Doxycycline

Mylan Pharmaceuticals Inc.

FULL PRESCRIBING INFORMATION: CONTENTS*

• DOXYCYCLINE DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Microbiology
• DOXYCYCLINE INDICATIONS AND USAGE
• DOXYCYCLINE CONTRAINDICATIONS
• WARNINGS
• PRECAUTIONS
  • General
  • Information for Patients
  • Laboratory Tests
  • Drug Interactions
  • Drug/Laboratory Test Interactions
  • Carcinogenesis, Mutagenesis, Impairment of Fertility
  • Pregnancy
  • Labor and Delivery
  • Nursing Mothers
  • Pediatric Use
• DOXYCYCLINE ADVERSE REACTIONS
• OVERDOSAGE
• DOXYCYCLINE DOSAGE AND ADMINISTRATION
  • Adults
  • For Pediatric Patients Above 8 Years of Age
  • Inhalational Anthrax (Postexposure)
• HOW SUPPLIED
• ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY
• REFERENCES

FULL PRESCRIBING INFORMATION

Rx only

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

DOXYCYCLINE DESCRIPTION

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. Doxycycline 50 mg, 75 mg, 100 mg and 150 mg film-coated tablets contain doxycycline monohydrate equivalent to 50 mg, 75 mg, 100 mg or 150 mg of doxycycline for oral administration. Inactive ingredients include colloidal silicon dioxide, crospovidone, magnesium stearate, and microcrystalline cellulose. Each tablet also contains the following colorant agents: hypromellose, polydextrose, polyethylene glycol, titanium dioxide and triacetin. In addition, the doxycycline 50 mg and 100 mg tablets contain: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, and FD&C Yellow No. 6 Aluminum Lake. The 75 mg and 150 mg tablets contain red iron oxide and yellow iron oxide.

Its molecular weight is 462.45. The chemical designation of the light yellow to pale yellow crystalline powder is 2-Naphthacenecarboxamide, 4-(dimethylamino)-1, 4,4a,5, 5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-,[4S-(4α,4aα,5α,5aα,6α,12aα)]-, monohydrate.

Structural formula:

Doxycycline, USP has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form.

CLINICAL PHARMACOLOGY

Tetracyclines are readily absorbed and are bound to plasma proteins in varying degrees. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations in a biologically active form. Doxycycline is virtually completely absorbed after oral administration.

Following a 200 mg dose of doxycycline monohydrate, 24 normal adult volunteers averaged the following serum concentration values:

Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1% to 5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min). Studies have shown no significant difference in serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function.

Hemodialysis does not alter serum half-life.

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. Cross resistance with other tetracyclines is common. Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for doxycycline tablets.

Gram-Negative Bacteria:

Acinetobacter species

Bartonella bacilliformis

Brucella species

Calymmatobacterium granulomatis

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

Gram-Positive Bacteria:

Bacillus anthracis

Streptococcus pneumoniae

Anaerobic Bacteria:

Clostridium species

Fusobacterium fusiforme

Propionibacterium acnes

Other Bacteria:

Nocardiae and other Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema pertenue

Ureaplasma urealyticum

Parasites:

Balantidium coli

Entamoeba species

Susceptibility Testing Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar).^1,2,4 The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds.

The zone size should be determined using a standardized test method.^1,3,4 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of microorganisms to doxycycline. The disk diffusion interpretive criteria are provided in Table 1.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method.⁵ The MIC values obtained should be interpreted according to the criteria provided in Table 1

A report of Susceptible (S) indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria 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 product is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test.^{1,2,3,4,5,6,7} Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria noted in Table 2 should be achieved.

DOXYCYCLINE INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline tablets and other antibacterial drugs, doxycycline tablets should be used only to treat or prevent 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.

Doxycycline tablets are indicated for the treatment of the following infections:

•  Rocky mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.
•  Respiratory tract infections caused by Mycoplasma pneumoniae.
•  Lymphogranuloma venereum caused by Chlamydia trachomatis.
•  Psittacosis (omithosis) caused by Chlamydia psittaci.
•  Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence.
•  Inclusion conjunctivitis caused by Chlamydia trachomatis.
•  Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis.
•  Nongonococcal urethritis caused by Ureaplasma urealyticum.
•  Relapsing fever due to Borrelia recurrentis.

