AUGMENTIN XR 1000 MG / 62.5 MG 12HR Extended Release Oral Tablet

WARNINGS

SERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC) REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY.

THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS.

THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS.

BEFORE INITIATING THERAPY WITH AUGMENTIN XR, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS.

IF AN ALLERGIC REACTION OCCURS, AUGMENTIN XR SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED.

SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE.

OXYGEN, INTRAVENOUS STEROIDS, AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including AUGMENTIN XR, 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.

AUGMENTIN XR should be used with caution in patients with evidence of hepatic dysfunction.

Hepatic toxicity associated with the use of amoxicillin/clavulanate potassium is usually reversible.

On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide).

These have generally been cases associated with serious underlying diseases or concomitant medications (see CONTRAINDICATIONS and ADVERSE REACTIONS—Liver).

OVERDOSAGE

Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea.

Rash, hyperactivity, or drowsiness have also been observed in a small number of patients.

In the case of overdosage, discontinue AUGMENTIN XR, treat symptomatically, and institute supportive measures as required.

If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed.

A prospective study of 51 pediatric patients at a poison control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.5 Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients.

In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria.

Renal impairment appears to be reversible with cessation of drug administration.

High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate.

Both amoxicillin and clavulanate are removed from the circulation by hemodialysis (see DOSAGE AND ADMINISTRATION).

DESCRIPTION

AUGMENTIN XR is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin (present as amoxicillin trihydrate and amoxicillin sodium) and the β-lactamase inhibitor clavulanate potassium (the potassium salt of clavulanic acid).

Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus 6-aminopenicillanic acid.

The amoxicillin trihydrate molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.45.

Chemically, amoxicillin trihydrate is (2S,5R ,6R)-6-[(R )-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate and may be represented structurally as: The amoxicillin sodium molecular formula is C16H18N3NaO5S, and the molecular weight is 387.39.

Chemically, amoxicillin sodium is [2S-[2α,5α,6β(S *)]]-6-[[Amino(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid monosodium salt and may be represented structurally as: Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus.

It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes.

Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins.

The clavulanate potassium molecular formula is C8H8KNO5, and the molecular weight is 237.25.

Chemically, clavulanate potassium is potassium (Z)-(2R ,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as: Inactive IngredientsCitric acid, colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, titanium dioxide, and xanthan gum.

Each tablet of AUGMENTIN XR contains 12.6 mg (0.32 mEq) of potassium and 29.3 mg (1.27 mEq) of sodium.

image of chemical structure 1 image of chemical structure 2 image of chemical structure 3

CLINICAL STUDIES

Acute Bacterial SinusitisAdults with a diagnosis of acute bacterial sinusitis (ABS) were evaluated in 3 clinical studies.

In one study, 363 patients were randomized to receive either AUGMENTIN XR 2,000 mg/125 mg orally every 12 hours or levofloxacin 500 mg orally daily for 10 days in a double-blind, multicenter, prospective trial.

These patients were clinically and radiologically evaluated at the test of cure (day 17-28) visit.

The combined clinical and radiological responses were 83.7% for AUGMENTIN XR and 84.3% for levofloxacin at the test of cure visit in clinically evaluable patients (95% CI for the treatment difference = -9.4, 8.3).

The clinical response rates at the test of cure were 87.0% and 88.6%, respectively.

The other 2 trials were non-comparative, multicenter studies designed to assess the bacteriological and clinical efficacy of AUGMENTIN XR (2,000 mg/125 mg orally every 12 hours for 10 days) in the treatment of 2288 patients with ABS.

Evaluation timepoints were the same as in the prior study.

Patients underwent maxillary sinus puncture for culture prior to receiving study medication.

At test of cure, the clinical success rates were 87.5% and 86.6% (intention-to-treat) and 92.5% and 92.1% (per protocol populations).

Patients with acute bacterial sinusitis due to S.

pneumoniae with reduced susceptibility to penicillin were accrued through enrollment in these 2 open-label non-comparative clinical trials.

