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BIAXIN® Filmtab®
(clarithromycin tablets, USP)
BIAXIN®
XL Filmtab®
(clarithromycin extended-release tablets)
BIAXIN®
Granules
(clarithromycin for oral suspension, USP)
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other antibacterial drugs, BIAXIN should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
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. The structural formula is:
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.
BIAXIN is available as immediate-release tablets, extended-release tablets, and granules for oral suspension.
Each yellow oval film-coated immediate-release BIAXIN tablet (clarithromycin tablets, USP) contains 250 mg or 500 mg of clarithromycin and the following inactive ingredients:
250 mg tablets: hypromellose, hydroxypropyl cellulose, croscarmellose sodium, D&C Yellow No. 10, FD&C Blue No. 1, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide, and vanillin.
500 mg tablets: 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.
Each yellow oval film-coated BIAXIN XL tablet (clarithromycin extended-release tablets) contains 500 mg of clarithromycin and the following inactive ingredients: cellulosic polymers, D&C Yellow No. 10, lactose monohydrate, magnesium stearate, propylene glycol, sorbic acid, sorbitan monooleate, talc, titanium dioxide, and vanillin.
After constitution, each 5 mL of BIAXIN suspension (clarithromycin for oral suspension, USP) contains 125 mg or 250 mg of clarithromycin. Each bottle of BIAXIN granules contains 1250 mg (50 mL size), 2500 mg (50 and 100 mL sizes) or 5000 mg (100 mL size) of clarithromycin and the following inactive ingredients: carbomer, castoroil, citric acid, hypromellose phthalate, maltodextrin, potassium sorbate, povidone, silicon dioxide, sucrose, xanthan gum, titanium dioxide and fruit punch flavor.
CLINICAL PHARMACOLOGY
Pharmacokinetics
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, BIAXIN 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 1 to 2 µg/mL with a 250 mg dose administered every 12 hours and 3 to 4 µg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH clarithromycin, attains a peak steady-state concentration of about 0.6µg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 µg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.
After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hours, approximately 40% is excreted in urine as clarithromycin. The renal clearance of clarithromycin is, however, relatively independent of the dose size and 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 either a 250 mg or a 500 mg tablet administered every 12 hours.
Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500- or 1000-mg doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 to 4 µg/mL and 5 to 10 µg/mL, respectively.
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 PRECAUTIONSand DOSAGE AND ADMINISTRATION.)
Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular concentrations, tissue concentrations are higher than serum concentrations. Examples of tissue and serum concentrations are presented below.
| Tissue Type | Tissue (µg/g) | Serum (µg/mL) |
| Tonsil | 1.6 | 0.8 |
| Lung | 8.8 | 1.7 |
Clarithromycin extended-release tablets provide extended absorption of clarithromycin from the gastrointestinal tract after oral administration. Relative to an equal total daily dose of immediate-release clarithromycin tablets, clarithromycin extended-release tablets provide lower and later steady-state peak plasma concentrations but equivalent 24-hour AUC's for both clarithromycin and its microbiologically-active metabolite, 14-OH clarithromycin. While the extent of formation of 14-OH clarithromycin following administration of BIAXIN XL tablets (2 x 500 mg once daily) is not affected by food, administration under fasting conditions is associated with approximately 30% lower clarithromycin AUC relative to administration with food. Therefore, BIAXIN XL tablets should be taken with food.
In healthy human subjects, steady-state peak plasma clarithromycin concentrations of approximately 2 to 3 µg/mL were achieved about 5 to 8 hours after oral administration of 2 x 500 mg BIAXIN XL tablets once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.8 µg/mL were attained about 6 to 9 hours after dosing. Steady-state peak plasma clarithromycin concentrations of approximately 1 to 2 µg/mL were achieved about 5 to 6 hours after oral administration of a single 500 mg BIAXIN XL tablet once daily; for 14-OH clarithromycin, steady-state peak plasma concentrations of approximately 0.6µg/mL were attained about 6 hours after dosing.
