Biaxin (Clarithromycin)

BIAXIN®

Abbott

Clarithromycin

Antibiotic

Note: When used in combination with acid antisecretory drugs and other antimicrobials for the eradication of helicobacter pylori, the product monograph for those agents should be consulted.

Action And Clinical Pharmacology: General: Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunit of susceptible bacteria and suppressing protein synthesis.

Eradication of H. pylori: H. pylori is now established as a major etiological factor in duodenal ulcer disease. The presence of H. pylori may damage the mucosal integrity due to the production of enzymes (catalase, lipases, phospholipases, proteases, and urease), adhesins and toxins; the generated inflammatory response contributes to mucosal damage.

The concomitant administration of an antimicrobial(s) such as clarithromycin and an antisecretory agent, improves the eradication of H. pylori as compared to individual drug administration. The higher pH resulting from antisecretory treatment, optimizes the environment for the pharmacologic action of the antimicrobial agent(s) against H. pylori.

Pharmacokinetics: Tablets: The absolute bioavailability of 250 mg and 500 mg clarithromycin tablets is approximately 50%. Food slightly delays the onset of clarithromycin absorption but does not affect the extent of bioavailability. Therefore, clarithromycin tablets may be given without regard to meals.

In fasting healthy human subjects, peak serum concentrations are attained within 2 hours after oral dosing. Steady-state peak serum clarithromycin concentrations, which are attained within 2 to 3 days, are approximately 1 mg/L with a 250 mg dose twice daily and 2 to 3 mg/L with a 500 mg dose twice daily. The elimination half-life of clarithromycin is about 3 to 4 hours with 250 mg twice daily dosing but increases to about 5 to 7 hours with 500 mg administered twice daily.

The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 mg and 500 mg administered twice daily. With 250 mg twice daily, the principal metabolite, 14-OH clarithromycin attains a peak steady-state concentration of about 0.6 mg/L and has an elimination half-life of 5 to 6 hours. With a 500 mg twice daily dose, the peak steady-state of 14-OH concentrations of clarithromycin are slightly higher (up to 1 mg/L) and its elimination half-life is about 7 hours. With either dose, the steady-state concentration of this metabolite is generally attained within 2 to 3 days.

Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500 mg doses of clarithromycin twice a day to adult patients with HIV infection were similar to those observed in healthy volunteers. However, at the higher clarithromycin doses which may be required to treat mycobacterial infections, clarithromycin concentrations can be much higher than those observed at 500 mg clarithromycin doses. In adult HIV-infected patients taking 2 000 mg/day in 2 divided doses, steady-state clarithromycin Cmax values ranged from 5 to 10 mg/mL. Cmax values as high as 27 mg/L have been observed in HIV-infected adult patients taking 4 000 mg/day in 2 divided doses of tablets.

Elimination half-lives appeared to be lengthened at these higher doses as well. The higher clarithromycin concentrations and longer elimination half-lives observed at these doses are consistent with the known nonlinearity in clarithromycin pharmacokinetics.

Clarithromycin 500 mg t.i.d. and omeprazole 40 mg once daily were studied in fasting healthy adult subjects. When clarithromycin was given alone as 500 mg q 8 h, the mean steady-state Cmax value was approximately 3.8 µg/mL and the mean Cmin value was approximately 1.8 g/mL. The mean AUC0-8 for clarithromycin was 22.9 gh/mL. The Tmax and half-life were 2.1 hours and 5.3 hours, respectively, when clarithromycin was dosed at 500 mg t.i.d.

When clarithromycin was administered with omeprazole, increases in omeprazole half-life and AUC0-24 were observed. For all subjects combined, the mean omeprazole AUC0-24 was 89% greater and the harmonic mean for omeprazole t 1/2 was 34% greater when omeprazole was administered with clarithromycin than when omeprazole was administered alone. When clarithromycin was administered with omeprazole, the steady-state Cmax, Cmin, and AUC0-8 of clarithromycin were increased by 10%, 27%, and 15%, respectively over values achieved when clarithromycin was administered with placebo.

Pediatric Granules for Suspension: Single and multiple dose adult volunteer studies showed that the suspension formulation was not significantly different from the tablet formulation in terms of Cmax of clarithromycin and AUC, although the onset and/or rate of absorption of the suspension formulation was slower than that of the tablet. As with the tablet formulation, steady state is achieved by the fifth dose of a 12-hour multiple dose suspension regimen.