Microbiologic eradication rates for key pathogens in these studies are shown in the following table: Clinical Outcome for ABS Penicillin MICs of S.

pneumoniae Isolates Intent-To-Treat Clinically Evaluable n/Na % 95% CIb n/Na % 95% CIb All S.

pneumoniae 344/370 93.0 — 318/326 97.5 — MIC ≥ 2.0 mcg/mLc 35/36 97.2 85.5, 99.9 30/31 95.8 83.3, 99.9 MIC = 2.0 mcg/mL 23/24 95.8 78.9, 99.9 19/20 95.0 75.1, 99.9 MIC ≥ 4.0 mcg/mLd 12/12 100 73.5, 100 11/11 100 71.5, 100 H.

influenzae 265/305 86.9 — 242/259 93.4 — M.

catarrhalis 94/105 89.5 — 86/90 95.6 — a n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.

b Confidence limits calculated using exact probabilities.

c S.

pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.

d Includes one patient each with S.

pneumoniae penicillin MICs of 8 and 16 mcg/mL.

Community-Acquired PneumoniaFour randomized, controlled, double-blind clinical studies and one non-comparative study were conducted in adults with community-acquired pneumonia (CAP).

In comparative studies, 904 patients received AUGMENTIN XR at a dose of 2,000 mg/125 mg orally every 12 hours for 7 or 10 days.

In the non-comparative study to assess both clinical and bacteriological efficacy, 1,122 patients received AUGMENTIN XR 2,000 mg/125 mg orally every 12 hours for 7 days.

In the 4 comparative studies, the combined clinical success rate at test of cure ranged from 86.3% to 94.7% in clinically evaluable patients who received AUGMENTIN XR; in the non-comparative study, the clinical success rate was 85.6%.

Data on the efficacy of AUGMENTIN XR in the treatment of community-acquired pneumonia due to S.

pneumoniae with reduced susceptibility to penicillin were accrued from the 4 controlled clinical studies and the 1 non-comparative study.

The majority of these cases were accrued from the non-comparative study.

Clinical Outcome for CAP due to S.

pneumoniae Penicillin MICs of S.

pneumoniae Isolates Intent-To-Treat Clinically Evaluable n/Na % 95% CIb n/N a % 95% CIb All S.

pneumoniae 318/367 86.6 — 275/297 92.6 — MIC ≥ 2.0 mcg/mLc 30/35 85.7 69.7, 95.2 24/25 96.0 79.6, 99.9 MIC = 2.0 mcg/mL 22/24 91.7 73.0, 99.0 18/18 100 81.5, 100 MIC ≥ 4.0 mcg/mLd 8/11 72.7 39.0, 94.0 6/7 85.7 42.1, 99.6 a n/N = patients with pathogen eradicated or presumed eradicated/total number of patients.

b Confidence limits calculated using exact probabilities.

c S.

pneumoniae strains with penicillin MICs of ≥ 2 mcg/mL are considered resistant to penicillin.

d Includes one patient each with S.

pneumoniae penicillin MICs of 8 and 16 mcg/mL in the Intent-To-Treat group only.

SafetyIn 2 randomized, double-blind, multicenter studies, AUGMENTIN XR (2,000 mg/125 mg orally every 12 hours, n = 577) was compared to AUGMENTIN (875 mg/125 mg orally every 12 hours, n = 570), administered for 7 days for the treatment of community-acquired pneumonia.

Adverse events, regardless of relationship to test drug, were reported by 44.4% of patients who received AUGMENTIN XR (versus 46.3% in comparator group).

Treatment-related adverse events were reported in 21.7% of patients who received AUGMENTIN XR (versus 21.2% in comparator group); most were mild and transient in nature.

Adverse events which led to withdrawal were reported by 2.8% of patients who received AUGMENTIN XR (versus 5.3% in comparator group).

In each group, the most frequently reported adverse events were diarrhea (14.4% versus 13.0%, p = 0.47), nausea (3.5 % versus 4.4%), and headache (3.5% versus 3.2%).

Only 2 patients (0.3%) who received AUGMENTIN XR and 3 patients (0.5%) in the comparator group withdrew due to diarrhea.

Serious adverse events considered suspected or probably related to test drug were reported in 0.3% of patients (versus 0.5% in comparator).

