Augmentin ES-600

Amoxicillin and clavulanate combination is used to treat bacterial infections in many different parts of the body.

Amoxicillin and clavulanate combination is an antibiotic that belongs to the group of medicines known as penicillins and beta-lactamase inhibitors. It works by killing the bacteria and preventing their growth. However, this medicine will not work for colds, flu, or other virus infections.

This medicine is available only with your doctor's prescription.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of amoxicillin and clavulanate chewable tablets and oral suspension in children.

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of amoxicillin and clavulanate tablets in children weighing 40 kilograms (kg) or more. However, safety and efficacy have not been established in children weighing less than 40 kg.

Appropriate studies have not been performed on the relationship of age to the effects of amoxicillin and clavulanate extended-release tablets in teenagers and children younger than 16 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of amoxicillin and clavulanate combination in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require an adjustment in the dose for patients receiving amoxicillin and clavulanate combination.

Pregnancy

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Chlortetracycline
• Cholera Vaccine, Live
• Demeclocycline
• Doxycycline
• Lymecycline
• Meclocycline
• Methacycline
• Methotrexate
• Minocycline
• Oxytetracycline
• Rolitetracycline
• Tetracycline
• Venlafaxine
• Warfarin

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol
• Khat
• Probenecid

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Diarrhea or
• Liver disease—Use with caution. May make these conditions worse.

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Kidney disease, severe—The extended-release tablets should not be used in patients with this condition.

• Liver disease (caused by Augmentin®), history of or
• Mononucleosis ("mono")—Should not be used in patients with these conditions.

• Phenylketonuria (PKU)—The chewable tablet and oral suspension contain phenylalanine, which can make this condition worse.

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PRESCRIBING INFORMATION

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Augmentin ES-600 Powder for Oral Suspension and other antibacterial drugs, Augmentin ES-600 Powder for Oral Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Augmentin ES-600 Powder for Oral Suspension is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin 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 molecular formula is C16H19N3O5S•3H2O, and the molecular weight is 419.46. Chemically, amoxicillin 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:

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 Ingredients:

Powder for Oral Suspension- Colloidal silicon dioxide, strawberry cream flavor, xanthan gum, aspartamea, sodium carboxymethylcellulose, and silicon dioxide.

a  See PRECAUTIONSInformation for the Patient/Phenylketonurics.

Each 5 mL of reconstituted 600 mg/42.9 mg per 5 mL oral suspension of Augmentin ES-600 contains 0.23 mEq potassium.

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 ES-600 POWDER FOR ORAL SUSPENSION, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, Augmentin ES-600 POWDER FOR ORAL SUSPENSION 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.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including amoxicillin/clavulanate potassium, and has ranged 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.

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

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

Augmentin ES-600 Powder for Oral Suspension 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 REACTIONSLiver.)

General:

While amoxicillin/clavulanate possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable if therapy is for longer than the drug is approved for administration.

A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash. Thus, ampicillin-class antibiotics should not be administered to patients with mononucleosis.

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted.

Prescribing Augmentin ES-600 Powder for Oral Suspension in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for the Patient:

Augmentin ES-600 Powder for Oral Suspension should be taken every 12 hours with a meal or snack to reduce the possibility of gastrointestinal upset. If diarrhea develops and is severe or lasts more than 2 or 3 days, call your doctor.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of Augmentin ES-600 Powder for Oral Suspension, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of Augmentin ES-600 Powder for Oral Suspension may contain more liquid than required. Follow your doctor’s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine.

Patients should be counseled that antibacterial drugs, including Augmentin ES-600 Powder for Oral Suspension, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Augmentin ES-600 Powder for Oral Suspension is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Augmentin ES-600 Powder for Oral Suspension or other antibacterial drugs in the future.

Phenylketonurics:

Each 5 mL of the 600 mg/42.9 mg per 5 mL suspension of Augmentin ES-600 Powder for Oral Suspension contains 7 mg phenylalanine.

Drug Interactions:

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with Augmentin ES-600 Powder for Oral Suspension may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid cannot be recommended.

Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported rarely in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with Augmentin ES-600 Powder for Oral Suspension and allopurinol administered concurrently.

In common with other broad-spectrum antibiotics, amoxicillin/clavulanate may reduce the efficacy of oral contraceptives.

Drug/Laboratory Test Interactions:

Oral administration of AUGMENTIN will result in high urine concentrations of amoxicillin. High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST®, Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with amoxicillin and therefore Augmentin ES-600 Powder for Oral Suspension, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX®) be used.

Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with amoxicillin and therefore Augmentin ES-600 Powder for Oral Suspension.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Long-term studies in animals have not been performed to evaluate carcinogenic potential. The mutagenic potential of AUGMENTIN was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test, and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay where weak activity was found at very high, cytotoxic concentrations. AUGMENTIN at oral doses of up to 1,200 mg/kg/day (5.7 times the maximum adult human dose based on body surface area) was found to have no effect on fertility and reproductive performance in rats, dosed with a 2:1 ratio formulation of amoxicillin:clavulanate.

Teratogenic Effects:

Pregnancy (Category B). Reproduction studies performed in pregnant rats and mice given AUGMENTIN at oral dosages up to 1,200 mg/kg/day (4.9 and 2.8 times the maximum adult human oral dose based on body surface area, respectively), revealed no evidence of harm to the fetus due to AUGMENTIN. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery:

Oral ampicillin-class antibiotics are generally poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of AUGMENTIN in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary. In a single study in women with premature rupture of fetal membranes, it was reported that prophylactic treatment with AUGMENTIN may be associated with an increased risk of necrotizing enterocolitis in neonates.

Nursing Mothers:

Ampicillin-class antibiotics are excreted in human milk; therefore, caution should be exercised when AUGMENTIN is administered to a nursing woman.

Pediatric Use:

Safety and efficacy of Augmentin ES-600 Powder for Oral Suspension in infants younger than 3 months have not been established. Safety and efficacy of Augmentin ES-600 Powder for Oral Suspension have been demonstrated for treatment of acute otitis media in infants and children 3 months to 12 years (see Description of Clinical Studies).

The safety and effectiveness of Augmentin ES-600 Powder for Oral Suspension have been established for the treatment of pediatric patients (3 months to 12 years) with acute bacterial sinusitis. This use is supported by evidence from adequate and well-controlled studies of AUGMENTIN XR™ Extended Release Tablets in adults with acute bacterial sinusitis, studies of Augmentin ES-600 Powder for Oral Suspension in pediatric patients with acute otitis media, and by similar pharmacokinetics of amoxicillin and clavulanate in pediatric patients taking Augmentin ES-600 Powder for Oral Suspension (see CLINICAL PHARMACOLOGY) and adults taking AUGMENTIN XR.

Augmentin ES-600 Powder for Oral Suspension is generally well tolerated. The majority of side effects observed in pediatric clinical trials of acute otitis media were either mild or moderate, and transient in nature; 4.4% of patients discontinued therapy because of drug-related side effects. The most commonly reported side effects with probable or suspected relationship to Augmentin ES-600 Powder for Oral Suspension were contact dermatitis, i.e., diaper rash (3.5%), diarrhea (2.9%), vomiting (2.2%), moniliasis (1.4%), and rash (1.1%). The most common adverse experiences leading to withdrawal that were of probable or suspected relationship to Augmentin ES-600 Powder for Oral Suspension were diarrhea (2.5%) and vomiting (1.4%).

The following adverse reactions have been reported for ampicillin-class antibiotics:

Gastrointestinal:

Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment. (See WARNINGS.)

Hypersensitivity Reactions:

Skin rashes, pruritus, urticaria, angioedema, serum sickness−like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme (rarely Stevens-Johnson syndrome), acute generalized exanthematous pustulosis, and an occasional case of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. These reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with oral penicillin. (See WARNINGS.)

Liver:

A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibiotics, but the significance of these findings is unknown. Hepatic dysfunction, including increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been infrequently reported with AUGMENTIN. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, 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.

Renal:

Interstitial nephritis and hematuria have been reported rarely. Crystalluria has also been reported (see OVERDOSAGE).

Hemic and Lymphatic Systems:

Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. A slight thrombocytosis was noted in less than 1% of the patients treated with AUGMENTIN. There have been reports of increased prothrombin time in patients receiving AUGMENTIN and anticoagulant therapy concomitantly.

Central Nervous System:

Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely.

Miscellaneous:

Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

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 ES-600 Powder for Oral Suspension, 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.4

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.

Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days. Store dry powder for oral suspension at or below 25°C (77°F). Dispense in original container.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• severe stomach pain, diarrhea that is watery or bloody;

• pale or yellowed skin, dark colored urine, fever, confusion or weakness;

• loss of appetite, upper stomach pain, jaundice (yellowing of the skin or eyes);

• easy bruising or bleeding;

• little or no urination; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• nausea, diarrhea; or

• vaginal itching or discharge;

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.