NDC 70518-2082 Amoxicillin And Clavulanate Potassium

Amoxicillin And Clavulanate Potassium

NDC Product Code 70518-2082

NDC Code: 70518-2082

Proprietary Name: Amoxicillin And Clavulanate Potassium What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Amoxicillin And Clavulanate Potassium What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

NDC Code Structure

  • 70518 - Remedyrepack Inc.
    • 70518-2082 - Amoxicillin And Clavulanate Potassium

NDC 70518-2082-0

Package Description: 75 mL in 1 BOTTLE

NDC Product Information

Amoxicillin And Clavulanate Potassium with NDC 70518-2082 is a a human prescription drug product labeled by Remedyrepack Inc.. The generic name of Amoxicillin And Clavulanate Potassium is amoxicillin and clavulanate potassium. The product's dosage form is powder, for suspension and is administered via oral form.

Labeler Name: Remedyrepack Inc.

Dosage Form: Powder, For Suspension - An intimate mixture of dry, finely divided drugs and/or chemicals, which, upon the addition of suitable vehicles, yields a suspension (a liquid preparation containing the solid particles dispersed in the liquid vehicle).

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Amoxicillin And Clavulanate Potassium Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • AMOXICILLIN 250 mg/5mL
  • CLAVULANATE POTASSIUM 62.5 mg/5mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • XANTHAN GUM (UNII: TTV12P4NEE)
  • ASPARTAME (UNII: Z0H242BBR1)
  • HYPROMELLOSES (UNII: 3NXW29V3WO)
  • MANNITOL (UNII: 3OWL53L36A)
  • SACCHARIN SODIUM (UNII: SB8ZUX40TY)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Penicillin-class Antibacterial - [EPC] (Established Pharmacologic Class)
  • Penicillins - [CS]
  • beta Lactamase Inhibitor - [EPC] (Established Pharmacologic Class)
  • beta Lactamase Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Remedyrepack Inc.
Labeler Code: 70518
FDA Application Number: NDA050725 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-15-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Amoxicillin And Clavulanate Potassium Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1 Indications & Usage

To reduce the development of drug‑resistant bacteria and maintain the effectiveness of Amoxicillin and Clavulanate Potassium and other antibacterial drugs, Amoxicillin and Clavulanate Potassium should be used only to treat 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. Amoxicillin and Clavulanate Potassium is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated in the treatment of infections due to susceptible isolates of the designated bacteria in the conditions listed below*:

1.1 Lower Respiratory Tract Infections

Caused by beta‑lactamase–producing isolates of


Haemophilus influenzae and Moraxella catarrhalis.

1.2 Acute Bacterial Otitis Media

Caused by beta‑lactamase–producing isolates of


H. influenzae and M. catarrhalis.

1.3 Sinusitis

Caused by beta‑lactamase–producing isolates of


H. influenzae and M. catarrhalis.

1.4 Skin And Skin Structure Infections

Caused by beta‑lactamase–producing isolates of


Staphylococcus aureus, Escherichia coli, and Klebsiella species.

1.5 Urinary Tract Infections

Caused by beta‑lactamase–producing isolates of


E. coli, Klebsiella species, and Enterobacter species.

1.6 Limitations Of Use

When susceptibility test results show susceptibility to amoxicillin, indicating no beta-lactamase production, Amoxicillin and Clavulanate Potassium should not be used.

2 Dosage & Administration

Amoxicillin and Clavulanate Potassium may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when Amoxicillin and Clavulanate Potassium is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, Amoxicillin and Clavulanate Potassium should be taken at the start of a meal.

