AMOXICILLIN AND CLAVULANATE POTASSIUM- amoxicillin and clavulanate potassium tablet, film coated
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1. Patient Information
2. Manufactured By:
3. Manufactured For:

Patient Information ⮝

17.1 Information for Patients

Patients should be informed that amoxicillin and clavulanate potassium tablets 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 tablets, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium tablets are 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 tablets 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 tablets contain a penicillin class drug product that can cause allergic reactions in some individuals.

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Micro Labs Limited.

Manufactured By: ⮝

Micro Labs Limited

Banglore-560 100, India.

Manufactured For: ⮝

Micro Labs USA Inc.

Basking Ridge, NJ 07920

Revised: September 2018

1. No Title 1572548722
2. No Title 1572555064
3. Highlights Of Prescribing Information
4. Indications And Usage
5. Dosage And Administration
6. Dosage Forms And Strengths
7. Contraindications
8. Warnings And Precautions
9. Adverse Reactions
10. Drug Interactions
11. Use In Specific Populations
12. 1 Indications And Usage
13. 2 Dosage And Administration
14. 3 Dosage Forms And Strengths
15. 4 Contraindications
16. 5 Warnings And Precautions
17. 6 Adverse Reactions
18. 7 Drug Interactions
19. 8 Use In Specific Populations
20. 10 Overdosage
21. 11 Description
22. 12 Clinical Pharmacology
23. 13 Nonclinical Toxicology
24. 14 Clinical Studies
25. 15 References
26. 16 How Supplied/storage And Handling
27. Package Label.principal Display Panel
28. No Title 1572451513
29. Description
30. Clinical Pharmacology
31. Warnings
32. Precautions
33. Overdosage
34. How Supplied
35. Clinical Studies
36. Label Image For 875/125mg
37. No Title 1572455522

No Title 1572548722 ⮝

AMOXICILLIN, 500 mg, as the trihydrate and CLAVULANIC ACID, 125 mg, as clavulanate potassium; or

AMOXICILLIN, 875 mg, as the trihydrate and CLAVULANIC ACID, 125 mg, as clavulanate potassium

Rx only

PRESCRIBING

INFORMATION

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

No Title 1572555064 ⮝

AMOXICILLIN AND CLAVULANATE POTASSIUM amoxicillin and clavulanate potassium tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55700-751(NDC:42571-162) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMOXICILLIN (UNII: 804826J2HU) (AMOXICILLIN ANHYDROUS - UNII:9EM05410Q9) AMOXICILLIN ANHYDROUS 875 mg CLAVULANATE POTASSIUM (UNII: Q42OMW3AT8) (CLAVULANIC ACID - UNII:23521W1S24) CLAVULANIC ACID 125 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) TALC (UNII: 7SEV7J4R1U)

Product Characteristics Color white (white to off-white) Score 2 pieces Shape CAPSULE (biconvex) Size 22mm Flavor Imprint Code I07 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55700-751-20 20 in 1 BOTTLE; Type 0: Not a Combination Product 05/10/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA204755 05/10/2019

Labeler - Quality Care Products, LLC (831276758)

Establishment
Name	Address	ID/FEI	Business Operations
Lake Erie Medical & Surgical Supply DBA Quality Care Products, LLC		092172824	relabel(55700-751)

Revised: 5/2019 Document Id: 330871dd-ee0d-46e7-a205-f358069bb31d 34391-3 Set id: fbffc027-a2c3-4078-89ea-b8d99e789664 Version: 1 Effective Time: 20190515 Quality Care Products, LLC

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS, USP safely and effectively. See full prescribing information for AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS, USP.



AMOXICILLIN and CLAVULANATE POTASSIUM tablets, for oral use

Initial U.S. Approval: 1984



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

Indications And Usage ⮝

Amoxicillin and clavulanate potassium tablets USP are combination penicillin-class antibacterial and beta-lactamase inhibitor indicated for treatment of the following:

Lower respiratory tract infections ( 1.1)
Acute bacterial otitis media ( 1.2)
Sinusitis ( 1.3)
Skin and skin structure infections ( 1.4)
Urinary tract infections ( 1.5)

Dosage And Administration ⮝

• Adults and Pediatric Patients > 40 kg: 500 mg/125 mg or 875 mg/125 mg every 12 hours or 250 mg/125 mg or 500 mg/125 mg every 8 hours. ( 2.1, 2.2)
• Pediatric patients aged 12 weeks (3 months) and older: 25 to 45 mg/kg/day every 12 hours or 20 to 40 mg/kg/day every 8 hours, up to the adult dose. ( 2.2)

