DRUG INTERACTIONS
7 Co-administration of BIAXIN is known to inhibit CYP3A, and a drug primarily metabolized by CYP3A may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug.
BIAXIN should be used with caution in patients receiving treatment with other drugs known to be CYP3A enzyme substrates, especially if the CYP3A substrate has a narrow safety margin (e.g., carbamazepine) and/or the substrate is extensively metabolized by this enzyme.
Adjust dosage when appropriate and monitor serum concentrations of drugs primarily metabolized by CYP3A closely in patients concurrently receiving clarithromycin.
Table 8: Clinically Significant Drug Interactions with BIAXIN Drugs That Are Affected By BIAXIN Drug(s) with Pharmacokinetics Affected by BIAXIN Recommendation Comments Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Not Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide.
Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3) ] .
Serum concentrations of these medications should also be monitored.
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine.
There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide.
Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin Use With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp.
When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin.
Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance.
Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias.
Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin Use With Caution Oral anticoagulants: 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 [see Warnings and Precautions (5.4) ] .
Antiepileptics: Carbamazepine Use With Caution Carbamazepine: 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.
Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin.
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Use With Caution Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect BIAXIN” in the table below).
Clarithromycin may increase the plasma concentrations of itraconazole.
Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole No Dose Adjustment Fluconazole: [see Pharmacokinetics (12.3) ] Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Contraindicated Colchicine: 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.
The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4) ] .
Colchicine (in patients with normal renal and hepatic function) Use With Caution Antipsychotics: Pimozide Contraindicated Pimozide: [See Contraindications (4.2) ] Quetiapine Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin.
Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities.
There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration.
Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity) Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6.
However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A.
In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine.
Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals: Atazanavir Use With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3) ] .
Saquinavir (in patients with decreased renal function) Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3) ] .
Ritonavir Etravirine Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3) ] .
Maraviroc Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism.
See Selzentry ® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine No Dose Adjustment Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered.
No dose adjustments are necessary for patients with normal renal function (see Victrelis ® prescribing information).
Zidovudine Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations.
Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3) ] .
The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers: Verapamil Use With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4) ] .
Amlodipine Diltiazem Amlodipine, Diltiazem: [See Warnings and Precautions (5.4) ] Nifedipine Nifedipine: Nifedipine is a substrate for CYP3A.
Clarithromycin and other macrolides are known to inhibit CYP3A.
There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin.
Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4) ] .
Ergot Alkaloids: Ergotamine Dihydroergotamine Contraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6) ] .
Gastroprokinetic Agents: Cisapride Contraindicated Cisapride: [See Contraindications (4.2) ] HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Contraindicated Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4) ] Atorvastatin Pravastatin Use With Caution Fluvastatin No Dose Adjustment Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Insulin Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Immunosuppressants: Cyclosporine Use With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil Use With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin.
Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors.
Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended.
Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole No Dose Adjustment Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3) ] (see also Omeprazole under “Drugs That Affect BIAXIN” in the table below).
Xanthine Derivatives: Theophylline Use With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3) ] .
Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Use With Caution Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3) ] .
Alprazolam Triazolam Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin.
There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam.
Monitoring the patient for increased CNS pharmacological effects is suggested.
In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam No Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin Use With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect BIAXIN” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St.
John’s Wort Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St.
John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate Use With Caution There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect BIAXIN Drug(s) that Affect the Pharmacokinetics of BIAXIN Recommendation Comments Antifungals: Itraconazole Use With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin.
Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By BIAXIN” in the table above).
Antivirals: Atazanavir Use With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3) ] .
Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex.
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function) Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3) ] .
Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function) Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3) ] .
Etravirine Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased.
Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function) No Dose Adjustment Ritonavir (in patients with normal renal function) Proton Pump Inhibitors: Omeprazole Use With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3) ] .
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine Use With Caution Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin.
Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.
Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A.
There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By BIAXIN” in the table above).
Co-administration of BIAXIN can alter the concentrations of other drugs.
The potential for drug-drug interactions must be considered prior to and during therapy.
(4, 5.2, 5.4, 7)
OVERDOSAGE
10 Overdosage of BIAXIN can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea.
Treat adverse reactions accompanying overdosage by the prompt elimination of unabsorbed drug and supportive measures.
As with other macrolides, BIAXIN serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.
DESCRIPTION
11 Clarithromycin is a semi-synthetic macrolide antimicrobial for oral use.
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: Figure 1: Structure of Clarithromycin 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 Filmtab 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 Filmtab 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.
Each 5 mL of BIAXIN reconstituted 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, castor oil, citric acid, hypromellose phthalate, maltodextrin, potassium sorbate, povidone, silicon dioxide, sucrose, xanthan gum, titanium dioxide and fruit punch flavor.
Chemical structure for clarithromycin
CLINICAL STUDIES
14 14.1 Mycobacterial Infections Prophylaxis of Mycobacterial Infections A randomized, double-blind clinical trial (trial 3) compared clarithromycin 500 mg twice a day to placebo in patients with CDC-defined AIDS and CD 4 counts less than 100 cells/µL.
This trial accrued 682 patients from November 1992 to January 1994, with a median CD 4 cell count at entry of 30 cells/mcL.
Median duration of BIAXIN was 10.6 months vs.
8.2 months for placebo.
More patients in the placebo arm than the BIAXIN arm discontinued prematurely from the trial (75.6% and 67.4%, respectively).
However, if premature discontinuations due to Mycobacterium avium complex (MAC) or death are excluded, approximately equal percentages of patients on each arm (54.8%) on BIAXIN and 52.5% on placebo) discontinued study drug early for other reasons.
The trial was designed to evaluate the following endpoints: MAC bacteremia, defined as at least one positive culture for Mycobacterium avium complex bacteria from blood or another normally sterile site Survival Clinically significant disseminated MAC disease, defined as MAC bacteremia accompanied by signs or symptoms of serious MAC infection, including fever, night sweats, weight loss, anemia, or elevations in liver function tests MAC Bacteremia In patients randomized to BIAXIN, the risk of MAC bacteremia was reduced by 69% compared to placebo.
The difference between groups was statistically significant (p < 0.001).
On an intent-to-treat basis, the one-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized to BIAXIN and 19.4% for patients randomized to placebo.
While only 19 of the 341 patients randomized to BIAXIN developed MAC, 11 of these cases were resistant to BIAXIN.
