Amoxicillin and Clavulanate Potassium

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium for oral suspension, USP and other antibacterial drugs, amoxicillin and clavulanate potassium for oral suspension, USP 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 for oral suspension, USP is indicated for the treatment of pediatric patients with recurrent or persistent acute otitis media due to S. pneumoniae (penicillin MICs ≤ 2 mcg/mL), H. influenzae (including beta-lactamase – producing strains), or M. catarrhalis (including beta-lactamase-­producing strains) characterized by the following risk factors: antibacterial drug exposure for acute otitis media within the preceding 3 months, and either of the following: -age 2 years or younger -daycare attendance [see CLINICAL PHARMACOLOGY , Microbiology (12.4) ] NOTE: Acute otitis media due to S. pneumoniae alone can be treated with amoxicillin. Amoxicillin and clavulanate potassium for oral suspension, USP is not indicated for the treatment of acute otitis media due to S. pneumoniae with penicillin MIC ≥ 4 mcg/mL. Therapy may be instituted prior to obtaining the results from bacteriological studies when there is reason to believe the infection may involve both S. pneumoniae (penicillin MIC ≤ 2 mcg/mL) and the beta-lactamase-producing organisms listed above.

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

Amoxicillin and clavulanate potassium for oral suspension does not contain the same amount of clavulanic acid (as the potassium salt) as any of the other suspensions of amoxicillin and clavulanate potassium. Amoxicillin and clavulanate potassium for oral suspension contains 42.9 mg of clavulanic acid per 5 mL, whereas the 200 mg/5 mL suspension of amoxicillin and clavulanate potassium contains 28.5 mg of clavulanic acid per 5 mL and the 400 mg/5 mL suspension contains 57 mg of clavulanic acid per 5 mL. Therefore, the 200 mg/28.5 mg/5 mL and 400 mg/57 mg/5 mL suspensions of amoxicillin and clavulanate potassium should not be substituted for amoxicillin and clavulanate potassium for oral suspension as they are not interchangeable. Dosage: Pediatric patients 3 months and older: Based on the amoxicillin component (600 mg/5 mL), the recommended dose of amoxicillin and clavulanate potassium for oral suspension is 90 mg/kg/day divided every 12 hours, administered for 10 days (see chart below). This dose provides 6.4 mg/kg/day of the clavulanic acid component. Body Weight (kg) Volume of Amoxicillin and Clavulanate Potassium Powder for Oral Suspension providing 90 mg/kg/day 8 3 mL twice daily 12 4.5 mL twice daily 16 6 mL twice daily 20 7.5 mL twice daily 24 9 mL twice daily 28 10.5 mL twice daily 32 12 mL twice daily 36 13.5 mL twice daily Pediatric patients weighing 40 kg and more: Experience with amoxicillin and clavulanate potassium for oral suspension in this group is not available. Adults: Experience with amoxicillin and clavulanate potassium for oral suspension in adults is not available and adults who have difficulty swallowing should not be given amoxicillin and clavulanate potassium for oral suspension in place of the 500 mg or 875 mg tablet of amoxicillin and clavulanate potassium. Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals [see WARNINGS and PRECAUTIONS (5) ]. Directions for Mixing Oral Suspension: Prepare a suspension at time of dispensing as follows: Tap bottle until all the powder flows freely. Add approximately 2/3 of the total amount of water for reconstitution (see table below) and shake vigorously to suspend powder. Add remainder of the water and again shake vigorously. Amoxicillin and Clavulanate Potassium for Oral Suspension Bottle Size Amount of Water Required for Reconstitution 75 mL 71 mL 125 mL 112 mL 200 mL 176 mL Each teaspoonful (5 mL) will contain 600 mg amoxicillin as the trihydrate and 42.9 mg of clavulanic acid as the potassium salt. NOTE: SHAKE ORAL SUSPENSION WELL BEFORE USING. Information for the Pharmacist: For patients who wish to alter the taste of amoxicillin and clavulanate potassium for oral suspension, immediately after reconstitution 1 drop of FLAVORx™ (apple, banana cream, bubble gum, cherry, or watermelon flavor) may be added for every 5 mL of amoxicillin and clavulanate potassium for oral suspension. The resulting suspension is stable for 10 days under refrigeration. Stability of amoxicillin and clavulanate potassium for oral suspension when mixed with other flavors distributed by FLAVORx has not been evaluated for flavors other than the five flavors listed above. Administration: To minimize the potential for gastrointestinal intolerance, amoxicillin and clavulanate potassium for oral suspension should be taken at the start of a meal. Absorption of clavulanate potassium may be enhanced when amoxicillin and clavulanate potassium for oral suspension is administered at the start of a meal.

