Biaxin and Biaxin XL: Indications, Dosage, Precautions, Adverse Effects
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Biaxin and Biaxin XL - Product Information

Manufacture: AbbVie
Country: United States
Condition: Bacterial Endocarditis Prevention (Bacterial Endocarditis Prophylaxis), Bronchitis, Dental Abscess, Helicobacter Pylori Infection, Legionella Pneumonia, Mycoplasma Pneumonia, Mycobacterium avium-intracellulare, Treatment, Mycobacterium avium-intracellulare, Prophylaxis, Nongonococcal Urethritis, Otitis Media, Pertussis, Pertussis Prophylaxis, Pharyngitis, Pneumonia, Sinusitis, Skin and Structure Infection, Skin or Soft Tissue Infection, Strep Throat (Streptococcal Pharyngitis), Toxoplasmosis, Tonsillitis/Pharyngitis, Upper Respiratory Tract Infection
Class: Macrolides
Form: Tablets
Ingredients: Сlarithromycin, croscarmellose sodium, d&c yellow no. 10, fd&c blue no. 1, magnesium stearate, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide, vanillin, hypromelloses, povidones, hydroxypropyl cellulose (type h), carbomer homopolymer type b (allyl pentaerythritol crosslinked).

Indications and Usage

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].

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].

Community-Acquired Pneumonia

BIAXIN (Filmtab, Granules) and BIAXIN XL Filmtab are indicated [see Indications and Usage] 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])

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.

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.

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].

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].

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].

  • 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 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 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.

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.

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.

Dosage and Administration

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.

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 FilmtabBIAXIN XL Filmtab
InfectionDosage
(every 12
hours)
Duration
(days)
Dosage
(every 24
hours)
Duration
(days)
Acute bacterial exacerbation of chronic bronchitis250 to 500mga7b-141 gram7
Acute maxillary sinusitis500 mg141 gram14
Community-acquired pneumonia250 mgc7d-141 gramc7
Pharyngitis/Tonsillitis250 mg10--
Uncomplicated skin and skin structure infections250 mg7-14--
Treatment and prophylaxis of disseminated Mycobacterium avium disease [see Dosage and Administration]500 mge---
H.pylori eradication to reduce the risk of duodenal ulcer recurrence with amoxicillin and omeprazole or lansoprazole [see Dosage and Administration]500 mg10-14--
H.pylori eradication to reduce the risk of duodenal ulcer recurrence with omeprazole [see Dosage and Administration]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.

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 and Clinical Studies].

  • 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 and Clinical Studies].

  • 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 and Clinical Studies].

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].

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].

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 and Clinical Studies].

BIAXIN therapy should continue if clinical response is observed. BIAXIN can be discontinued when the patient is considered at low risk of disseminated infection.

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].

Table 2. BIAXIN Dosage Adjustments in Patients with Renal Impairment
 Recommended BIAXIN
Dosage Reduction
Patients with severe renal impairment (CLcr of <30 mL/min)Reduce the dosage of BIAXIN by 50%
Patients with moderate renal impairment (CLcr of 30 to 60 mL/min) taking concomitant atazanavir or ritonavir-containing regimensReduce the dosage of BIAXIN by 50%
Patients with severe renal impairment (CLcr of <30 mL/min) taking concomitant atazanavir or ritonavir-containing regimensReduce the dosage of BIAXIN by 75%

Dosage Adjustment Due to Drug Interactions

Decrease the dose of BIAXIN by 50 % when co-administered with atazanavir [see Drug Interactions]. Dosage adjustments for other drugs when co-administered with BIAXIN may be recommended due to drug interactions [see Drug Interactions].

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:

  1. Add half the volume of water to the bottle containing the BIAXIN granules and shake vigorously.
  2. Add the remainder of water to the bottle and

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 mL125 mg/5 mL27 mL
100 mL125 mg/5 mL55 mL
50 mL250 mg/5 mL27 mL
100 mL250 mg/5 mL55 mL

Dosage Forms and Strengths

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

Contraindications

Hypersensitivity

BIAXIN is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibacterial drugs [see Warnings and Precautions].

Cardiac Arrhythmias

Concomitant administration of BIAXIN with cisapride and pimozide is contraindicated [see Drug Interactions].