2.1 Adults

The usual adult dose is one 500 mg tablet of Amoxicillin and Clavulanate Potassium every 12 hours or one 250 mg tablet of Amoxicillin and Clavulanate Potassium every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one 875 mg tablet of Amoxicillin and Clavulanate Potassium every 12 hours or one 500 mg tablet of Amoxicillin and Clavulanate Potassium every 8 hours. Adults who have difficulty swallowing may be given the 125 mg/5 mL or 250 mg/5 mL suspension in place of the 500 mg tablet. The 200 mg/5 mL suspension or the 400 mg/5 mL suspension may be used in place of the 875 mg tablet. Two 250 mg tablets of Amoxicillin and Clavulanate Potassium should


not be substituted for one 500 mg tablet of Amoxicillin and Clavulanate Potassium. Since both the 250 mg and 500 mg tablets of Amoxicillin and Clavulanate Potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets are not equivalent to one 500 mg tablet of Amoxicillin and Clavulanate Potassium.


The 250 mg tablet of Amoxicillin and Clavulanate Potassium and the 250 mg chewable tablet should


not be substituted for each other, as they are not interchangeable. The 250 mg tablet of Amoxicillin and Clavulanate Potassium and the 250 mg chewable tablet do not contain the same amount of clavulanic acid (as the potassium salt). The 250 mg tablet of Amoxicillin and Clavulanate Potassium contains 125 mg of clavulanic acid, whereas the 250 mg chewable tablet contains 62.5 mg of clavulanic acid.

2.2 Pediatric Patients

Based on the amoxicillin component, Amoxicillin and Clavulanate Potassium should be dosed as follows:Neonates and Infants Aged <12 weeks (<3 months): The recommended dose of Amoxicillin and Clavulanate Potassium is 30 mg/kg/day divided every 12 hours, based on the amoxicillin component. Experience with the 200 mg/5 mL formulation in this age group is limited, and thus, use of the 125 mg/5 mL oral suspension is recommended.


Patients Aged 12 weeks (3 months) and Older: See dosing regimens provided in Table 1. The every 12 hour regimen is recommended as it is associated with significantly less diarrhea


[see


Clinical Studies (14.2)]


. However, the every 12 hour suspension (200 mg/5 mL and 400 mg/5 mL) and chewable tablets (200 mg and 400 mg) contain aspartame and should not be used by phenylketonurics.


[see


Warnings and Precautions (5.6)]


Patients Weighing 40 kg or More: Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations.


The 250 mg tablet of Amoxicillin and Clavulanate Potassium should


not be used until the child weighs at least 40 kg, due to the different amoxicillin to clavulanic acid ratios in the 250 mg tablet of Amoxicillin and Clavulanate Potassium (250/125) versus the 250 mg chewable tablet of Amoxicillin and Clavulanate Potassium (250/62.5).

2.3 Patients With Renal Impairment

Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Renal impairment patients with a glomerular filtration rate of <30 mL/min should not receive the 875 mg dose. Patients with a glomerular filtration rate of 10 to 30 mL/min should receive 500 mg or 250 mg every 12 hours, depending on the severity of the infection. Patients with a glomerular filtration rate less than 10 mL/min should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. Hemodialysis patients should receive 500 mg or 250 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis.

2.4 Directions For Mixing Oral Suspension

Prepare a suspension at time of dispensing as follows: Tap bottle to loosen ALL powder. Measure a total (see Table 2 below for total amount of water for reconstitution) OF WATER. Add approximately 2/3 of the water to the powder. Replace cap and shake VIGOROUSLY. Add remaining water. Replace cap and shake VIGOROUSLY."


Note: Shake oral suspension well before using. Reconstituted suspension must be stored under refrigeration and discarded after 10 days. Some color change is normal during dosing period.

3 Dosage Forms & Strengths

Tablets:


·  


250 mg/125 mg Tablets: Each white oval film-coated tablet, debossed with AUGMENTIN on one side and 250/125 on the other side, contains 250 mg of amoxicillin and 125 mg clavulanic acid as the potassium salt.


·  


500 mg/125 mg Tablets: Each white oval film-coated tablet, debossed with AUGMENTIN on one side and 500/125 on the other side, contains 500 mg   amoxicillin and 125 mg of clavulanic acid as the potassium salt.


