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Prinsocin

Prinsocin Product

Prinsocin Description

Prinsocin Description

Details About Product!
 
 
 

      DRUG DESCRIPTION

Clarithromycin is a semi-synthetic macrolide antibiotic. Chemically, it is 6- 0-methylerythromycin. The molecular formula is C38H69NO13, and the molecular weight is 747.96. The structural formula is:

 

 

Clarithromycin is a white to off-white crystalline powder. It is soluble in acetone, slightly soluble in methanol, ethanol, and acetonitrile, and practically insoluble in water.

Prinsocin is available as immediate-release tablets and granules for oral suspension.

Each yellow oval film-coated immediate-release Prinsocin 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.

After constitution, each 5 mL of Prinsocin suspension (clarithromycin for oral suspension, USP) contains 125 mg or 250 mg of clarithromycin. Each bottle of Prinsocin granules contains 1250 mg (50 mL size), 2500 mg (50 size) 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.

 

 

 

 

Prinsocin 500mg tab (clarithromycin tablets, USP) and Prinsocin Granules (clarithromycin for oral suspension, USP) are indicated for the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions as listed below:

Adults (Prinsocin Tablets and Granules for Oral Suspension)

Pharyngitis/Tonsillitis due to Streptococcus pyogenes (The usual drug of choice in the treatment and prevention of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the intramuscular or the oral route. Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of clarithromycin in the subsequent prevention of rheumatic feverare not available at present).

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Acute bacterial exacerbation of chronic bronchitis due to Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.

Community-Acquired Pneumonia due to Haemophilus influenzae, Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR).

Uncomplicated skin and skin structure infections due to Staphylococcus aureus , or Streptococcus pyogenes (Abscesses usually require surgical drainage).

Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare Prinsocin (clarithromycin) Filmtab tablets in combination with amoxicillin and PREVACID (lansoprazole) or PRILOSEC (omeprazole) Delayed-Release Capsules, as triple therapy, are indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or five-year history of duodenal ulcer) to eradicate H. pylori. Prinsocin Filmtab tablets in combination with PRILOSEC (omeprazole) capsules or TRITEC (ranitidine bismuth citrate) tablets are also indicated for the treatment of patients with an active duodenal ulcer associated with H. pylori infection. However, regimens which contain clarithromycin as the single antimicrobial agent are more likely to be associated with the development of clarithromycin resistance among patients who fail therapy. Clarithromycin-containing regimens should not be used in patients with known or suspected clarithromycin resistant isolates because the efficacy of treatment is reduced in this setting.

In patients who fail therapy, susceptibility testing should be done if possible. If resistance to clarithromycin is demonstrated, a non-clarithromycin-containing therapy is recommended. (For information on development of resistance see Microbiology section.) The eradication of H. pylori has been demonstrated to reduce the risk of duodenal ulcer recurrence.

Children (Prinsocin Tablets and Granules for Oral Suspension)

Pharyngitis/Tonsillitis due to Streptococcus pyogenes.

Community-Acquired Pneumonia due to Mycoplasma pneumoniae, Streptococcus pneumoniae, or Chlamydia pneumoniae (TWAR)

Acute maxillary sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

Acute otitis media due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae

NOTE:For information on otitis media, see Clinical Studies - Otitis Media.

Uncomplicated skin and skin structure infections due to Staphylococcus aureus, or Streptococcus pyogenes (Abscesses usually require surgical drainage.)

Disseminated mycobacterial infections due to Mycobacterium avium, or Mycobacterium intracellulare

Prophylaxis

Prinsocin Filmtab tablets and Prinsocin Granules for oral suspension are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Prinsocin and other antibacterial drugs, Prinsocin 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.

 

Prinsocin Filmtab (clarithromycin tablets, USP) and Prinsocin Granules (clarithromycin for oral suspension, USP) may be given with or without food.

 

 

 

 

Infection

 

Prinsocin Tablets

Dosage (q12h)

Duration (days)

Pharyngitis/Tonsillitis due to

 

S. pyogenes

 

250 mg

 

 

10

 

Acute maxillary sinusitis due to

 

H. influenza

 

M. catarrhalis

 

S. pneumonia

 

 

500 mg

 

500 mg

 

500 mg

 

 

 

 

14

 

14

 

14

 

Acute exacerbation of chronic bronchitis due to

 

H. influenzae

 

H. parainfluenzae

 

M. catarrhalis

 

S. pneumoniae

 

 

 

 

500 mg

 

500 mg

 

250 mg

 

250 mg

 

 

 

7 - 14

 

7

 

7 – 14

 

7 - 14

Community-Acquired Pneumonia due to

 

H. influenzae

 

H. parainfluenzae

 

M. catarrhalis

 

S. pneumoniae

 

C. pneumoniae

 

M. pneumonia

 

 

 

250 mg

 

-

 

-

 

250mg

 

250 mg

 

250 mg

 

 

 

7

 

-

 

-

 

7 - 14

 

7 - 14

 

7 - 14

 

Uncomplicated skin and skin structure

S. aureus

S. pyogenes

 

250 mg

250 mg

 

 

7 - 14

7 - 14

 

 

 
         
         
         
         
 
         
         
         
         
         
         
 

 

PEDIATRIC DOSAGE GUIDELINES

Based on Body Weight Dosing Calculated on 7.5 mg/kg q12h

 

         

 

         

 

         

 

         

 

         

 

         

 

 

Weight Kg

 

 

lbs

 

Dose (q12h)

 

125 mg/5 mL

 

250 mg/5 mL

9

20

62.5 mg

2.5 mL q12h

1.25 mL q12h

17

37

125 mg

5 mL q12h

2.5 mL q12h

25

55

187.5 mg

7.5 mL q12h

3.75 mL q12h

33

73

250 mg

10 mL q12h

5 mL q12h

             
 

Clarithromycin may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function. However, in the presence of severe renal impairment (CRCL < 30 mL/min), with or without coexisting hepatic impairment, the dose should be halved or the dosing interval doubled.

Mycobacterial Infections

 

The recommended dose of Prinsocin for the prevention of disseminated Mycobacterium avium disease is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. No studies of clarithromycin for MAC prophylaxis have been performed in pediatric populations and the doses recommended for prophylaxis are derived from MAC treatment studies in children. Dosing recommendations for children are in the table above.

 

Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to Mycobacterium avium complex. Clarithromycin should be used in combination with other antimycobacterial drugs that have shown in vitro activity against MAC or clinical benefit in MAC treatment. (See Clinical Studies.) The recommended dose for mycobacterial infections in adults is 500 mg b.i.d. In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. Dosing recommendations for children are in the table above.

Clarithromycin therapy should continue for life if clinical and mycobacterial improvements are observed.

Constituting Instructions

The table below indicates the volume of water to be added when constituting:

Total Volume After Constitution Clarithromycin Concentration After Constitution Amount of Water to be Added*

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

* see instructions below.

 

 

Add half the volume of water to the bottle and shake vigorously. Add the remainder of water to the bottle and shake.

Shake well before each use. Oversize bottle provides shake space. Keep tightly closed. Do not refrigerate. After mixing, store at 15° to 30°C (59° to 86°F) and use within 14 days.

 

Prinsocin 125 mg oral suspension .

Prinsocin 250 mg oral suspension .

Prinsocin 500 mg Tablet .

 

The majority of side effects observed in clinical trials were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections and fewer than 2% of pediatric patients without mycobacterial infections discontinued therapy because of drug-related side effects.

The most frequently reported events in adults taking Prinsocin tablets (clarithromycin tablets, USP) were diarrhea (3%), nausea (3%), abnormal taste (3%), dyspepsia (2%), abdominal pain/discomfort (2%), and headache (2%). In pediatric patients, the most frequently reported events were diarrhea (6%), vomiting (6%), abdominal pain (3%), rash (3%), and headache (2%). Most of these events were described as mild or moderate in severity. Of the reported adverse events, only 1% was described as severe.

In the acute exacerbation of chronic bronchitis and acute maxillary sinusitis studies overall gastrointestinal adverse events were reported by a similar proportion of patients taking Prinsocin tablets .

In community-acquired pneumonia studies conducted in adults comparing clarithromycin to erythromycin base or erythromycin stearate, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to erythromycin-treated patients (13% vs 32%; p < 0.01). Twenty percent of erythromycin-treated patients discontinued therapy due to adverse events compared to 4% of clarithromycin-treated patients.

In two U.S. studies of acute otitis media comparing clarithromycin to amoxicillin/potassium clavulanate in pediatric patients, there were fewer adverse events involving the digestive system in clarithromycin-treated patients compared to amoxicillin/potassium clavulanate-treated patients (21% vs. 40%, p < 0.001). One-third as many clarithromycin-treated patients reported diarrhea as did amoxicillin/potassium clavulanate-treated patients.

Post-Marketing Experience

Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis, Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred. Other spontaneously reported adverse events include glossitis, stomatitis, oral moniliasis, anorexia, vomiting, pancreatitis, tongue discoloration, thrombocytopenia, leukopenia, neutropenia, and dizziness. There have been reports of tooth discoloration in patients treated with Prinsocin. Tooth discoloration is usually reversible with professional dental cleaning. There have been isolated reports of hearing loss, which is usually reversible, occurring chiefly in elderly women. Reports of alterations of the sense of smell, usually in conjunction with taste perversion or taste loss have also been reported.