In children taking 15 to 30 mg/kg/day in 2 divided doses, steady-state clarithromycin Cmax values generally ranged from 8 to 20 g/mL. Cmax values as high as 23 µg/mL have been observed in HIV-infected pediatric patients taking 30 mg/kg/day in 2 divided doses.

In children requiring antibiotic therapy, administration of 7.5 mg/kg q 12 h 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 g/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 g/mL.

A single and multiple dose study conducted in pediatric patients showed that food leads to a slight delay in the onset of absorption, but does not affect the overall bioavailability of clarithromycin.

Clarithromycin and its 14-OH metabolite penetrate into middle ear effusion (MEE) of patients with secretory otitis media.

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

Patients With Hepatic and Renal Impairment: 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 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).

Indications And Clinical Uses: Tablets: In the treatment of mild to moderate infections caused by susceptible strains of the designated microorganisms in the diseases listed below:

Upper Respiratory Tract: Pharyngitis/tonsillitis, caused by S. pyogenes (Group A beta-hemolytic streptococci).

Acute maxillary sinusitis caused by S. pneumoniae. H. influenzae and M. (Branhamella) catarrhalis.

Lower Respiratory Tract: Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, H. influenzae (including beta-lactamase producing strains), M. (Branhamella) catarrhalis (including beta-lactamase producing strains).

Pneumonia caused by S. pneumoniae and M. pneumoniae.

Uncomplicated Skin and Skin Structure Infections: caused by S. pyogenes, S. aureus.

Mycobacterial Infections: For the prevention of disseminated M. avium complex (MAC) disease in patients with advanced HIV infection, and for the treatment of disseminated mycobacterial infections due to M. avium and M. intracellulare.

Eradication of H. pylori: In the presence of acid suppression (with omeprazole), with another antibiotic (amoxicillin) is indicated for the eradication of H. pylori that may result in decreased recurrence of duodenal ulcer in patients with active duodenal ulcers and who are H. pylori positive.

(For additional information on the use of clarithromycin in triple therapy for the treatment of H. pylori infection and active duodenal ulcer recurrence, refer to the Hp-PAC product monograph.)

Pediatric Granules for Suspension: Indicated for the treatment of infections due to susceptible organisms, in the following conditions: Upper Respiratory Tract: Pharyngitis caused by S. pyogenes (Group A B-hemolytic streptococci). Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae.

Lower Respiratory Tract: Mild to moderate community-acquired pneumonia caused by S. pneumoniae, C. pneumoniae or M. pneumoniae.

Uncomplicated Skin and Skin Structure Infections (i.e., impetigo and cellulitis) caused by S. aureus or S. pyogenes.

Mycobacterial Infections: Disseminated mycobacterial infections due to M. avium and M. intracellulare.

Contra-Indications: Patients with a known hypersensitivity to clarithromycin, erythromycin or other macrolide antibacterial agents.

Concurrent therapy with astemizole, terfenadine, cisapride or pimozide (see Precautions, Drug Interactions).

Manufacturers’ Warnings In Clinical States: Clarithromycin should be administered with caution to any patient who has demonstrated some form of drug allergy, particularly to structurally related drugs. If an allergic reaction to clarithromycin occurs, administration of the drug should be discontinued.

Serious hypersensitivity reactions may require epinephrine, antihistamines or corticosteroids.

Several studies of HIV positive patients receiving clarithromycin for treatment of M. avium complex infection (MAC) have shown poorer survival in those patients randomized to receive doses higher than 500 mg b.i.d. The explanation for the poorer survival associated with doses higher than 500 mg b.i.d. has not been determined. Treatment or prophylaxis of MAC infection with clarithromycin should not exceed the approved dose of 500 mg b.i.d.

Pregnancy: Clarithromycin should not be used in pregnancy except where no alternative therapy is appropriate, particularly during the first 3 months of pregnancy. If pregnancy occurs while taking the drug, the patient should be apprised of the potential hazard to the fetus. Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryo-fetal development in monkeys, mice, rats and rabbits at doses that produced plasma levels 2 to 17 times the serum levels obtained in humans treated at the maximum recommended doses.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents, including clarithromycin.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C. difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile.