·  


875 mg/125 mg Tablets: Each scored white capsule‑shaped tablet, debossed with AUGMENTIN 875 on one side and scored on the other side, contains 875 mg amoxicillin and 125 mg clavulanic acid as the potassium salt. 


Powder for Oral Suspension:  


·  


125 mg/31.25 mg per 5 mL: Banana-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 125 mg amoxicillin and 31.25   mg of clavulanic acid as the potassium salt).


·  


200 mg/28.5 mg per 5 mL: Orange-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 200 mg amoxicillin and 28.5 mg   of clavulanic acid as the potassium salt).


·  


250 mg/62.5 mg per 5 mL: Orange-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 250 mg amoxicillin and 62.5 mg   of clavulanic acid as the potassium salt).


·  


400 mg/57 mg per 5 mL Orange-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 400 mg amoxicillin and 57.0 mg of   clavulanic acid as the potassium salt).


Chewable Tablets: 


·  


125 mg/31.25 mg Chewable Tablets: Each mottled yellow, round, lemon-lime-flavored tablet, debossed with BMP 189 contains 125 mg amoxicillin and 31.25 mg clavulanic acid as the potassium salt. 


·  


200 mg/28.5 mg Chewable Tablets: Each mottled pink, round, biconvex cherry-banana-flavored tablet, debossed with Amoxicillin and Clavulanate         Potassium 200 contains 200 mg amoxicillin and 28.5 mg clavulanic acid as the potassium salt.


·  


250 mg/62.5 mg Chewable Tablets: Each mottled yellow, round, lemon-lime-flavored tablet, debossed with BMP 190 contains 250 mg amoxicillin and   62.5 mg clavulanic acid as the potassium salt.


·  


400 mg/57 mg Chewable Tablets: Each mottled pink, round, biconvex cherry-banana-flavored tablet, debossed with Amoxicillin and Clavulanate           Potassium 400 contains 400 mg amoxicillin and 57.0 mg clavulanic acid as the potassium salt.


The 250 mg tablet of Amoxicillin and Clavulanate Potassium and the 250 mg chewable tablet should NOT be substituted for each other, as they are not interchangeable and the 250 mg tablet should not be used in children weighing less than 40 kg. The 250 mg tablet of Amoxicillin and Clavulanate Potassium and the 250 mg chewable tablet do not contain the same amount of clavulanic acid. The 250 mg tablet of Amoxicillin and Clavulanate Potassium contains 125 mg of clavulanic acid whereas the 250 mg chewable tablet contains 62.5 mg of clavulanic acid.


Two 250 mg tablets of Amoxicillin and Clavulanate Potassium should NOT be substituted for one 500 mg tablet of Amoxicillin and Clavulanate Potassium. Since both the 250 mg and 500 mg tablets of Amoxicillin and Clavulanate Potassium contain the same amount of clavulanic acid (125 mg, as the potassium salt), two 250 mg tablets of Amoxicillin and Clavulanate Potassium are not equivalent to one 500 mg tablet of Amoxicillin and Clavulanate Potassium.

4.1 Serious Hypersensitivity Reactions

Amoxicillin and Clavulanate Potassium is contraindicated in patients with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin, clavulanate or to other beta‑lactam antibacterial drugs (e.g., penicillins and cephalosporins).

4.2 Cholestatic Jaundice/Hepatic Dysfunction

Amoxicillin and Clavulanate Potassium is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with Amoxicillin and Clavulanate Potassium.

5.1 Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including Amoxicillin and Clavulanate Potassium. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. Before initiating therapy with Amoxicillin and Clavulanate Potassium, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, Amoxicillin and Clavulanate Potassium should be discontinued and appropriate therapy instituted.

5.2 Hepatic Dysfunction

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of Amoxicillin and Clavulanate Potassium. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

5.3 Clostridium Difficile Associated Diarrhea (Cdad)

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


C. difficile.


C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of


C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.