Doxycycline tablets are also indicated for the treatment of infections caused by the following gram-negative microorganisms:

•  Chancroid caused by Haemophilus ducreyi.
•  Plague due to Yersinia pestis (formerly Pasteurella pestis).
•  Tularemia due to Francisella tularensis (formerly Pasteurella tularensis).
•  Cholera caused by Vibrio cholerae (formerly Vibrio comma).
•  Campylobacter fetus infections caused by Campylobacter fetus (formerly Vibrio fetus).
•  Brucellosis due to Brucella species (in conjunction with streptomycin).
•  Bartonellosis due to Bartonella bacilliformis.
•  Granuloma inguinale caused by Calymmatobacterium granulomatis.

Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.

Doxycycline tablets are indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug:

•   Escherichia coli
•   Enterobacter aerogenes (formerly Aerobacter aerogenes)
•   Shigella species
•   Acinetobacter species (formerly Mima species and Herellea species)
•  Respiratory tract infections caused by Haemophilus influenzae.
•  Respiratory tract and urinary tract infections caused by Klebsiella species.

Doxycycline tablets are indicated for treatment of infections caused by the following gram-positive microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug:

•  Upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae).
•  Skin and skin structure infections caused by Staphylococcus aureus.
•  Anthrax due to Bacillus anthracis, including inhalational anthrax (postexposure); to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

Doxycycline tablets are not the drug of choice in the treatment of any type of staphylococcal infections.

When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections:

•  Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.
•  Syphilis caused by Treponema pallidum.
•  Yaws caused by Treponema pertenue.
•  Listeriosis due to Listeria monocytogenes.
•  Vincent's infection caused by Fusobacterium fusiforme.
•  Actinomycosis caused by Actinomyces israelii.
•  Infections caused by Clostridium species.

In acute intestinal amebiasis, doxycycline tablets may be a useful adjunct to amebicides.

In severe acne, doxycycline tablets may be useful adjunctive therapy.

DOXYCYCLINE CONTRAINDICATIONS

This drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines.

WARNINGS

THE USE OF DRUGS OF THE TETRACYCLINE-CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY, AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN).

This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POSTEXPOSURE), UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including doxycycline, and may range 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 a primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug 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 Clostridium difficile colitis.

All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryo toxicity has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus.

The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

PRECAUTIONS

General

Prescribing doxycycline tablets 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-resistant bacteria.

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued.

Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy when indicated.

Information for Patients

Patients should be counseled that antibacterial drugs, including doxycycline tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline 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 tablets or other antibacterial drugs in the future.

Laboratory Tests

In venereal disease when coexistent syphilis is suspected, a dark-field examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months.

In long-term therapy, periodic laboratory evaluations of organ systems, including hematopoietic, renal, and hepatic studies should be performed.

Drug Interactions

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron containing preparations.

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.

Concurrent use of tetracycline may render oral contraceptives less effective.

Drug/Laboratory Test Interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals to evaluate the carcinogenic potential of doxycycline have not been conducted.

However, there has been evidence of oncogenic activity in rats in studies with related antibiotics, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibiotics (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied.

Pregnancy

Teratogenic Effects. Pregnancy Category D

There are no adequate and well controlled studies on the use of doxycycline in pregnant short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS – the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk⁸.

A case control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. (Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline.) This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases⁹.

A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at one year of age¹⁰.

Labor and Delivery

The effect of tetracyclines on labor and delivery is unknown.

Nursing Mothers

Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown¹¹. Because of the potential for adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See WARNINGS.)

Pediatric Use

See WARNINGS and DOSAGE AND ADMINISTRATION.

DOXYCYCLINE ADVERSE REACTIONS

Due to oral doxycycline's virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines.

Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION.)

Skin: Maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See WARNINGS.)

Renal Toxicity: Rise in BUN has been reported and is apparently dose related. (See WARNINGS.)

Hypersensitivity Reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis, and exacerbation of systemic lupus erythematosus.

Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported with tetracyclines.

Other: Bulging fontanels in infants and intracranial hypertension in adults. (See PRECAUTIONS: General.)

When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function are known to occur.

OVERDOSAGE

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life, and it would not be of benefit in treating cases of overdosage.

DOXYCYCLINE DOSAGE AND ADMINISTRATION

THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE TABLETS DIFFERS FROM THAT OF THE OTHER TETRACYCLINES. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS.

