AMOXICILLIN AND CLAVULANATE POTASSIUM: Package Insert and Label Information (Page 3 of 4)

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 concentrations that were also associated with decreased cell survival. Amoxicillin and Clavulanate Potassium was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test and was negative in each of these assays.

Amoxicillin and Clavulanate Potassium (2:1 ratio formulation of amoxicillin:clavulanate) at oral doses of up to 1,200 mg/kg/day was found to have no effect on fertility and reproductive performance in rats. Based on body surface area (assuming a 20 kg child), this dose of amoxicillin is approximately 2 times the recommended clinical Amoxicillin and Clavulanate Potassium for oral suspension dose of 90/6.4 mg/kg/day. For clavulanate, the dose multiple is approximately 15 times higher than the recommended clinical daily dose, also based on body surface area.

14 CLINICAL STUDIES

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 to 18 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 3. Bacteriologic Eradication Rates in the Per Protocol Population

*CI equals confidence intervals; 95% CIs are not adjusted for multiple comparisons.

Bacteriologic Eradication on Therapy
Pathogen n/N % 95% CI*
All S. pneumoniae 121/123 98 (94.3, 99.8)
S. pneumoniae with penicillinMIC equal to 2 mcg/mL 19/19 100 (82.4, 100.0)
S. pneumoniae with penicillinMIC equal to 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, 100.0)

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. Non-responders at 2 to 4 days post-therapy were considered failures at the latter timepoint.

Table 4. Clinical Assessments in the Per Protocol Population (Includes S. pneumoniae Patients with Penicillin MICs equal to 2 or 4 mcg/mL*)

2 to 4 Days Post-Therapy (Primary Endpoint)
Pathogen n/N % 95% CI
All S. pneumoniae 122/137 89 (82.6, 93.7)
S. pneumoniae with penicillinMIC equal to 2 mcg/mL 17/20 85 (62.1, 96.8)
S. pneumoniae with penicillinMIC equal to 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)

* S. pneumoniae strains with penicillin MICs of 2 or 4 mcg/mL are considered resistant to penicillin.

† CI equals 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.

15 to 18 Days Post-Therapy(Secondary Endpoint)
Pathogen n/N % 95% CI
All S. pneumoniae 95/136 70 (61.4, 77.4)
S. pneumoniae with penicillinMIC equal to 2 mcg/mL 11/20 55 (31.5, 76.9)
S. pneumoniae with penicillinMIC equal to 4 mcg/mL 5/14 36 (12.8, 64.9)
H. influenzae 106/156 68 (60.0, 75.2)
M. catarrhalis 14/25 56 (34.9, 75.6)

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 equal to 2 mcg/mL and 4 mcg/mL were 29/41 (71%) and 17/41 (42%), respectively.

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

How Supplied

Amoxicillin and Clavulanate Potassium for oral suspension USP:

600 mg/42.9 mg per 5 mL: Strawberry cream-flavored powder for oral suspension. Following constitution, each 5 mL of oral suspension contains 600 mg of amoxicillin as the trihydrate and 42.9 mg of clavulanic acid as the potassium salt (equivalent to 51.1 mg of clavulanate potassium).

NDC 81964-203-51 75 mL bottle
NDC 81964-203-69 125 mL bottle
NDC 81964-203-54 200 mL bottle

Storage

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

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information)

Administration Instructions

Inform patients to 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.

Allergic Reactions

Counsel patients that Amoxicillin and Clavulanate Potassium for oral suspension contains a penicillin class drug product that can cause allergic reactions in some individuals.

Severe Cutaneous Adverse Reactions (SCAR)

Advise patients about the signs and symptoms of serious skin manifestations. Instruct patients to stop taking Amoxicillin and Clavulanate Potassium for oral suspension immediately and promptly report the first signs or symptoms of skin rash, mucosal lesions, or any other sign of hypersensitivity [see Warnings and Precautions (5.2)].

Diarrhea

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

Antibacterial Resistance

Patients should be counseled 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, 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 for oral suspension or other antibacterial drugs in the future.

Storage Instructions

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.

Phenylketonuria

Counsel patients with phenylketonuria: Each 5 mL of reconstituted Amoxicillin and Clavulanate Potassium contains 7 mg phenylalanine.

Manufactured by:

USAntibiotics, LLC
Bristol, TN 37620 (USA)

CLINITEST is a registered trademark of Miles, Inc.

FLAVORx is a trademark of FLAVORx. Inc.

PRINCIPAL DISPLAY PANEL: Container Label — 75 mL

NDC 81964-203 -51
600 mg/42.9 mg per 5 mL

AMOXICILLIN AND
CLAVULANATE
POTASSIUM

for oral suspension, USP

When reconstituted, each 5 mL contains:
AMOXICILLIN, 600 mg
as the trihydrate, and
CLAVULANIC ACID, 42.9 mg
(equivalent to 51.1 mg of clavulanate potassium)

75 mL
(when reconstituted)

US

ANTIBIOTICS Rx only

label-75ml
(click image for full-size original)

PRINCIPAL DISPLAY PANEL: Container Label — 125 mL

NDC 81964-203 -69
600 mg/42.9 mg per 5 mL

AMOXICILLIN AND
CLAVULANATE
POTASSIUM

for oral suspension, USP

When reconstituted, each 5 mL contains:
AMOXICILLIN, 600 mg
as the trihydrate, and
CLAVULANIC ACID, 42.9 mg
(equivalent to 51.1 mg of clavulanate potassium)

125 mL
(when reconstituted)

US

ANTIBIOTICS Rx only

label-125mg
(click image for full-size original)

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