HOW SUPPLIED

AUGMENTIN XR Extended Release TabletsEach white, oval film-coated bilayer scored tablet, debossed with AUGMENTIN XR, contains amoxicillin trihydrate and amoxicillin sodium equivalent to a total of 1,000 mg of amoxicillin and clavulanate potassium equivalent to 62.5 mg of clavulanic acid.

NDC 54868-4735-0 Bottles of 20 NDC 54868-4735-2 Bottles of 28 (7 day XR pack) NDC 54868-4735-1 Bottles of 40 (10 day XR pack)

INDICATIONS AND USAGE

AUGMENTIN XR Extended Release Tablets are indicated for the treatment of patients with community-acquired pneumonia or acute bacterial sinusitis due to confirmed, or suspected β-lactamase−producing pathogens (i.e., H.

influenzae, M.

catarrhalis, H.

parainfluenzae, K.

pneumoniae, or methicillin-susceptible S.

aureus) and S.

pneumoniae with reduced susceptibility to penicillin (i.e., penicillin MICs = 2 mcg/mL).

AUGMENTIN XR is not indicated for the treatment of infections due to S.

pneumoniae with penicillin MICs ≥ 4 mcg/mL.

Data are limited with regard to infections due to S.

pneumoniaewith penicillin MICs ≥ 4 mcg/mL (see CLINICAL STUDIES).

Of the common epidemiological risk factors for patients with resistant pneumococcal infections, only age > 65 years was studied.

Patients with other common risk factors for resistant pneumococcal infections (e.g., alcoholism, immune-suppressive illness, and presence of multiple co-morbid conditions) were not studied.

In patients with community-acquired pneumonia in whom penicillin-resistant S.

pneumoniae is suspected, bacteriological studies should be performed to determine the causative organisms and their susceptibility when AUGMENTIN XR is prescribed.

Acute bacterial sinusitis or community-acquired pneumonia due to a penicillin-susceptible strain of S.

pneumoniae plus a β-lactamase−producing pathogen can be treated with another AUGMENTIN® (amoxicillin/clavulanate potassium) product containing lower daily doses of amoxicillin (i.e., 500 mg every 8 hours or 875 mg every 12 hours).

Acute bacterial sinusitis or community-acquired pneumonia due to S.

pneumoniae alone can be treated with amoxicillin.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of AUGMENTIN XR and other antibacterial drugs, AUGMENTIN XR should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy.

In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION

AUGMENTIN XR should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance.

Absorption of the amoxicillin component is decreased when AUGMENTIN XR is taken on an empty stomach (see CLINICAL PHARMACOLOGY).

The recommended dose of AUGMENTIN XR is 4,000 mg/250 mg daily according to the following table: Indication Dose Duration Acute bacterial sinusitis 2 tablets q12h 10 days Community-acquired pneumonia 2 tablets q12h 7-10 days Tablets of AUGMENTIN (250 mg or 500 mg) CANNOT be used to provide the same dosages as AUGMENTIN XR Extended Release Tablets.

This is because AUGMENTIN XR contains 62.5 mg of clavulanic acid, while the AUGMENTIN 250-mg and 500-mg tablets each contain 125 mg of clavulanic acid.

In addition, the Extended Release Tablet provides an extended time course of plasma amoxicillin concentrations compared to immediate-release Tablets.

Thus, two AUGMENTIN 500-mg tablets are not equivalent to one AUGMENTIN XR tablet.

Scored AUGMENTIN XR Extended Release Tablets are available for greater convenience for adult patients who have difficulty swallowing.

The scored tablet is not intended to reduce the dosage of medication taken; as stated in the table above, the recommended dose of AUGMENTIN XR is two tablets twice a day (every 12 hours).

Renally Impaired PatientsThe pharmacokinetics of AUGMENTIN XR have not been studied in patients with renal impairment.

AUGMENTIN XR is contraindicated in patients with a creatinine clearance of < 30 mL/min.

and in hemodialysis patients (see CONTRAINDICATIONS).

Hepatically Impaired PatientsHepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals (see WARNINGS).

Pediatric UsePediatric patients who weigh 40 kg or more and can swallow tablets should receive the adult dose.

Geriatric UseNo dosage adjustment is required for the elderly (see PRECAUTIONS, Geriatric Use).