Precautions: General: Clarithromycin is principally excreted by the liver and kidney (see Dosage). In patients with both hepatic and renal impairments or in the presence of severe renal impairment, decreased dosage of clarithromycin or prolonged dosing intervals might be appropriate.

The development of resistance (11 out of 19 breakthrough isolates in one study) has been seen in HIV positive patients receiving clarithromycin for prophylaxis and treatment of MAC infection.

H. pylori Eradication and Compliance: To avoid failure of the eradication treatment with a potential for developing antimicrobial resistance and a risk of failure with subsequent therapy, patients should be instructed to follow closely the prescribed regimen.

For the eradication of H. pylori, amoxicillin and clarithromycin should not be administered to patients with renal impairment since the appropriate dosage in this patient population has not yet been established.

Antibiotic Resistance in Relation to H. pylori Eradication: Triple and Dual Therapy with Omeprazole: Among the 113 triple therapy recipients with pretreatment H. pylori isolates susceptible to clarithromycin, 2/102 patients (2%) developed resistance after treatment with omeprazole, clarithromycin, and amoxicillin. Among patients who received triple therapy, 6/108 (5.6%) patients had pretreatment H. pylori isolates resistant to clarithromycin. Of these 6 patients, 3 (50%) had H. pylori eradicated at follow-up, and 3 (50%) remained positive after treatment. In 5/113 (4.4%) patients, no susceptibility data for clarithromycin pretreatment were available. Twenty-six patients 26/104 (25%) with pretreatment isolates susceptible to clarithromycin developed resistance after treatment with omeprazole and clarithromycin.

Development of clarithromycin resistance should be considered as a possible risk especially when less efficient treatment regimens are used.

Drug Interactions: Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.

Carbamazepine: Clarithromycin administration in patients receiving carbamazepine has been reported to cause increased levels of carbamazepine. Blood level monitoring of carbamazepine may be considered.

Terfenadine/Astemizole: Macrolides have been reported to alter the metabolism of terfenadine resulting in increased serum levels of terfenadine which has occasionally been associated with cardiac arrhythmias such as QT prolongation, ventricular tachycardia, ventricular fibrillation and torsades de pointes (see Contraindications).

In a study involving 14 healthy volunteers, the concomitant administration of clarithromycin tablets and terfenadine resulted in a 2- to 3-fold increase in the serum level of the acid metabolite of terfenadine, MDL 16, 455, and in prolongation of the QT interval which did not lead to any clinically detectable effect. Similar effects have been observed with concomitant administration of astemizole and other macrolides.

Cisapride/Pimozide: Elevated cisapride levels have been reported in patients receiving clarithromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed in patients taking clarithromycin and pimozide concomitantly (see Contraindications).

Zidovudine: Simultaneous oral administration of clarithromycin tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Clarithromycin appears to interfere with the absorption of simultaneously administered oral zidovudine, therefore this interaction can be largely avoided by staggering the doses of clarithromycin and zidovudine.

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

Fluconazole: 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.

Digoxin: Elevated digoxin serum concentrations have been reported in patients receiving clarithromycin tablets and digoxin concomitantly. In postmarketing surveillance, some patients have shown clinical signs consistent with digoxin toxicity, including arrhythmias. Serum digoxin levels should be carefully monitored while patients are receiving digoxin and clarithromycin simultaneously.

Ritonavir: A pharmacokinetic study demonstrated that the concomitant administration of ritonavir 200 mg q 8 hours and clarithromycin 500 mg q 12 hours resulted in a marked inhibition of the metabolism of clarithromycin. The clarithromycin Cmax increased by 31%, Cmin increased 182% and AUC increased by 77% with concomitant administration of ritonavir. An essentially complete inhibition of the formation of 14-[R]-hydroxy-clarithromycin was noted. Because of the large therapeutic window for clarithromycin, no dosage reduction should be necessary in patients with normal renal function. 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%.

Lovastatin/Simvastatin: Rhabdomyolysis coincident with the coadministration of clarithromycin and the HMG-CoA reductase inhibitors, lovastatin and simvastatin, has rarely been reported.

Combination Therapy With Omeprazole and/or Amoxicillin: For more information on drug interactions for omeprazole and amoxicillin, refer to their respective product monographs, under Precautions, Drug Interactions.

Others: As with other macrolide antibiotics, the use of clarithromycin in patients concurrently taking drugs metabolized by the cytochrome P450 system (e.g., warfarin, ergot alkaloids, triazolam, midazolam, lovastatin, disopyramide, phenytoin, cyclosporine and rifabutin) may be associated with elevations in serum levels of these other drugs.