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Powder for Oral Suspension: 600 mg/42.9 mg per 5 mL: Strawberry-flavored powder for oral suspension (each 5 mL of reconstituted suspension contains 600 mg amoxicillin and 42.9 mg of clavulanic acid as the potassium salt).

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness has also been observed in a small number of patients. In the case of overdosage, discontinue amoxicillin and clavulanate potassium for oral suspension, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison control center suggested that overdosage of less than 250 mg/kg of amoxicillin is not associated with significant clinical symptoms and does not require gastric emptying 1 . 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.

11 DESCRIPTION

DESCRIPTION SECTION

Amoxicillin and clavulanate potassium for oral suspension, USP is an oral antibacterial combination consisting of the semisynthetic antibacterial 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 16 H 19 N 3 0 5 S•3H 2 O, and the molecular weight is 419.46. Chemically, amoxicillin is (2 S ,5 R ,6 R )-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 a wide variety of beta - lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C 8 H 8 KN0 5 and the molecular weight is 237.25. Chemically, clavulanate potassium 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: Amoxicillin and clavulanate potassium for oral suspension, USP is white to off-white granular powder and becomes white to pale yellow suspension with strawberry flavor after reconstitution. Inactive Ingredients: —Aspartame*, colloidal silicon dioxide, hypromellose, silicon dioxide, strawberry cream permaseal, succinic acid, and xanthan gum [see Warnings and Precautions (5.6) ]. Each 5 mL of reconstituted amoxicillin and clavulanate potassium for oral suspension USP, 600 mg/42.9 mg per 5 mL contains 600 mg amoxicillin as the trihydrate and 42.9 mg clavulanic acid as the potassium salt (clavulanate potassium). The potassium content per 5 mL is 0.21 mEq.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

Two clinical studies were conducted in pediatric patients with acute otitis media. A non-comparative, open-label study assessed the bacteriologic and clinical efficacy of amoxicillin and clavulanate potassium for oral suspension (90/6.4 mg/kg/day, divided every 12 hours) for 10 days in 521 pediatric patients (3 to 50 months) with acute otitis media. The primary objective was to assess bacteriological response in children with acute otitis media due to S. pneumoniae with amoxicillin/clavulanic acid MICs of 4 mcg/mL. The study sought the enrollment of patients with the following risk factors: Failure of antibacterial therapy for acute otitis media in the previous 3 months, history of recurrent episodes of acute otitis media, 2 years or younger, or daycare attendance. Prior to receiving amoxicillin and clavulanate potassium for oral suspension, all patients had tympanocentesis to obtain middle ear fluid for bacteriological evaluation. Patients from whom S. pneumoniae (alone or in combination with other bacteria) was isolated had a second tympanocentesis 4 to 6 days after the start of therapy. Clinical assessments were planned for all patients during treatment (4 to 6 days after starting therapy), as well as 2 to 4 days post-treatment and 15 to18 days post-treatment. Bacteriological success was defined as the absence of the pretreatment pathogen from the on-therapy tympanocentesis specimen. Clinical success was defined as improvement or resolution of signs and symptoms. Clinical failure was defined as lack of improvement or worsening of signs and/or symptoms at any time following at least 72 hours of amoxicillin and clavulanate potassium for oral suspension; patients who received an additional systemic antibacterial drug for otitis media after 3 days of therapy were considered clinical failures. Bacteriological eradication on therapy (day 4 to 6 visit) in the per protocol population is summarized in the following table: Table 5. Bacteriologic Eradication Rates in the Per Protocol Population Pathogen Bacteriologic Eradication on Therapy n/N % 95% CI* All S. pneumoniae 121/123 98 (94.3, 99.8) S. pneumoniae with penicillin MIC = 2 mcg/mL 19/19 100 (82.4, 100) S. pneumoniae with penicillin MIC = 4 mcg/mL 12/14 86 (57.2, 98.2) H. influenzae 75/81 93 (84.6, 97.2) M. catarrhalis 11/11 100 (71.5, 100) * CI = confidence intervals; 95% CIs are not adjusted for multiple comparisons. Clinical assessments were made in the per protocol population 2 to 4 days post-therapy and 15 to 18 days post-therapy. Patients who responded to therapy 2 to 4 days post-therapy were followed for 15 to 18 days post-therapy to assess them for acute otitis media. Nonresponders at 2 to 4 days post-therapy were considered failures at the latter timepoint. Table 6. Clinical Assessments in the Per Protocol Population (Includes S. pneumoniae Patients With Penicillin MICs = 2 mcg/mL or 4 mcg/mL*) Pathogen 2 to 4 Days Post-Therapy (Primary Endpoint) Clinical Response 95% CI† n/N % All S. pneumoniae 122/137 89 (82.6, 93.7) S. pneumoniae with penicillin MIC = 2 mcg/mL 17/20 85 (62.1, 96.8) S. pneumoniae with penicillin MIC = 4 mcg/mL 11/14 79 (49.2, 95.3) H. influenzae 141/162 87 (80.9, 91.8) M. catarrhalis 22/26 85 (65.1, 95.6) Pathogen 15 to 18 Days Post-Therapy ‡ (Secondary Endpoint) Clinical Response 95% CI† n/N % All S. pneumoniae 95/136 70 (61.4, 77.4) S. pneumoniae with penicillin MIC = 2 mcg/mL 11/20 55 (31.5, 76.9) S. pneumoniae with penicillin MIC = 4 mcg/mL 5/14 36 (12.8, 64.9) H. influenzae 106/156 68 (60, 75.2) M. catarrhalis 14/25 56 (34.9, 75.6) *S.pneumoniae strains with penicillin MICs of 2 mcg/mL or 4 mcg/mL are considered resistant to penicillin. † CI = confidence intervals; 95% CIs are not adjusted for multiple comparisons. ‡ Clinical assessments at 15 to 18 days post-therapy may have been confounded by viral infections and new episodes of acute otitis media with time elapsed post-treatment. In the intent-to-treat analysis, overall clinical outcomes at 2 to 4 days and 15 to 18 days post treatment in patients with S. pneumoniae with penicillin MIC = 2 mcg/mL and 4 mcg/mL were 29/41 (71%) and 17/41 (42%), respectively.