When 250 mg doses of clarithromycin as BIAXIN suspension were administered to fasting healthy adult subjects, peak plasma concentrations were attained around 3 hours after dosing. Steady-state peak plasma concentrations were attained in 2 to 3 days and were approximately 2 µg/mL for clarithromycin and 0.7 µg/mL for 14-OH clarithromycin when 250-mg doses of the clarithromycin suspension were administered every 12 hours. Elimination half-life of clarithromycin (3 to 4 hours) and that of 14-OH clarithromycin (5 to 7 hours) were similar to those observed at steady state following administration of equivalent doses of BIAXIN tablets.
For adult patients, the bioavailability of 10 mL of the 125 mg/5 mL suspension or 10 mL of the 250 mg/5 mL suspension is similar to a 250 mg or 500 mg tablet, respectively.
In children requiring antibiotic therapy, administration of 7.5 mg/kg q12h doses of clarithromycin as the suspension generally resulted in steady-state peak plasma concentrations of 3 to 7 µg/mL for clarithromycin and 1 to 2 µg/mL for 14-OH clarithromycin.
In HIV-infected children taking 15 mg/kg every 12 hours, steady-state clarithromycin peak concentrations generally ranged from 6 to 15 µg/mL.
Clarithromycin penetrates into the middle ear fluid of children with secretory otitis media.
| Analyte | Middle Ear Fluid (µg/mL) | Serum (µg/mL) |
| Clarithromycin | 2.5 | 1.7 |
| 14-OH Clarithromycin | 1.3 | 0.8 |
In adults given 250 mg clarithromycin as suspension (n = 22), food appeared to decrease mean peak plasma clarithromycin concentrations from 1.2 (± 0.4) µg/mL to 1.0 (± 0.4) µg/mLand the extent of absorption from 7.2 (± 2.5) hr•µg/mL to 6.5 (± 3.7) hr•µg/mL.
When children (n = 10) were administered a single oral dose of 7.5 mg/kg suspension, food increased mean peak plasma clarithromycin concentrations from 3.6 (± 1.5) µg/mL to 4.6 (± 2.8) µg/mL and the extent of absorption from 10.0 (± 5.5) hr•µg/mL to 14.2 (± 9.4) hr•µg/mL.
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult males. The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.
| Treatment | N | antrum | fundus | N | mucus |
| Clarithromycin | 5 | 10.48 ± 2.01 | 20.81 ± 7.64 | 4 | 4.15 ± 7.74 |
| Clarithromycin + Omeprazole | 5 | 19.96 ± 4.71 | 24.25 ± 6.37 | 4 | 39.29 ± 32.79 |
For information about other drugs indicated in combination with BIAXIN, refer to the CLINICAL PHARMACOLOGY section of their package inserts.
Microbiology
Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.
Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms as well as most Mycobacterium avium complex (MAC) microorganisms.
Additionally, the 14-OH clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH clarithromycin is twice as active against Haemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than clarithromycin. The clinical significance of this activity against Mycobacterium avium complex is unknown.
Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:
Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes
In the omeprazole/clarithromycin/amoxicillin triple-therapy clinical trials, 84.9% (157/185) of the patients who had pretreatment amoxicillin susceptible MICs (< 0.25 µg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results, and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.
In the lansoprazole/clarithromycin/amoxicillin 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 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 following in vitro data are available, but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Susceptibility Testing Excluding Mycobacteria and Helicobacter
INDICATIONS AND USAGE
BIAXIN Filmtab (clarithromycin tablets, USP) and BIAXIN Granules (clarithromycin for oral suspension, USP) are indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions as uled below:
Adults (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
Pharyngitis/Tonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the intramuscular or the oral route. Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of clarithromycin in the subsequent prevention of rheumatic fever are not available at present).
Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.
Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR).
Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes (Abscesses usually require surgical drainage).
Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare
BIAXIN (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to eradicate H. pylori.
BIAXIN Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. However, regimens which contain clarithromycin as the single antimicrobial agent are more likely to be associated with the development of clarithromycin resistance among patients who fail therapy. Clarithromycin-containing regimens should not be used in patients with known or suspected clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting.
In patients who fail therapy, susceptibility testing should be done if possible. If resistance to clarithromycin is demonstrated, a non-clarithromycin-containing therapy is recommended. (For information on development of resistance see Microbiology section.) The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence.
Children (BIAXIN Filmtab Tablets and Granules for Oral Suspension)
Pharyngitis/Tonsillitis due to Streptococcus pyogenes.
Community-Acquired Pneumonia due to Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR)
Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae
Acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis , or Streptococcus pneumoniae
NOTE: For information on otitis media, see CLINICAL STUDIES - Otitis Media .
Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes (Abscesses usually require surgical drainage.)
Disseminated mycobacterial infections due to Mycobacterium avium , or Mycobacterium intracellulare
Adults (BIAXIN XL Filmtab Tablets)
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are indicated for the treatment of adults with mild to moderate infection caused by susceptible strains of the designated microorganisms in the conditions uled below:
Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae
Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae , Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae
Community-Acquired Pneumonia due to Haemophilus influenzae, Haemophilus parainfluenzae , Moraxella catarrhalis, Streptococcus pneumoniae , Chlamydia pneumoniae (TWAR), or Mycoplasma pneumoniae
THE EFFICACY AND SAFETY OF BIAXIN XL IN TREATING OTHER INFECTIONS FOR WHICH OTHER FORMULATIONS OF BIAXIN ARE APPROVED HAVE NOT BEEN ESTABLISHED.
Prophylaxis
BIAXIN Filmtab tablets and BIAXIN Granules for oral suspension are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of BIAXIN and other antibacterial drugs, BIAXIN 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.
CONTRAINDICATIONS
Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics.
Concomitant administration of clarithromycin and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, and ergotamine or dihydroergotamine (see Drug Interactions). There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are coadministered 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 indicated in combination with BIAXIN, refer to the CONTRAINDICATIONS section of their package inserts.
WARNINGS
CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING THIS DRUG, 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.)
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BIAXIN, 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.
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 indicated in combination with BIAXIN, refer to the WARNINGS section of their package inserts.
PRECAUTIONS
General
Prescribing BIAXIN 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.
Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than 25 mL/min. (See DOSAGE AND ADMINISTRATION.)
Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria.
For information about precautions of other drugs indicated in combination with BIAXIN, refer to the PRECAUTIONS section of their package inserts.
Information to Patients
Patients should be counseled that antibacterial drugs including BIAXIN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When BIAXIN 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 BIAXIN 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.
BIAXIN may interact with some drugs; therefore patients should be advised to report to their doctor the use of any other medications.
BIAXIN tablets and oral suspension can be taken with or without food and can be taken with milk; however, BIAXIN XL tablets should be taken with food. Do NOT refrigerate the suspension.
Drug Interactions
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 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.)
Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and T½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin.
Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant.
Simultaneous oral administration of BIAXIN tablets and zidovudine to HIV-infected adult patients resulted in decreased steady-state zidovudine concentrations. When 500 mg of clarithromycin were administered twice daily, steady-state zidovudine AUC was reduced by a mean of 12% (n = 4). Individual values ranged from a decrease of 34% to an increase of 14%. Based on limited data in 24 patients, when BIAXIN tablets were administered two to four hours prior to oral zidovudine, the steady-state zidovudine Cmax was increased by approximately 2-fold, whereas the AUC was unaffected.
Simultaneous administration of BIAXIN tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.
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 Cmin and AUC of 33% and 18%, respectively. Steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole.