Transient CNS events including anxiety, behavioral changes, confusional states, convulsions, depersonalization, disorientation, hallucinations, insomnia, depression, manic behavior, nightmares, psychosis, tinnitus, tremor, and vertigo have been reported during post-marketing surveillance. Events usually resolve with discontinuation of the drug.

Hepatic dysfunction, including increased liver enzymes, and hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with clarithromycin. This hepatic dysfunction may be severe and is usually reversible. In very rare instances, hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and/or concomitant medications.

There have been rare reports of hypoglycemia, some of which have occurred in patients taking oral hypoglycemic agents or insulin.

As with other macrolides, clarithromycin has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and torsades de pointes.

There have been reports of interstitial nephritis coincident with clarithromycin use.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients. (See WARNINGS and PRECAUTIONS.)

Changes in LaboratoryValues

Changes in laboratory values with possible clinical significance were as follows:

Hepatic

Elevated SGPT (ALT) < 1%; SGOT (AST) < 1%; GGT < 1%; alkaline phosphatase < 1%; LDH < 1%; total bilirubin < 1%

Hematologic

Decreased WBC < 1%; elevated prothrombin time 1%

Renal

Elevated BUN 4%; elevated serum creatinine < 1%

GGT, alkaline phosphatase, and prothrombin time data are from adult studies only.

 

 

 

Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serumtheophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. In two studies in which theophylline was administered with clarithromycin (a theophylline sustained-release formulation was dosed at either 6.5 mg/kg or 12 mg/kg together with 250 or 500 mg q12h clarithromycin), the steady-state levels of Cmax, Cmin, and the area under the serum concentration time curve (AUC) of theophylline increased about 20%.

Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, belonging to the calcium channel blockers drug class.

Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered.

When clarithromycin and terfenadine were coadministered, plasma concentrations of the active acid metabolite of terfenadine were threefold higher, on average, than the values observed when terfenadine was administered alone. The pharmacokinetics of clarithromycin and the 14-Ohclarithromycin were not significantly affected by coadministration of terfenadine once clarithromycin reached steady-state conditions. Concomitant administration of clarithromycin with terfenadine is contraindicated. (See CONTRAINDICATIONS.)

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult subjects. The steady-state plasma concentrations of omeprazole were increased (Cmax, AUC0-24 , and t½ increases of 30%, 89%, and 34%, respectively), by the concomitant administration of clarithromycin. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin.

Coadministration of clarithromycin with ranitidine bismuth citrate resulted in increased plasma ranitidine concentrations (57%), increased plasma bismuth trough concentrations (48%), and increased 14-hydroxy-clarithromycin plasma concentrations (31%). These effects are clinically insignificant.

Simultaneous oral administration of Prinsocin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Because clarithromycin appears to interfere with absorption of simultaneously administered oral zidovudine, this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine. This interaction does not appear to occur in pediatric HIV-infected patients taking clarithromycin suspension with zidovudine or dideoxyinosine. Similar interaction studies have not been conducted with clarithromycin extended release and zidovudine.

Simultaneous administration of Prinsocin tablets and didanosine to 12 HIV-infected adult patients resulted in no statistically significant change in didanosine pharmacokinetics.

Concomitant administration of fluconazole 200 mg daily and clarithromycin 500 mg twice daily to 21 healthy volunteers led to increases in the mean steady-state clarithromycin Cmin and AUC of 33% and 18%, respectively. Steady-state concentrations of 14-OH clarithromycin were not significantly affected by concomitant administration of fluconazole. No clarithromycin dose adjustment is necessary.

Concomitant administration of clarithromycin and ritonavir (n = 22) resulted in a 77% increase in clarithromycin AUC and a 100% decrease in the AUC of 14-OH clarithromycin. Clarithromycin may be administered without dosage adjustment to patients with normal renal function taking ritonavir.

However, for patients with renal impairment, the following dosage adjustments should be considered. For patients with CLCR 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%. For patients with CLCR < 30 mL/min, the dose of clarithromycin should be decreased by 75%.

Spontaneous reports in the post-marketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously.

Digoxin is thought to be a substrate for the efflux transporter, P-glycoprotein (Pgp). Clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are administered together, inhibition of Pgp by clarithromycin may lead to increased exposure to digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have also been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Serum digoxin concentrations should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. When clarithromycin and colchicine are administered together, inhibition of Pgp and/or CYP3A by clarithromycin may lead to increased exposure to colchicine. Patients should be monitored for clinical symptoms of colchicine toxicity. (See WARNINGS.)

Co-administration of clarithromycin, 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.

Clarithromycin 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. Dosage adjustments may be considered, and when possible, serum concentrations of drugs primarily metabolized by CYP3A should be monitored closely in patients concurrently receiving clarithromycin.

The following are examples of some clinically significant CYP3A based drug interactions. Interactions with other drugs metabolized by the CYP3A isoform are also possible.

Carbamazepine and Terfenadine

Increased serum concentrations of carbamazepine and the active acid metabolite of terfenadine were observed in clinical trials with clarithromycin.

Efavirenz, Nevirapine, Rifampicin, Rifabutin, and Rifapentine

Strong inducers of the cytochrome P450 metabolism system such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine may accelerate the metabolism of clarithromycin and thus lower the plasma levels of clarithromycin, while increasing those of 14-OH-clarithromycin, a metabolite that is also microbiologically active. Since the microbiological activities of clarithromycin and 14-Ohclarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers.

Sildenafil, Tadalafil, and Vardenafil

Each of these phosphodiesterase inhibitors is metabolized, at least in part, by CYP3A, and CYP3A may be inhibited by concomitantly administered clarithromycin.

Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil would likely result in increased phosphodiesterase inhibitor exposure. Reduction of sildenafil, tadalafil and vardenafil dosages should be considered when these drugs are co-administered with clarithromycin.

Tolterodine

The primary route of metabolism for tolterodine is via the 2D6 isoform of cytochrome P450 (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. A reduction in tolterodine dosage may be necessary in the presence of CYP3A inhibitors, such as clarithromycin in the CYP2D6 poor metabolizer population.

Triazolobenzodiazepines (e.g., alprazolam, midazolam, triazolam)

When midazolam was co-administered with clarithromycin tablets (500 mg twice daily), midazolam AUC was increased 2.7-fold after intravenous administration of midazolam and 7-fold after oral administration. Concomitant administration of oral midazolam and clarithromycin should be avoided. If intravenous midazolam is co-administered with clarithromycin, the patient must be closely monitored to allow dose adjustment.

The same precautions should also apply to other benzodiazepines that are metabolized by CYP3A, including triazolam and alprazolam. For benzodiazepines which are not dependent on CYP3A for their elimination (temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely. There have been post-marketing 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.

Atazanavir

Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Co-administration of clarithromycin (500 mg twice daily) with atazanavir (400 mg once daily) resulted in a 2-fold increase in exposure to clarithromycin and a 70% decrease in exposure to 14-OH-clarithromycin, with a 28% increase in the AUC of atazanavir.

Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. For patients with moderate renal function (creatinine clearance 30 to 60 mL/min), the dose of clarithromycin should be decreased by 50%. For patients with creatinine clearance < 30 mL/min, the dose of clarithromycin should be decreased by 75% using an appropriate clarithromycin formulation. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

Itraconazole

Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, leading to a bidirectional drug interaction. Clarithromycin may increase the plasma levels of itraconazole, while itraconazole may increase the plasma levels of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects.

Saquinavir

Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction. Concomitant administration of clarithromycin (500 mg bid) and saquinavir (soft gelatin capsules, 1200 mg tid) to 12 healthy volunteers resulted in steady-state AUC and Cmax values of saquinavir which were 177% and 187% higher than those seen with saquinavir alone. Clarithromycin AUC and Cmax values were approximately 40% higher than those seen with clarithromycin alone. No dose adjustment is required when the two drugs are co-administered for a limited time at the doses/formulations studied. Observations from drug interaction studies using the soft gelatin capsule formulation may not be representative of the effects seen using the saquinavir hard gelatin capsule. Observations from drug interactions studies performed with saquinavir alone may not be representative of the effects seen with saquinavir/ritonavir therapy. When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (see PRECAUTIONS - DRUG INTERACTIONS).

The following CYP3A based drug interactions have been observed with erythromycin products and/or with clarithromycin in post-marketing experience:

Antiarrhythmics

There have been post-marketing 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. Serum concentrations of these medications should also be monitored.

Ergotamine/Dihydroergotamine

Post-marketing 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. Concomitant administration of clarithromycin with ergotamine or dihydroergotamine is contraindicated (see CONTRAINDICATIONS).

Triazolobenziodidiazepines (Such as Triazolam and Alprazolam) and Related Benzodiazepines (Such as Midazolam)

Erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. There have been post-marketing reports of drug interactions and CNS effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam.

HMG-CoA Reductase Inhibitors

As with other macrolides, clarithromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g., lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

Sildenafil (Viagra)

Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. A similar interaction may occur with clarithromycin; reduction of sildenafil dosage should be considered. (See Viagra package insert.)

There have been spontaneous or published reports of CYP3A based interactions of erythromycin and/or clarithromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methylprednisolone, cilostazol, bromocriptine and vinblastine.

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, or terfenadine is contraindicated (see CONTRAINDICATIONS.)

In addition, there have been reports of interactions of erythromycin or clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.