If CDAD is suspected or confirmed, ongoing antibacterial use not directed against


C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of


C. difficile, and surgical evaluation should be instituted as clinically indicated.

5.4 Skin Rash In Patients With Mononucleosis

A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, Amoxicillin and Clavulanate Potassium should not be administered to patients with mononucleosis.

5.5 Potential For Microbial Overgrowth

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted.

5.6 Phenylketonurics

Amoxicillin and Clavulanate Potassium Chewable tablets and Amoxicillin and Clavulanate Potassium Powder for Oral Solution contain aspartame which contains phenylalanine. Each 200 mg chewable tablet of Amoxicillin and Clavulanate Potassium contains 2.1 mg phenylalanine; each 400 mg chewable tablet contains 4.2 mg phenylalanine; each 5 mL of either the 200 mg/5 mL or 400 mg/5 mL oral suspension contains 7 mg phenylalanine. The other formulations of Amoxicillin and Clavulanate Potassium do not contain phenylalanine.

5.7 Development Of Drug-Resistant Bacteria

Prescribing Amoxicillin and Clavulanate Potassium in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug‑resistant bacteria.

6 Adverse Reactions

The following are discussed in more detail in other sections of the labeling:·   Anaphylactic reactions


[see


Warnings and Precautions (5.1)  ]


·   Hepatic Dysfunction


[see


Warnings and Precautions (5.2)  ]


·   CDAD


[see


Warnings and Precautions (5.3)  ]

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug‑related adverse reactions. The overall incidence of adverse reactions, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported adverse reactions (<1%) include: Abdominal discomfort, flatulence, and headache. In pediatric patients (aged 2 months to 12 years), 1 US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of Amoxicillin and Clavulanate Potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of Amoxicillin and Clavulanate Potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes.


[See


Clinical Studies (14.2) ]

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following have been identified during postmarketing use of Amoxicillin and Clavulanate Potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to Amoxicillin and Clavulanate Potassium. Gastrointestinal: 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 and Precautions (5.3)  ]


Hypersensitivity Reactions: Pruritus, angioedema, serum sickness–like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens‑Johnson syndrome, acute generalized exanthematouspustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported.


[see


Warnings and Precautions (5.1)  ]


Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with Amoxicillin and Clavulanate Potassium. 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. Deaths have been reported.


[see


Contraindications (4.2),


Warnings and Precautions (5.2) ]


Renal:Interstitial nephritis, hematuria, and crystalluria have been reported.


[see


Overdosage (10) ]


Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with Amoxicillin and Clavulanate Potassium. There have been reports of increased prothrombin time in patients receiving Amoxicillin and Clavulanate Potassium and anticoagulant therapy concomitantly.


[see


Drug Interactions (7.2)  ]


Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported.


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

7.1 Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin but does not delay renal excretion of clavulanic acid. Concurrent use with Amoxicillin and Clavulanate Potassium may result in increased and prolonged blood concentrations of amoxicillin. Coadministration of probenecid is not recommended.

7.2 Oral Anticoagulants

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

7.3 Allopurinol

The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

7.4 Oral Contraceptives

Amoxicillin and Clavulanate Potassium may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

7.5 Effects On Laboratory Tests

High urine concentrations of amoxicillin 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 Clavulanate Potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.


Following administration of amoxicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted.

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category B. Reproduction studies performed in pregnant rats and mice given Amoxicillin and Clavulanate Potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses up to 1200 mg/kg/day revealed no evidence of harm to the fetus due to Amoxicillin and Clavulanate Potassium. The amoxicillin doses in rats and mice (based on body surface area) were approximately 4 and 2 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, these dose multiples were approximately 9 and 4 times the maximum recommended adult human oral dose (125 mg every 8 hours). 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.

