Amoxicillin (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate. Amoxicillin and potassium clavulanate was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Amoxicillin and potassium clavulanate 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 potassium clavulanate 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. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 2 times the 3 g human dose based on body surface area).

14 CLINICAL STUDIES

14.1 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Randomized, double-blind clinical studies performed in the United States in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within 1 year) evaluated the efficacy of lansoprazole in combination with amoxicillin capsules and clarithromycin tablets as triple 14-day therapy, or in combination with amoxicillin capsules as dual 14-day therapy, for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of 2 different eradication regimens were established:
Triple Therapy: Amoxicillin 1 gram twice daily/clarithromycin 500 mg twice daily/lansoprazole 30 mg twice daily (see Table 6).Dual Therapy: Amoxicillin 1 gram three times daily/lansoprazole 30 mg three times daily (see Table 7). All treatments were for 14 days. H. pylori eradication was defined as 2 negative tests (culture and histology) at 4 to 6 weeks following the end of treatment. Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.

Table 6. H. pylori Eradication Rates When Amoxicillin is Administered as Part of a Triple Therapy Regimen
Study Triple Therapy Triple Therapy
Evaluable Analysisa [95% Confidence Interval] (number of patients) Intent-to-Treat Analysisb [95% Confidence Interval] (number of patients)
a This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 positive endoscopic tests from CLOtest® , histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within 1 year). All dropouts were included as failures of therapy.

Study 1

92 [80 — 97.7] (n = 48)

86 [73.3 — 93.5] (n = 55)

Study 2

86[75.7 — 93.6] (n = 66)

83 [72 — 90.8] (n = 70)

Table 7. H. pylori Eradication Rates When Amoxicillin is Administered as Part of a Dual Therapy Regimen
Study Dual Therapy Dual Therapy
Evaluable Analysisa [95% Confidence Interval] (number of patients) Intent-to-Treat Analysisb [95% Confidence Interval] (number of patients)
a This analysis was based on evaluable patients with confirmed duodenal ulcer (active or within 1 year) and H. pylori infection at baseline defined as at least 2 of 3 positive endoscopic tests from CLOtest® , histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. b Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within 1 year). All dropouts were included as failures of therapy.

Study 1

77 [62.5 — 87.2] (n = 51)

70 [56.8 — 81.2] (n = 60)

Study 2

66 [51.9 — 77.5] (n = 58)

61 [48.5 — 72.9] (n = 67)

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.
2.
Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – 8th ed. CLSI Document M7-A8, Vol. 29, No.2. CLSI, Wayne, PA, Jan. 2009.
3.
Clinical and Laboratory Standards Institute (CLSI). Performance Standard for Antimicrobial Disk Susceptibility Tests; Approved Standard – 10th ed. CLSI Document M2-A10, Vol. 29, No. 1. CLSI, Wayne, PA, 2009.
4.
Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing: 21st Informational Supplement. Approved Standard CLSI Document M100-S21 CLSI, Wayne, PA, January 2011.

16 HOW SUPPLIED/STORAGE AND HANDLING


Amoxicillin Tablets, USP contains 500 mg or 875 mg amoxicillin as the trihydrate.
500 mg Tablet
Pink colored, capsule shaped, film coated tablets debossed with “A” on one side and “66” on the other side.
Bottles of 20 NDC 65862-014-20
Bottles of 100 NDC 65862-014-01
Bottles of 500 NDC 65862-014-05
875 mg Tablet
Pink colored, capsule shaped, film coated tablets debossed with “A” on one side and with a score line in between “6” and “7” on the other side.
Bottles of 20 NDC 65862-015-20
Bottles of 100 NDC 65862-015-01
Bottles of 500 NDC 65862-015-05
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight container.

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