 

CLARITHROMYCIN SHOULD NOT BE USED IN PREGNANT WOMEN EXCEPT IN CLINICAL CIRCUMSTANCES WHERE NO ALTERNATIVE THERAPY IS APPROPRIATE. IF PREGNANCY OCCURS WHILE TAKING THIS DRUG, THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS. CLARITHROMYCIN HAS DEMONSTRATED ADVERSE EFFECTS OF PREGNANCY OUTCOME AND/OR EMBRYO-FETAL DEVELOPMENT IN MONKEYS, RATS, MICE, AND RABBITS AT DOSES THAT PRODUCED PLASMA LEVELS 2 TO 17 TIMES THE SERUM LEVELS ACHIEVED IN HUMANS TREATED AT THE MAXIMUM RECOMMENDED HUMAN DOSES. (See PRECAUTIONS - Pregnancy.)

Clostridium difficileassociated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Prinsocin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

There have been post-marketing reports of colchicine toxicity with concomitant use of clarithromycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency.

Deaths have been reported in some such patients. (See PRECAUTIONS.)

For information about warnings of other drugs indicated in combination with BIAXIN, refer to the WARNINGS section of their package inserts.

 

General

Prescribing Prinsocin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Clarithromycin is principally excreted via the liver and kidney. Clarithromycin may be administered without dosage adjustment to patients with hepatic impairment and normal renal function. However, in the presence of severe renal impairment with or without coexisting hepatic impairment, decreased dosage or prolonged dosing intervals may be appropriate.

Clarithromycin in combination with ranitidine bismuth citrate therapy is not recommended in patients with creatinine clearance less than 25 mL/min. (See DOSAGE AND ADMINISTRATION.)

Clarithromycin in combination with ranitidine bismuth citrate should not be used in patients with a history of acute porphyria.

Exacerbation of symptoms of myasthenia gravis and new onset of symptoms of myasthenic syndrome has been reported in patients receiving clarithromycin therapy.

For information about precautions of other drugs indicated in combination with Prinsocin, refer to the PRECAUTIONS section of their package inserts.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The following in vitromutagenicity tests have been conducted with clarithromycin:

Salmonella/Mammalian Microsomes Test

Bacterial Induced Mutation Frequency Test

In VitroChromosome Aberration Test

Rat Hepatocyte DNA Synthesis Assay

Mouse Lymphoma Assay

Mouse Dominant Lethal Study

Mouse Micronucleus Test

All tests had negative results except the In Vitro Chromosome Aberration Test which was weakly positive in one test and negative in another.

In addition, a Bacterial Reverse-Mutation Test (Ames Test) has been performed on clarithromycin metabolites with negative results.

Fertility and reproduction studies have shown that daily doses of up to 160 mg/kg/day (1.3 times the recommended maximum human dose based on mg/m²) to male and female rats caused no adverse effects on the estrous cycle, fertility, parturition, or number and viability of offspring. Plasma levels in rats after 150 mg/kg/day were 2 times the human serum levels.

In the 150 mg/kg/day monkey studies, plasma levels were 3 times the human serum levels. When given orally at 150 mg/kg/day (2.4 times the recommended maximum human dose based on mg/m²), clarithromycin was shown to produce embryonic loss in monkeys. This effect has been attributed to marked maternal toxicity of the drug at this high dose.

In rabbits, in utero fetal loss occurred at an intravenous dose of 33 mg/m², which is 17 times less than the maximum proposed human oral daily dose of 618 mg/m².

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of clarithromycin.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Four teratogenicity studies in rats (three with oral doses and one with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral doses up to 125 mg/kg/day (approximately 2 times the recommended maximum human dose based on mg/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 2 times the human serum levels. Four studies in mice revealed a variable incidence of cleft palate following oral doses of 1000 mg/kg/day (2 and 4 times the recommended maximum human dose based on mg/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 (an approximate equidose of the recommended maximum human dose based on mg/m²) produced fetal growth retardation at plasma levels that were 2 times the human serum levels.

There are no adequate and well-controlled studies in pregnant women. Clarithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS.)

Nursing Mothers

It is not known whether clarithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when clarithromycin is administered to a nursing woman. It is known that clarithromycin is excreted in the milk of lactating animals and that other drugs of this class are excreted in human milk. Preweaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg/day for 3 weeks, were not adversely affected, despite data indicating higher drug levels in milk than in plasma.

Pediatric Use

Safety and effectiveness of clarithromycin in pediatric patients under 6 months of age have not been established. The safety of clarithromycin has not been studied in MAC patients under the age of 20 months. Neonatal and juvenile animals tolerated clarithromycin in a manner similar to adult animals. Young animals were slightly more intolerant to acute overdosage and to subtle reductions in erythrocytes, platelets and leukocytes but were less sensitive to toxicity in the liver, kidney, thymus, and genitalia.

Geriatric Use

In a steady-state study in which healthy elderly subjects (age 65 to 81 years old) were given 500 mg every 12 hours, the maximum serum concentrations and area under the curves of clarithromycin and 14-OH clarithromycin were increased compared to those achieved in healthy young adults. These changes in pharmacokinetics parallel known age-related decreases in renal function. In clinical trials, elderly patients did not have an increased incidence of adverse events when compared to younger patients. Dosage adjustment should be considered in elderly patients with severe renal impairment. (See WARNINGS and PRECAUTIONS.)

 

Overdosage of clarithromycin can cause gastrointestinal symptoms such as abdominal pain, vomiting, nausea, and diarrhea.

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, clarithromycin serum concentrations are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

 

Clarithromycin is contraindicated in patients with a known hypersensitivity to clarithromycin, erythromycin, or any of the macrolide antibiotics.

Concomitant administration of clarithromycin and any of the following drugs is contraindicated: cisapride, pimozide, astemizole, terfenadine, and ergotamine or dihydroergotamine (see DRUG INTERACTIONS). There have been post-marketing reports of drug interactions when clarithromycin and/or erythromycin are coadministered with cisapride, pimozide, astemizole, or terfenadine resulting in cardiac arrhythmias (QT prolongation, ventricular tachycardia, ventricular fibrillation, and torsades de pointes) most likely due to inhibition of metabolism of these drugs by erythromycin and clarithromycin. Fatalities have been reported.

For information about contraindications of other drugs indicated in combination with Prinsocin, refer to the CONTRAINDICATIONS section of their package inserts.

 

Pharmacokinetics

Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin tablets was approximately 50%. For a single 500 mg dose of clarithromycin, food slightly delays the onset of clarithromycin absorption, increasing the peak time from approximately 2 to 2.5 hours. Food also increases the clarithromycin peak plasma concentration by about 24%, but does not affect the extent of clarithromycin bioavailability. Food does not affect the onset of formation of the antimicrobially active metabolite, 14-OH clarithromycin or its peak plasma concentration but does slightly decrease the extent of metabolite formation, indicated by an 11% decrease in area under the plasma concentration-time curve (AUC). Therefore, Prinsocin tablets may be given without regard to food.

In nonfasting healthy human subjects (males and females), peak plasma concentrations were attained within 2 to 3 hours after oral dosing. Steady-state peak plasma clarithromycin concentrations were attained within 3 days and were approximately 1 to 2 μg/mL with a 250 mg dose administered every 12 hours and 3 to 4 μg/mL with a 500 mg dose administered every 8 to 12 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours. The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH clarithromycin, attains a peak steady-state concentration of about 0.6 μg/mL and has an elimination half-life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 μg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.

After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hours, approximately 40% is excreted in urine as clarithromycin. The renal clearance of clarithromycin is, however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10% to 15% of the dose with either a 250 mg or a 500 mg tablet administered every 12 hours.

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin every 12 hours to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500- or 1000-mg doses of clarithromycin every 12 hours, steady-state clarithromycin Cmax values ranged from 2 to 4 μg/mL and 5 to 10 μg/mL, respectively.

The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.

The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular concentrations, tissue concentrations are higher than serum concentrations. Examples of tissue and serum concentrations are presented below.

 

 

 

CONCENTRATION (after 250 mg q12h)

Tissue Type

Tissue (μg/g)

Serum (μg/mL)

Tonsil

1.6

0.8

Lung

8.8

1.7

Steady - State Clarithromycin Plasma Concentration-Time Profiles

 

When 250 mg doses of clarithromycin as Prinsocin suspension were administered to fasting healthy adult subjects, peak plasma concentrations were attained around 3 hours after dosing. Steady-state peak plasma concentrations were attained in 2 to 3 days and were approximately 2 μg/mL for clarithromycin and 0.7 μg/mL for 14-OH clarithromycin when 250-mg doses of the clarithromycin suspension were administered every 12 hours. Elimination half-life of clarithromycin (3 to 4 hours) and that of 14-OH clarithromycin (5 to 7 hours) were similar to those observed at steady state following administration of equivalent doses of Prinsocin tablets.

For adult patients, the bioavailability of 10 mL of the 125 mg/5 mL suspension or 10 mL of the 250 mg/5 mL suspension is similar to a 250 mg or 500 mg tablet, respectively.

In children requiring antibiotic therapy, administration of 7.5 mg/kg q12h doses of clarithromycin as the suspension generally resulted in steady-state peak plasma concentrations of 3 to 7 μg/mL for clarithromycin and 1 to 2 μg/mL for 14-OH clarithromycin. In HIV-infected children taking 15 mg/kg every 12 hours, steady-state clarithromycin peak concentrations generally ranged from 6 to 15 μg/mL.

Clarithromycin penetrates into the middle ear fluid of children with secretory otitis media.