8.2 Labor & Delivery

Oral ampicillin‑class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin/clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood of the necessity for an obstetrical intervention.

8.3 Nursing Mothers

Amoxicillin has been shown to be excreted in human milk. Amoxicillin/clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin/clavulanate potassium is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets have been established in pediatric patients. Use of Amoxicillin and Clavulanate Potassium in pediatric patients is supported by evidence from studies of Amoxicillin and Clavulanate Potassium Tablets in adults with additional data from a study of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension in pediatric patients aged 2 months to 12 years with acute otitis media.


[see


Clinical Studies (14.2 )]


Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of Amoxicillin and Clavulanate Potassium should be modified in pediatric patients aged <12 weeks (<3 months).


[see Dosage and Administration


 (2.2 )]

8.5 Geriatric Use

Of the 3,119 patients in an analysis of clinical studies of Amoxicillin and Clavulanate Potassium, 32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Dosing In Renal Impairment

Amoxicillin is primarily eliminated by the kidney and dosage adjustment is usually required in patients with severe renal impairment (GFR <30 mL/min). See Patients with Renal Impairment (2.3) for specific recommendations in patients with renal impairment.

10 Overdosage

In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. 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


1.


Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxicillin/clavulanate potassium. Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin/clavulanate potassium overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin/clavulanate potassium 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 amoxicillin/clavulanate potassium. Amoxicillin/clavulanate potassium may be removed from circulation by hemodialysis


. [see


Dosage and Administration (2.3 )]

11 Description

Amoxicillin and Clavulanate Potassium is an oral antibacterial combination consisting of amoxicillin and the beta‑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 C


16H


19N


3O


5S•3H


2O, 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 beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta‑lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula is C


8H


8KNO


5, 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:  


·   Tablets- Colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide. Each tablet of Amoxicillin and Clavulanate Potassium contains 0.63 mEq potassium. ·   Powder for Oral Suspension, 125 mg/5mL and 250 mg/5mL - Colloidal silicon dioxide, flavorings, xanthan gum, mannitol, succinic acid, silica gel and sodium saccharin. ·   Powder for Oral Suspension, 200 mg/5mL and 400 mg/5mL - Colloidal silicon dioxide, flavorings, xanthan gum, silica gel, hypromellose and aspartame


[see


Warnings and Precautions (5.6)]


·   Chewable Tablets, 125 mg and 250 mg - Colloidal silicon dioxide, flavorings, magnesium stearate, mannitol, sodium saccharin, glycine, and D&C Yellow No.10.·   Each 125 mg chewable tablet and each 5 mL of reconstituted 125/5 mL oral suspension of Amoxicillin and Clavulanate Potassium contains 0.16 mEq potassium ·   Each 250 mg chewable tablet and each 5 mL of reconstituted 250/5 mL oral suspension of Amoxicillin and Clavulanate Potassium contains 0.32 mEq potassium ·   Chewable Tablets, 200 mg and 400 mg - Colloidal silicon dioxide, flavorings, magnesium stearate, mannitol, FD&C Red No. 40 and aspartame.


[see


Warnings and Precautions (5.6)]


 ·   Each 200 mg chewable tablet and each 5 mL of reconstituted 200/5 mL oral suspension of Amoxicillin and Clavulanate Potassium contains 0.14 mEq potassium


 ·   Each 400 mg chewable tablet and each 5 mL of reconstituted 400/5 mL oral suspension of Amoxicillin and Clavulanate Potassium contains 0.29 mEq potassium

12.1 Mechanism Of Action

Amoxicillin and Clavulanate Potassium is an antibacterial drug.


[see


Microbiology 12.4 ]

12.3 Pharmacokinetics

Mean amoxicillin and clavulanate potassium pharmacokinetic parameters in normal adults following administration of Amoxicillin and Clavulanate Potassium Tablets are shown in Table 3 and following administration of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets are shown in Table 4. 