The patients with resistant MAC bacteremia had a median baseline CD 4 count of 10 cells/mm 3 (range 2 cells/mm 3 to 25 cells/mm 3 ).
Information regarding the clinical course and response to treatment of the patients with resistant MAC bacteremia is limited.
The 8 patients who received BIAXIN and developed susceptible MAC bacteremia had a median baseline CD 4 count of 25 cells/mm 3 (range 10 cells/mm 3 to 80 cells/mm 3 ).
Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to BIAXIN.
The median baseline CD 4 count was 15 cells/mm 3 (range 2 cells/mm 3 to 130 cells/mm 3 ) for placebo patients that developed MAC.
Survival A statistically significant survival benefit of BIAXIN compared to placebo was observed (see Figure 3 and Table 13).
Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of BIAXIN may be underestimated.
Figure 3.
Survival of All Randomized AIDS Patients Over Time in Trial 3 Table 13.
Mortality Rates at 18 months in Trial 3 Mortality Rates Reduction in Mortality Rates on BIAXIN Placebo BIAXIN 6 month 9.4% 6.5% 31% 12 month 29.7% 20.5% 31% 18 month 46.4% 37.5% 20% Survival Graph Clinically Significant Disseminated MAC Disease In association with the decreased incidence of MAC bacteremia, patients in the group randomized to BIAXIN showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, and anemia.
Treatment of Mycobacterial Infections Dose-Ranging Monotherapy Trials in Adult AIDS Patients with MAC Two randomized clinical trials (Trials 1 and 2) compared different dosages of BIAXIN in patients with CDC-defined AIDS and CD 4 counts less than100 cells/mcL.
These trials accrued patients from May 1991 to March 1992.
Trial 500 was a randomized, double-blind trial; trial 577 was an open-label compassionate use trial.
Both trials used 500 mg and 1000 mg twice daily dosing of BIAXIN; trial 1 also had a 2000 mg twice daily BIAXIN group.
Trial 1 enrolled 154 adult patients and trial 2 enrolled 469 adult patients.
The majority of patients had CD 4 cell counts less than 50 cells/mcL at study entry.
The trials were designed to evaluate the following end points: Change in MAC bacteremia or blood cultures negative for M.
avium .
Change in clinical signs and symptoms of MAC infection including one or more of the following: fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly.
The results for trial 1 are described below.
The trial 2 results were similar to the results of trial 1.
MAC Bacteremia Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all BIAXIN dosage groups.
The mean reductions in MAC colony forming units (CFU) from baseline after 4 weeks of therapy in the 1000 mg (n=32) twice daily and 2000 mg (n=26) twice daily regimen was 2.3 Log CFU compared to 1.5 Log CFU in the BIAXIN 500 mg twice daily (n=35) regimen.
A separate trial with a four drug regimen 6 (ciprofloxacin, ethambutol, rifampicin, and clofazimine) had a mean reduction of 1.4 Log CFU.
Clinical outcomes evaluated with the different dosing regimens of clarithromycin monotherapy are shown in Table 14.
The 1000 mg and 2000 mg twice daily doses showed significantly better control of bacteremia during the first four weeks of therapy.
No significant differences were seen beyond that point.
All of the isolates had MIC less than 8 mcg/mL at pre-treatment.
Relapse was almost always accompanied by an increase in MIC.
Table 14.
Outcome with the Different Dosing Regimens of BIAXIN Outcome BIAXIN 500 mg twice daily BIAXIN 1000 mg twice daily BIAXIN 2000 mg twice daily One or more negative blood cultures at any time during acute therapy 61% (30/49) 59% (29/49) 52% (25/48) Two or more negative blood cultures during acute therapy sustained through study day 84 25% (12/49) 25% (12/49) 8% (4/48) Death or discontinuation by day 84 23% (11/49) 37% (18/49) 56% (27/48) Relapse by day 84 14% (7/49) 12% (6/49) 13% (6/48) Median time to first negative culture (in days) 54 41 29 Median time to first decrease of at least 1 log CFU (in days) 29 16 15 Median time to first positive culture or study discontinuation following the first negative culture (in days) 43 59 43 Clinically Significant Disseminated MAC Disease Among patients experiencing night sweats prior to therapy, 84% showed resolution or improvement at some point during the 12 weeks of BIAXIN at 500 mg to 2000 mg twice daily doses.
Similarly, 77% of patients reported resolution or improvement in fevers at some point.
Response rates for clinical signs of MAC are given in Table 15 below.
The median duration of response, defined as improvement or resolution of clinical signs and symptoms, was 2 weeks to 6 weeks.
Since the trial was not designed to determine the benefit of monotherapy beyond 12 weeks, the duration of response may be underestimated for the 25% to 33% of patients who continued to show clinical response after 12 weeks.
Table 15.
Response Rates for Clinical Signs of MAC During 6 Weeks to 12 Weeks of Treatment Resolution of Fever Resolution of Night Sweats BIAXIN twice daily dose (mg) % ever afebrile % afebrile 6 weeks or more BIAXIN twice daily dose (mg) % ever resolving % resolving 6 weeks or more 500 67% 23% 500 85% 42% 1000 67% 12% 1000 70% 33% 2000 62% 22% 2000 72% 36% Weight Gain Greater Than 3% Hemoglobin Increase Greater Than 1 gm BIAXIN twice daily dose (mg) % ever gaining % gaining 6 weeks or more BIAXIN twice daily dose (mg) % ever increasing % increasing 6 weeks or more 500 33% 14% 500 58% 26% 1000 26% 17% 1000 37% 6% 2000 26% 12% 2000 62% 18% Survival Median survival time from trial entry (trial 1) was 249 days at the 500 mg twice daily dose compared to 215 days with the 1000 mg twice daily dose.
However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg twice daily group versus 13 deaths in 51 patients in the 1000 mg twice daily group.
The reason for this apparent mortality difference is not known.
Survival in the two groups was similar beyond 12 weeks.
The median survival times for these dosages were similar to recent historical controls with MAC when treated with combination therapies.
6 Median survival time from entry in trial 2 was 199 days for the 500 mg twice a day dose and 179 days for the 1000 mg twice a day dose.
During the first four weeks of therapy, while patients were maintained on their originally assigned dose, there were 11 deaths in 255 patients taking 500 mg twice daily and 18 deaths in 214 patients taking 1000 mg twice daily.