CONCENTRATION (after 7.5 mg/kg q12h for 5 doses)

Analyte

Middle Ear
(μg/mL)

Fluid Serum
(μg/mL)

Clarithromycin

2.5

1.7

14-OH Clarithromycin

1.3

0.8

In adults given 250 mg clarithromycin as suspension (n = 22), food appeared to decrease mean peak plasma clarithromycin concentrations from 1.2 (± 0.4) μg/mL to 1.0 (± 0.4) μg/mL and the extent of absorption from 7.2 (± 2.5) hr•μg/mL to 6.5 (± 3.7) hr•μg/mL.

When children (n = 10) were administered a single oral dose of 7.5 mg/kg suspension, food increased mean peak plasma clarithromycin concentrations from 3.6 (± 1.5) μg/mL to 4.6 (± 2.8) μg/mL and the extent of absorption from 10.0 (± 5.5) hr.μg/mL to 14.2 (± 9.4) hr.μg/mL.

Clarithromycin 500 mg every 8 hours was given in combination with omeprazole 40 mg daily to healthy adult males. The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

Clarithromycin Tissue Concentrations 2 hours after Dose (μg/mL)/(μg/g)

Treatment

N

Antrum

fundus

N

mucus

Clarithromycin

5

10.48 ± 2.01

20.81 ± 7.64

4

4.15 ± 7.74

Clarithromycin + Omeprazole

5

19.96 ± 4.71

24.25 ± 6.37

4

39.29 ± 32.79

For information about other drugs indicated in combination with BIAXIN, refer to the CLINICAL PHARMACOLOGY section of their package inserts.

Microbiology

Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible microorganisms resulting in inhibition of protein synthesis.

Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gramnegative microorganisms as well as most Mycobacterium avium complex (MAC) microorganisms.

Additionally, the 14-OH clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH clarithromycin is twice as active against Haemophilus influenzae microorganisms as the parent compound. However, for Mycobacterium avium complex (MAC) isolates the 14-OH metabolite is 4 to 7 times less active than clarithromycin. The clinical significance of this activity against Mycobacterium avium complex is unknown.

Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Aerobic Gram-positive Microorganisms

Staphylococcus aureus
Streptococcus pneumoniae
Streptococcus pyogenes

Aerobic Gram-negative Microorganisms

Haemophilus influenzae
Haemophilus parainfluenzae
Moraxella catarrhalis

Other Microorganisms

Mycoplasma pneumoniae
Chlamydia pneumoniae (TWAR)

Mycobacteria

Mycobacterium aviumcomplex (MAC) consisting of:
Mycobacterium avium
Mycobacterium intracellulare

Beta-lactamase production should have no effect on clarithromycin activity.

NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.

Omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; and lansoprazole/clarithromycin/amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Helicobacter
 
Pretreatment Resistance

Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (M93-067, M93-100) and 9.3% (41/439) in the omeprazole/clarithromycin/amoxicillin triple therapy studies (126, 127, M96-446). Clarithromycin pretreatment resistance was 12.6% (44/348) in the ranitidine bismuth citrate/clarithromycin b.i.d. versus t.i.d. clinical study (H2BA3001). Clarithromycin pretreatment resistance rates were 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the lansoprazole/clarithromycin/amoxicillin triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pretreatment susceptible isolates ( < 0.25 μg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin clinical studies (126, 127, M96-446). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 μg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin/amoxicillin study arm. Amoxicillin pretreatment susceptible isolates ( < 0.25 μg/mL) occurred in 97.8% (936/957) and 98.0% (98/100) of the patients in the lansoprazole/clarithromycin/amoxicillin triple-therapy clinical trials by E-test and agar dilution, respectively. Twenty-one of the 957 patients (2.2%) by E-test and 2 of 100 patients (2.0%) by agar dilution had amoxicillin pretreatment MICs of > 0.25 μg/mL. Two patients had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 μg/mL by E-test.

 

 

 

 

Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomesa

Clarithromycin Pretreatment Results

Clarithromycin Post-treatment Results

H. pylori negative – eradicated

H. pylori positive - not eradicated
Post-treatment susceptibility results

Sb

Ib

Rb

No MIC

Omeprazole 40 mg q.d./clarithromycin 500 mg t.i.d. for 14 days followed by omeprazole 20 mg q.d. for another 14 days (M93-067, M93-100)

Susceptibleb

108

72

1

 

26

9

Intermediateb

1

     

1

 

Resistantb

4

     

4

 

Ranitidine bismuth citrate 400 mg b.i.d./clarithromycin 500 mg t.i.d. for 14 days followed by ranitidine bismuth citrate 400 mg b.i.d. for another 14 days (H2BA3001)

Susceptibleb

124

98

4

 

14

8

Intermediateb

3

2

     

1

Resistantb

17

1

   

15

1

Ranitidine bismuth citrate 400 mg b.i.d./clarithromycin 500 mg b.i.d. for 14 days followed by ranitidine bismuth citrate 400 mg b.i.d. for another 14 days (H2BA3001)

Susceptible

125

106

1

1

12

5

Intermediateb

2

2

       

Resistantb

20

1

   

19

 

Omeprazole 20 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days (126, 127, M96-446)

Susceptibleb

171

153

7

 

3

8

Intermediateb

14

4

1

 

6

3

Resistantb

           

Lansoprazole 30 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 14 days (M95-399, M93-131, M95-392)

Susceptibleb

112

105

     

7

Intermediateb

3

3

       

Resistantb

17

6

   

7

4

Lansoprazole 30 mg b.i.d./clarithromycin 500 mg b.i.d./amoxicillin 1 g b.i.d. for 10 days (M95-399)

Susceptibleb

42

40

1

 

1

 

Intermediateb

           

Resistantb

4

1

   

3

 

aIncludes only patients with pretreatment clarithromycin susceptibility tests
b Susceptible (S) MIC < 0.25 μg/mL, Intermediate (I) MIC 0.5-1.0 μg/mL, Resistant (R) MIC > 2 μg/mL

 

 

 

Patients not eradicated of H. pylori following omeprazole/clarithromycin, ranitidine bismuth citrate/clarithromycin, omeprazole/clarithromycin/amoxicillin, or lansoprazole/clarithromycin/amoxicillin therapy would likely have clarithromycin resistant H. pylori isolates. Therefore, for patients who fail therapy, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy; ranitidine bismuth citrate/clarithromycin dual therapy; omeprazole/clarithromycin/amoxicillin triple therapy; lansoprazole/clarithromycin/amoxicillin triple therapy; or other regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes

In the omeprazole/clarithromycin/amoxicillin triple-therapy clinical trials, 84.9% (157/185) of the patients who had pretreatment amoxicillin susceptible MICs ( < 0.25 μg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no posttreatment susceptibility test results, and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs.

In the lansoprazole/clarithromycin/amoxicillin triple-therapy clinical trials, 82.6% (195/236) of the patients that had pretreatment amoxicillin susceptible MICs ( < 0.25 μg/mL) were eradicated of H. pylori. Of those with pretreatment amoxicillin MICs of > 0.25 μg/mL, three of six had the H. pylori eradicated. A total of 12.8% (22/172) of the patients failed the 10- and 14-day triple-therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple-therapy regimen also had clarithromycin resistant H. pylori isolates.

The following in vitro data are available,but their clinical significance is unknown. Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-positive Microorganisms

Streptococcus agalactiae
Streptococci
(Groups C, F, G)
Viridans group streptococci

Aerobic Gram-negative Microorganisms

Bordetella pertussis
Legionella pneumophila
Pasteurella multocida

Anaerobic Gram-positive Microorganisms

Clostridium perfringens
Peptococcus niger
Propionibacterium acnes

Anaerobic Gram-negative Microorganisms

Prevotella melaninogenica (formerlyBacteriodes melaninogenicus)

Susceptibility Testing Excluding Mycobacteria and Helicobacter

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of clarithromycin powder. The MIC values should be interpreted according to the following criteria:

For testing Staphylococcus spp.

MIC (μg/mL)

Interpretation

≤ 2.0

Susceptible (S)

4.0

Intermediate (I)

≥ 8.0

Resistant (R)

For testing Streptococcus spp. including Streptococcus pneumoniaea

MIC (μg/mL)

Interpretation

≤ 0.25

Susceptible (S)

0.5

Intermediate (I)

≥ 1.0

Resistant (R)

a These interpretive standards are applicable only to broth microdilution susceptibility tests using cationadjusted Mueller-Hinton broth with 2-5% lysed horse blood.

 

 

 

 

For testing Haemophilus spp.b

MIC (μg/mL)

Interpretation

≤ 8.0

Susceptible (S)

16.0

Intermediate (I)

≥ 32.0

Resistant (R)

b These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Testing Medium (HTM).1
Note: When testing Streptococcus spp., including Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin powder should provide the following MIC values:

Microorganism

 

MIC (μg/mL)

S. aureus

ATCC 29213

0.12 to 0.5

S. pneumoniaec

ATCC 49619

0.03 to 0.12

Haemophilus influenzaed

ATCC 49247

4 to 16

c This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a microdilution procedure using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
d This quality control range is applicable only to H. influenzae ATCC 49247 tested by a microdilution procedure using HTM1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-μg clarithromycin to test the susceptibility of microorganisms to clarithromycin.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15- μg clarithromycin disk should be interpreted according to the following criteria:

For testing Staphylococcus spp.