Dosage Forms And Strengths ⮝

Tablets: 250 mg/125 mg, 500 mg/125 mg and 875 mg/125 mg ( 3)

Contraindications ⮝

• History of a serious hypersensitivity reaction (e.g., anaphylaxis or Stevens-Johnson syndrome) to amoxicillin and clavulanate potassium or to other beta-lactams (e.g., penicillins or cephalosporins) ( 4)
• History of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium. ( 4)

Warnings And Precautions ⮝

• Serious (including fatal) hypersensitivity reactions: Discontinue amoxicillin and clavulanate potassium if a reaction occurs. ( 5.1)
• Hepatic dysfunction and cholestatic jaundice: Discontinue if signs/symptoms of hepatitis occur. Monitor liver function tests in patients with hepatic impairment. ( 5.2)
• Clostridium difficile-associated diarrhea (CDAD): Evaluate patients if diarrhea occurs. ( 5.3)
• Patients with mononucleosis who receive amoxicillin and clavulanate potassium develop skin rash. Avoid amoxicillin and clavulanate potassium use in these patients. ( 5.4)
• Overgrowth: The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. ( 5.5)

Adverse Reactions ⮝

The most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%) ( 6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• Co-administration with probenecid is not recommended. ( 7.1)
• Concomitant use of amoxicillin and clavulanate potassium and oral anticoagulants may increase the prolongation of prothrombin time. ( 7.2)
• Coadministration with allopurinol increases the risk of rash. ( 7.3)
• Amoxicillin and clavulanate potassium may reduce efficacy of oral contraceptives. ( 7.4)

Use In Specific Populations ⮝

• Pediatric Use: Modify dose in patients 12 weeks or younger. ( 8.4)
• Renal impairment; Dosage adjustment is recommended for severe renal impairment (GFR< 30 mL/min). ( 2.3, 8.6)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 5/2019

1 Indications And Usage ⮝

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium tablets USP, 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 tablets USP 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, USP, indicating no beta-lactamase production, amoxicillin and clavulanate potassium tablets USP should not be used.

2 Dosage And 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/125 mg amoxicillin and clavulanate potassium tablet every 12 hours or one 250 mg/125 mg amoxicillin and clavulanate potassium tablet every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be one 875 mg/125 mg amoxicillin and clavulanate potassium tablet every 12 hours or one 500 mg/125 mg amoxicillin and clavulanate potassium tablet every 8 hours. Adults who have difficulty swallowing may be given the 125 mg/31.25 mg per 5 mL or 250 mg/62.5 mg per 5 mL suspension in place of the 500 mg/125 mg tablet. The 200 mg/28.5 mg per 5 mL suspension or the 400 mg/57 mg per 5 mL suspension may be used in place of the 875 mg/125 mg tablet.

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

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

Table 1: Dosing in Patients Aged 12 weeks (3 months) and Older

INFECTION	DOSING REGIMEN
	Every 12 hours	Every 12 hours
	200 mg/5 mL or 400 mg/5 mL oral suspension a	125 mg/5 mL or 250 mg/5 mL oral suspension a
Otitis media b, sinusitis, lower respiratory tract infections, and more severe infections	45 mg/kg/day every 12 hours	40 mg/kg/day every 8 hours
Less severe infections	25 mg/kg/day every 12 hours	20 mg/kg/day every 8 hours

a Each strength of suspension of amoxicillin and clavulanate potassium is available as a chewable tablet for use by older children.

b Duration of therapy studied and recommended for acute otitis media is 10 days.

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

The 250 mg/125 mg amoxicillin and clavulanate potassium tablets 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/125 mg amoxicillin and clavulanate potassium tablets (250/125) versus the 250 mg/62.5 mg amoxicillin and clavulanate potassium tablets (Chewable).

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/125 mg dose. Patients with a glomerular filtration rate of 10 to 30 mL/min should receive 500 mg/125 mg or 250 mg/125 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/125 mg or 250 mg/125 mg every 24 hours, depending on severity of the infection.

Hemodialysis patients should receive 500 mg/125 mg or 250 mg/125 mg every 24 hours, depending on severity of the infection. They should receive an additional dose both during and at the end of dialysis.

3 Dosage Forms And Strengths ⮝

250 mg/125 mg Tablets: White to off-white colored, capsule shaped, biconvex, film-coated tablets, debossed with I 05 on one side and plain on the other side. Each tablet contains 250 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

500 mg/125 mg Tablets: White to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with I 06 on one side and plain on the other side. Each tablet contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

875 mg/125 mg Tablets: white to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with I 07 on one side score line on the other side. Each tablet contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.

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

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

4 Contraindications ⮝

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 Warnings And Precautions ⮝

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 tablets 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 tablets 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 and clavulanate potassium should be discontinued and appropriate therapy instituted.