Oral administration of 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium or the equivalent dose of 10 mL of 125 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg*h/mL for amoxicillin and 2.9 mcg*h/mL for clavulanic acid when 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium or equivalent dose of 10 mL of 125 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium were administered to normal adults. One 250 mg chewable tablet of Amoxicillin and Clavulanate Potassium or two 125 mg chewable tablets of Amoxicillin and Clavulanate Potassium are equivalent to 5 mL of 250 mg/5 mL suspension of Amoxicillin and Clavulanate Potassium and provide similar serum concentrations of amoxicillin and clavulanic acid. 


Amoxicillin serum concentrations achieved with Amoxicillin and Clavulanate Potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. Time above the minimum inhibitory concentration of 1 mcg/mL for amoxicillin has been shown to be similar after corresponding every 12 hour and every 8 hour dosing regimens of Amoxicillin and Clavulanate Potassium in adults and children. Absorption: Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Amoxicillin and Clavulanate Potassium can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when Amoxicillin and Clavulanate Potassium was dosed at 30 and 150 minutes after the start of a high‑fat breakfast.


Distribution: Neither component in Amoxicillin and Clavulanate Potassium is highly protein‑bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. 


Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Two hours after oral administration of a single 35 mg/kg dose of suspension of Amoxicillin and Clavulanate Potassium to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions. Metabolism and Excretion: The half‑life of amoxicillin after the oral administration of Amoxicillin and Clavulanate Potassium is 1.3 hours and that of clavulanic acid is 1 hour.


Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250 mg or 500 mg tablet of Amoxicillin and Clavulanate Potassium.

12.4 Microbiology

Amoxicillin is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. Amoxicillin is, however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance.         The formulation of amoxicillin and clavulanic acid in Amoxicillin and Clavulanate Potassium protects amoxicillin from degradation by some beta-lactamase enzymes and extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin. Amoxicillin/clavulanic acid has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Gram-positive bacteria 


Staphylococcus aureus 


Gram-negative bacteria 


Enterobacter species 


Escherichia coli 


Haemophilus influenzae 


Klebsiella species 


Moraxella catarrhalis 


The following in vitro data are available,


but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for amoxicillin/clavulanic acid. However, the efficacy of amoxicillin/clavulanic acid in treating clinical infections due to these bacteria


has not been established in adequate and well-controlled clinical trials.


Gram-positive bacteria 


Enterococcus faecalis 


Staphylococcus epidermidis 


Staphylococcus saprophyticus 


Streptococcus pneumoniae 


Streptococcus pyogenes 


Viridans group Streptococcus 


 Gram-negative Bacteria 


Eikenellacorrodens 


Proteus mirabilis 


Anaerobic Bacteria 


Bacteroidesspecies including


Bacteroides fragilis Fusobacterium species 


Peptostreptococcus species Susceptibility Test MethodsFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see:   https://www.fda.gov/STIC .

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

Long‑term studies in animals have not been performed to evaluate carcinogenic potential. Amoxicillin and Clavulanate Potassium (4:1 ratio formulation of amoxicillin:clavulanate) was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and Clavulanate Potassium was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Amoxicillin and Clavulanate Potassium was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. Amoxicillin and Clavulanate Potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area, this dose of amoxicillin is approximately 4 times the maximum recommended adult human oral dose (875 mg every 12 hours). For clavulanate, the dose multiple is approximately 9 times higher than the maximum recommended adult human oral dose (125 mg every 8 hours), also based on body surface area.