Zone diameter (mm)

Interpretation

≥ 18

Susceptible (S)

14 to 17

Intermediate (I)

≤ 13

Resistant (R)

 

 

 

For testing Streptococcus spp. including Streptococcus pneumoniaee

Zone diameter (mm)

Interpretation

≥ 21

Susceptible (S)

17 to 20

Intermediate (I)

≤ 16

Resistant (R)

e These zone diameter standards only apply to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.

 

For testing Haemophilus spp.f

Zone diameter (mm)

Interpretation

≥ 13

Susceptible (S)

11 to 12

Intermediate (I)

≤ 10

Resistant (R)

f These zone diameter standards are applicable only to tests with Haemophilus spp. using HTm².
Note: When testing Streptococcus spp., including Streptococcus pneumoniae, susceptibility and resistance to clarithromycin can be predicted using erythromycin.

 

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for clarithromycin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 15-μg clarithromycin disk should provide the following zone diameters in this laboratory test quality control strain:

Microorganism

 

Zone diameter (mm)

S. aureus

ATCC 25923

26 to 32

S. pneumoniaeg

ATCC 49619

25 to 31

Haemophilus influenzaeh

ATCC 49247

11 to 17

g This quality control range is applicable only to tests performed by disk diffusion using Mueller-Hinton agar supplemented with 5% defibrinated sheep blood.
h This quality control limit applies to tests conducted with Haemophilus influenzae ATCC 49247 using HTM2.

 
In vitro Activity of Clarithromycin against Mycobacteria

Clarithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) microorganisms isolated from both AIDS and non-AIDS patients. While gene probe techniques may be used to distinguish M. avium species from M. intracellulare, many studies only reported results on M. avium complex (MAC) isolates.

Various in vitro methodologies employing broth or solid media at different pH's, with and without oleic acid-albumin-dextrose-catalase (OADC), have been used to determine clarithromycin MIC values for mycobacterial species. In general, MIC values decrease more than 16-fold as the pH of Middlebrook 7H12 broth media increases from 5.0 to 7.4. At pH 7.4, MIC values determined with Mueller-Hinton agar were 4- to 8-fold higher than those observed with Middlebrook 7H12 media. Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values.

Clarithromycin activity against 80 MAC isolates from AIDS patients and 211 MAC isolates from non- AIDS patients was evaluated using a microdilution method with Middlebrook 7H9 broth. Results showed an MIC value of ≤ 4.0 μg/mL in 81% and 89% of the AIDS and non-AIDS MAC isolates, respectively. Twelve percent of the non-AIDS isolates had an MIC value ≤ 0.5 μg/mL. Clarithromycin was also shown to be active against phagocytized M. avium complex (MAC) in mouse and human macrophage cell cultures as well as in the beige mouse infection model.

Clarithromycin activity was evaluated against Mycobacterium tuberculosis microorganisms. In one study utilizing the agar dilution method with Middlebrook 7H10 media, 3 of 30 clinical isolates had an MIC of 2.5 μg/mL. Clarithromycin inhibited all isolates at > 10.0 μg/mL.

Susceptibility Testing for Mycobacterium avium Complex (MAC)

The disk diffusion and dilution techniques for susceptibility testing against gram-positive and gramnegative bacteria should not be used for determining clarithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Clarithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of the media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to clarithromycin have not been established.

Susceptibility Test for Helicobacter pylori

The reference methodology for susceptibility testing of H. pylori is agar dilution MICs.3 One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107-1 x 108 CFU/mL for H. pylori ) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood ( > 2-weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter species. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

 

 

Clarithromycin MIC (μg/mL)i

Interpretation

< 0.25

Susceptible (S)

0.5-1.0

Intermediate (I)

> 2.0

Resistant (R)

 

 

Amoxicillin MIC (μg/mL)i,j

Interpretation

< 0.25

Susceptible (S)

i These are tentative breakpoints for the agar dilution methodology, and they should not be used to interpret results obtained using alternative methods.
j There were not enough organisms with MICs > 0.25 μg/mL to determine a resistance breakpoint.

 

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

Microorganisms

 

Antimicrobial Agent

MIC (μg/mL)k

H. pylori

ATCC 43504

Clarithromycin

0.015-0.12 μg/mL

H. pylori

ATCC 43504

Amoxicillin

0.015-0.12 μg/mL

kThese are quality control ranges for the agar dilution methodology and they should not be used to control test results obtained using alternative methods.

 

Clinical Studies

Mycobacterial Infections

 

A randomized, double-blind study (561) compared clarithromycin 500 mg b.i.d. to placebo in patients with CDC-defined AIDS and CD4 counts < 100 cells/μL. This study accrued 682 patients from November 1992 to January 1994, with a median CD4 cell count at study entry of 30 cells/μL. Median duration of clarithromycin was 10.6 months vs. 8.2 months for placebo. More patients in the placebo arm than the clarithromycin arm discontinued prematurely from the study (75.6% and 67.4%, respectively). However, if premature discontinuations due to MAC or death are excluded, approximately equal percentages of patients on each arm (54.8% on clarithromycin and 52.5% on placebo) discontinued study drug early for other reasons. The study was designed to evaluate the following endpoints:

  1. MAC bacteremia, defined as at least one positive culture for M. avium complex bacteria from blood or another normally sterile site.
  2. Survival.
  3. 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 clarithromycin, 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-totreat basis, the one-year cumulative incidence of MAC bacteremia was 5.0% for patients randomized to clarithromycin and 19.4% for patients randomized to placebo. While only 19 of the 341 patients randomized to clarithromycin developed MAC, 11 of these cases were resistant to clarithromycin. The patients with resistant MAC bacteremia had a median baseline CD4 count of 10 cells/mm³ (range 2 to 25 cells/mm³). Information regarding the clinical course and response to treatment of the patients with resistant MAC bacteremia is limited. The 8 patients who received clarithromycin and developed susceptible MAC bacteremia had a median baseline CD4 count of 25 cells/mm³ (range 10 to 80 cells/mm³). Comparatively, 53 of the 341 placebo patients developed MAC; none of these isolates were resistant to clarithromycin. The median baseline CD4 count was 15 cells/mm³ (range 2 to 130 cells/mm³) for placebo patients that developed MAC.

Survival

A statistically significant survival benefit was observed.

Survival All Randomized Patients

 

 

 

Mortality

Reduction in Mortality on Clarithromycin

Placebo

Clarithromycin

6 month

9.4%

6.5%

31%

12 month

29.7%

20.5%

31%

18 month

46.4%

37.5%

20%

 

 

 

Since the analysis at 18 months includes patients no longer receiving prophylaxis the survival benefit of clarithromycin may be underestimated.

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients in the group randomized to clarithromycin showed reductions in the signs and symptoms of disseminated MAC disease, including fever, night sweats, weight loss, and anemia.

Safety

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

Treatment-related* Adverse Event Incidence Rates (%) in Immunocompromised Adult Patients Receiving Prophylaxis Against M. avium Complex

 

Body System‡
Adverse Event

Clarithromycin
(n = 339)%

Placebo
(n = 339)%

Body as a Whole

Abdominal pain

5.0%

3.5%

Headache

2.7%

0.9%

Digestive

Diarrhea

7.7%

4.1%

Dyspepsia

3.8%

2.7%

Flatulence

2.4%

0.9%

Nausea

11.2%

7.1%

Vomiting

5.9%

3.2%

Skin & Appendages

Rash

3.2%

3.5%

Special Senses

Taste Perversion

8.0%

0.3%

* Includes those events possibly or probably related to study drug and excludes concurrent conditions.
‡ > 2% Adverse Event Incidence Rates for either treatment group.

 

 

 

 

 

Among these events, taste perversion was the only event that had significantly higher incidence in the clarithromycin-treated group compared to the placebo-treated group.

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

Changes in Laboratory Values of Potential Clinical Importance

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.

Percentage of Patients(a) Exceeding Extreme Laboratory Value in Patients Receiving Prophylaxis Against M. avium Complex

 

Clarithromycin 500 mg b.i.d.

Placebo

Hemoglobin

< 8 g/dL

4/118 3%

5/103 5%

Platelet Count

< 50 x 109/L

11/249 4%

12/250 5%

WBC Count

< 1 x 109/L

2/103 4%

0/95 0%

SGOT

> 5 x ULN(b)

7/196 4%

5/208 2%

SGPT

> 5 x ULN(b)

6/217 3%

4/232 2%

Alk. Phos.

> 5 x ULN(b)

5/220 2%

5/218 2%

(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables).
(b) ULN = Upper Limit of Normal

 

Treatment

Three randomized studies (500, 577, and 521) compared different dosages of clarithromycin in patients with CDC-defined AIDS and CD4 counts < 100 cells/μL. These studies accrued patients from May 1991 to March 1992. Study 500 was randomized, double-blind; Study 577 was open-label compassionate use. Both studies used 500 and 1000 mg b.i.d. doses; Study 500 also had a 2000 mg b.i.d. group. Study 521 was a pediatric study at 3.75, 7.5, and 15 mg/kg b.i.d. Study 500 enrolled 154 adult patients, Study 577 enrolled 469 adult patients, and Study 521 enrolled 25 patients between the ages of 1 to 20. The majority of patients had CD4 cell counts < 50/μL at study entry. The studies were designed to evaluate the following end points:

  1. Change in MAC bacteremia or blood cultures negative for M. avium.
  2. 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 the 500 study are described below. The 577 study results were similar to the results of the 500 study. Results with the 7.5 mg/kg b.i.d. dose in the pediatric study were comparable to those for the 500 mg b.i.d. regimen in the adult studies.