There have been postmarketing reports of drug interactions when clarithromycin is co- administered with cisapride or pimozide, 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 BIAXIN. Fatalities have been reported.

Cholestatic Jaundice/Hepatic Dysfunction

BIAXIN is contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior use of clarithromycin.

Colchicine

Concomitant administration of BIAXIN and colchicine is contraindicated in patients with renal or hepatic impairment.

HMG-CoA Reductase Inhibitors

Do not use BIAXIN concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolized by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis [see Warnings and Precautions and Drug Interactions].

Ergot Alkaloids

Concomitant administration of clarithromycin and ergotamine or dihydroergotamine is contraindicated [see Drug Interactions].

Contraindications for Co-administered Drugs

For information about contraindications of other drugs indicated in combination with BIAXIN, refer to their full prescribing information (contraindications section).

Warnings and Precautions

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.

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]
  • 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].

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.

Serious Adverse Reactions Due to Concomitant Use with Other Drugs

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 and Drug Interactions].

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 and Drug Interactions].

HMG-CoA Reductase Inhibitors (Statins)

Concomitant use of BIAXIN with lovastatin or simvastatin is contraindicated [see Contraindications] 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.

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].

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].

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].

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].

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.

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].

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.

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.

Adverse Reactions

The following serious adverse reactions are described below and elsewhere in the labeling:

  • Acute Hypersensitivity Reactions [see Warnings and Precautions]
  • QT Prolongation [see Warnings and Precautions]
  • Hepatotoxicity [see Warnings and Precautions]
  • Serious Adverse Reactions Due to Concomitant Use with Other Drugs [see Warnings and Precautions]
  • Clostridium difficile Associated Diarrhea [see Warnings and Precautions]
  • Exacerbation of Myasthenia Gravis [see Warnings and Precautions]

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Based on pooled data across all indications, the most frequent adverse reactions for both adult and pediatric populations observed in clinical trials are abdominal pain, diarrhea, nausea, vomiting and dysgeusia. Also reported were dyspepsia, liver function test abnormal, anaphylactic reaction, candidiasis, headache, insomnia, and rash.

The subsequent subsections list the most common adverse reactions for prophylaxis and treatment of mycobacterial infections and duodenal ulcer associated with H. pylori infection. In general, these profiles are consistent with the pooled data described above.

Prophylaxis of Mycobacterial Infections

In AIDS patients treated with BIAXIN over long periods of time for prophylaxis against M. avium, it was often difficult to distinguish adverse reactions possibly associated with BIAXIN administration from underlying HIV disease or intercurrent illness. Median duration of treatment was 10.6 months for the BIAXIN group and 8.2 months for the placebo group.

Table 4. Incidence Rates (%) of Selected Adverse Reactionsa in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex
Body SystembBIAXIN
(n=339)
%
Placebo
(n=339)
%
Adverse Reaction
Body as a Whole  
 Abdominal pain5%4%
 Headache3%1%
Digestive  
 Diarrhea8%4%
 Dyspepsia4%3%
 Flatulence2%1%
 Nausea11%7%
 Vomiting6%3%
Skin & Appendages  
 Rash3%4%
Special Senses  
 Taste Perversion8%c0.3%

a Includes those events possibly or probably related to study drug and excludes concurrent conditions

b 2% or greater Adverse Reaction Incidence Rates for either treatment group

c Significant higher incidence compared to the placebo-treated group

Discontinuation due to adverse reactions occurred in 18% of patients receiving BIAXIN compared to 17% of patients receiving placebo in this trial. Primary reasons for discontinuation in BIAXIN treated patients include headache, nausea, vomiting, depression, and taste perversion.

Changes in Laboratory Values

Selected laboratory adverse experiences that were reported during therapy in greater than 2 % of adult patients treated with BIAXIN in a randomized double-blind clinical trial involving 682 patients are presented in Table 5.

In immunocompromised patients receiving prophylaxis against M. avium, evaluations of laboratory values were made by analyzing those values outside the seriously abnormal value (i.e., the extreme high or low limit) for the specified test.