5.7 Development of Drug-Resistant Bacteria

Prescribing amoxicillin and clavulanate potassium tablets 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 Trials 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 exanthematous pustulosis, 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 Drug Interactions ⮝

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 Use In Specific Populations ⮝

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/125 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 and Delivery

Oral ampicillin-class antibiotics are poorly absorbed during labor. It is not known whether use of amoxicillin and 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 and clavulanate potassium use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin and clavulanate potassium is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of amoxicillin and clavulanate potassium 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 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 and clavulanate potassium.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin and 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 and 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 and clavulanate potassium. Amoxicillin and clavulanate potassium may be removed from circulation by hemodialysis. [see Dosage and Administration (2.3)]

11 Description ⮝

Amoxicillin and clavulanate potassium tablets, USP is an oral antibacterial combination consisting of amoxicillin and the -lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin, USP is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. Chemically, amoxicillin, USP 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:

C 16H 19N 3O 5S 3H 2O M.W. 419.45

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, USP is potassium ( Z)-(2 R,5 R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate, and may be represented structurally as:

C 8H 8KNO 5 M.W. 237.25


Each tablet contains 250 mg, 500 mg or 875 mg amoxicillin, USP as the trihydrate and 125 mg clavulanic acid as the potassium salt. Each Amoxicillin and Clavulanate Potassium Tablet USP contains 0.63 mEq potassium.

Inactive Ingredients: colloidal silicon dioxide, ethylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide.

Meets USP Dissolution Test 1

12 Clinical Pharmacology ⮝

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 for oral suspension and chewable tablets are shown in Table 4.

Table 3: Mean ( S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters ab With Amoxicillin and Clavulanate Potassium Tablets
Dose and Regimen		C max (mcg/mL)		AUC 0 to 24 (mcg*h/mL)
Amoxicillin and Clavulanate Potassium		Amoxicillin	Clavulanate Potassium	Amoxicillin	Clavulanate Potassium
250 mg/125 mg every 8 hours		3.3 1.12	1.5 0.70	26.7 4.56	12.6 3.25
500 mg/125 mg every 12 hours		6.5 1.41	1.8 0.61	33.4 6.76	8.6 1.95
500 mg/125 mg every 8 hours		7.2 2.26	2.4 0.83	53.4 8.87	15.7 3.86
875 mg/125 mg every 12 hours		11.6 2.78	2.2 0.99	53.5 12.31	10.2 3.04
a	Mean ( standard deviation) values of 14 normal adults (N=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose.
b	Amoxicillin and clavulanate potassium administered at the start of a light meal.

Table 4: Mean ( S.D.) Amoxicillin and Clavulanate Potassium Pharmacokinetic Parameters a,b with Amoxicillin and Clavulanate Potassium Powder for Oral Suspension and Chewable Tablets

Dose	C max (mcg/mL)		AUC 0 to 24 (mcg*h/mL)
Amoxicillin/Clavulanate potassium	Amoxicillin	Clavulanate potassium	Amoxicillin	Clavulanate potassium
400/57 mg (5 mL of suspension)	6.94 1.24	1.10 0.42	17.29 2.28	2.34 0.94
400/57 mg (1 chewable tablet)	6.67 1.37	1.03 0.33	17.24 2.64	2.17 0.73

a Mean ( standard deviation) values of 28 normal adults. Peak concentrations occurred approximately 1 hour after the dose.

b Amoxicillin/clavulanate potassium administered at the start of a light meal.

Oral administration of 5 mL of 250 mg/62.5 mg per 5 mL suspension of amoxicillin and clavulanate potassium or the equivalent dose of 10 mL of 125 mg/31.5 mg per 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/62.5 mg chewable tablet of amoxicillin and clavulanate potassium or two 125 mg/31.25 mg chewable tablet 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/125 mg or 500 mg/125 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 tablets 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

Eikenella corrodens

Proteus mirabilis

Anaerobic Bacteria

Bacteroides species including Bacteroides fragilis

Fusobacterium species

Peptostreptococcus species

For 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 Nonclinical Toxicology ⮝

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 tablets (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 Clinical Studies ⮝

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/125 mg amoxicillin and clavulanate potassium tablets every 12 hours to 500 mg/125 mg amoxicillin and clavulanate potassium tablets 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/125 mg every 12 hours and 500 mg/125 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/125 mg every 12 hours regimen versus 2% for the 500 mg/125 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/125 mg amoxicillin and clavulanate potassium tablets every 12 hours (n = 308) or 500 mg/125 mg amoxicillin and clavulanate potassium tablets every 8 hours (n = 321).