Dosage-Ranging Monotherapy Trials in Pediatric AIDS Patients with MAC Trial 4 was a pediatric trial of 3.75 mg/kg, 7.5 mg/kg, and 15 mg/kg of BIAXIN twice daily in patients with CDC-defined AIDS and CD 4 counts less than 100 cells/mcL.
The trial enrolled 25 patients between the ages of 1 to 20.
The trial evaluated the same endpoints as in the adult trials 1 and 2.
Results with the 7.5 mg/kg twice daily dose in the pediatric trial were comparable to those for the 500 mg twice daily regimen in the adult trials.
Combination Therapy in AIDS Patients with Disseminated MAC Trial 5 compared the safety and efficacy of BIAXIN in combination with ethambutol versus BIAXIN in combination with ethambutol and clofazimine for the treatment of disseminated MAC (dMAC) infection.
This 24-week trial enrolled 106 patients with AIDS and dMAC, with 55 patients randomized to receive BIAXIN and ethambutol, and 51 patients randomized to receive clarithromycin, ethambutol, and clofazime.
Baseline characteristics between treatment arms were similar with the exception of median CFU counts being at least 1 log higher in the BIAXIN, ethambutol, and clofazime arm.
Compared to prior experience with clarithromycin monotherapy, the two-drug regimen of clarithromycin and ethambutol extended the time to microbiologic relapse, largely through suppressing the emergence of clarithromycin resistant strains.
However, the addition of clofazimine to the regimen added no additional microbiologic or clinical benefit.
Tolerability of both multidrug regimens was comparable with the most common adverse events being gastrointestinal in nature.
Patients receiving the clofazimine-containing regimen had reduced survival rates; however, their baseline mycobacterial colony counts were higher.
The results of this trial support the addition of ethambutol to clarithromycin for the treatment of initial dMAC infections but do not support adding clofazimine as a third agent.
14.2 Otitis Media Otitis Media Trial of BIAXIN vs.
Oral Cephalosporin In a controlled clinical trial of pediatric patients with acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, BIAXIN was compared to an oral cephalosporin.
In this trial, 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 BIAXIN and 91% for the cephalosporin.
In a smaller number of patients, microbiologic determinations were made at the pre-treatment visit.
The presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) are shown in Table 16.
Table 16.
Clinical Success Rates of Otitis Media Treatment by Pathogen Pathogen Clinical Success Rates BIAXIN Oral Cephalosporin S.
pneumoniae 13/15 (87%) 4/5 H.
influenzae a 10/14 (71%) 3/4 M.
catarrhalis 4/5 1/1 S.
pyogenes 3/3 0/1 All Pathogens Combined 30/37 (81%) 8/11 (73%) a None of the H.
influenzae isolated pre-treatment was resistant to BIAXIN; 6% were resistant to the control agent.
Otitis Media Trials of BIAXIN vs.
Antimicrobial/Beta-lactamase Inhibitor In two other controlled clinical trials of acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, BIAXIN was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor.
In these trials, strict evaluability criteria were used to determine the clinical responses.
In the 233 patients who were evaluated for clinical efficacy, the combined clinical success rate (i.e., cure and improvement) at the post-therapy visit was 91% for both BIAXIN and the control.
For the patients who had microbiologic determinations at the pre-treatment visit, the presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) are shown in Table 17.
Table 17.
Clinical Success Rates of Acute Otitis Media Treatment by Pathogen Clinical Success Rates PATHOGEN BIAXIN Antimicrobial/Beta-lactamase Inhibitor S.
pneumoniae 43/51 (84%) 55/56 (98%) H.
influenzae a 36/45 (80%) 31/33 (94%) M.
catarrhalis 9/10 (90%) 6/6 S.
pyogenes 3/3 5/5 All Pathogens Combined 91/109 (83%) 97/100 (97%) a Of the H.
influenzae isolated pre-treatment, 3% were resistant to BIAXIN and 10% were resistant to the control agent.
14.3 H.
pylori Eradication to Decrease the Risk of Duodenal Ulcer Recurrence BIAXIN + Lansoprazole and Amoxicillin Two U.S.
randomized, double-blind clinical trials (trial 6 and trial 7) in patients with H.
pylori and duodenal ulcer disease (defined as an active ulcer or history of an active ulcer within one year) evaluated the efficacy of BIAXIN 500 mg twice daily in combination with lansoprazole 30 mg twice daily and amoxicillin 1 gm twice daily as 14-day triple therapy for eradication of H.
pylori .
H.
pylori eradication was defined as two negative tests (culture and histology) at 4 weeks to 6 weeks following the end of treatment.
The combination of BIAXIN plus lansoprazole and amoxicillin as triple therapy was effective in eradication of H.
pylori (see results in Table 18).
Eradication of H.
pylori has been shown to reduce the risk of duodenal ulcer recurrence.
A randomized, double-blind clinical trial (trial 8) 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 BIAXIN in combination with lansoprazole and amoxicillin as triple therapy for 10 days and 14 days.
This trial established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H.
pylori (see results in Table 18).
Table 18.
H.
pylori Eradication Rates-Triple Therapy (BIAXIN/lansoprazole/amoxicillin) Percent of Patients Cured [95% Confidence Interval] (number of patients) Trial Duration Triple Therapy Evaluable Analysis a Triple Therapy Intent-to-Treat Analysis b Trial 6 14 days 92 c [80-97.7] (n = 48) 86 c [73.3-93.5] (n = 55) Trial 7 14 days 86 d [75.7-93.6] (n = 66) 83 d [72-90.8] (n = 70) Trial 8 e 14 days 85 [77-91] (N = 113) 82 [73.9-88.1] (N = 126) 10 days 84 [76-89.8] (N = 123) 81 [73.9-87.6] (N = 135) a Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H.
pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest (Delta West LTD., Bentley, Australia), histology, and/or culture.
Patients were included in the analysis if they completed the trial.
Additionally, if patients were dropped out of the trial due to an adverse reaction related to the drug, they were included in the analysis as evaluable failures of therapy.
b Patients were included in the analysis if they had documented H.
pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year).
All dropouts were included as failures of therapy.
c (p < 0.05) versus BIAXIN/lansoprazole and lansoprazole/amoxicillin dual therapy.
d (p < 0.05) versus BIAXIN/amoxicillin dual therapy.
e The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day, is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.