Study 069 compared the safety and efficacy of clarithromycin in combination with ethambutol versus clarithromycin in combination with ethambutol and clofazimine for the treatment of disseminated MAC (dMAC) infection.4 This 24-week study enrolled 106 patients with AIDS and dMAC, with 55 patients randomized to receive clarithromycin and ethambutol, and 51 patients randomized to receive clarithromycin, ethambutol, and clofazimine. Baseline characteristics between study arms were similar with the exception of median CFU counts being at least 1 log higher in the clarithromycin, ethambutol, and clofazimine arm.

Compared to prior experience with clarithromycin monotherapy, the two-drug regimen of clarithromycin and ethambutol was well tolerated and 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.

MAC Bacteremia

Decreases in MAC bacteremia or negative blood cultures were seen in the majority of patients in all dose groups. Mean reductions in colony forming units (CFU) are shown below. Included in the table are results from a separate study with a four drug regimen5 (ciprofloxacin, ethambutol, rifampicin, and clofazimine). Since patient populations and study procedures may vary between these two studies, comparisons between the clarithromycin results and the combination therapy results should be interpreted cautiously.

 

 

Mean Reductions in Log CFU from Baseline (After 4 Weeks of Therapy)

500 mg b.i.d.
(N = 35)

1000 mg b.i.d.
(N = 32)

2000 mg b.i.d.
(N = 26)

Four Drug Regimen
(N = 24)

1.5

2.3

2.3

1.4

 

Although the 1000 mg and 2000 mg b.i.d. doses showed significantly better control of bacteremia during the first four weeks of therapy, no significant differences were seen beyond that point. The percent of patients whose blood was sterilized as shown by one or more negative cultures at any time during acute therapy was 61% (30/49) for the 500 mg b.i.d. group and 59% (29/49) and 52% (25/48) for the 1000 and 2000 mg b.i.d. groups, respectively. The percent of patients who had 2 or more negative cultures during acute therapy that were sustained through study Day 84 was 25% (12/49) in both the 500 and 1000 mg b.i.d. groups and 8% (4/48) for the 2000 mg b.i.d. group. By Day 84, 23% (11/49), 37% (18/49), and 56% (27/48) of patients had died or discontinued from the study, and 14% (7/49), 12% (6/49), and 13% (6/48) of patients had relapsed in the 500, 1000, and 2000 mg b.i.d. dose groups, respectively. All of the isolates had an MIC < 8 μg/mL at pre-treatment. Relapse was almost always accompanied by an increase in MIC. The median time to first negative culture was 54, 41, and 29 days for the 500, 1000, and 2000 mg b.i.d. groups, respectively. The time to first decrease of at least 1 log in CFU count was significantly shorter with the 1000 and 2000 mg b.i.d. doses (median equal to 16 and 15 days, respectively) in comparison to the 500 mg b.i.d. group (median equal to 29 days). The median time to first positive culture or study discontinuation following the first negative culture was 43, 59 and 43 days for the 500, 1000, and 2000 mg b.i.d. groups, respectively.

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 clarithromycin at 500 to 2000 mg b.i.d. doses. Similarly, 77% of patients reported resolution or improvement in fevers at some point. Response rates for clinical signs of MAC are given below:

Resolution of Fever

Resolution of Night Sweats

b.i.d. dose (mg)

% ever afebrile

% afebrile ≥ 6 weeks

b.i.d. dose (mg)

% ever resolving

% resolving ≥ 6 weeks

500

67%

23%

500

85%

42%

1000

67%

12%

1000

70%

33%

2000

62%

22%

2000

72%

36%

Weight Gain > 3%

Hemoglobin Increase > 1 gm

b.i.d. dose (mg)

% eve rgaining

% gaining ≥ 6 weeks

b.i.d. dose (mg)

% ever increasing

% increasing ≥ 6 weeks

500

33%

14%

500

58%

26%

1000

26%

17%

1000

37%

6%

2000

26%

12%

2000

62%

18%

 

The median duration of response, defined as improvement or resolution of clinical signs and symptoms, was 2 to 6 weeks.

Since the study 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.

Survival

Median survival time from study entry (Study 500) was 249 days at the 500 mg b.i.d. dose compared to 215 days with the 1000 mg b.i.d. dose. However, during the first 12 weeks of therapy, there were 2 deaths in 53 patients in the 500 mg b.i.d. group versus 13 deaths in 51 patients in the 1000 mg b.i.d. 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.5

Median survival time from study entry in Study 577 was 199 days for the 500 mg b.i.d. dose and 179 days for the 1000 mg b.i.d. 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 b.i.d. and 18 deaths in 214 patients taking 1000 mg b.i.d.

Safety

The adverse event profiles showed that both the 500 and 1000 mg b.i.d. doses were well tolerated. The 2000 mg b.i.d. dose was poorly tolerated and resulted in a higher proportion of premature discontinuations.

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

The following analyses summarize experience during the first 12 weeks of therapy with clarithromycin. Data are reported separately for Study 500 (randomized, double-blind) and Study 577 (open-label, compassionate use) and also combined. Adverse events were reported less frequently in Study 577, which may be due in part to differences in monitoring between the two studies. In adult patients receiving clarithromycin 500 mg b.i.d., the most frequently reported adverse events, considered possibly or probably related to study drug, with an incidence of 5% or greater, are listed below. Most of these events were mild to moderate in severity, although 5% (Study 500: 8%; Study 577: 4%) of patients receiving 500 mg b.i.d. and 5% (Study 500: 4%; Study 577: 6%) of patients receiving 1000 mg b.i.d. reported severe adverse events. Excluding those patients who discontinued therapy or died due to complications of their underlying non-mycobacterial disease, approximately 8% (Study 500: 15%; Study 577: 7%) of the patients who received 500 mg b.i.d. and 12% (Study 500: 14%; Study 577: 12%) of the patients who received 1000 mg b.i.d. discontinued therapy due to drugrelated events during the first 12 weeks of therapy. Overall, the 500 and 1000 mg b.i.d. doses had similar adverse event profiles.

Treatment-related* Adverse Event Incidence Rates (%) in Immunocompromised Adult Patients During the First 12 Weeks of Therapy with 500 mg b.i.d. Clarithromycin Dose

Adverse Event

Study 500
(n = 53)

Study 577
(n = 255)

Combined
(n = 308)

Abdominal Pain

7.5

2.4

3.2

Diarrhea

9.4

1.6

2.9

Flatulence

7.5

0.0

1.3

Headache

7.5

0.4

1.6

Nausea

28.3

9.0

12.3

Rash

9.4

2.0

3.2

Taste Perversion

18.9

0.4

3.6

Vomiting

24.5

3.9

7.5

* 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 clarithromycin suspension for mycobacterial infections. The most frequently reported adverse events, excluding those due to the patient's concurrent condition, were consistent with those observed in adult patients.

Changes in Laboratory Values

In immunocompromised patients treated with clarithromycin for mycobacterial infections, evaluations of laboratory values were made by analyzing those values outside the seriously abnormal level (i.e., the extreme high or low limit) for the specified test.

Percentage of Patients(a) Exceeding Extreme Laboratory Value Limits During First 12 Weeks of Treatment 500 mg b.i.d. Dose(b)

   

Study 500

Study 577

Combined

BUN

> 50 mg/dL

0%

< 1%

< 1%

Platelet Count

< 50 x 109/L

0%

< 1%

< 1%

SGOT

> 5 x ULN(c)

0%

3%

2%

SGPT

> 5 x ULN(c)

0%

2%

1%

WBC

< 1 x 109/L

0%

1%

1%

(a) Includes only patients with baseline values within the normal range or borderline high (hematology variables) and within the normal range or borderline low (chemistry variables)
(b) Includes all values within the first 12 weeks for patients who start on 500 mg b.i.d.
(c) ULN = Upper Limit of Normal

 

 

Otitis Media

In a controlled clinical study of acute otitis media performed in the United States, where significant rates of beta-lactamase producing organisms were found, clarithromycin was compared to an oral cephalosporin. In this study, very strict evaluability criteria were used to determine clinical response. For the 223 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the post-therapy visit was 88% for clarithromycin and 91% for the cephalosporin.

In a smaller number of patients, microbiologic determinations were made at the pre-treatment visit. The following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained:

U.S. Acute Otitis Media Study Clarithromycin vs. Oral Cephalosporin EFFICACY RESULTS

PATHOGEN

OUTCOME

S. pneumoniae

clarithromycin success rate, 13/15 (87%), control 4/5

H. influenzae*

clarithromycin success rate, 10/14 (71%), control 3/4

M. catarrhalis

clarithromycin success rate, 4/5,control 1/1

S. pyogenes

clarithromycin success rate, 3/3,control 0/1

Overall

clarithromycin success rate, 30/37 (81%), control 8/11 (73%)

* None of the H. influenzae isolated pre-treatment was resistant to clarithromycin; 6% were resistant to the control agent.

 

Safety

The incidence of adverse events in all patients treated, primarily diarrhea and vomiting, did not differ clinically or statistically for the two agents.

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, clarithromycin was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. In these studies, very 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 clarithromycin and the control.