The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin and clavulanate potassium tablets 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.

Table 7: Bacteriologic efficacy rates for amoxicillin and clavulanate potassium tablets
Time Post Therapy	875 mg/125 mg every 12 hours % (n)	500 mg/125 mg every 8 hours % (n)
2 to 4 days	81% (58)	80% (54)
5 to 9 days	58% (41)	52% (52)
2 to 4 weeks	52% (101)	55% (104)

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 U.S./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., 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 to 4 days after the completion of therapy) and at the follow-up visit (defined as 22 to 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.

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 ⮝

Amoxicillin and Clavulanate Potassium Tablets USP are supplied as follows:

Amoxicillin and clavulanate potassium tablets USP, 250 mg/125 mgare white to off-white colored, capsule shaped, biconvex, film-coated tablets, debossed with I 05 on one side and plain on the other side. Each tablet contains 250 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. They are available as follows.

Amoxicillin and clavulanate potassium tablets USP, 500 mg/125 mg are white to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with I 06 on one side and plain on the other side. Each tablet contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. They are available as follows.

Amoxicillin and clavulanate potassium tablets USP, 875 mg/125 mg are white to off-white colored, capsule shaped, biconvex, film-coated tablets debossed with I 07 on one side score line on the other side. Each tablet contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. They are available as follows.

Bottles of 20 NDC 55700-751-20

Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Dispense in tightly closed, moisture-proof containers.

KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

Package Label.principal Display Panel ⮝

NDC 42571-160-30
Amoxicillin and Clavulanate
Potassium Tablets, USP
250 mg/125 mg*
Rx Only
30 Tablets
MICRO LABS

NDC 42571-160-11
Amoxicillin and Clavulante
Potassium Tablets, USP
250 mg/125 mg*
Rx Only
100 Tablets (10x10 Unit-dose)
MICRO LABS

NDC 42571-161-42
Amoxicillin and Clavulante
Potassium Tablets, USP
500 mg/125 mg*
Rx Only
20 Tablets
MICRO LABS

NDC 42571-161-11
Amoxicillin and Clavulante
Potassium Tablets, USP
500 mg/125 mg*
Rx Only
100 Tablets (10x10 Unit-dose)

NDC 42571-162-42
Amoxicillin and Clavulanate
Potassium Tablets, USP
875 mg/125 mg*
Rx Only
20 Tablets
MICRO LABS LIMITED

NDC 42571-162-44
Amoxicillin and Clavulanate
Potassium Tablets, USP
875 mg/125 mg*
Rx Only
40 Tablets (4 x 10 Unit-dose)
MICRO LABS LIMITED

AMOXICILLIN AND CLAVULANATE POTASSIUM amoxicillin and clavulanate potassium tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42571-160 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMOXICILLIN (UNII: 804826J2HU) (AMOXICILLIN ANHYDROUS - UNII:9EM05410Q9) AMOXICILLIN ANHYDROUS 250 mg CLAVULANATE POTASSIUM (UNII: Q42OMW3AT8) (CLAVULANIC ACID - UNII:23521W1S24) CLAVULANIC ACID 125 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) TALC (UNII: 7SEV7J4R1U)

Product Characteristics Color white (white to off-white) Score no score Shape CAPSULE (biconvex) Size 17mm Flavor Imprint Code I05 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42571-160-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 03/01/2017 2 NDC:42571-160-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 03/01/2017 3 NDC:42571-160-11 10 in 1 CARTON 03/01/2017 3 NDC:42571-160-32 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA205707 03/01/2017

AMOXICILLIN AND CLAVULANATE POTASSIUM amoxicillin and clavulanate potassium tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42571-161 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMOXICILLIN (UNII: 804826J2HU) (AMOXICILLIN ANHYDROUS - UNII:9EM05410Q9) AMOXICILLIN ANHYDROUS 500 mg CLAVULANATE POTASSIUM (UNII: Q42OMW3AT8) (CLAVULANIC ACID - UNII:23521W1S24) CLAVULANIC ACID 125 mg

Inactive Ingredients Ingredient Name Strength POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) TALC (UNII: 7SEV7J4R1U)

Product Characteristics Color white (white to off-white) Score no score Shape CAPSULE (biconvex) Size 19mm Flavor Imprint Code I06 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42571-161-42 20 in 1 BOTTLE; Type 0: Not a Combination Product 03/01/2017 2 NDC:42571-161-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 03/01/2017 3 NDC:42571-161-11 10 in 1 CARTON 03/01/2017 3 NDC:42571-161-32 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA205707 03/01/2017