BIAXIN + Omeprazole and Amoxicillin Therapy Three U.S., randomized, double-blind clinical trials in patients with H.
pylori infection and duodenal ulcer disease (n = 558) compared BIAXIN plus omeprazole and amoxicillin to BIAXIN plus amoxicillin.
Two trials (trials 9 and 10) were conducted in patients with an active duodenal ulcer, and the third trial (trial 11) was conducted in patients with a duodenal ulcer in the past 5 years, but without an ulcer present at the time of enrollment.
The dosage regimen in the trials was BIAXIN 500 mg twice a day plus omeprazole 20 mg twice a day plus amoxicillin 1 gram twice a day for 10 days.
In trials 9 and 10, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg once a day.
Endpoints studied were eradication of H.
pylori and duodenal ulcer healing (trials 9 and 10 only).
H.
pylori status was determined by CLOtest ® , histology, and culture in all three trials.
For a given patient, H.
pylori was considered eradicated if at least two of these tests were negative, and none was positive.
The combination of BIAXIN plus omeprazole and amoxicillin was effective in eradicating H.
pylori (see results in Table 19).
Table 19.
H.
pylori Eradication Rates: % of Patients Cured [95% Confidence Interval] BIAXIN + omeprazole + amoxicillin BIAXIN + amoxicillin Per-Protocol a Intent-to-Treat b Per-Protocol a Intent-to-Treat b Trial 9 c 77 [64, 86] (n = 64) 69 [57, 79] (n = 80) 43 [31, 56] (n = 67) 37 [27, 48] (n = 84) Trial 10 c 78 [67, 88] (n = 65) 73 [61, 82] (n = 77) 41 [29, 54] (n = 68) 36 [26, 47] (n = 84) Trial 11 c 90 [80, 96] (n = 69) 83 [74, 91] (n = 84) 33 [24, 44] (n = 93) 32 [23, 42] (n = 99) a Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer trials 9 and 10; history of ulcer within 5 years, trial 11) and H.
pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest ® , histology, and/or culture.
Patients were included in the analysis if they completed the trial.
Additionally, if patients dropped out of the trial due to an adverse reaction related to the study drug, they were included in the analysis as failures of therapy.
The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer.
b Patients were included in the analysis if they had documented H.
pylori infection at baseline and had confirmed duodenal ulcer disease.
All dropouts were included as failures of therapy.
c p < 0.05 versus BIAXIN plus amoxicillin.
BIAXIN + Omeprazole Therapy Four randomized, double-blind, multi-center trials (trials 12, 13, 14, and 15) evaluated BIAXIN 500 mg three times a day plus omeprazole 40 mg once a day for 14 days, followed by omeprazole 20 mg once a day (trials 12, 13, and 15) or by omeprazole 40 mg once a day (trial 14) for an additional 14 days in patients with active duodenal ulcer associated with H.
pylori .
Trials 12 and 13 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 trial 12 and 228 patients in trial 13.
These trials compared the combination regimen to omeprazole and BIAXIN monotherapies.
Trials 14 and 15were conducted in Europe and enrolled 154 and 215 patients, respectively.
H.
pylori infection and duodenal ulcer were confirmed in 148 patients in trial 14 and 208 patients in trial 15.
These trials compared the combination regimen to omeprazole monotherapy.
The results for the efficacy analyses for these trials are described in Tables 20, 21, and 22.
Duodenal Ulcer Healing The combination of BIAXIN and omeprazole was as effective as omeprazole alone for healing duodenal ulcer (see Table 20).
Table 20.
End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (n/N) Trial BIAXIN + Omeprazole Omeprazole BIAXIN U.S.
Trials Trial 13 94% (58/62) a 88% (60/68) 71% (49/69) Trial 12 88% (56/64) a 85% (55/65) 64% (44/69) Non-U.S.
Trials Trial 15 99% (84/85) 95% (82/86) N/A Trial 14 b 100% (64/64) 99% (71/72) N/A a p < 0.05 for BIAXIN + omeprazole versus BIAXIN monotherapy.
b In trial 14 patients received omeprazole 40 mg daily for days 15 to 28.
Eradication of H.
pylori Associated with Duodenal Ulcer The combination of BIAXIN and omeprazole was effective in eradicating H.
pylori (see Table 21).
H.
pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated.
In the per-protocol analysis, the following patients were excluded: dropouts, patients with major protocol violations, patients with missing H.
pylori tests post-treatment, and patients that were not assessed for H.
pylori eradication at 4 weeks after the end of treatment because they were found to have an unhealed ulcer at the end of treatment.
Table 21.
H.
pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (n/N) Trial BIAXIN + Omeprazole Omeprazole BIAXIN U.S.
Trials Trial 13 64% (39/61) a,b 0% (0/59) 39% (17/44) Trial 12 74% (39/53) a,b 0% (0/54) 31% (13/42) Non-U.S.
Trials Trial 15 74% (64/86) b 1% (1/90) N/A Trial 14 83% (50/60) b 1% (1/74) N/A a Statistically significantly higher than BIAXIN monotherapy (p < 0.05).
b Statistically significantly higher than omeprazole monotherapy (p < 0.05).
Duodenal Ulcer Recurrence Ulcer recurrence at 6-months and at 12 months following the end of treatment was assessed for patients in whom ulcers were healed post-treatment (see the results in Table 22).
Thus, in patients with duodenal ulcer associated with H.
pylori infection, eradication of H.
pylori reduced ulcer recurrence.
Table 22.
Duodenal Ulcer Recurrence at 6 months and 12 months in Patients with Healed Ulcers H.
pylori Negative at 4-6 Weeks H.
pylori Positive at 4-6 Weeks U.S.
Trials Recurrence at 6 Months Trial 100 BIAXIN + Omeprazole 6% (2/34) 56% (9/16) Omeprazole (0/0) 71% (35/49) BIAXIN 12% (2/17) 32% (7/22) Trial 067 BIAXIN + Omeprazole 38% (11/29) 50% (6/12) Omeprazole (0/0) 67% (31/46) BIAXIN 18% (2/11) 52% (14/27) Non-U.S.
Trials Recurrence at 6 Months Trial 058 BIAXIN + Omeprazole 6% (3/53) 24% (4/17) Omeprazole 0% (0/3) 55% (39/71) Trial 812b BIAXIN + Omeprazole 5% (2/42) 0% (0/7) Omeprazole 0% (0/1) 54% (32/59) Non-U.S.
