam and, thus, may increase the pharmacologic effect of triazolam. There have been postmarketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam.
There have been reports of an interaction between erythromycin and astemizole resulting in QT prolongation and torsades de pointes. Concomitant administration of erythromycin and astemizole is contraindicated. Because clarithromycin is also metabolized by cytochrome P 450 , concomitant administration of clarithromycin with astemizole is not recommended.
As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin), through inhibition of cytochrome P 450 metabolism of these drugs. Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.
The use of erythromycin and clarithromycin in patients concurrently taking drugs metabolized by the cytochrome P 450 system may be associated with elevations in serum levels of these other drugs. There have been reports of interactions of erythromycin and/or clarithromycin with carbamazepine, cyclosporine, tacrolimus, hexobarbital, phenytoin, alfentanil, disopyramide, lovastatin, bromocriptine, valproate, terfenadine, cisapride, pimozide, rifabutin, and astemizole. Serum concentrations of drugs metabolized by the cytochrome P 450 system should be monitored closely in patients concurrently receiving these drugs.
PREVACID:
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) given the recommended human dose of 30 mg/day (22.2 mg/m 2 ). Lansoprazole produced dose-related gastric enterochromaffin-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 15 to 150 mg/kg/day (4 to 40 times the recommended human dose based on body surface area) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. Testicular interstitial cell adenoma also occurred in 1 of 30 rats treated with 50 mg/kg/day (13 times the recommended human dose based on body surface area) in a 1-year toxicity study.
In a 24-month carcinogenicity study, CD-1 mice were treated orally with doses of 15 to 600 mg/kg/day, 2 to 80 times the recommended human dose based on body surface area. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. 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 body surface area) and female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on body surface area) 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 600 mg/kg/day (10 to 80 times the recommended human dose based on body surface area).
Lansoprazole was not genotoxic in the Ames test, the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test. It was positive in in vitro human lymphocyte chromosomal aberration assays.
Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance of male and female rats.
Long-term studies in animals have not been performed with amoxicillin.
Clarithromycin:
The following in vitro mutagenicity tests have been conducted with clarithromycin:
Salmonella /Mammalian Microsomes Test
Bacterial Induced Mutation Frequency Test
In Vitro Chromosome Aberration Test
Rat Hepatocyte DNA Synthesis Assay
All tests had negative results except the In Vitro Chromosome Aberration Test which was weakly positive in one test and negative in another.
In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin metabolites with negative results.
Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day (1.3 times the recommended maximum human dose based on mg/m 2 ) to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were 2 times the human serum levels.
In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum levels. When given orally at 150 mg/kg/day (2.4 times the recommended maximum human dose based on mg/m 2 ), clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.
In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m 2 , which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m 2 .
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.
Category C is based on the pregnancy category for clarithromycin.
Four teratogenicity studies in rats (three with oral doses and one with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral doses up to 125 mg/kg/day (approximately 2 times the recommended maximum human dose based on mg/m 2 ) or intravenous doses of 30 mg/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 150 mg/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 1000 mg/kg/day (2 and 4 times the recommended maximum human dose based on mg/m 2 , respectively) during gestation days 6 to 15. Cleft palate was also seen at 500 mg/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 (an approximate equidose of the recommended maximum human dose based on mg/m 2 ) produced fetal growth retardation at plasma levels that were 2 times the human serum levels.
There were no adequate and well-controlled studies of PREVPAC in pregnant women. PREVPAC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See .)
Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions, but moderately increased the height and duration of contractions. However, it is not known whether use of these drugs in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.
Amoxicillin is excreted in human milk in very small amounts. Because of the potential for serious adverse reactions in nursing infants from PREVPAC, a decision should be made whether to discontinue nursing or to discontinue the drug therapy, taking into account the importance of the therapy to the mother.
Safety and effectiveness of PREVPAC in pediatric patients infected with H. pylori have not been established (See CONTRAINDICATIONS and ).
Elderly patients may suffer from asymptomatic renal and hepatic dysfunction. Care should be taken when administering PREVPAC to this patient population.