Concomitant administration of clarithromycin and ritonavir (n = 22) resulted in a 77% increase in clarithromycin AUC and a 100% decrease in the AUC of 14-OH clarithromycin. Clarithromycin may be administered without dosage adjustment to patients with normal renal function taking ritonavir. However, for patients with renal impairment, the following dosage adjustments should be considered. For patients with CLCR 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%. For patients with CLCR< 30 mL/min, the dose of clarithromycin should be decreased by 75%.
Spontaneous reports in the post-marketing 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 post-marketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.
Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity. (See WARNINGS.)
Erythromycin and clarithromycin are substrates and inhibitors of the 3A isoform subfamily of the cytochrome P450 enzyme system (CYP3A). Coadministration of erythromycin or clarithromycin and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both the therapeutic and adverse effects of the concomitant drug. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin or erythromycin.
The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible. Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine were observed in clinical trials with clarithromycin.
The following CYP3A based drug interactions have been observed with erythromycin products and/or with clarithromycin in post-marketing experience:
Carcinogenesis, Mutagenesis, Impairment of Fertility
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
Mouse Lymphoma Assay
Mouse Dominant Lethal Study
Mouse Micronucleus Test
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/m2) 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/m2), 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/m2, which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m2.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.
Pregnancy
Teratogenic Effects
Nursing Mothers
It is not known whether clarithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clarithromycin is administered to a nursing woman. It is known that clarithromycin is excreted in the milk of lactating animals and that other drugs of this class are excreted in human milk. Preweaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma.
Pediatric Use
Safety and effectiveness of clarithromycin in pediatric patients under 6 months of age have not been established. 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.
Geriatric Use
In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. (See WARNINGS and PRECAUTIONS.)
ADVERSE REACTIONS
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 and fewer than 2% of pediatric patients without mycobacterial infections discontinued therapy because of drug-related side effects. Fewer than 2% of adult patients taking BIAXIN XL tablets discontinued therapy because of drug-related side effects.
The most frequently reported events in adults taking BIAXIN tablets (clarithromycin tablets, USP) were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). In pediatric patients, the most frequently reported events were diarrhea (6%), vomiting (6%), abdominal pain (3%), rash (3%), 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.
The most frequently reported events in adults taking BIAXIN XL (Clarithromycin extended-release tablets) were diarrhea (6%), abnormal taste (7%), and nausea (3%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, less than 1% were described as severe.
In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse events were reported by a similar proportion of patients taking either BIAXIN tablets or BIAXIN XL tablets; however, patients taking BIAXIN XL tablets reported significantly less severe gastrointestinal symptoms compared to patients taking BIAXIN tablets. In addition, patients taking BIAXIN XL tablets had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse events compared to BIAXIN tablets.
In community-acquired pneumonia studies conducted in adults comparing clarithromycin to erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs 32%; p < 0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse events compared to 4% of clarithromycin-treated patients.
In two U.S. studies of acute otitis media comparing clarithromycin to amoxicillin/potassium clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to amoxicillin/potassium clavulanate-treated patients (21% vs. 40%, p < 0.001). One-third as many clarithromycin-treated patients reported diarrhea as did amoxicillin/potassium clavulanate-treated patients.
Post-Marketing Experience
Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred. Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness. There have been reports of tooth discoloration in patients treated with BIAXIN. 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, convulsions, depersonalization, disorientation, hallucinations, insomnia, manic behavior, nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing 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.
There have been post-marketing reports of BIAXIN XL tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times.
As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.
There have been reports of interstitial nephritis coincident with clarithromycin use.
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 WARNINGS and PRECAUTIONS .)
Changes in Laboratory Values
Changes in laboratory values with possible clinical significance were as follows:
OVERDOSAGE
Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea.
Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.