Trials Recurrence at 12-Months in Trial 14 BIAXIN + Omeprazole 3% (1/40) 0% (0/6) Omeprazole 0% (0/1) 67% (29/43)
HOW SUPPLIED
16 /STORAGE AND HANDLING BIAXIN Filmtab (clarithromycin tablets, USP) is supplied as yellow oval film-coated tablets in the following packaging sizes: 250 mg tablets: (imprinted in blue with the “a” logo and KT) Bottles of 60 ( NDC 0074-3368-60) and unit dose strip packages of 100 ( NDC 0074-3368-11).
Store BIAXIN Filmtab 250 mg 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 “a” logo on one side and KL on the opposite side) Bottles of 60 ( NDC 0074-2586-60) and unit dose strip packages of 100 ( NDC 0074-2586-11).
Store BIAXIN Filmtab 500 mg at controlled room temperature 20° to 25°C (68° to 77°F) in a well-closed container.
BIAXIN XL Filmtab (clarithromycin extended-release tablets) is supplied as yellow oval film-coated tablets in the following packaging sizes: 500 mg tablets: (debossed with the “a” logo and KJ) Bottles of 60 ( NDC 0074-3165-60), unit dose strip packages of 100 ( NDC 0074-3165-11), and BIAXIN XL PAC carton of 4 blister packages 14 tablets each ( NDC 0074-3165-41).
Store BIAXIN XL Filmtab 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 as white to off-white granules 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 below 25°C (77°F) in a well-closed container.
Do not refrigerate the reconstituted BIAXIN granules.
RECENT MAJOR CHANGES
Warnings and Precautions, Serious Adverse Reactions with Concomitant Use with Other Drugs (5.4) 10/2015
GERIATRIC USE
8.5 Geriatric Use In a steady-state study in which healthy elderly subjects (65 years to 81 years of age) were given 500 mg of BIAXIN 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 reactions when compared to younger patients.
Consider dosage adjustment in elderly patients with severe renal impairment.
Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients [see Warnings and Precautions (5.3) ] .
Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine) involved elderly patients 65 years of age or older [see Warnings and Precautions (5.4) ] .
Especially in elderly patients, there have been reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, some of which occurred in patients with renal insufficiency.
Deaths have been reported in some patients [see Contraindications (4.4) and Warnings and Precautions (5.4) ] .
DOSAGE FORMS AND STRENGTHS
3 BIAXIN is available as: BIAXIN Filmtab (yellow oval film-coated tablet): 250 mg: imprinted in blue with the “a” logo and KT 500 mg: debossed with the “a” logo on one side and KL on the opposite side BIAXIN XL Filmtab (yellow oval film-coated extended-release tablet): 500 mg: debossed with the “a” logo and KJ BIAXIN Granules (white to off-white granules before reconstitution; white to off-white opaque suspension after reconstitution): 125 mg/5 mL concentration available in 50 mL and 100 mL bottles 250 mg/5 mL concentration available in 50 mL and 100 mL bottles Tablets: 250 mg and 500 mg (3) Extended-release Tablets: 500 mg (3) Granules for Oral Suspension: 125 mg/5 mL and 250 mg/5 mL (3)
MECHANISM OF ACTION
12.1 Mechanism of Action Clarithromycin is a macrolide antimicrobial drug [see Microbiology (12.4) ] .
INDICATIONS AND USAGE
1 BIAXIN is a macrolide antimicrobial indicated for mild to moderate infections caused by designated, susceptible bacteria in the following: Acute Bacterial Exacerbation of Chronic Bronchitis in Adults (1.1) Acute Maxillary Sinusitis (1.2) Community-Acquired Pneumonia (1.3) Pharyngitis/Tonsillitis (1.4) Uncomplicated Skin and Skin Structure Infections (1.5) Acute Otitis Media in Pediatric Patients (1.6) Treatment and Prophylaxis of Disseminated Mycobacterial Infections (1.7) Helicobacter pylori Infection and Duodenal Ulcer Disease in Adults (1.8) Limitations of Use BIAXIN XL Filmtab is indicated only for acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, and community-acquired pneumonia in adults.
(1.9) 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.
(1.9) 1.1 Acute Bacterial Exacerbation of Chronic Bronchitis BIAXIN (Filmtab, Granules) and BIAXIN XL Filmtab are indicated in adults for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae , Haemophilus parainfluenzae , Moraxella catarrhalis , or Streptococcus pneumoniae [see Indications and Usage (1.9) ] .
1.2 Acute Maxillary Sinusitis BIAXIN (Filmtab, Granules) and BIAXIN XL Filmtab (in adults) are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae , Moraxella catarrhalis , or Streptococcus pneumoniae [see Indications and Usage (1.9) ] .
1.3 Community-Acquired Pneumonia BIAXIN (Filmtab, Granules) and BIAXIN XL Filmtab are indicated [see Indications and Usage (1.9) ] for the treatment of mild to moderate infections caused by susceptible isolates due to: Haemophilus influenzae (in adults) Haemophilus parainfluenzae (BIAXIN XL Filmtab in adults) Moraxella catarrhalis (BIAXIN XL Filmtab in adults) Mycoplasma pneumoniae , Streptococcus pneumoniae , Chlamydophila pneumoniae (BIAXIN XL Filmtab [in adults]; BIAXIN Filmtab and BIAXIN Granules [in adults and pediatric patients]) 1.4 Pharyngitis/Tonsillitis BIAXIN Filmtab and BIAXIN Granules are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Streptococcus pyogenes as an alternative in individuals who cannot use first line therapy.
1.5 Uncomplicated Skin and Skin Structure Infections BIAXIN Filmtab and BIAXIN Granules are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Staphylococcus aureus , or Streptococcus pyogenes .
1.6 Acute Otitis Media BIAXIN Filmtab and BIAXIN Granules are indicated in pediatric patients for the treatment of mild to moderate infections caused by susceptible isolates due to Haemophilus influenzae , Moraxella catarrhalis , or Streptococcus pneumoniae [see Clinical Studies (14.2) ] .
1.7 Treatment and Prophylaxis of Disseminated Mycobacterial Infections BIAXIN Filmtab and BIAXIN Granules are indicated for the treatment of mild to moderate infections caused by susceptible isolates due to Mycobacterium avium or Mycobacterium intracellulare in patients with advanced HIV infection [see Clinical Studies (14.1) ] .