The most common adverse reactions (>/= 3%) reported in clinical trials when all three components of this therapy were given concomitantly for 14 days are listed in the table below.
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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 System --dark stools, dry mouth/thirst, glossitis, rectal itching, nausea, oral moniliasis, stomatitis, tongue discoloration, tongue disorder, vomiting; Musculoskeletal System --myalgia; Nervous System --confusion, dizziness; Respiratory System --respiratory disorders; Skin and Appendages --skin reactions; Urogenital System --vaginitis, vaginal moniliasis. There were no statistically significant differences in the frequency of reported adverse events between the 10- and 14-day triple therapy regimens.
PREVACID:
The following adverse reactions from the labeling for lansoprazole are provided for information.
Worldwide, over 6100 patients have been treated with lansoprazole in Phase II-III clinical trials involving various dosages and duration of treatment. In general, lansoprazole treatment has been well tolerated in both short-term and long-term trials.
The following adverse events were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of patients treated with PREVACID capsules and occurred at a greater rate in patients treated with PREVACID capsules than placebo-treated patients:
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Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea is similar between placebo and lansoprazole 15 mg and 30 mg patients, but higher in the lansoprazole 60 mg patients (2.9%, 1.4%, 4.2%, and 7.4%, respectively).
The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea.
Additional adverse experiences occurring in <1% of patients or subjects in domestic and/or international trials, or occurring since the drug was marketed, are shown below within each body system.
In short-term and long-term studies, the following adverse events were reported in <1% of the lansoprazole-treated patients:
Body as a Whole --anaphylactoid-like reaction, asthenia, candidiasis, chest pain (not otherwise specified), edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise; Cardiovascular System --angina, cerebrovascular accident, hypertension/hypotension, myocardial infarction, palpitations, shock (circulatory failure), vasodilation; Digestive System --melena, anorexia, bezoar, cardiospasm, cholelithiasis, constipation, dry mouth/thirst, dyspepsia, dysphagia, eructation, esophageal stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastroenteritis, gastrointestinal hemorrhage, hematemesis, increased appetite, increased salivation, rectal hemorrhage, stomatitis, tenesmus, ulcerative colitis, vomiting; Endocrine System --diabetes mellitus, goiter, hyperglycemia/hypoglycemia; Hematologic and Lymphatic System *--agranulocytosis, anemia, aplastic anemia, hemolysis, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura; Metabolic and Nutritional Disorders --gout, weight gain/loss; Musculoskeletal System --arthritis/arthralgia, musculoskeletal pain, myalgia; Nervous System --agitation, amnesia, anxiety, apathy, confusion, depression, dizziness/syncope, hallucinations, hemiplegia, hostility aggravated, libido decreased, nervousness, paresthesia, thinking abnormality; Respiratory System --asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, pneumonia, upper respiratory inflammation/infection; Skin and Appendages --acne, alopecia, pruritus, rash, urticaria; Special Senses --blurred vision, deafness, eye pain, visual field defect, otitis media, taste perversion, tinnitus; Urogenital System --abnormal menses, albuminuria, breast enlargement/gynecomastia, breast tenderness, glycosuria, hematuria, impotence, kidney calculus.
*The majority of hematologic cases received were foreign-sourced and their relationship to lansoprazole was unclear.
The following changes in laboratory parameters were reported as adverse events.
Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased 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 SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (1/250) placebo patients and 0.3% (2/795) lansoprazole patients had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients reported jaundice at any time during the study.
Amoxicillin:
The following adverse reactions from the labeling for amoxicillin are provided for information.
As with other penicillins, it may be expected that untoward reactions will be essentially limited to sensitivity phenomena. They are more likely to occur in individuals who have previously demonstrated hypersensitivity to penicillins and in those with a history of allergy, asthma, hay fever, or urticaria. Glossitis, stomatitis, black "hairy" tongue, nausea, vomiting, and diarrhea have been reported as associated with the use of penicillin. (These reactions are usually associated with oral dosage forms.)
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. Urticaria, other skin rashes, and serum sickness-like reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, penicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life threatening and amenable only to penicillin therapy. Serious anaphylactic reactions require the immediate use of epinephrine, oxygen, and intravenous steroids.