There have been reports of drug interactions when erythromycin, another macrolide, has been given concomitantly with drugs metabolized by the cytochrome P450 system, such as hexobarbital, alfentanil, bromocriptine or valproate. Serum concentrations of drugs metabolized by the cytochrome P450 system should be monitored closely in patients concurrently receiving erythromycin.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. The benefits against risk, particularly during the first 3 months of pregnancy should be carefully weighed by a physician (see Warnings). Four teratogenicity studies in rats (3 with oral doses and 1 with i.v. doses up to 160 mg/kg/day administered during the period of major organogenesis) and 2 in rabbits (at oral doses up to 125 mg/kg/day or i.v. 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 1 000 mg/kg/day during gestation days 6 to 15. Cleft palate was also seen at 500 mg/kg/day. The 1 000 mg/kg/day exposure resulted in plasma levels 17 times the human serum levels. In monkeys, an oral dose of 70 mg/kg/day produced fetal growth retardation at plasma levels that were 2 times the human serum levels.

Embryonic loss has been seen in monkeys and rabbits.

Lactation: The safety of clarithromycin for use during breast-feeding of infants has not been established. Clarithromycin is 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.

Children: Use of clarithromycin tablets in children under 12 years of age has not been studied.

Use of clarithromycin granules for suspension in children under 6 months has not been studied. In pneumonia, clarithromycin granules were not studied in children younger than 3 years.

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.

Increased valproate and phenobarbital concentrations and extreme sedation were noted in a 3-year-old patient coincident with clarithromycin therapy. Cause and effect relationship cannot be established. However, monitoring of valproate and phenobarbital concentrations may be considered.

Geriatrics: Dosage adjustment should be considered in elderly patients with severe renal impairment. 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 concentrations of clarithromycin and 14-OH clarithromycin were increased. The AUC was also increased. 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.

Adverse Reactions: Tablets: Patients With Respiratory Tract or Skin Infections: The majority of side effects observed in clinical trials involving 3 563 patients treated with clarithromycin were of a mild and transient nature. Fewer than 3% of adult patients without mycobacterial infections discontinued therapy because of drug-related side effects.

The following adverse reactions were reported during these clinical studies or during postmarketing surveillance: Body as a Whole: headache (2%), asthenia, infection, back pain, pain and chest pain.

Digestive: nausea (4%), diarrhea (3%), abdominal pain (2%), dyspepsia (2%), vomiting (1%), constipation, flatulence, dry mouth, glossitis, stomatitis, gastrointestinal disorder, anorexia, oral moniliasis, tongue discoloration, hepatomegaly and pseudomembranous colitis. There have been reports of tooth discoloration in patients treated with clarithromycin. Tooth discoloration is usually reversible with professional dental cleaning.

As with other macrolides, 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.

Metabolic: There have been rare reports of hypoglycemia, some of which have occurred in patients on concomitant oral hypoglycemic agents or insulin.

Nervous System: dizziness, vertigo, tinnitus, nervousness, anxiety, insomnia, nightmares, somnolence, depression, confusion, disorientation, depersonalization, hallucinations and psychosis.

Respiratory: rhinitis, cough increased, dyspnea, pharyngitis and asthma.

Skin and Appendages: pruritus, rash, sweating; allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis and Stevens-Johnson syndrome have occurred with orally administered clarithromycin.

Special Senses: taste perversion (2%), ear disorder, abnormal vision and conjunctivitis. There have been reports of hearing loss with clarithromycin which is usually reversible upon withdrawal of therapy. Reports of alteration of the sense of smell, usually in conjunction with taste perversion have also been reported.

Urogenital: hematuria, vaginal moniliasis, vaginitis and dysmenorrhea.

Hemic and Lymphatic: eosinophilia, anemia, leukopenia and thrombocythemia. Isolated cases of thrombocytopenia have been reported.

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

Hepatic: elevated ALT
Hematologic: decreased WBC
Renal: elevated BUN (4%) and elevated serum creatinine
Others: The following adverse reactions have not been observed in clinical trials with clarithromycin but they have been occasionally reported with erythromycin, another macrolide: cardiac arrhythmias such as ventricular tachycardia and torsades de pointes in individuals with prolonged QT intervals and CNS side effects (including seizures).