14.1 Lower Respiratory Tract And Complicated Urinary Tract Infections

Data from 2 pivotal trials in 1,191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg tablets of Amoxicillin and Clavulanate Potassium every 12 hours to 500 mg tablets of Amoxicillin and Clavulanate Potassium dosed every 8 hours (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the every 12 hours and every 8 hours dosing regimens. There was no significant difference in the percentage of adverse events in each group. The most frequently reported adverse event was diarrhea; incidence rates were similar for the 875 mg every 12 hours and 500 mg every 8 hours dosing regimens (15% and 14%, respectively); however, there was a statistically significant difference (p < 0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1% for 875 mg every 12 hours regimen versus 2% for the 500 mg every 8 hours regimen. In one of these pivotal trials, patients with either pyelonephritis (n = 361) or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication, n = 268) were randomized (1:1) to receive either 875 mg tablets of Amoxicillin and Clavulanate Potassium every 12 hours (n=308) or 500 mg tablets of Amoxicillin and Clavulanate Potassium every 8 hours (n=321). The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and Clavulanate Potassium produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow‑up visits (5 to 9 days post‑therapy) and at a late post‑therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in Table 7. 


 


As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens.

14.2 Acute Bacterial Otitis Media And Diarrhea In Pediatric Patients

One US/Canadian clinical trial was conducted which compared 45/6.4 mg/kg/day (divided every 12 hours) of Amoxicillin and Clavulanate Potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of Amoxicillin and Clavulanate Potassium for 10 days in the treatment of acute otitis media. Only the suspension formulations were used in this trial. A total of 575 pediatric patients (aged 2 months to 12 years) were enrolled, with an even distribution among the 2 treatment groups and a comparable number of patients were evaluable (i.e., ³ 84%) per treatment group. Otitis media‑specific criteria were required for eligibility and a strong correlation was found at the end of therapy and follow‑up between these criteria and physician assessment of clinical response. The clinical efficacy rates at the end of therapy visit (defined as 2‑4 days after the completion of therapy) and at the follow‑up visit (defined as 22‑28 days post‑completion of therapy) were comparable for the 2 treatment groups, with the following cure rates obtained for the evaluable patients: At end of therapy, 87% (n = 265) and 82% (n = 260) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. At follow‑up, 67% (n = 249) and 69% (n = 243) for 45 mg/kg/day every 12 hours and 40 mg/kg/day every 8 hours, respectively. Diarrhea was defined as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR (b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive days. The incidence of diarrhea was significantly lower in patients who received the every 12 hours regimen compared to patients who received the every 8 hours regimen (14% and 34%, respectively). In addition, the number of patients with either severe diarrhea or who were withdrawn with diarrhea was significantly lower in the every 12 hours treatment group (3% and 8% for the every 12 hours/10 day and every 8 hours/10 day, respectively). In the every 12 hours treatment group, 3 patients (1%) were withdrawn with an allergic reaction, while 1 patient in the every 8 hours group was withdrawn for this reason. The number of patients with a candidal infection of the diaper area was 4% and 6% for the every 12 hours and every 8 hours groups, respectively. It is not known if the finding of a statistically significant reduction in diarrhea with the oral suspensions dosed every 12 hours, versus suspensions dosed every 8 hours, can be extrapolated to the chewable tablets. The presence of mannitol in the chewable tablets may contribute to a different diarrhea profile. The every 12 hour oral suspensions (200 mg/5 mL and 400 mg/5 mL) are sweetened with aspartame.

15 References

1. Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol. 1988; 30: 66‑67.

16 How Supplied/Storage And Handling

Tablets: 


250 mg/125 mg Tablets: Each white oval film-coated tablet, debossed with AUGMENTIN on one side and 250/125 on the other side, contains 250


mg amoxicillin as the trihydrate and 125


mg clavulanic acid as the potassium salt.


NDC 72508-218-30               bottles of 30NDC 72508-218-78               Unit Dose (10x10) 100 tablets 500 mg/125 mg Tablets: Each white oval film-coated tablet, debossed with AUGMENTIN on one side and 500/125 on the other side, contains 500


mg amoxicillin as the trihydrate and 125


mg clavulanic acid as the potassium salt.