Liver --A moderate rise in serum glutamic oxaloacetic transaminase (SGOT) has been noted, particularly in infants, but the significance of this finding is unknown.
Hemic and Lymphatic Systems --Anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with the penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena.
Clarithromycin:
The following adverse reactions from the labeling for clarithromycin are provided for information.
The majority of side effects observed in clinical trials 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 most frequently reported events in adults were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, only 1% was described as severe.
Postmarketing Experience:
Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have occurred. Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, vomiting, tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness. There have been reports of tooth discoloration in patients treated with clarithromycin. Tooth discoloration is usually reversible with professional dental cleaning. There have been isolated reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell, usually in conjunction with taste perversion or taste loss have also been reported.
Transient CNS events including anxiety, behavioral changes, confusional states, depersonalization, disorientation, hallucinations, insomnia, manic behavior, nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during postmarketing surveillance. Events usually resolve with discontinuation of the drug.
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.
There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral hypoglycemic agents or insulin.
Rarely, erythromycin and clarithromycin have been associated with ventricular arrhythmias, including ventricular tachycardia and torsades de pointes in individuals with prolonged QT C intervals.
Changes in Laboratory Values: Changes in laboratory values with possible clinical significance were as follows: Hepatic --elevated SGPT (ALT) <1%, SGOT (AST) <1%, GGT <1%, alkaline phosphatase <1%, LDH <1%, total bilirubin <1%; Hematologic --decreased WBC <1%, elevated prothrombin time 1%; Renal --elevated BUN 4%, elevated serum creatinine <1%. GGT, alkaline phosphatase, and prothrombin time are from adult studies only.
In case of an overdose, patients should contact a physician, poison control center, or emergency room. There is neither a pharmacologic basis nor data suggesting an increased toxicity of the combination compared to individual components.
Lansoprazole:
Oral doses up to 5000 mg/kg in rats (approximately 1300 times the 30 mg human dose based on body surface area) and mice (about 675.7 times the 30 mg human dose based on body surface area) did not produce deaths or any clinical signs.
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.
Amoxicillin:
In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures as required. Amoxicillin can be removed from circulation by hemodialysis.
The recommended adult oral dose is 30 mg PREVACID, 1 g amoxicillin, and 500 mg clarithromycin administered together twice daily (morning and evening) for 10 or 14 days. (See .)
PREVPAC is not recommended in patients with creatinine clearance less than 30mL/min.
PREVPAC is supplied as an individual daily administration pack, each containing:
PREVACID:
-- two opaque, hard gelatin, black and pink PREVACID 30-mg capsules,
with the TAP logo and "PREVACID 30" imprinted on the capsules.
TRIMOX:
-- four maroon and light-pink amoxicillin 500-mg capsules, USP, with
"BRISTOL 7279" imprinted on the capsules.
BIAXIN Filmtab:
-- two yellow oval film-coated clarithromycin 500-mg tablets with the Abbott logo
and "KL" imprinted in blue on one side of the tablets.
NDC 0300-3702-01 Daily administration pack
NDC 0300-3702-11 Daily administration card
Storage: Protect from light and moisture.
Store at a controlled room temperature between 59°F and 86°F (15°C and 30°C).
Rx only
U.S. Patent No. 5,013,743
PREVPAC is distributed by TAP Pharmaceuticals Inc.
PREVACID ® (lansoprazole) Delayed-Release Capsules
Manufactured for TAP Pharmaceuticals Inc.
Deerfield, Illinois 60015-1595, U.S.A.
by Takeda Chemical Industries, Limited,
Osaka, Japan 541
Distributed by TAP Pharmaceuticals Inc.
TRIMOX ® (amoxicillin, USP)
Manufactured by APOTHECON ® A Bristol-Myers Squibb Company Princeton, NJ 08540, U.S.A.
BIAXIN ® Filmtab ® (clarithromycin tablets)
Manufactured by Abbott Laboratories North Chicago, IL 60064, U.S.A.
Ref. 03-4943-R2; Revised: January, 1999
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