Doxycycline Hyclate (Page 4 of 5)

12.4 Microbiology

Mechanism of Action

Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria.

Resistance

Cross resistance with other tetracyclines is common.

Antimicrobial Activity

Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-negative bacteria

Acinetobacter species
Bartonella bacilliformis
Brucella species
Campylobacter fetus
Enterobacter aerogenes
Escherichia coli
Francisella tularensis
Haemophilus ducreyi
Haemophilus influenzae
Klebsiella granulomatis
Klebsiella species
Neisseria gonorrhoeae
Shigella species
Vibrio cholerae
Yersinia pestis

Gram-positive bacteria

Bacillus anthracis
Listeria monocytogenes
Streptococcus pneumoniae

Anaerobic bacteria

Clostridium species
Fusobacterium fusiforme
Propionibacterium acnes

Other bacteria

Nocardiae and other aerobic Actinomyces species
Borrelia recurrentis
Chlamydophila psittaci
Chlamydia trachomatis
Mycoplasma pneumoniae
Rickettsiae species
Treponema pallidum
Treponema pallidum subspecies pertenue
Ureaplasma urealyticum

Parasites

Balantidium coli
Entamoeba species Plasmodium falciparum 1


1
Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum, but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate carcinogenic potential of doxycycline hyclate tablets have not been conducted. However, a 2 year carcinogenicity study with doxycycline administered daily by oral gavage to adult rats (20, 75, 200 mg/kg/day) demonstrated an increase in uterine polyps in female rats at 200 mg/kg/day (10 times the maximum recommended daily adult dose of doxycycline hyclate tablets based on body surface area comparison) with no change in tumor incidence in male rats at the same dose. A 2-year carcinogenicity study with doxycycline administered daily by oral gavage to adult male (maximum dose 150 mg/kg/day) and female (maximum dose 300 mg/kg/day) mice showed no changes in tumor incidence, at approximately 4 and 7 times the maximum recommended daily adult dose of doxycycline hyclate tablets, based on a body surface area comparison, respectively .

Mutagenesis and fertility studies have not been conducted with doxycycline hyclate tablets. Mutagenesis studies with doxycycline demonstrated no potential to cause genetic toxicity in an in vitro point mutation study with mammalian cells or in an in vivo micronucleus assay in CD-1 mice. However, data from an in vitro mammalian chromosomal aberration assay conducted in CHO cells suggest that doxycycline is a weak clastogen. Oral administration of doxycycline to Sprague-Dawley rats showed adverse effects on fertility and reproduction including increased time for mating, reduced sperm motility, velocity and concentration as well as increased pre and post implantation loss. Reduced sperm velocity was seen at the lowest dosage tested, 50 mg/kg/day which is 2.5 times the maximum recommended daily adult dose of doxycycline hyclate tablets. Although doxycycline impairs the fertility of rats when administered at sufficient dosages, the effect of doxycycline hyclate tablets on human fertility is unknown.

13.2 Animal Toxicology and/or Pharmacology

Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4 , and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4 , and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO 4 , methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl, were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.

Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.

15 REFERENCES

  1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195.
  2. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524­ 528.
  3. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317.
  4. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); [Last Revision Date 2018 Oct 31; cited 2019 Jun]. Doxycycline; LactMed Record Number: 100; [about 3 screens]. Available from: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Doxycycline hyclate tablets, 75 mg are round, convex, blue colored, film-coated, tablets debossed with “75” on one side of the tablet and plain on the other. Each 75 mg tablet contains 86.6 mg of doxycycline hyclate equivalent to 75 mg of doxycycline.

Bottles of 60 tablets: NDC 51862-695-06

Doxycycline hyclate tablets, 150 mg are oval-shaped, convex, mossy-green, film-coated tablets. Each side of the functionally scored tablet has two parallel score lines for splitting into 3 equal portions with “m” debossed on each portion of one side of the tablet, and no debossing on the other. Each 150 mg tablet contains 173.2 mg of doxycycline hyclate equivalent to 150 mg of doxycycline.

Bottles of 60 tablets: NDC 51862-696-06

Storage

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]. Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

Important Administration and Safety Information for Patients and Caregivers

Advise patients taking doxycycline hyclate tablets for malaria prophylaxis:

  • that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria.
  • to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (for example, staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent).
  • that doxycycline prophylaxis:
    • should begin 1 day to 2 days before travel to the malarious area,
    • should be continued daily while in the malarious area and after leaving the malarious area,
    • should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area,
    • should not exceed 4 months.

Advise all patients taking doxycycline hyclate tablets:

  • that doxycycline hyclate tablets (150 mg) can be broken into two-thirds or one-third at the scored lines to provide 100 mg or 50 mg strength doses, respectively.
  • to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (for example, skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered [see Warnings and Precautions (5.4)].
  • to drink fluids liberally along with doxycycline hyclate tablets to reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6)] .
  • that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium [see Drug Interactions (7.3)]. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk [see Clinical Pharmacology (12.3)] .
  • that if gastric irritation occurs, doxycycline hyclate tablets may be given with food or milk [see Clinical Pharmacology (12.3)].
  • that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see Drug Interactions (7.3)].
  • that the use of doxycycline might increase the incidence of vaginal candidiasis.

Tooth Discoloration and Inhibition of Bone Growth

Advise patients that doxycycline hyclate tablets, like other tetracycline-class drugs, may cause permanent tooth discoloration of deciduous teeth and reversible inhibition of bone growth when administered during pregnancy. Tell your healthcare provider right away if you become pregnant during treatment [see Warnings and Precautions (5.1, 5.2)and Use in Specific Populations (8.1, 8.4)].

Lactation

Advise women not to breastfeed during treatment with doxycycline hyclate tablets and for 5 days after the last dose [see Use in Specific Populations (8.2)].

Diarrhea

Advise 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 two or more months after having taken the last dose of antibacterial. If this occurs, patients should contact their physician as soon as possible.

Development of Resistance

Counsel patients that antibacterial drugs including doxycycline hyclate tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When doxycycline hyclate 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 doxycycline hyclate tablets or other antibacterial drugs in the future.

Manufactured by:
Mayne Pharma
Greenville, NC 27834

61295

FDA-Approved Patient Labeling

Instructions for Use
Doxycycline hyclate tablets
(DOX-i-SYE-kleen HYE-klate) for oral use

Read this Instructions for Use before you start using doxycycline hyclate tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Note:

  • Your healthcare provider may need to change your dose of doxycycline hyclate tablets during treatment as needed.
  • Doxycycline hyclate tablets can be taken whole or broken at scored lines.
  • Doxycycline hyclate tablets are marked with scored lines and may be broken at these scored lines to provide the following doses:

150 mg treatment (take the entire whole tablet)

Figure
(click image for full-size original)

100 mg treatment (take two-thirds of the tablet)

Figure
(click image for full-size original)

50 mg treatment (take one-third of the tablet)

Figure
(click image for full-size original)

How to break your doxycycline hyclate tablets:

  • Hold the tablet between your thumb and index finger close to the scored line for your dose of doxycycline hyclate tablets as shown above.
  • Apply enough pressure to break the tablet at the scored line.
  • Do not break the doxycycline hyclate tablets in any other way.

Manufactured by:
Mayne Pharma
Greenville, NC 27834

12/2019
61295

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Rx only

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