DOSAGE AND ADMINISTRATION
BIAXIN Filmtab (clarithromycin tablets, USP) and BIAXIN Granules (clarithromycin for oral suspension, USP) may be given with or without food. BIAXIN XL Filmtab (clarithromycin extended-release tablets) should be taken with food. BIAXIN XL tablets should be swallowed whole and not chewed, broken or crushed.
| BIAXIN Tablets | BIAXIN XL Tablets | |||
| Infection | Dosage (q12h) | Duration (days) | Dosage (q24h) | Duration (days) |
| Pharyngitis/Tonsillitis due to | ||||
| S. pyogenes | 250 mg | 10 | - | - |
| Acute maxillary sinusitis due to | 500 mg | 14 | 2 x 500 mg | 14 |
| H. influenzae | ||||
| M. catarrhalis | ||||
| S. pneumoniae | ||||
| Acute exacerbation of chronic bronchitis due to | ||||
| H. influenzae | 500 mg | 7-14 | 2 x 500 mg | 7 |
| H. parainfluenzae | 500 mg | 7 | 2 x 500 mg | 7 |
| M. catarrhalis | 250 mg | 7-14 | 2 x 500 mg | 7 |
| S. pneumoniae | 250 mg | 7-14 | 2 x 500 mg | 7 |
| Community-Acquired Pneumonia due to | ||||
| H. influenzae | 250 mg | 7 | 2 x 500 mg | 7 |
| H. parainfluenzae | - | - | 2 x 500 mg | 7 |
| M. catarrhalis | - | - | 2 x 500 mg | 7 |
| S. pneumoniae | 250 mg | 7-14 | 2 x 500 mg | 7 |
| C. pneumoniae | 250 mg | 7-14 | 2 x 500 mg | 7 |
| M. pneumoniae | 250 mg | 7-14 | 2 x 500 mg | 7 |
| Uncomplicated skin and skin structure | 250 mg | 7-14 | - | - |
| S. aureus | ||||
| S. pyogenes | ||||
H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
| Based on Body Weight | ||||
| Dosing Calculated on 7.5 mg/kg q12h | ||||
| Weight | Dose | |||
| Kg | lbs | (q12h) | 125 mg/5 mL | 250 mg/5 mL |
| 9 17 25 33 | 20 37 55 73 | 62.5 mg 125 mg 187.5 mg 250 mg | 2.5 mL q12h 5 mL q12h 7.5 mL q12h 10 mL q12h | 1.25 mL q12h 2.5 mL q12h 3.75 mL q12h 5 mL q12h |
Clarithromycin may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function. However, in the presence of severe renal impairment (CRCL< 30 mL/min), with or without coexisting hepatic impairment, the dose should be halved or the dosing interval doubled.
Mycobacterial Infections
Constituting Instructions
The table below indicates the volume of water to be added when constituting:
| Total Volume After Constitution | Clarithromycin Concentration After Constitution | Amount of Water to be Added* |
| * see instructions below. | ||
| 50 mL | 125 mg/5 mL | 27 mL |
| 100 mL | 125 mg/5 mL | 55 mL |
| 50 mL | 250 mg/5 mL | 27 mL |
| 100 mL | 250 mg/5 mL | 55 mL |
Add half the volume of water to the bottle and shake vigorously. Add the remainder of water to the bottle and shake.
Shake well before each use. Oversize bottle provides shake space. Keep tightly closed. Do not refrigerate. After mixing, store at 15° to 30°C (59° to 86°F) and use within 14 days.
HOW SUPPLIED
BIAXIN Filmtab (clarithromycin tablets, USP) are supplied as yellow oval film-coated tablets in the following packaging sizes:
250 mg tablets: (imprinted in blue with the Abbott logo and Abbo-Code KT)
Bottles of 60 (NDC 0074-3368-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-3368-11).
Store BIAXIN 250 mg tablets at controlled room temperature 15° to 30°C (59° to 86°F) in a well-closed container. Protect from light.
500 mg tablets: (debossed with the Abbott logo on one side and Abbo-Code KL on the opposite side)
Bottles of 60 (NDC 0074-2586-60) and ABBO-PAC unit dose strip packages of 100 (NDC 0074-2586-11).