For the patients who had microbiologic determinations at the pre-treatment visit, the following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained:

 

Two U.S. Acute Otitis Media Studies Clarithromycin vs. Antimicrobial/Beta-lactamase Inhibitor EFFICACY RESULTS

PATHOGEN

OUTCOME

S. pneumoniae

clarithromycin success rate, 43/51 (84%), control 55/56 (98%)

H. influenzae*

clarithromycin success rate, 36/45 (80%), control 31/33 (94%)

M. catarrhalis

clarithromycin success rate, 9/10 (90%), control 6/6

S. pyogenes

clarithromycin success rate, 3/3, control 5/5

Overall

clarithromycin success rate, 91/109 (83%), control 97/100 (97%)

* Of the H. influenzae isolated pre-treatment, 3% were resistant to clarithromycin and 10% were resistant to the control agent.

 

Safety

The incidence of adverse events in all patients treated, primarily diarrhea (15% vs. 38%) and diaper rash (3% vs. 11%) in young children, was clinically and statistically lower in the clarithromycin arm versus the control arm.

Duodenal Ulcer Associated with H. pylori Infection

Clarithromycin + Lansoprazole and Amoxicillin
H. pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence

Two U.S. randomized, double-blind clinical studies 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 clarithromycin in combination with lansoprazole and amoxicillin capsules as triple 14-day therapy for eradication of H. pylori . Based on the results of these studies, the safety and efficacy of the following eradication regimen were established:

Triple therapy: Prinsocin (clarithromycin) 500 mg b.i.d. + lansoprazole 30 mg b.i.d. + amoxicillin 1 gm b.i.d.

Treatment was for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.

The combination of Prinsocin plus lansoprazole and amoxicillin as triple therapy was effective in eradicatingH. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of clarithromycin in combination with lansoprazole and amoxicillin as triple therapy for 10 and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori.

H. pylori Eradication Rates-Triple Therapy (Prinsocin/lansoprazole/amoxicillin) Percent of Patients Cured [95% Confidence Interval] (number of patients)

Study

Duration

Triple Therapy
Evaluable Analysis*

Triple Therapy
Intent-to-Treat Analysis#

M93-131

14 days

92† [80.0-97.7]

86† [73.3-93.5]

(n = 48)

(n = 55)

M95-392

14 days

86‡ [75.7-93.6]

83‡ [72.0-90.8]

(n = 66)

(n = 70)

M95-399

14 days

85 [77.0-91.0]

82 [73.9-88.1]

(N = 113)

(N = 126)

10 days

84 [76.0-89.8]

81 [73.9-87.6]

(N = 123)

(N = 135)

* 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 study. Additionally, if patients were dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as evaluable failures of therapy.
# 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.
(p < 0.05) versus Prinsocin/lansoprazole and lansoprazole/amoxicillin dual therapy.
(p < 0.05) versus Prinsocin/amoxicillin dual therapy.
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.

 
Clarithromycin + Omeprazole and Amoxicillin Therapy
H. pylori Eradication for Reducing the Risk of Duodenal Ulcer Recurrence

Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n = 558) compared clarithromycin plus omeprazole and amoxicillin to clarithromycin plus amoxicillin. Two studies (Studies 126 and 127) were conducted in patients with an active duodenal ulcer, and the third study (Study 446) 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 studies was clarithromycin 500 mg b.i.d. plus omeprazole 20 mg b.i.d. plus amoxicillin 1 gram b.i.d. for 10 days. In Studies 126 and 127, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg q.d. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 126 and 127 only). H. pylori status was determined by CLOtest®, histology, and culture in all three studies. 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 clarithromycin plus omeprazole and amoxicillin was effective in eradicating H. pylori .

Per-Protocol and Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval]

 

Clarithromycin + omeprazole + amoxicillin

Clarithromycin + amoxicillin

Per-Protocol †

Intent-to-Treat ‡

Per-Protocol †

Intent-to-Treat ‡

Study 126

*77 [64, 86]

69 [57, 79]

43 [31, 56]

37 [27, 48]

(n = 64)

(n = 80)

(n = 67)

(n = 84)

Study 127

*78 [67, 88]

73 [61, 82]

41 [29, 54]

36 [26, 47]

(n = 65)

(n = 77)

(n = 68)

(n = 84)

Study M96-446

*90 [80, 96]

83 [74, 91]

33 [24, 44]

32 [23, 42]

(n = 69)

(n = 84)

(n = 93)

(n = 99)

†Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer studies 126 and 127; history of ulcer within 5 years, study M96-446) and H. pyloriinfection 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 study. Additionally, if patients dropped out of the study due to an adverse event 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.
‡ 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.
* p < 0.05 versus clarithromycin plus amoxicillin.

 

Safety

In clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin, no adverse reactions peculiar 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 clarithromycin, omeprazole, or amoxicillin.

The most frequent adverse experiences observed in clinical trials using combination therapy with clarithromycin plus omeprazole and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%).

For information about adverse reactions with omeprazole or amoxicillin, refer to the ADVERSE REACTIONS section of their package inserts.

Clarithromycin + Omeprazole Therapy

Four randomized, double-blind, multi-center studies (067, 100, 812b, and 058) evaluated clarithromycin 500 mg t.i.d. plus omeprazole 40 mg q.d. for 14 days, followed by omeprazole 20 mg q.d. (067, 100, and 058) or by omeprazole 40 mg q.d. (812b) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori . Studies 067 and 100 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 067 and 228 patients in Study 100. These studies compared the combination regimen to omeprazole and clarithromycin monotherapies. Studies 812b and 058 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 812b and 208 patients in Study 058. These studies compared the combination regimen to omeprazole monotherapy. The results for the efficacy analyses for these studies are described below.

Duodenal Ulcer Healing

The combination of clarithromycin and omeprazole was as effective as omeprazole alone for healing duodenal ulcer.

End-of-Treatment Ulcer Healing Rates Percent of Patients Healed (n/N)

Study

Clarithromycin + Omeprazole

Omeprazole

Clarithromycin

U.S. Studies

Study 100

94% (58/62)†

88% (60/68)

71% (49/69)

Study 067

88% (56/64)†

85% (55/65)

64% (44/69)

Non-U.S. Studies

Study 058

99% (84/85)

95% (82/86)

N/A

Study 812b1

100% (64/64)

99% (71/72)

N/A

† p < 0.05 for clarithromycin + omeprazole versus clarithromycin monotherapy.
1 In Study 812b patients received omeprazole 40 mg daily for days 15 to 28.

 
Eradication of H. pylori Associated with Duodenal Ulcer

The combination of clarithromycin and omeprazole was effective in eradicating H. pylori.

H. pylori Eradication Rates (Per-Protocol Analysis) at 4 to 6 weeks Percent of Patients Cured (n/N)

Study

Clarithromycin + Omeprazole

Omeprazole

Clarithromycin

U.S. Studies

Study 100

64% (39/61)†‡

0% (0/59)

39% (17/44)

Study 067

74% (39/53)†‡

0% (0/54)

31% (13/42)

Non-U.S. Studies

Study 058

74% (64/86)‡

1% (1/90)

N/A

Study 812b

83% (50/60)‡

1% (1/74)

N/A

† Statistically significantly higher than clarithromycin monotherapy (p < 0.05).
‡ Statistically significantly higher than omeprazole monotherapy (p < 0.05).

 

 

 

 

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.

Ulcer recurrence at 6-months following the end of treatment was assessed for patients in whom ulcers were healed post-treatment.

Ulcer Recurrence at 6 months by H. pylori Status at 4-6 Weeks

 

H. pylori Negative

H. pylori Positive

U.S. Studies

   

Study 100

Clarithromycin + Omeprazole

6% (2/34)

56% (9/16)

Omeprazole

- (0/0)

71% (35/49)

Clarithromycin

12% (2/17)

32% (7/22)

Study 067

Clarithromycin + Omeprazole

38% (11/29)

50% (6/12)

Omeprazole

- (0/0)

67% (31/46)

Clarithromycin

18% (2/11)

52% (14/27)

Non-U.S. Studies

   

Study 058

Clarithromycin + Omeprazole

6% (3/53)

24% (4/17)

Omeprazole

0% (0/3)

55% (39/71)

Study 812b*

Clarithromycin + Omeprazole

5% (2/42)

0% (0/7)

Omeprazole

0% (0/1)

54% (32/59)

*12-month recurrence rates:

 

Thus, in patients with duodenal ulcer associated with H. pylori infection, eradication of H. pylori reduced ulcer recurrence.

Safety

The adverse event profiles for the four studies showed that the combination of clarithromycin 500 mg t.i.d. and omeprazole 40 mg q.d. for 14 days, followed by omeprazole 20 mg q.d. (067, 100, and 058) or 40 mg q.d. (812b) for an additional 14 days was well tolerated. Of the 346 patients who received the combination, 12 (3.5%) patients discontinued study drug due to adverse events.

 

 

Adverse Events with an Incidence of 3% or Greater

Adverse Event

Clarithromycin + Omeprazole
(N = 346)
% of Patients

Omeprazole
(N = 355)
% of Patients

Clarithromycin
(N = 166)
% of Patients*

Taste Perversion

15%

1%

16%

Nausea

5%

1%

3%

Headache

5%

6%

9%

Diarrhea

4%

3%

7%

Vomiting

4%

< 1%

1%

Abdominal Pain

3%

2%

1%

Infection

3%

4%

2%

* Studies 067 and 100, only.

 

Most of these events were mild to moderate in severity.