Table 5. Percentage of Patientsa Exceeding Extreme Laboratory Values in Patients Receiving Prophylaxis Against M. avium Complex
 BIAXIN 500 mg twice a dayPlacebo
WBC Count<1 x 109/L2/103 (4%)0/95
SGOT>5 x ULNb7/196 (4%)5/208 (2%)
SGPT>5 x ULNb6/217 (3%)4/232 (2%)

a Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within normal range or borderline low (chemistry variables)

b ULN= Upper Limit of Normal

Treatment of Mycobacterial Infections

The adverse reaction profiles for both the 500 mg and 1000 mg twice a day dose regimens were similar.

In AIDS patients and other immunocompromised patients treated with the higher doses of BIAXIN over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse reactions possibly associated with BIAXIN administration from underlying signs of HIV disease or intercurrent illness.

The following analysis summarizes experience during the first 12 weeks of therapy with BIAXIN. Data are reported separately for trial 1 (randomized, double-blind) and trial 2 (open- labeled, compassionate use) and also combined. Adverse reactions were reported less frequently in trial 2, which may be due in part to differences in monitoring between the two studies.

In adult patients receiving BIAXIN 500 mg twice a day, the most frequently reported adverse reactions, considered possibly or possibly related to study drug, with an incidence of 5% or greater, are listed below (Table 6). Approximately 8% of the patients who received 500 mg twice a day and 12% of the patients who received 1000 mg twice a day discontinued therapy due to drug related adverse reactions during the first 12 weeks of therapy; adverse reactions leading to discontinuation in at least 2 patients included nausea, vomiting, abdominal pain, diarrhea, rash, and asthenia.

Table 6. Selected Treatment-Relateda Adverse Reaction Incidence Rates (%) in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg
Twice a Day BIAXIN Dose
Adverse ReactionTrial 1
(n=53)
Trial 2
(n=255)
Combined
(n=308)
Abdominal Pain823
Diarrhea923
Flatulence801
Headache802
Nausea28912
Rash923
Taste Perversion1904
Vomiting2548

a Includes those events possibly or probably related to study drug and excludes concurrent conditions

A limited number of pediatric AIDS patients have been treated with BIAXIN suspension for mycobacterial infections. The most frequently reported adverse reactions excluding those due to the patient’s concurrent conditions were consistent with those observed in adult patients.

Changes in Laboratory Values

In the first 12 weeks of starting on BIAXIN 500 mg twice a day, 3% of patients has SGOT increases and 2% of patients has SGPT increases > 5 times the upper limit of normal in trial 2 (469 enrolled adult patients) while trial 1 (154 enrolled patients) had no elevation of transaminases. This includes only patients with baseline values within the normal range or borderline low.

Duodenal Ulcer Associated With H. Pylori Infection

In clinical trials using combination therapy with BIAXIN plus omeprazole and amoxicillin, no adverse reactions specific to the combination of these drugs have been observed. Adverse reactions that have occurred have been limited to those that have been previously reported with BIAXIN, omeprazole or amoxicillin.

The adverse reaction profiles are shown below (Table 7) for four randomized double-blind clinical trials in which patients received the combination of BIAXIN 500 mg three times a day, and omeprazole 40 mg daily for 14 days, followed by omeprazole 20 mg once a day, (three studies) or 40 mg once a day (one study) for an additional 14 days. Of the 346 patients who received the combination, 3.5% of patients discontinued drug due to adverse reactions.

Table 7. Adverse Reactions with an Incidence of 3% or Greater
Adverse ReactionBIAXIN + Omeprazole
(n=346)
% of Patients
Omeprazole
(n=355)
% of Patients
BIAXIN
(n=166)
% of Patientsa
Taste Perversion15116
Nausea513
Headache569
Diarrhea437
Vomiting4<11
Abdominal Pain321
Infection342

a Only two of four studies

Changes in Laboratory Values

Changes in laboratory values with possible clinical significance in patients taking BIAXIN and omeprazole in four randomized double-blind trials in 945 patients are as follows:

Hepatic: elevated direct bilirubin <1%; GGT <1%; SGOT (AST) <1%; SGPT (ALT) <1%,

Renal: elevated serum creatinine <1%.