AMOXICILLIN AND CLAVULANATE POTASSIUM amoxicillin and clavulanate potassium tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:42571-162 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMOXICILLIN (UNII: 804826J2HU) (AMOXICILLIN ANHYDROUS - UNII:9EM05410Q9) AMOXICILLIN ANHYDROUS 875 mg CLAVULANATE POTASSIUM (UNII: Q42OMW3AT8) (CLAVULANIC ACID - UNII:23521W1S24) CLAVULANIC ACID 125 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) TALC (UNII: 7SEV7J4R1U)

Product Characteristics Color white (white to off-white) Score 2 pieces Shape CAPSULE (biconvex) Size 22mm Flavor Imprint Code I07 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42571-162-42 20 in 1 BOTTLE; Type 0: Not a Combination Product 03/01/2017 2 NDC:42571-162-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 03/01/2017 3 NDC:42571-162-44 4 in 1 CARTON 03/01/2017 3 NDC:42571-162-43 4 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA204755 03/01/2017

Labeler - Micro Labs Limited (862174955)

Registrant - Micro Labs Limited (862174955)

Revised: 1/2019 Document Id: 801ef7bf-de11-5241-e053-2a91aa0a03e6 34391-3 Set id: 0c2d1fbc-f80c-4737-a15e-9cfa6bf99769 Version: 10 Effective Time: 20190123 Micro Labs Limited

No Title 1572451513 ⮝

AMOXICILLIN, 500 mg, as the trihydrate and CLAVULANIC ACID, 125 mg, as clavulanate potassium; or

AMOXICILLIN, 875 mg, as the trihydrate and CLAVULANIC ACID, 125 mg, as clavulanate potassium

Rx only

PRESCRIBING

INFORMATION

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

Description ⮝

Amoxicillin and Clavulanate Potassium Tablet USP is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the -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 -lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of -lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid mediated -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:

Each film coated tablet contains 500 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt or 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt. In addition, each 500 mg/125 mg and 875 mg/125 mg amoxicillin and clavulanate potassium tablet contains 0.63 mEq potassium.

Inactive Ingredients: Colloidal silicon dioxide, croscarmellose sodium dried, crospovidone dried, ethylcellulose, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose dried, polysorbate 80, talc, titanium dioxide, triethyl citrat.

Clinical Pharmacology ⮝

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of amoxicillin/clavulanate potassium. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin/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 1 study, the relative bioavailability of clavulanate was reduced when amoxicillin/clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast. The safety and efficacy of amoxicillin/clavulanate potassium have been established in clinical trials where amoxicillin/clavulanate potassium was taken without regard to meals.

Mean* amoxicillin and clavulanate potassium pharmacokinetic parameters are shown in the table below:

Dose and regimen	AUC0-24 (mcg hr/mL)		Cmax (mcg/mL)
amoxicillin/clavulanate potassium	amoxicillin ( S.D.)	clavulanate potassium ( S.D.)	amoxicillin ( S.D.)	clavulanate potassium ( S.D.)
250/125 mg q8h	26.7 4.56	12.6 3.25	3.3 1.12	1.5 0.70
500/125 mg q12h	33.4 6.76	8.6 1.95	6.5 1.41	1.8 0.61
500/125 mg q8h	53.4 8.87	15.7 3.86	7.2 2.26	2.4 0.83
875/125 mg q12h	53.5 12.31	10.2 3.04	11.6 2.78	2.2 0.99

*Mean values of 14 normal volunteers (n=15 for clavulanate potassium in the low-dose regimens). Peak concentrations occurred approximately 1.5 hours after the dose.

Administered at the start of a light meal.

Amoxicillin serum concentrations achieved with amoxicillin/clavulanate potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of amoxicillin/clavulanate potassium is 1.3 hours and that of clavulanic acid is 1.0 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/clavulanate potassium.

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

Neither component in amoxicillin/clavulanate potassium is highly protein-bound; clavulanic acid has been found to be 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. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

Microbiology

Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by -lactamases and, therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a -lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of -lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated -lactamases frequently responsible for transferred drug resistance.

The formulation of amoxicillin and clavulanic acid in amoxicillin/clavulanate potassium protects amoxicillin from degradation by -lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other -lactam antibiotics. Thus, amoxicillin/clavulanate potassium possesses the properties of a broad-spectrum antibiotic and a -lactamase inhibitor.

Amoxicillin/clavulanic acid has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Gram-Positive Aerobes:

Staphylococcus aureus ( -lactamase and non- -lactamase producing).

Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.

Gram-Negative Aerobes:

Enterobacter species (Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with amoxicillin/clavulanate potassium in urinary tract infections caused by these organisms.)

Escherichia coli ( -lactamase and non- -lactamase producing)

Haemophilus influenzae ( -lactamase and non- -lactamase producing)

Klebsiella species (All known strains are -lactamase producing.)