Adults

The usual dose of oral doxycycline tablets is 200 mg on the first day of treatment (administered 100 mg every 12 hours or 50 mg every 6 hours) followed by a maintenance dose of 100 mg/day. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended.

For Pediatric Patients Above 8 Years of Age

The recommended dosage schedule for pediatric patients weighing 100 pounds or less is 2 mg/lb of body weight divided into two doses on the first day of treatment, followed by 1 mg/lb of body weight given as a single daily dose or divided into two doses, on subsequent days. For more severe infections up to 2 mg/lb of body weight may be used. For pediatric patients over 100 pounds the usual adult dose should be used.

Uncomplicated Gonococcal Infections in Adults (Except Anorectal Infections in Men): 100 mg, by mouth, twice a day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose.

Acute Epididymo-Orchitis Caused by N. Gonorrhoeae: 100 mg, by mouth, twice a day for at least 10 days.

Primary and Secondary Syphilis: 300 mg a day in divided doses for at least 10 days.

Uncomplicated Urethral, Endocervical, or Rectal Infection in Adults Caused by Chlamydia Trachomatis: 100 mg, by mouth, twice a day for at least 7 days.

Nongonococcal Urethritis Caused by C. Trachomatis and U. Urealyticum: 100 mg, by mouth, twice a day for at least 7 days.

Acute Epididymo-Orchitis Caused by C. Trachomatis: 100 mg, by mouth, twice a day for at least 10 days.

Inhalational Anthrax (Postexposure)

Adults: 100 mg of doxycycline tablets, by mouth, twice a day for 60 days.

Children: Weighing less than 100 pounds (45 kg): 1 mg/lb (2.2 mg/kg) of body weight, by mouth, twice a day for 60 days. Children weighing 100 pounds or more should receive the adult dose.

When used in streptococcal infections, therapy should be continued for 10 days.

Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline-class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS.) If gastric irritation occurs, doxycycline tablets may be given with food. Ingestion of a high fat meal has been shown to delay the time to peak plasma concentrations by an average of one hour and 20 minutes. However, in the same study, food enhanced the average peak concentration by 7.5% and the area under the curve by 5.7%.

HOW SUPPLIED

Doxycycline Tablets, USP are available as 50 mg, 75 mg, 100 mg or 150 mg tablets.

The 50 mg tablet is a light yellow film-coated, round, unscored tablet debossed with M on one side of the tablet and D21 on the other side. They are available as follows:

NDC 0378-6021-01
bottles of 100 tablets

The 75 mg tablet is an orange film-coated, round, unscored tablet debossed with M on one side of the tablet and D22 on the other side. They are available as follows:

NDC 0378-6022-01
bottles of 100 tablets

The 100 mg tablet is a light yellow film-coated, round, unscored tablet debossed with M on one side of the tablet and D23 on the other side. They are available as follows:

NDC 0378-6023-89
bottles of 50 tablets

The 150 mg tablet is an orange film-coated, round tablet debossed with M on one side of the tablet and D above the score and 24 below the score on the other side. They are available as follows:

NDC 0378-6124-93
bottles of 30 tablets

Store at 20° to 25 °C (68° to 77°F). [See USP Controlled Room Temperature.]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. 

ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY

Hyperpigmentation of the thyroid has been produced by members of the tetracycline-class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline hydrochloride and tetracycline hydrochloride 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.

REFERENCES

• 1.Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100S23, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2013.
• 2.Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Ninth Edition. CLSI document M07-A9, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012.
• 3.Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012.
• 4.Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Second Edition. CLSI document M45A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2010.
• 5.Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eighth Edition. CLSI document M11-A8, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2012.
• 6.Clinical and Laboratory Standards Institute (CLSI). Methods for Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard – Second Edition. CLSI document M24-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011.
• 7.Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011.
• 8.Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195.
• 9.Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528.
• 10.Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317.
• 11.Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing 2000; 225-226.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

REVISED APRIL 2014
DXYM:R4

PRINCIPAL DISPLAY PANEL - 50 mg

NDC 0378-6021-01

Doxycycline
Tablets, USP
50 mg*

Rx only        100 Tablets

*Each film-coated tablet contains
doxycycline monohydrate equivalent
to 50 mg of doxycycline.

Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.

Keep container tightly closed.

Keep this and all medication
out of the reach of children.

Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]

Protect from light.

Usual Dosage: See accompanying
prescribing information.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Mylan.com

RM6021A2