Less Frequent Adverse Reactions Observed During Clinical Trials of Clarithromycin

Based on pooled data across all indications, the following adverse reactions were observed in clinical trials with clarithromycin at a rate less than 1%:

Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocythemia, eosinophilia

Cardiac Disorders: Electrocardiogram QT prolonged, cardiac arrest, atrial fibrillation, extrasystoles, palpitations

Ear and Labyrinth Disorders: Vertigo, tinnitus, hearing impaired

Gastrointestinal Disorders: Stomatitis, glossitis, esophagitis, gastrooesophageal reflux disease, gastritis, proctalgia, abdominal distension, constipation, dry mouth, eructation, flatulence

General Disorders and Administration Site Conditions: Malaise, pyrexia, asthenia, chest pain, chills, fatigue

Hepatobiliary Disorders: Cholestasis, hepatitis

Immune System Disorders: Hypersensitivity

Infections and Infestations: Cellulitis, gastroenteritis, infection, vaginal infection

Investigations: Blood bilirubin increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, albumin globulin ratio abnormal

Metabolism and Nutrition Disorders: Anorexia, decreased appetite

Musculoskeletal and Connective Tissue Disorders: Myalgia, muscle spasms, nuchal rigidity

Nervous System Disorders: Dizziness, tremor, loss of consciousness, dyskinesia, somnolence

Psychiatric Disorders: Anxiety, nervousness

Renal and Urinary Disorders: Blood creatinine increased, blood urea increased

Respiratory, Thoracic and Mediastinal Disorders: Asthma, epistaxis, pulmonary embolism

Skin and Subcutaneous Tissue Disorders: Urticaria, dermatitis bullous, pruritus, hyperhidrosis, rash maculo-papular

Gastrointestinal Adverse Reactions

In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse reactions were reported by a similar proportion of patients taking either BIAXIN Filmtab or BIAXIN XL Filmtab; however, patients taking BIAXIN XL Filmtab reported significantly less severe gastrointestinal symptoms compared to patients taking BIAXIN Filmtab. In addition, patients taking BIAXIN XL Filmtab had significantly fewer premature discontinuations for drug-related gastrointestinal or abnormal taste adverse reactions compared to BIAXIN Filmtab.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of BIAXIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System: Thrombocytopenia, agranulocytosis

Cardiac: Ventricular arrhythmia, ventricular tachycardia, torsades de pointes

Ear and Labyrinth: Deafness was reported chiefly in elderly women and was usually reversible.

Gastrointestinal: Pancreatitis acute, tongue discoloration, tooth discoloration was reported and was usually reversible with professional cleaning upon discontinuation of the drug.

There have been reports of BIAXIN XL Filmtab 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. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different clarithromycin formulation (e.g. suspension) or another antibacterial drug.

Hepatobiliary: Hepatic failure, jaundice hepatocellular. Adverse reactions related to hepatic dysfunction have been reported with clarithromycin [see Warnings and Precautions].

Infections and Infestations: Pseudomembranous colitis [see Warnings and Precautions]

Immune System: Anaphylactic reactions, angioedema

Investigations: Prothrombin time prolonged, white blood cell count decreased, international normalized ratio increased. Abnormal urine color has been reported, associated with hepatic failure.

Metabolism and Nutrition: Hypoglycemia has been reported in patients taking oral hypoglycemic agents or insulin.

Musculoskeletal and Connective Tissue: Myopathy rhabdomyolysis was reported and in some of the reports, clarithromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol [see Contraindications and Warnings and Precautions].

Nervous System: Parosmia, anosmia, ageusia, paresthesia and convulsions

Psychiatric: Abnormal behavior, confusional state, depersonalization, disorientation, hallucination, depression, manic behavior, abnormal dream, psychotic disorder. These disorders usually resolve upon discontinuation of the drug.

Renal and Urinary: Nephritis interstitial, renal failure

Skin and Subcutaneous Tissue: Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms (DRESS), Henoch-Schonlein purpura, acne

Vascular: Hemorrhage

Drug Interactions

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
RecommendationComments
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].

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.