1.8 Helicobacter pylori Infection and Duodenal Ulcer Disease BIAXIN Filmtab is given in combination with other drugs in adults as described below to eradicate H.
pylori .
The eradication of H.
pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.3) ] .
BIAXIN Filmtab 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 in combination with PRILOSEC (omeprazole) capsules are indicated for the treatment of patients with an active duodenal ulcer associated with H.
pylori infection.
Regimens which contain BIAXIN Filmtab as the single antibacterial 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.
1.9 Limitations of Use BIAXIN XL Filmtab is indicated only for acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia in adults.
The efficacy and safety of BIAXIN XL Filmtab in treating other infections for which BIAXIN Filmtab and BIAXIN Granules are approved have not been established.
There is resistance to macrolides in certain bacterial infections caused by Streptococcus pneumoniae and Staphylococcus aureus .
Susceptibility testing should be performed when clinically indicated.
1.10 Usage 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.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of BIAXIN Filmtab and BIAXIN Granules have been established for the treatment of the following conditions or diseases in pediatric patients 6 months and older.
Use in these indications is based on clinical trials in pediatric patients or adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients: Pharyngitis/Tonsillitis Community-Acquired Pneumonia Acute maxillary sinusitis Acute otitis media [see Clinical Studies (14.2) ] Uncomplicated skin and skin structure infections The safety and effectiveness of BIAXIN Filmtab and BIAXIN Granules have been established for the prevention of disseminated Mycobacterium avium complex (MAC) disease in pediatric patients 20 months and older with advanced HIV infection.
No studies of BIAXIN for MAC prophylaxis have been performed in pediatric populations and the doses recommended for prophylaxis are derived from MAC pediatric treatment studies.
The safety and effectiveness of BIAXIN XL Filmtab in the treatment of pediatric patients has not been established.
Safety and effectiveness of BIAXIN in pediatric patients under 6 months of age have not been established.
The safety of BIAXIN has not been studied in MAC patients under the age of 20 months.
PREGNANCY
8.1 Pregnancy Teratogenic Effects Pregnancy Category C 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 [see Warnings and Precautions (5.6) ] .
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 twice 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 twice 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 produced fetal growth retardation at plasma levels that were twice the human serum levels.
NUSRING MOTHERS
8.3 Nursing Mothers Caution should be exercised when BIAXIN is administered to nursing women.
The development and health benefits of human milk feeding should be considered along with the mother’s clinical need for BIAXIN and any potential adverse effects on the human milk fed child from the drug or from the underlying maternal condition.
Clarithromycin and its active metabolite 14-hydroxy clarithromycin are excreted in human milk.
Serum and milk samples were obtained after 3 days of treatment, at steady state, from one published study of 12 lactating women who were taking BIAXIN 250 mg orally twice daily.
Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen.
This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than 6 months of age.
A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibacterial (6 were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin.
Adverse reactions were comparable in both groups.
Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Severe acute hypersensitivity reactions: Discontinue BIAXIN if occurs (5.1) QT prolongation: Avoid BIAXIN in patients with known QT prolongation or receiving drugs known to prolong the QT interval, ventricular arrhythmia (torsade de pointes), hypokalemia/hypomagnesemia, significant bradycardia, or taking Class IA or III antiarrhythmics (5.2) Hepatotoxicity: Discontinue if signs and symptoms of hepatitis occur (5.3) Serious adverse reactions can occur due to drug interactions of BIAXIN with colchicine, some HMG CoA reductase inhibitors, some calcium channel blockers, and other drugs (5.4) Clostridium difficile associated diarrhea (CDAD): Evaluate if diarrhea occurs (5.5) Embryofetal toxicity: BIAXIN should not be used in pregnant women except in clinical circumstances where no alternative therapy is appropriate (5.6) Exacerbation of myasthenia gravis (5.7) 5.1 Acute Hypersensitivity Reactions In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), and Henoch-Schonlein purpura, discontinue BIAXIN therapy immediately and institute appropriate treatment.
5.2 QT Prolongation BIAXIN has been associated with prolongation of the QT interval and infrequent cases of arrhythmia.
Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving BIAXIN.
Fatalities have been reported.
Avoid BIAXIN in the following patients: patients with known prolongation of the QT interval, ventricular cardiac arrhythmia, including torsades de pointes patients receiving drugs known to prolong the QT interval [see also Contraindications (4.2) ] patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.
Elderly patients may be more susceptible to drug-associated effects on the QT interval [see Use in Specific Populations (8.5) ] .
5.3 Hepatotoxicity Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with clarithromycin.
This hepatic dysfunction may be severe and is usually reversible.
In some instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.
Symptoms of hepatitis can include anorexia, jaundice, dark urine, pruritus, or tender abdomen.
Discontinue BIAXIN immediately if signs and symptoms of hepatitis occur.
5.4 Serious Adverse Reactions Due to Concomitant Use with Other Drugs Serious adverse reactions have been reported in patients taking BIAXIN concomitantly with CYP3A4 substrates.
These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; ; hypotension and with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, ).
.
Use BIAXIN with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme.
The use of BIAXIN with simvastatin, lovastatin, ergotamine, or dihydroergotamine is contraindicated .
Drugs metabolized by CYP3A4: Serious adverse reactions have been reported in patients taking BIAXIN concomitantly with CYP3A4 substrates.
These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; hypoglycemia with disopyramide; hypotension and acute kidney injury with calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, amlodipine, diltiazem, nifedipine).
Most reports of acute kidney injury with calcium channel blockers metabolized by CYP3A4 involved elderly patients 65 years of age or older.
Use BIAXIN with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme.
The use of BIAXIN with simvastatin, lovastatin, ergotamine, or dihydroergotamine is contraindicated [see Contraindications (4.5, 4.6) and Drug Interactions (7) ] .
Life-threatening and fatal drug interactions have been reported in patients treated with BIAXIN and colchicine.
Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses.
If co-administration of BIAXIN and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine.
Monitor patients for clinical symptoms of colchicine toxicity.
Concomitant administration of BIAXIN and colchicine is contraindicated in patients with renal or hepatic impairment .
Colchicine: Life-threatening and fatal drug interactions have been reported in patients treated with BIAXIN and colchicine.