Moraxella catarrhalis ( -lactamase and non- -lactamase producing)

The following in vitro data are available, but their clinical significance is unknown.

Amoxicillin/clavulanic acid exhibits in vitro minimal inhibitory concentrations (MICs) of 2 mcg/mL or less against most ( 90%) strains of Streptococcus pneumoniae ; MICs of 0.06 mcg/mL or less against most ( 90%) strains of Neisseria gonorrhoeae; MICs of 4 mcg/mL or less against most ( 90%) strains of staphylococci and anaerobic bacteria; and MICs of 8 mcg/mL or less against most ( 90%) strains of other listed organisms. However, with the exception of organisms shown to respond to amoxicillin alone, the safety and effectiveness of amoxicillin/clavulanic acid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Because amoxicillin has greater in vitro activity against S. pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin.

Gram-Positive Aerobes:

Enterococcus faecalisII

Staphylococcus epidermidis ( -lactamase and non- -lactamase producing)

Staphylococcus saprophyticus ( -lactamase and non- -lactamase producing)

Streptococcus pneumoniae II ,

Streptococcus pyogenes II

viridans group Streptococcus II

Gram-Negative Aerobes:

Eikenella corrodens ( -lactamase and non- -lactamase producing)

Neisseria gonorrhoeae II ( -lactamase and non- -lactamase producing)

Proteus mirabilis II ( -lactamase and non- -lactamase producing)

Anaerobic Bacteria:

Bacteroides species, including Bacteroides fragilis ( -lactamase and non- -lactamase producing)

Fusobacterium species ( -lactamase and non- -lactamase producing)

Peptostreptococcus species

II Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to these organisms.

Those are non- -lactamase-producing organisms and, therefore, are susceptible to amoxicillin alone.

Susceptibility Testing:

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). Those MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of amoxicillin/clavulanate potassium powder.

The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For Gram-Negative Enteric Aerobes:
MIC (mcg/mL)	Interpretation
8/4	Susceptible (S)
16/8	Intermediate (I)
32/16	Resistant (R)
For Staphylococcus** and Haemophilus species:
MIC (mcg/mL)	Interpretation
4/2	Susceptible (S)
8/4	Resistant (R)

**Staphylococci which are susceptible to amoxicillin/clavulanic acid but resistant to methicillin/oxacillin must be considered as resistant.

For Streptococcus pneumoniae from non-meningitis sources:

Isolates should be tested using amoxicillin/clavulanic acid and the following criteria should be used:

MIC (mcg/mL)	Interpretation
2/1	Susceptible (S)
4/2	Intermediate (I)
8/4	Resistant (R)

Note: These interpretive criteria are based on the recommended doses for respiratory tract infections.

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

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

MicroorganismMIC Range (mcg/mL)
Escherichia coli	ATCC 25922	2 to 8
Escherichia coli	ATCC 35218	4 to 16
Enterococcus faecalis	ATCC 29212	0.25 to 1.0
Haemophilus influenzae	ATCC 49247	2 to 16
Staphylococcus aureus	ATCC 29213	0.12 to 0.5
Streptococcus pneumoniae	ATCC 49619	0.03 to 0.12

Expressed as concentration of amoxicillin in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid.

Diffusion Techniques:

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg of amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test the susceptibility of microorganisms to amoxicillin/clavulanic acid.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) disk should be interpreted according to the following criteria:

RECOMMENDED RANGES FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For Staphylococcus species and H.influenzaea

Zone Diameter (mm)	Interpretation
20	Susceptible (S)
19	Resistant (R)

For Other Organisms Except S. pneumoniaeb and N. gonorrhoeaec

Zone Diameter (mm)	Interpretation
18	Susceptible (S)
14 to 17	Intermediate (I)
13	Resistant (R)

Staphylococci which are resistant to methicillin/oxacillin must be considered as resistant to amoxicillin/clavulanic acid.

a A broth microdilution method should be used for testing H. influenzae. Beta-lactamase negative, ampicillin-resistant strains must be considered resistant to amoxicillin/clavulanic acid.

b Susceptibility of S. pneumoniae should be determined using a 1-mcg oxacillin disk. Isolates with oxacillin zone sizes of 20 mm are susceptible to amoxicillin/clavulanic acid. An amoxicillin/clavulanic acid MIC should be determined on isolates of S.pneumoniae with oxacillin zone sizes of 19 mm.

c A broth microdilution method should be used for testing N. gonorrhoeae and interpreted according to penicillin breakpoints.

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

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10-mcg clavulanate potassium) disk should provide the following zone diameters in these laboratory quality control strains.