In studies of adults with pneumonia comparing clarithromycin to erythromycin base or erythromycin stearate, there were significantly fewer adverse events involving the digestive system in patients treated with clarithromycin.

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

(Other adverse reactions have been observed in different patient populations. Please also refer to Patients With Respiratory Tract or Skin Infections.)

Prophylaxis: Discontinuation due to adverse events was required in 18% of AIDS patients receiving clarithromycin 500 mg b.i.d., compared to 17% of patients receiving placebo in a randomized, double-blind study (561). Primary reasons for discontinuation in the clarithromycin-treated patients include headache, nausea, vomiting, depression and taste perversion. The most frequently reported adverse events with an incidence of 2% or greater, excluding those due to the patient’s concurrent condition, are listed in Table I. Among these events, taste perversion was the only event that had significantly higher incidence in the clarithromycin-treated compared to the placebo-treated group.

Changes in Laboratory Values: In immunocompromised patients receiving prophylaxis against M. avium, those laboratory values outside the extreme high or low limit for the specified test were analyzed (see Table II).

Treatment of Patients with Mycobacterial Infections: Excluding those patients who discontinued therapy due to complications of their underlying nonmycobacterial diseases (including death), approximately 14% of the patients discontinued therapy due to drug-related adverse events.

In adult patients, the most frequently reported adverse events with an incidence of 3% or greater, excluding those due to the patient’s concurrent condition, are listed in Table III by the total daily dose the patient was receiving at the time of the event. A total of 867 patients were treated with clarithromycin for mycobacterial infections. Of these, 43% reported one or more adverse events. Most of these events were described as mild to moderate in severity, although 14% were described as severe.

Incidence of adverse events was higher in patients taking 4 000 mg doses compared to lower doses (see Table III).

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, are listed in Table IV by the total daily dose of clarithromycin the patient received.

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 (see Tables V and VI).

Patients With H. pylori Infection: Triple Therapy: Clarithromycin/omeprazole/amoxicillin: Forty-four percent (60/137) of the patients in the triple therapy group and 43% (56/130) of the patients in the dual therapy group reported at least 1 adverse event; this difference between the two treatment groups was not statistically significant (p > 0.999).

Similarly, there was no statistically significant difference (p > 0.999) between the treatment groups for the number of patients reporting one or more drug-related adverse events. Thirty-three percent (33%; 45/137) of the patients in the triple therapy group reported adverse events considered possibly or probably related to study drug, compared with 32% (42/130) of the patients in the dual therapy group (p > 0.999). The rate of drug-related adverse events when evaluated by body system was very similar for both treatment groups. However, a trend toward statistical significance was noted for drug-related adverse events associated with special senses. The most common special sense adverse event was taste perversion, which was reported more frequently in patients treated with dual therapy as compared to triple therapy (18%, 23/130 vs 9%, 13/137, respectively; p = 0.072).

Patients With H. pylori Infection: Dual Therapy: Clarithromycin/omeprazole: Of 346 patients, 156 (45%) reported at least one adverse event. Adverse events associated with the digestive, body as a whole, and special senses body systems were the most commonly reported adverse events among clarithromycin/omeprazole-treated patients. Eighty-three patients (24%) reported digestive system adverse events. The adverse events occurring most frequently in the digestive system were gastrointestinal events, of which nausea (5%), diarrhea (4%), vomiting (3%), and abdominal pain (3%) were the most common. Fifty-seven patients (16%) reported adverse events in the body as a whole body system. Headache (5%), infection (3%), and pain (2%) were the most frequently reported events in the body as a whole category. Fifty-four patients (16%) reported adverse events in the special senses body system; taste perversion was reported by 53 of these patients.

(Other adverse reactions have been observed in different patient populations. Please also refer to Patients With Respiratory Tract or Skin Infections.)

The most commonly reported adverse events for the 346 patients who received clarithromycin and omeprazole were: taste perversion (15%), nausea (5%), headache (5%), diarrhea (4%), vomiting (3%), abdominal pain (3%), and infection (3%). Table IX presents adverse events reported by 1% or more of clarithromycin/omeprazole-treated patients.

Twelve (4%) of the clarithromycin/omeprazole-treated patients prematurely discontinued from study drug therapy due to adverse events. The most frequently reported adverse events leading to withdrawal included taste perversion, nausea, and headache.