Changes in Laboratory Values

Changes in laboratory values with possible clinical significance in patients taking clarithromycin and omeprazole were as follows:

Hepatic - elevated direct bilirubin < 1%; GGT < 1%; SGOT (AST) < 1%; SGPT (ALT) < 1%.

Renal - elevated serum creatinine < 1%.

Clarithromycin + Ranitidine Bismuth Citrate Therapy

In a U.S. double-blind, randomized, multicenter, dose-comparison trial, ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks plus clarithromycin 500 mg b.i.d. for the first 2 weeks was found to have an equivalent H. pylori eradication rate (based on culture and histology) when compared to ranitidine bismuth citrate 400 mg b.i.d. for 4 weeks plus clarithromycin 500 mg t.i.d. for the first 2 weeks. The intent-to-treat H. pylori eradication rates are shown below:

H. pylori Eradication Rates in Study H2BA-3001

Analysis

RBC 400 mg + Clarithromycin
500 mg b.i.d.

RBC 400 mg + Clarithromycin
500 mg t.i.d.

95% CI Rate Difference

ITT

65% (122/188)

63% (122/195)

(-8%, 12%)

[58%, 72%]

[55%, 69%]

 

Per-Protocol

72% (117/162)

71% (120/170)

(-9%, 12%)

[65%, 79%]

[63%, 77%]

 
 

H. pylorieradication was defined as no positive test at 4 weeks following the end of treatment. Patients must have had two tests performed, and these must have been negative to be considered eradicated of H. pylori . The following patients were excluded from the per-protocol analysis: patients not infected with H. pylori prestudy, dropouts, patients with major protocol violations, patients with missing H. pylori tests. Patients excluded from the intent-to-treat analysis included those not infected with H. pylori prestudy and those with missing H. pylori tests prestudy. Patients were assessed for H. pylori eradication (4 weeks following treatment) regardless of their healing status (at the end of treatment).

The relationship between H. pylori eradication and duodenal ulcer recurrence was assessed in a combined analysis of six U.S. randomized, double-blind, multicenter, placebo-controlled trials using ranitidine bismuth citrate with or without antibiotics. The results from approximately 650 U.S. patients showed that the risk of ulcer recurrence within 6 months of completing treatment was two times less likely in patients whose H. pylori infection was eradicated compared to patients in whom H. pylori infection was not eradicated.

Safety

In clinical trials using combination therapy with clarithromycin plus ranitidine bismuth citrate, no adverse reactions peculiar to the combination of these drugs (using clarithromycin twice daily or three times a day) were observed. Adverse reactions that have occurred have been limited to those reported with clarithromycin or ranitidine bismuth citrate. The most frequent adverse experiences observed in clinical trials using combination therapy with clarithromycin (500 mg three times a day) with ranitidine bismuth citrate (n = 329) were taste disturbance (11%), diarrhea (5%), nausea and vomiting (3%). The most frequent adverse experiences observed in clinical trials using combination therapy with clarithromycin (500 mg twice daily) with ranitidine bismuth citrate (n = 196) were taste disturbance (8%), nausea and vomiting (5%), and diarrhea (4%).

Animal Pharmacology And Toxicology

Clarithromycin is rapidly and well-absorbed with dose-linear kinetics, low protein binding, and a high volume of distribution. Plasma half-life ranged from 1 to 6 hours and was species dependent. High tissue concentrations were achieved, but negligible accumulation was observed. Fecal clearance predominated. Hepatotoxicity occurred in all species tested (i.e., in rats and monkeys at doses 2 times greater than and in dogs at doses comparable to the maximum human daily dose, based on mg/m²). Renal tubular degeneration (calculated on a mg/m² basis) occurred in rats at doses 2 times, in monkeys at doses 8 times, and in dogs at doses 12 times greater than the maximum human daily dose. Testicular atrophy (on a mg/m² basis) occurred in rats at doses 7 times, in dogs at doses 3 times, and in monkeys at doses 8 times greater than the maximum human daily dose. Corneal opacity (on a mg/m² basis) occurred in dogs at doses 12 times and in monkeys at doses 8 times greater than the maximum human daily dose. Lymphoid depletion (on a mg/m² basis) occurred in dogs at doses 3 times greater than and in monkeys at doses 2 times greater than the maximum human daily dose. These adverse events were absent during clinical trials.

 

IMPORTANT NOTE:

This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

 

(kla-RITH-row-MYE-sin)

USES:

Clarithromycin is used to treat a wide variety of bacterial infections. This medication can also be used in combination with anti-ulcer medications to treat certain types of stomach ulcers. It may also be used to prevent certain bacterial infections. Clarithromycin is a macrolide antibiotic that works by stopping the growth of bacteria.

This antibiotic treats only bacterial infections. It will not work for viral infections (e.g., common cold, flu). Unnecessary use or overuse of any antibiotic can lead to its decreased effectiveness.

HOW TO USE:

Take this medication by mouth with or without food, usually twice daily or as directed by your doctor. If stomach upset occurs, you may take it with food or milk.

Antibiotics work best when the amount of medicine in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals, at the same time(s) each day.

The dosage and duration of therapy is based on your medical condition and response to therapy.

If you are using this medication to treat an infection, continue to take this medication until the full-prescribed amount is finished, even if symptoms disappear after a few days. Stopping the medication too early may allow bacteria to continue to grow, which may result in a relapse of the infection. Inform your doctor if your condition persists or worsens.

If you are taking this medication for the prevention of certain bacterial infections, take it exactly as directed by your doctor. Do not stop taking the medication without your doctor's approval.

SIDE EFFECTS:

Diarrhea, nausea, vomiting, stomach upset, changes in taste, and headache may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: hearing loss, mental/mood changes.

Seek immediate medical attention if any of these rare but very serious side effects occur: severe dizziness, fainting, fast/irregular heartbeat.

Tell your doctor immediately if any of these rare but very serious side effects occur: new signs of infection (e.g., fever, persistent sore throat), muscle weakness, persistent nausea/vomiting, severe stomach/abdominal pain, dark urine, yellowing of eyes or skin, change in the amount of urine.

This medication may rarely cause a severe intestinal condition (pseudomembranous colitis) due to a type of resistant bacteria. This condition may occur during treatment or weeks to months after treatment has stopped. Do not use anti-diarrhea products or narcotic pain medications if you have any of the following symptoms because these products may make them worse. Tell your doctor immediately if you develop: persistent diarrhea, abdominal or stomach pain/cramping, blood/mucus in your stool.

Use of this medication for prolonged or repeated periods may result in oral thrush or a new vaginal yeast infection (oral or vaginal fungal infection). Contact your doctor if you notice white patches in your mouth, a change in vaginal discharge or other new symptoms.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects.Something will be added later .

PRECAUTIONS:

Before taking clarithromycin, tell your doctor or pharmacist if you are allergic to it; or to other macrolide antibiotics (e.g., erythromycin, azithromycin); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver or kidney disease, a certain type of muscle disease (myasthenia gravis), certain heart problems (QT prolongation in the EKG, slow heartbeat, heart failure), low potassium or magnesium blood levels, family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death).

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

Based on information for similar drugs, this medication may pass into breast milk. Therefore, consult your doctor before breast-feeding.

DRUG INTERACTIONS:

Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: eletriptan, eplerenone, ergot alkaloids (e.g., ergotamine, dihydroergotamine), ivabradine, quinupristin-dalfopristin, ranolazine, drugs which may affect the heart rhythm (cisapride, pimozide).

If you are currently using any of these medications, tell your doctor or pharmacist before starting clarithromycin.

Other drugs besides clarithromycin and those listed above that may affect the heart rhythm (QT prolongation) include amiodarone, dofetilide, quinidine, sotalol, moxifloxacin, gatifloxacin, thioridazine, propafenone, among others. Before using clarithromycin, report all medications you are currently using to your doctor or pharmacist. QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical attention. Ask your doctor or pharmacist for more details and for instructions on how you may reduce the risk of this effect.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs affecting liver enzymes that remove clarithromycin from your body (such as rifamycins - including rifabutin and rifampin, and azole antifungals - including itraconazole and fluconazole), certain HIV medications (e.g., zidovudine, delavirdine, protease inhibitors such as atazanavir, ritonavir), certain anti-seizure medications (e.g., carbamazepine, phenytoin, valproate), "blood thinners" (e.g., warfarin), colchicine, digoxin, live bacterial vaccines, certain "water pills" (potassium-wasting diuretics such as hydrochlorothiazide, furosemide).

This drug can slow down the removal of other drugs from your body by affecting certain liver enzymes. Some examples of these affected drugs include alfentanil, certain benzodiazepines (e.g., alprazolam, midazolam, triazolam), bromocriptine, cilostazol, corticosteroids (e.g., methylprednisolone), cyclosporine, disopyramide, fentanyl, repaglinide, sildenafil, certain statins (atorvastatin, lovastatin, simvastatin), tacrolimus, tolterodine, theophylline.

This medication may decrease the effectiveness of combination-type birth control pills. This can result in pregnancy. You may need to use an additional form of reliable birth control while using this medication. Consult your doctor or pharmacist for details.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE:

If overdose is suspected, contact your local poison control center or emergency room immediately. Something will be added later .

NOTES:

Do not share this medication with others.

This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases.

Laboratory and/or medical tests (e.g., blood counts, cultures, liver or kidney function tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE:

If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE:

Store at controlled room temperature away from light and moisture. Consult your pharmacist for the specific temperature range for your product. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.