NDC 72508-206-14               bottles of 20NDC 72508-206-78               Unit Dose (10x10) 100 tablets875 mg/125 mg Tablets: Each scored white capsule‑shaped tablet, debossed with AUGMENTIN 875 on one side and scored on the other side, contains 875


mg amoxicillin as the trihydrate and 125


mg clavulanic acid as the potassium salt.


NDC 72508-221-14               bottles of 20NDC 72508-221-78               Unit Dose (10x10) 100 tabletsPowder for Oral Suspension:


125 mg/31.25 mg per 5 mL: Banana-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 125 mg amoxicillin and 31.25 mg of clavulanic acid as the potassium salt).


NDC 72508-212-01               75 mL bottleNDC 72508-212-03               100 mL bottleNDC 72508-212-05               150 mL bottle200 mg/28.5 mg per 5 mL: Orange-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 200 mg amoxicillin and 28.5 mg of clavulanic acid as the potassium salt).


NDC 72508-213-50               50 mL bottleNDC 72508-213-51               75 mL bottleNDC 72508-213-52               100 mL bottle250 mg/62.5 mg per 5 mL: Orange-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 250 mg amoxicillin and 62.5 mg of clavulanic acid as the potassium salt).


NDC 72508-204-07               75 mL bottleNDC 72508-204-10               100 mL bottleNDC 72508-204-15               150 mL bottle  400 mg/57 mg per 5 mL Orange-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 400 mg amoxicillin and 57.0 mg of clavulanic acid as the potassium salt).


NDC 72508-208-50               50 mL bottleNDC 72508-208-51               75 mL bottleNDC 72508-208-52               100 mL bottleChewable Tablets:


125 mg/31.25 mg Chewable Tablets: Each mottled yellow, round, lemon-lime-flavored tablet, debossed with BMP 189, contains 125 mg amoxicillin and 31.25 mg clavulanic acid as the potassium salt.


NDC 72508-214-31               carton of 30 tablets200 mg/28.5 mg Chewable Tablets: Each mottled pink, round, biconvex, cherry-banana-flavored tablet, debossed with Amoxicillin and Clavulanate Potassium 200, contains 200 mg amoxicillin and 28.5 mg clavulanic acid as the potassium salt.


NDC 72508-215-14               carton of 20 tablets250 mg/62.5 mg Chewable Tablets: Each mottled yellow, round, lemon-lime-flavored tablet, debossed with BMP 190, contains 250 mg amoxicillin and 62.5 mg clavulanic acid as the potassium salt.


NDC 72508-216-31               carton of 30 tablets400 mg/57 mg Chewable Tablets: Each mottled pink, round, biconvex, cherry-banana-flavored tablet, debossed with Amoxicillin and Clavulanate Potassium 400, contains 400 mg amoxicillin and 57.0 mg clavulanic acid as the potassium salt.


NDC 72508-217-14   carton of 20 tabletsDispense in original container.Store tablets and dry powder at or below 25°C (77°F).Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days.Keep out of the reach of children.

17.1 Information For Patients

Patients should be informed that Amoxicillin and Clavulanate Potassium may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset. Patients should be counseled that antibacterial drugs, including Amoxicillin and Clavulanate Potassium, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Amoxicillin and Clavulanate Potassium 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 Amoxicillin and Clavulanate Potassium or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, 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 their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician. Patients should be advised to keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of Amoxicillin and Clavulanate Potassium, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of Amoxicillin and Clavulanate Potassium 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 aware that Amoxicillin and Clavulanate Potassium contains a penicillin class drug product that can cause allergic reactions in some individuals. AUGMENTIN is a registered trademark of GlaxoSmithKline and is licensed to Neopharma Inc.CLINITEST is a registered trademark of Miles, Inc.Manufactured By:Neopharma Tennessee LLC.Bristol, TN 37620Manufactured for:Neopharma Inc.Princeton, NJ 08540Revised: 01/2019

* Please review the disclaimer below.

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