Microorganism	Zone Diameter (mm)
Escherichia coli
ATCC 25922	19 to 25
Escherichia coli
ATCC 35218	18 to 22
Staphylococcus aureus
ATCC 25923	28 to 36

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 AMOXICILLIN/CLAVULANATE POTASSIUM, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN/CLAVULANATE POTASSIUM 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.

Amoxicillin/clavulanate potassium 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.)

Precautions ⮝

General

While amoxicillin/clavulanate potassium 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 during prolonged therapy.

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 amoxicillin/clavulanate potassium 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 resistance bacteria.

Drug Interactions

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin/clavulanate potassium may result in increased and prolonged blood levels of amoxicillin. Coadministration of probenecid cannot be recommended.

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 amoxicillin/clavulanate potassium and allopurinol administered concurrently.

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

Drug/Laboratory Test Interactions

Oral administration of amoxicillin/clavulanate potassium 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 amoxicillin/clavulanate potassium, 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 amoxicillin/clavulanate potassium.

Information for Patients:

Patients should be counseled that antibacterial drugs including amoxicillin/clavulanate potassium, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin/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 effectivness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by amoxicillin/clavulanate potassium or other antibacterial drugs in the future.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Mutagenesis:

The mutagenic potential of amoxicillin/clavulanate potassium 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.

Impairment of Fertility:

Amoxicillin/clavulanate potassium at oral doses of up to 1200 mg/kg/day (5.7 times the maximum human dose, 1480 mg/m2/day, 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 amoxicillin/clavulanate potassium at oral dosages up to 1200 mg/kg/day, equivalent to 7200 and 4080 mg/m2/day, respectively (4.9 and 2.8 times the maximum human oral dose based on body surface area), revealed no evidence of harm to the fetus due to amoxicillin/clavulanate potassium. 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 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 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 amoxicillin/clavulanate potassium may be associated with an increased risk of necrotizing enterocolitis in neonates.

Nursing Mothers:

Ampicillin-class antibiotics are excreted in the milk; therefore, caution should be exercised when amoxicillin/clavulanate potassium is administered to a nursing woman.

Pediatric Use:

Pediatric patients weighing 40 Kg or more should be dosed according to the adult recommendations (see DOSAGE AND ADMINISTRATION: Pediatric Patients). Safety and effectiveness of Amoxicillin and Clavulanate Potassium Tablets in pediatric patients weighing less than 40 kg have not been established. (See prescribing information for Amoxicillin and Clavulanate Powder for Oral Suspension and Chewable Tablets).

Geriatric Use:

An analysis of clinical studies of Amoxicillin and Clavulanate Potassium Tablets was conducted to determine whether subjects aged 65 and over respond differently from younger subjects. Of the 3,119 patients in this analysis, 68% were < 65 years old, 32% were 65 years old and 14% were 75 years old. This analysis and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but a 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 toxic 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.

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 amoxicillin/clavulanate potassium, 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 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.3 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 for recommended dosing for patients with impaired renal function.)

How Supplied ⮝

Amoxicillin and Clavulanate Potassium Tablets, USP 500/125 mg are white to off-white, oblong film coated tablets with beveled edges, debossed with 500/125 on one side and AMC on the other side.

Amoxicillin and Clavulanate Potassium Tablets, USP 875/125 mg are white to off-white, oblong film coated tablets with beveled edges, scored and debossed with 875/125 on one side and AMC on the other side.

They are supplied by State of Florida DOH Central Pharmacy as follows:

NDC	Strength	Quantity/Form	Color	Source Prod. Code
53808-0740-1	875 mg / 125 mg	1 Tablet in a Dose Pack, 30 Dose Packs in a Carton	WHITE	66685-1001

Store tablets at 20 - 25 C (68 - 77 F) [See USP Controlled Room Temperature]. Dispense in tightly closed, moisture-proof containers.

Clinical Studies ⮝

Data from 2 pivotal studies in 1.191 patients treated for either lower respiratory tract infections or complicated urinary tract infections compared a regimen of 875 mg/125 mg amoxicillin/clavulanate potassium tablets q12h to 500 mg/125 mg amoxicillin/clavulanate potassium tablets dosed q8h (584 and 607 patients, respectively). Comparable efficacy was demonstrated between the q12h and q8h 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/125 mg q12h and 500 mg/125 mg q8h dosing regimens (14.9% and 14.3%, respectively); however, there was a statistically significant difference (p<0.05) in rates of severe diarrhea or withdrawals with diarrhea between the regimens: 1.0% for 875 mg/125 mg q12h dosing versus 2.5% for the 500 mg/125 mg q8h dosing.