Store BIAXIN 500 mg tablets at controlled room temperature 20° to 25°C (68° to 77°F) in a well-closed container.
BIAXIN XL Filmtab (clarithromycin extended-release tablets) are supplied as yellow oval film-coated 500 mg tablets debossed (on one side) with the Abbott logo and a two-letter Abbo-Code designation, KJ in the following packaging sizes:
500 mg tablets:
Bottles of 60 (NDC 0074-3165-60), ABBO-PAC unit dose strip packages of 100 (NDC 0074-3165-11), and BIAXIN XL PAC carton of 4 buler packages 14 tablets each (NDC 0074-3165-41).
Store BIAXIN XL tablets at 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.]
BIAXIN Granules (clarithromycin for oral suspension, USP) is supplied in the following strengths and sizes:
| Total Volume After Constitution | Clarithromycin Concentration After Constitution | Clarithromycin Contents Per Bottle | NDC |
| 50 mL | 125 mg/5 mL | 1250 mg | 0074-3163-50 |
| 100 mL | 125 mg/5 mL | 2500 mg | 0074-3163-13 |
| 50 mL | 250 mg/5 mL | 2500 mg | 0074-3188-50 |
| 100 mL | 250 mg/5 mL | 5000 mg | 0074-3188-13 |
Store BIAXIN granules for oral suspension at controlled room temperature 15° to 30°C (59° to 86°F) in a well-closed container. Do not refrigerate BIAXIN suspension.
CLINICAL STUDIES
Mycobacterial Infections
Survival
A statistically significant survival benefit was observed.
| Mortality | Reduction in | ||
| Placebo | Clarithromycin | Mortality on Clarithromycin | |
| 6 month | 9.4% | 6.5% | 31% |
| 12 month | 29.7% | 20.5% | 31% |
| 18 month | 46.4% | 37.5% | 20% |
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of clarithromycin may be underestimated.
Otitis Media
In a controlled clinical study of acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin was compared to an oral cephalosporin. In this study, very strict evaluability criteria were used to determine clinical response. For the 223 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the post-therapy visit was 88% for clarithromycin and 91% for the cephalosporin.
In a smaller number of patients, microbiologic determinations were made at the pre-treatment visit. The following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained:
| PATHOGEN | OUTCOME |
* None of the H. influenzae isolated pre-treatment was resistant to clarithromycin; 6% were resistant to the control agent. | |
| S. pneumoniae | clarithromycin success rate, 13/15 (87%), control 4/5 |
| H. influenzae* | clarithromycin success rate, 10/14 (71%), control 3/4 |
| M. catarrhalis | clarithromycin success rate, 4/5,control 1/1 |
| S. pyogenes | clarithromycin success rate, 3/3,control 0/1 |
| Overall | clarithromycin success rate, 30/37 (81%), control 8/11 (73%) |
Duodenal Ulcer Associated with H. pylori Infection
Clarithromycin + Lansoprazole and Amoxicillin
Clarithromycin + Omeprazole and Amoxicillin Therapy
Clarithromycin + Omeprazole Therapy
Four randomized, double-blind, multi-center studies (067, 100, 812b, and 058) evaluated clarithromycin 500 mg t.i.d. plus omeprazole 40 mg q.d. for 14 days, followed by omeprazole 20 mg q.d. (067, 100, and 058) or by omeprazole 40 mg q.d. (812b) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 067 and 100 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067 and 228 patients in Study 100. These studies compared the combination regimen to omeprazole and clarithromycin monotherapies. Studies 812b and 058 were conducted in Europe and enrolled 154 and 215 patients, respectively.H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b and 208 patients in Study 058. These studies compared the combination regimen to omeprazole monotherapy. The results for the efficacy analyses for these studies are described below.