Three patients treated with clarithromycin and omeprazole died during follow-up periods; none of the deaths were considered by the investigator to be related to study drug administration.

Few laboratory abnormalities were observed among clarithromycin/omeprazole-treated patients. The incidence of possibly clinically significant hematology and serum chemistry variables was
Pediatric Granules for Suspension: The safety profile of clarithromycin pediatric granules for suspension is similar to that of the 250 mg tablet in adult patients. (Please also refer to Patients With Respiratory Tract or Skin Infections).

As with other macrolides, 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.

Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis and Stevens-Johnson syndrome have occurred with orally administered clarithromycin.

571/1 829 (31%) of the patients who received clarithromycin pediatric granules reported at least 1 adverse event.

The majority of the patients with adverse events reported events in the digestive (302; 17%) and body as a whole (168; 9%) body systems.

The events occurring most frequently in the digestive system were gastrointestinal events of which diarrhea (7%), vomiting (7%), abdominal pain (3%), dyspepsia (3%) and nausea (1%) were the most common. Glossitis, stomatitis and oral monilia have also been reported with clarithromycin therapy.

Other adverse events included infection (3%), rhinitis (2.2%), rash (2.2%), increased cough (2.1%), fever (2.2%), headache (1.6%), conjunctivitis (1.1%), taste perversion (3%) and transient elevation of AST (0.9%).

The majority of adverse events were considered by the investigators to have either mild or moderate severity. 375/1 829 patients (21%) had a mild adverse events, 175/1 829 patients (10%) had moderate adverse events and 20/1 829 patients (1%) had severe adverse events.

In the 2 U.S. acute otitis media studies of clarithromycin vs antimicrobial/beta-lactamase inhibitor, 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 or statistically lower in the clarithromycin arm vs the control arm.

In another U.S. otitis media study of clarithromycin vs cephalosporin, the incidence of adverse events in all patients treated, primarily diarrhea and vomiting, did not differ clinically or statistically for the two agents.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Reports indicate that the ingestion of large amounts of clarithromycin can be expected to produce gastrointestinal symptoms. Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures.

Clarithromycin is protein bound (70%). No data are available on the elimination of clarithromycin by hemodialysis or peritoneal dialysis.

Dosage And Administration: May be given with or without meals.

Tablets: Adults with Respiratory Tract or Skin Infections: The usual adult dosage is 250 to 500 mg every 12 hours for 7 to 14 days.

For more severe infections or those caused by less susceptible organisms, the upper dosage should be used.

In the treatment of Group A streptococcus infections, therapy should be continued for 10 days. The usual drug of choice in the treatment of streptococcal infections and the prophylaxis of rheumatic fever is penicillin administered by either the i.m. or the oral route. Clarithromycin is generally effective in the eradication of S. pyogenes from the nasopharynx; however, data establishing the efficacy of clarithromycin in the subsequent prevention of rheumatic fever are not presently available.

In patients with renal impairment and a creatinine clearance less than 30 mL/min, the dosage of clarithromycin should be reduced by one-half, i.e., 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients.

In patients with both hepatic and renal impairments or in the presence of severe renal impairment, decreased dosage of clarithromycin or prolonged dosing intervals may be appropriate. Clarithromycin may be administered without dosage adjustment in the presence of hepatic impairment if there is normal renal function.

Eradication of H. pylori: Triple Therapy: Clarithromycin/ omeprazole/amoxicillin: The recommended dose is clarithromycin 500 mg b.i.d. in conjunction with amoxicillin 1 g b.i.d. and omeprazole 20 mg daily for 10 days.

For more information on omeprazole or amoxicillin, refer to their respective Product Monographs, under Dosage.

(For additional information on the use of clarithromycin in triple therapy for the treatment of H. pylori infection and active duodenal ulcer recurrence, refer to the Hp-PAC product monograph.)

Dual Therapy: Clarithromycin/omeprazole: In patients who are sensitive to penicillin-based therapy (e.g., amoxicillin), dual therapy with clarithromycin and omeprazole may provide a feasible alternative.

The recommended dose is clarithromycin 500 mg t.i.d plus omeprazole 40 mg daily for 14 days, followed by 20 mg omeprazole daily for 14 days.

Optimal therapeutic regimens consisting of a shorter treatment duration for the eradication of H. pylori are yet to be determined.

Adults with Mycobacterial Infections: Prophylaxis: The recommended dose of clarithromycin for the prevention of disseminated M. avium disease is 500 mg b.i.d.

Treatment: Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to M. avium complex. Clarithromycin should be used in combination with other antimycobacterial drugs which have shown in vitro activity against MAC, including ethambutol, clofazimine, and rifampin. Although no controlled clinical trial information is available for combination therapy with clarithromycin, the U.S. Public Health Service Task Force has provided recommendations for the treatment of MAC.

The recommended dose for mycobacterial infections in adults is 500 mg b.i.d.

Treatment of disseminated MAC infections in AIDS patients should continue for life if clinical and mycobacterial improvement are observed.

Pediatric Granules for Suspension: The recommended daily dosage of clarithromycin is 15 mg/kg/day, in divided doses every 12 hours, not to exceed 1 000 mg/day. The usual duration of treatment is for 5 to 10 days depending on the pathogen involved and the severity of the condition. Treatment for pharyngitis caused by Streptococcal spp. should be 10 days.

In children with renal impairment and a creatinine clearance less than 30 mL/min, the dosage of clarithromycin should be reduced by one-half, i.e., up to 250 mg once daily, or 250 mg twice daily in more severe infections. Dosage should not be continued beyond 14 days in these patients. Table XII is a suggested guide for determining dosage.

The reconstituted suspension must not be refrigerated.

Children with Mycobacterial Infections: Clarithromycin is recommended as the primary agent for the treatment of disseminated infection due to M. avium complex. Clarithromycin should be used in combination with other antimycobacterial drugs which have shown in vitro activity against MAC, including ethambutol, clofazimine, and rifampin. Although no controlled clinical trial information is available for combination therapy with clarithromycin, the U.S. Public Health Service Task Force has provided recommendations for the treatment of MAC.

In children, the recommended dose is 7.5 mg/kg b.i.d. up to 500 mg b.i.d. clarithromycin/day in 2 divided doses. Dosing recommendations for children are in Table XII.

Treatment of disseminated MAC infections in AIDS patients should continue for life if clinical and mycobacterial improvement are observed.

Availability And Storage: Pediatric Granules for Suspension: HDPE bottle which allows capacity for shaking consists of a: granulation of clarithromycin and carbopol which is coated with HP-55 polymer (hydroxypropylmethylcellulose phthalate). Nonmedicinal ingredients: castor oil, citric acid, flavor, potassium sorbate, povidone (K90), saccharine, silicon dioxide, sodium chloride, sucrose and xanthan gum. Water is added to reconstitute the suspension prior to use. When reconstituted, the concentration of clarithromycin is 125 mg/5 mL. HDPE bottles of 55, 105 and 150 mL. Store granules for suspension between 15 and 25°C in a tightly closed bottle. Protect from light. Do not refrigerate suspension.

Directions for reconstitution: 150 mL size: 80 mL of water should be added to the granules in the bottle and shaken to yield 150 mL of reconstituted suspension.

105 mL size: 56 mL of water should be added to the granules in the bottle and shaken to yield 105 mL of reconstituted suspension.

55 mL size: 29 mL of water should be added to the granules in the bottle and shaken to yield 55 mL of reconstituted suspension.

The reconstituted suspension must not be refrigerated. Any reconstituted unused medication should be discarded after 14 days.

Tablets: 250 mg: Each oval, debossed, yellow, film-coated tablet contains: clarithromycin 250 mg. Nonmedicinal ingredients: cellulosic polymers, crosscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, pregelatinized starch, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide and vanillin. Tartrazine-free. HDPE bottles of 100, 250 and 500.

500 mg: Each oval, debossed, pale yellow, film-coated tablet contains: clarithromycin 500 mg. Nonmedicinal ingredients: cellulosic polymers, crosscarmellose sodium, D&C Yellow No. 10, magnesium stearate, povidone, propylene glycol, silicon dioxide, sorbic acid, sorbitan monooleate, stearic acid, talc, titanium dioxide and vanillin. Tartrazine-free. HDPE bottles of 100 and 250.

Store tablets between 15 and 25°C in a tightly closed container. Protect from light.

BIAXIN® Abbott Clarithromycin Antibiotic Note: When used in combination with acid antisecretory drugs and other antimicrobials for the eradication of helicobacter pylori, the product monograph for those agents should be consulted.

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