Clarithromycin is a strong CYP3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses.
If co-administration of BIAXIN and colchicine is necessary in patients with normal renal and hepatic function, reduce the dose of colchicine.
Monitor patients for clinical symptoms of colchicine toxicity.
Concomitant administration of BIAXIN and colchicine is contraindicated in patients with renal or hepatic impairment [see Contraindications (4.4) and Drug Interactions (7) ] .
Concomitant use of BIAXIN with lovastatin or simvastatin is contraindicated as these statins are extensively metabolized by CYP3A4, and concomitant treatment with BIAXIN increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis.
Cases of rhabdomyolysis have been reported in patients taking BIAXIN concomitantly with these statins.
If treatment with BIAXIN cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
HMG-CoA Reductase Inhibitors (statins): Concomitant use of BIAXIN with lovastatin or simvastatin is contraindicated [see Contraindications (4.5) ] as these statins are extensively metabolized by CYP3A4, and concomitant treatment with BIAXIN increases their plasma concentration, which increases the risk of myopathy, including rhabdomyolysis.
Cases of rhabdomyolysis have been reported in patients taking BIAXIN concomitantly with these statins.
If treatment with BIAXIN cannot be avoided, therapy with lovastatin or simvastatin must be suspended during the course of treatment.
Exercise caution when prescribing BIAXIN with atorvastatin or pravastatin.
In situations where the concomitant use of BIAXIN with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily.
Use of a statin that is not dependent on CYP3A metabolism (e.g.
fluvastatin) can be considered.
It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided.Exercise caution when prescribing BIAXIN with atorvastatin or pravastatin.
In situations where the concomitant use of BIAXIN with atorvastatin or pravastatin cannot be avoided, atorvastatin dose should not exceed 20 mg daily and pravastatin dose should not exceed 40 mg daily.
Use of a statin that is not dependent on CYP3A metabolism (e.g.
fluvastatin) can be considered.
It is recommended to prescribe the lowest registered dose if concomitant use cannot be avoided.
The concomitant use of BIAXIN and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia.
With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly.
Careful monitoring of glucose is recommended .
Oral Hypoglycemic Agents/Insulin: The concomitant use of BIAXIN and oral hypoglycemic agents and/or insulin can result in significant hypoglycemia.
With certain hypoglycemic drugs such as nateglinide, pioglitazone, repaglinide and rosiglitazone, inhibition of CYP3A enzyme by clarithromycin may be involved and could cause hypoglycemia when used concomitantly.
Careful monitoring of glucose is recommended [see Drug Interactions (7) ] .
Quetiapine: Use quetiapine and clarithromycin concomitantly with caution.
Co-administration could result in increased quetiapine exposure and quetiapine related toxicities such as somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation.
Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin [see Drug Interactions (7) ] .
There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when BIAXIN is co-administered with warfarin.
Monitor INR and prothrombin times frequently while patients are receiving BIAXIN and oral anticoagulants concurrently .
Oral Anticoagulants: There is a risk of serious hemorrhage and significant elevations in INR and prothrombin time when BIAXIN is co-administered with warfarin.
Monitor INR and prothrombin times frequently while patients are receiving BIAXIN and oral anticoagulants concurrently [see Drug Interactions (7) ] .
Increased sedation and prolongation of sedation have been reported with concomitant administration of BIAXIN and triazolobenzodiazepines, such as triazolam and midazolam .
Benzodiazepines: Increased sedation and prolongation of sedation have been reported with concomitant administration of BIAXIN and triazolobenzodiazepines, such as triazolam and midazolam [see Drug Interactions (7) ] .
5.5 Clostridium difficile Associated Diarrhea 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 antibacterial 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 antibacterial use not directed against C.
difficile may need to be discontinued.
Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C.
difficile , and surgical evaluation should be instituted as clinically indicated.
5.6 Embryofetal Toxicity Clarithromycin should not be used in pregnant women except in clinical circumstances where no alternative therapy is appropriate.
If BIAXIN is used during pregnancy, or if pregnancy occurs while the patient is taking this drug, the patient should be apprised of the potential hazard to the fetus.
Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryo-fetal development in monkeys, rats, mice, and rabbits at doses that produced plasma levels 2 times to 17 times the serum levels achieved in humans treated at the maximum recommended human doses [see Use in Specific Populations (8.1) ] .
5.7 Exacerbation of Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving BIAXIN therapy.
5.8 Development of Drug Resistant Bacteria 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Provide the following instructions or information about BIAXIN to patients: Counsel patients that antibacterial drugs including BIAXIN (clarithromycin) 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.
Advise patients that diarrhea is a common problem caused by antibacterials including BIAXIN (clarithromycin) which usually ends when the antibacterial is discontinued.
Sometimes after starting treatment with antibacterials, 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 antibacterial.
If this occurs, instruct patients to contact their healthcare provider as soon as possible.
Advise patients that BIAXIN (clarithromycin) may interact with some drugs; therefore, advise patients to report to their healthcare provider the use of any other medications.
Advise patients that BIAXIN (clarithromycin) Filmtab and oral suspension can be taken with or without food and can be taken with milk; however, BIAXIN XL Filmtab (clarithromycin extended-release tablets) should be taken with food.
Do not refrigerate the suspension.
There are no data on the effect of BIAXIN (clarithromycin) on the ability to drive or use machines.
However, counsel patients regarding the potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication.
The potential for these adverse reactions should be taken into account before patients drive or use machines.
Advise patients that if pregnancy occurs while taking this drug, there is a potential hazard to the fetus [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1) ] .
DOSAGE AND ADMINISTRATION
2 Adults: BIAXIN 250 mg or 500 mg every 12 hours for 7–14 days; BIAXIN XL 1 gram every 24 hours for 7–14 days (2.2) H.
pylori eradication (in combination with lansoprazole/amoxicillin, omeprazole/amoxicillin, or omeprazole): BIAXIN 500 mg every 8 or 12 hours for 10–14 days.
See full prescribing information (FPI) for additional information.
(2.3) Pediatric Patients: BIAXIN 15 mg/kg/day divided every 12 hours for 10 days (2.4) Mycobacterial Infections: BIAXIN 500 mg every 12 hours; BIAXIN 7.5 mg/kg up to 500 mg every 12 hours in pediatric patients (2.5) Reduce dose in moderate renal impairment with concomitant atazanavir or ritonavir-containing regimens and in severe renal impairment (2.6) 2.1 Important Administration Instructions BIAXIN Filmtab and BIAXIN Granules may be given with or without food.