In one of these pivotal studies, 629 patients with either pyelonephritis or a complicated urinary tract infection (i.e., patients with abnormalities of the urinary tract that predispose to relapse of bacteriuria following eradication) were randomized to receive either 875 mg/125 mg amoxicillin/clavulanate potassium tablets q12h or 500 mg/125 mg amoxicillin/clavulanate potassium tablets q8h in the following distribution:

875 mg/125 mg q12 h		500 mg/125 mg q8h
Pyelonephritis	173 patients	188 patients
Complicated UTI	135 patients	133 patients
Total patients	308	321

The number of bacteriologically evaluable patients was comparable between the two dosing regimens. Amoxicillin/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 the table below:

875 mg/125 mg q12h		500 mg/125 mg q8h
2 to 4 days	81%, n=58	80%, n=54
5 to 9 days	58.5%, n=41	51.9%, n=52
2 to 4 weeks	52.5%, n=101	54.8%, n=104

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.

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25. NCCLS, Villanova, PA, December 1993.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24. NCCLS, Villanova, PA, December 1993.

3. 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.

CLINITEST is a registered trademark of Miles, Inc.

CLINISTIX is a registered trademark of Bayer Corporation

Manufactured in Slovenia

By Lek Pharmaceuticals d.d.

Distributed by Lek Pharmaceuticals Inc.

An affiliate of Sandoz Inc.,

Princeton, NJ 08540

This Product was Repackaged By:

State of Florida DOH Central Pharmacy
104-2 Hamilton Park Drive
Tallahassee, FL 32304
United States

Label Image For 875/125mg ⮝

AMOXICILLIN AND CLAVULANATE POTASSIUM amoxicillin and clavulanate potassium tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:53808-0740(NDC:66685-1001) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMOXICILLIN (UNII: 804826J2HU) (AMOXICILLIN - UNII:804826J2HU) AMOXICILLIN 875 mg CLAVULANATE POTASSIUM (UNII: Q42OMW3AT8) (CLAVULANIC ACID - UNII:23521W1S24) CLAVULANATE POTASSIUM 125 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) CROSPOVIDONE (UNII: 68401960MK) ETHYLCELLULOSE (UNII: 7Z8S9VYZ4B) HYDROXYPROPYL CELLULOSE (UNII: RFW2ET671P) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYSORBATE 80 (UNII: 6OZP39ZG8H) TALC (UNII: 7SEV7J4R1U) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIETHYL CITRATE (UNII: 8Z96QXD6UM)

Product Characteristics Color white (WHITE) Score no score Shape OVAL (OVAL) Size 13mm Flavor Imprint Code 875;125;AMC Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:53808-0740-1 30 in 1 CARTON 1 1 in 1 DOSE PACK

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA065093 07/01/2009

Labeler - State of Florida DOH Central Pharmacy (829348114)

Establishment
Name	Address	ID/FEI	Business Operations
State of Florida DOH Central Pharmacy		829348114	repack

Revised: 6/2010 Document Id: d8728514-ee4d-474e-a002-fa8a70f9eb10 34391-3 Set id: f1e72f44-561a-4905-ab29-15ef83eac928 Version: 1 Effective Time: 20100604 State of Florida DOH Central Pharmacy

No Title 1572455522 ⮝

AMOXICILLIN AND CLAVULANATE POTASSIUM amoxicillin and clavulanate potassium tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55700-751(NDC:42571-162) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength AMOXICILLIN (UNII: 804826J2HU) (AMOXICILLIN ANHYDROUS - UNII:9EM05410Q9) AMOXICILLIN ANHYDROUS 875 mg CLAVULANATE POTASSIUM (UNII: Q42OMW3AT8) (CLAVULANIC ACID - UNII:23521W1S24) CLAVULANIC ACID 125 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) ETHYLCELLULOSE (10 MPA.S) (UNII: 3DYK7UYZ62) TALC (UNII: 7SEV7J4R1U)

Product Characteristics Color white (white to off-white) Score 2 pieces Shape CAPSULE (biconvex) Size 22mm Flavor Imprint Code I07 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55700-751-20 20 in 1 BOTTLE; Type 0: Not a Combination Product 05/10/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA204755 05/10/2019

Labeler - Quality Care Products, LLC (831276758)

Establishment
Name	Address	ID/FEI	Business Operations
Lake Erie Medical & Surgical Supply DBA Quality Care Products, LLC		092172824	relabel(55700-751)

Revised: 5/2019 Document Id: 330871dd-ee0d-46e7-a205-f358069bb31d 34391-3 Set id: fbffc027-a2c3-4078-89ea-b8d99e789664 Version: 1 Effective Time: 20190515 Quality Care Products, LLC