Clarithromycin + Ranitidine Bismuth Citrate Therapy
In a U.S. double-blind, randomized, multicenter, dose-comparison trial, ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks plus clarithromycin 500 mg b.i.d. for the first 2 weeks was found to have an equivalent H. pylori eradication rate (based on culture and histology) when compared to ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks plus clarithromycin 500 mg t.i.d. for the first 2 weeks. The intent-to-treat H. pylori eradication rates are shown below:
| Analysis | RBC 400 mg + Clarithromycin 500 mg b.i.d. | RBC 400 mg + Clarithromycin 500 mg t.i.d. | 95% CI Rate Difference |
| ITT | 65% (122/188) [58%, 72%] | 63% (122/195) [55%, 69%] | (-8%, 12%) |
| Per-Protocol | 72% (117/162) [65%, 79%] | 71% (120/170) [63%, 77%] | (-9%, 12%) |
H. pylori eradication was defined as no positive test at 4 weeks following the end of treatment. Patients must have had two tests performed, and these must have been negative to be considered eradicated of H. pylori. The following patients were excluded from the per-protocol analysis: patients not infected with H. pylori prestudy, dropouts, patients with major protocol violations, patients with missing H. pylori tests. Patients excluded from the intent-to-treat analysis included those not infected with H. pylori prestudy and those with missing H. pylori tests prestudy. Patients were assessed for H. pylori eradication (4 weeks following treatment) regardless of their healing status (at the end of treatment).
The relationship between H. pylori eradication and duodenal ulcer recurrence was assessed in a combined analysis of six U.S. randomized, double-blind, multicenter, placebo-controlled trials using ranitidine bismuth citrate with or without antibiotics. The results from approximately 650 U.S. patients showed that the risk of ulcer recurrence within 6 months of completing treatment was two times less likely in patients whose H. pylori infection was eradicated compared to patients in whom H. pylori infection was not eradicated.
ANIMAL PHARMACOLOGY AND TOXICOLOGY
Clarithromycin is rapidly and well-absorbed with dose-linear kinetics, low protein binding, and a high volume of distribution. Plasma half-life ranged from 1 to 6 hours and was species dependent. High tissue concentrations were achieved, but negligible accumulation was observed. Fecal clearance predominated. Hepatotoxicity occurred in all species tested (i.e., in rats and monkeys at doses 2 times greater than and in dogs at doses comparable to the maximum human daily dose, based on mg/m2). Renal tubular degeneration (calculated on a mg/m2 basis) occurred in rats at doses 2 times, in monkeys at doses 8 times, and in dogs at doses 12 times greater than the maximum human daily dose. Testicular atrophy (on a mg/m2 basis) occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose. Corneal opacity (on a mg/m2 basis) occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose. Lymphoid depletion (on a mg/m2 basis) occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose. These adverse events were absent during clinical trials.
REFERENCES
- National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically - Fourth Edition. Approved Standard NCCLS Document M7-A4, Vol. 17, No. 2, NCCLS, Wayne, PA, January, 1997.
- National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Sixth Edition. Approved Standard NCCLS Document M2-A6, Vol. 17, No. 1, NCCLS, Wayne, PA, January, 1997.
- National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL. January 11-13, 1998.
- Chaisson RE, et al. Clarithromycin and Ethambutol with or without Clofazimine for the Treatment of Bacteremic Mycobacterium avium Complex Disease in Patients with HIV Infection. AIDS. 1997;11:311-317.
- Kemper CA, et al. Treatment of Mycobacterium avium Complex Bacteremia in AIDS with a Four-Drug Oral Regimen.Ann Intern Med. 1992;116:466-472.
Filmtab – Film-sealed tablets, Abbott
Biaxin Filmtab 250 mg and 500 mg and Biaxin XL 500 mg
Mfd.
by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617
Biaxin Granules for Oral Suspension, 125mg/5mL and 250mg/5mL
Mfd.
by Abbott Laboratories, North Chicago, IL 60064
For Abbott Laboratories, North Chicago, IL 60064, U.S.A.