BIAXIN XL Filmtab should be taken with food.
Swallow BIAXIN XL Filmtab whole; do not chew, break or crush BIAXIN XL Filmtab.
2.2 Adult Dosage The recommended dosages of BIAXIN Filmtab and BIAXIN XL Filmtab for the treatment of mild to moderate infections in adults are listed in Table 1.
Table 1.
Adult Dosage Guidelines BIAXIN Filmtab BIAXIN XL Filmtab Infection Dosage (every 12 hours) Duration (days) Dosage (every 24 hours) Duration (days) Acute bacterial exacerbation of chronic bronchitis 250 to 500 mg a 7 b -14 1 gram 7 Acute maxillary sinusitis 500 mg 14 1 gram 14 Community-acquired pneumonia 250 mg c 7 d -14 1 gram c 7 Pharyngitis/Tonsillitis 250 mg 10 – – Uncomplicated skin and skin structure infections 250 mg 7-14 – – Treatment and prophylaxis of disseminated Mycobacterium avium disease [see Dosage and Administration (2.5) ] 500 mg e – – – H.pylori eradication to reduce the risk of duodenal ulcer recurrence with amoxicillin and omeprazole or lansoprazole [see Dosage and Administration (2.3) ] 500 mg 10-14 – – H.pylori eradication to reduce the risk of duodenal ulcer recurrence with omeprazole [see Dosage and Administration (2.3) ] 500 mg every 8 hours 14 – – a For M.
catarrhalis and S.
pneumoniae use 250 mg.
For H.
influenzae and H.
parainfluenzae , use 500 mg.
b For H parainfluenzae , the duration of therapy is 7 days.
c For H.
parainfluenzae and M.
catarrhalis use BIAXIN XL tablets only.
d For H.
influenzae , the duration of therapy is 7 days.
e BIAXIN therapy should continue if clinical response is observed.
BIAXIN can be discontinued when the patient is considered at low risk of disseminated infection.
2.3 Combination Dosing Regimens for H.
pylori Infection Triple therapy: BIAXIN Filmtab/lansoprazole/amoxicillin The recommended adult dosage is 500 mg BIAXIN Filmtab, 30 mg lansoprazole, and 1 gram amoxicillin, all given every 12 hours for 10 or 14 days [see Indications and Usage (1.8) and Clinical Studies (14.3) ] .
Triple therapy: BIAXIN Filmtab/omeprazole/amoxicillin The recommended adult dosage is 500 mg BIAXIN Filmtab, 20 mg omeprazole, and 1 gram amoxicillin; all given every 12 hours for 10 days.
In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief [see Indications and Usage (1.8) and Clinical Studies (14.3) ] .
Dual therapy: BIAXIN Filmtab/omeprazole The recommended adult dosage is 500 mg BIAXIN Filmtab given every 8 hours and 40 mg omeprazole given once every morning for 14 days.
An additional 14 days of omeprazole 20 mg once daily is recommended for ulcer healing and symptom relief [see Indications and Usage (1.8) and Clinical Studies (14.3) ] .
2.4 Pediatric Dosage The recommended daily dosage is 15 mg/kg/day divided every 12 hours for 10 days (up to the adult dose).
Refer to dosage regimens for mycobacterial infections in pediatric patients for additional dosage information [see Dosage and Administration (2.5) ] .
2.5 Dosage Regimens for Mycobacterial Infections For the treatment of disseminated infection due to Mycobacterium avium complex (MAC), BIAXIN Filmtab and BIAXIN Granules are recommended as the primary agents.
BIAXIN Filmtab and BIAXIN Granules should be used in combination with other antimycobacterial drugs (e.g.
ethambutol) that have shown in vitro activity against MAC or clinical benefit in MAC treatment [see Clinical Studies (14.1) ] .
Adult Patients For treatment and prophylaxis of mycobacterial infections in adults, the recommended dose of BIAXIN is 500 mg every 12 hours.
Pediatric Patients For treatment and prophylaxis of mycobacterial infections in pediatric patients, the recommended dose is 7.5 mg/kg every 12 hours up to 500 mg every 12 hours.
[See Use in Specific Populations (8.4) and Clinical Studies (14.1) ] .
BIAXIN therapy should continue if clinical response is observed.
BIAXIN can be discontinued when the patient is considered at low risk of disseminated infection.
2.6 Dosage Adjustment in Patients with Renal Impairment See Table 2 for dosage adjustment in patients with moderate or severe renal impairment with or without concomitant atazanavir or ritonavir-containing regimens [see Drug Interactions (7) ] .
Table 2.
BIAXIN Dosage Adjustments in Patients with Renal Impairment Recommended BIAXIN Dosage Reduction Patients with severe renal impairment (CL cr of <30 mL/min) Reduce the dosage of BIAXIN by 50% Patients with moderate renal impairment (CL cr of 30 to 60 mL/min) taking concomitant atazanavir or ritonavir-containing regimens Reduce the dosage of BIAXIN by 50% Patients with severe renal impairment (CL cr of <30 mL/min) taking concomitant atazanavir or ritonavir-containing regimens Reduce the dosage of BIAXIN by 75% 2.7 Dosage Adjustment Due to Drug Interactions Decrease the dose of BIAXIN by 50 % when co-administered with atazanavir [see Drug Interactions (7) ] .
Dosage adjustments for other drugs when co-administered with BIAXIN may be recommended due to drug interactions [see Drug Interactions (7) ] .
2.8 Reconstitution of BIAXIN Granules The supplied BIAXIN Granules must be reconstituted with water prior to administration of BIAXIN for oral suspension.
Table 3 below indicates the volume of water to be added when reconstituting.
To reconstitute: Add half the volume of water to the bottle containing the BIAXIN granules and shake vigorously.
Add the remainder of water to the bottle and shake.
Shake well before each use.
After mixing, store at 15° to 30°C (59° to 86°F) and use within 14 days.
Do not refrigerate.
Table 3.
Volume of Water to be Added When Reconstituting BIAXIN Granules Total Volume After Reconstitution Clarithromycin Concentration After Reconstitution Amount of Water to be Added 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