DigoxinUse With CautionDigoxin: 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:  
WarfarinUse With CautionOral 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].
Antiepileptics:  
CarbamazepineUse With CautionCarbamazepine: 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:  
ItraconazoleUse With CautionItraconazole: 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.
FluconazoleNo Dose AdjustmentFluconazole: [see Pharmacokinetics]
Anti-Gout Agents:  
Colchicine (in patients with renal or hepatic impairment)ContraindicatedColchicine: 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 and Warnings and Precautions].
Colchicine (in patients with normal renal and hepatic function)Use With Caution
Antipsychotics:  
PimozideContraindicatedPimozide: [See Contraindications]
QuetiapineQuetiapine: 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 CautionTolterodine: 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:  
AtazanavirUse With CautionAtazanavir: 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].
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].
Ritonavir Etravirine Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics].
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) DidanosineNo Dose AdjustmentBoceprevir: 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].

The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.

Calcium Channel Blockers:  
VerapamilUse With CautionVerapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions].
Amlodipine Diltiazem Amlodipine, Diltiazem: [See Warnings and Precautions]
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].
Ergot Alkaloids:  
ErgotamineDihydroergotamineContraindicatedErgotamine, 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].
Gastroprokinetic Agents:  
CisaprideContraindicatedCisapride: [See Contraindications]
HMG-CoA Reductase Inhibitors:  
LovastatinSimvastatinContraindicatedLovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications and Warnings and Precautions]
AtorvastatinPravastatinUse With Caution 
FluvastatinNo Dose Adjustment 
Hypoglycemic Agents:  
Nateglinide Pioglitazone Repaglinide RosiglitazoneUse With CautionNateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions and Adverse Reactions]
Insulin Insulin: [See Warnings and Precautions and Adverse Reactions]
Immunosuppressants:  
CyclosporineUse With CautionCyclosporine: 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 TadalafilVardenafilUse With CautionSildenafil, 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:  
OmeprazoleNo Dose AdjustmentOmeprazole: 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] (see also Omeprazole under “Drugs That Affect BIAXIN” in the table below).
Xanthine Derivatives:  
TheophyllineUse With CautionTheophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics]. 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:  
MidazolamUse With CautionMidazolam: 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 and Pharmacokinetics].
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 LorazepamNo Dose AdjustmentTemazepam, 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:  
RifabutinUse With CautionRifabutin: 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 WortUse With CautionThere 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 ValproateUse With CautionThere 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 BIAXINRecommendationComments
Antifungals:  
ItraconazoleUse With CautionItraconazole: 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:  
AtazanavirUse With CautionAtazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology].

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].

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].
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:  
OmeprazoleUse With CautionOmeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics].
Miscellaneous Cytochrome P450 Inducers:  
Efavirenz Nevirapine Rifampicin RifabutinRifapentineUse With CautionInducers 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).

Use in Specific Populations

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].

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/m2) 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/m2, 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.

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.

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]
  • 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.

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].

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].

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 and Warnings and Precautions].

Renal and Hepatic Impairment

BIAXIN is principally excreted via the liver and kidney. BIAXIN 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 [see Dosage and Administration].

Overdosage

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.

How Supplied/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 ConstitutionClarithromycin Concentration After ConstitutionClarithromycin Contents Per BottleNDC
50 mL125 mg/5 mL1250 mg0074-3163-50
100 mL125 mg/5 mL2500 mg0074-3163-13
50 mL250 mg/5 mL2500 mg0074-3188-50
100 mL250 mg/5 mL5000 mg0074-3188-13

Store BIAXIN Granules below 25°C (77°F) in a well-closed container. Do not refrigerate the reconstituted BIAXIN granules.

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
  • Advise patients that diarrhea is a common problem caused by antibacterials including BIAXIN (clarithromycin) which usually ends when the antibacterial is 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
  • 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
  • Advise patients that if pregnancy occurs while taking this drug, there is a potential hazard to the fetus [see Warnings and Precautions and Use in Specific Populations].

Filmtab—Film-sealed tablets is a registered trademark of AbbVie Inc.

BIAXIN Filmtab 250 mg and 500 mg and BIAXIN XL Filmtab 500 mg

Mfd. by AbbVie LTD, Barceloneta, PR 00617

BIAXIN Granules, 125 mg/5 mL and 250 mg/5 mL

Mfd. by AbbVie Inc., North Chicago, IL 60064

For AbbVie Inc., North Chicago, IL 60064, U.S.A.

03-B248 May, 2016