15 REFERENCES

REFERENCES SECTION

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

HOW SUPPLIED SECTION

How Supplied Amoxicillin and Clavulanate Potassium for Oral Suspension USP, 600 mg/42.9 mg per 5 mL is a white to off-white granular powder – Each 5 mL of reconstituted white to pale yellow, strawberry flavored suspension contains 600 mg amoxicillin and 42.9 mg clavulanic acid as the potassium salt. NDC 68071-2355-5 BOTTLE OF 75mL Storage Store reconstituted suspension under refrigeration. Discard unused suspension after 10 days. Store dry powder for oral suspension at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in original container.

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Take amoxicillin and clavulanate potassium for oral suspension every 12 hours with a meal or snack to reduce the possibility of gastrointestinal upset. If diarrhea develops and is severe or lasts more than 2 or 3 days, call your doctor. Counsel patients that antibacterial drugs, including amoxicillin and clavulanate potassium for oral suspension, should only be used to treat bacterial infections. Antibacterial drugs do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium for oral suspension is prescribed to treat a bacterial infection, tell patients 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 for oral suspension or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial drug is discontinued. Sometimes after starting treatment with antibacterial drugs, patient can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible. Keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of amoxicillin and clavulanate potassium for oral suspension, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of amoxicillin and clavulanate potassium for oral suspension may contain more liquid than required. Follow your doctor’s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine. Counsel patients that amoxicillin and clavulanate potassium for oral suspension contains a penicillin class drug product that can cause allergic reactions in some individuals. Counsel patients with phenylketonuria: Each 5 mL of the 600 mg/42.9 mg per 5 mL suspension of amoxicillin and clavulanate potassium for oral suspension contains 7.02 mg phenylalanine. The brands listed are trademarks of their respective owners and are not trademarks of the Aurobindo Pharma Limited. Manufactured for: Northstar Rx LLC Memphis, TN 38141. Manufactured by: Aurobindo Pharma Limited Hyderabad-500 090, India. M.L.No.: 57/RR/AP/2003/F/R Revised: 12/2018

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 600 mg/42.9 mg per 5 mL (75 mL Bottle)

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL