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Doryx (doxycycline hyclate 200 mg) Dailymed

  1. Human Prescription
  2. Tetracycline-class Drug
  3. Mayne Pharma Commercial LLC

Generic: doxycycline hyclate is used for the treatment of Anthrax Campylobacter Infections Child, Preschool Cholera Granuloma Inguinale Liver Diseases Malaria Mycoplasma Infections Psittacosis Plague Pleural Effusion Pregnancy Relapsing Fever Rocky Mountain Spotted Fever Sclerosis Syphilis Trachoma Pneumonia, Bacterial

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1 Indications And Usage



DORYX is a tetracycline-class drug indicated for:
  • Rickettsial infections ( 1.1)
  • Sexually transmitted infections ( 1.2)
  • Respiratory tract infections ( 1.3)
  • Specific bacterial infections ( 1.4)
  • Ophthalmic infections ( 1.5)
  • Anthrax, including inhalational anthrax (post-exposure) ( 1.6)
  • Alternative treatment for selected infections when penicillin is contraindicated ( 1.7)
  • Adjunctive therapy in acute intestinal amebiasis and severe acne ( 1.8)
  • Prophylaxis of malaria ( 1.9)

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORYX and other antibacterial drugs, DORYX should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.10)

1.1Rickettsial Infections


DORYX is indicated for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.

1.2Sexually Transmitted Infections


DORYX is indicated for treatment of the following sexually transmitted infections:
  • Uncomplicated urethral, endocervical or rectal infections caused by Chlamydia trachomatis.
  • Nongonococcal urethritis caused by Ureaplasma urealyticum.
  • Lymphogranuloma venereum caused by Chlamydia trachomatis.
  • Granuloma inguinale caused by Klebsiella granulomatis.
  • Uncomplicated gonorrhea caused by Neisseria gonorrhoeae.
  • Chancroid caused by Haemophilus ducreyi.

1.3Respiratory Tract Infections


DORYX is indicated for treatment of the following respiratory infections:
  • Respiratory tract infections caused by Mycoplasma pneumoniae. Psittacosis (ornithosis) caused by Chlamydophila psittaci.
  • Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.
  • Doxycycline is indicated for treatment of infections caused by the following micro- organisms, when bacteriological testing indicates appropriate susceptibility to the drug:
    • Respiratory tract infections caused by Haemophilus influenzae.
    • Respiratory tract infections caused by Klebsiella species.
    • Upper respiratory infections caused by Streptococcus pneumoniae.

1.4Specific Bacterial Infections


DORYX is indicated for treatment of the following specific bacterial infections:
  • Relapsing fever due to Borrelia recurrentis.
  • Plague due to Yersinia pestis.
  • Tularemia due to Francisella tularensis.
  • Cholera caused by Vibrio cholerae.
  • Campylobacter fetus infections caused by Campylobacter fetus.
  • Brucellosis due to Brucella species (in conjunction with streptomycin).
  • Bartonellosis due to Bartonella bacilliformis.

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

DORYX is indicated for treatment of infections caused by the following gram- negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug:
  • Escherichia coli
  • Enterobacter aerogenes
  • Shigella species
  • Acinetobacter species
  • Urinary tract infections caused by Klebsiella species.

1.5Ophthalmic Infections


DORYX is indicated for treatment of the following ophthalmic infections:
  • Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence.
  • Inclusion conjunctivitis caused by Chlamydia trachomatis.

1.6Anthrax Including Inhalational Anthrax (Post-Exposure)


DORYX is indicated for the treatment of Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

1.7Alternative Treatment for Selected Infections When Penicillin is Contraindicated


DORYX is indicated as an alternative treatment for the following selected infections when penicillin is contraindicated:
  • Syphilis caused by Treponema pallidum.
  • Yaws caused by Treponema pallidum subspecies pertenue.
  • Vincent's infection caused by Fusobacterium fusiforme.
  • Actinomycosis caused by Actinomyces israelii.
  • Infections caused by Clostridium species.

1.8Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne


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

In severe acne, doxycycline may be useful adjunctive therapy.

1.9Prophylaxis of Malaria


DORYX is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains [ see Dosage and Administration (2.2) and Patient Counseling Information (17) ].

1.10Usage


To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORYX and other antibacterial drugs, DORYX 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.

2 Dosage And Administration


  • Dosage in Adult Patients:
    • The usual dosage is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg daily. ( 2.1)
    • In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. ( 2.1)
  • Dosage in Pediatric Patients:
    • For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dose is 2.2 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose. ( 2.1)
    • For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dose is 4.4 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into two doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. ( 2.1)

2.1Important Dosage and Administration Instructions

  • DORYX is not substitutable on a mg per mg basis with other oral doxycyclines. To avoid prescribing errors, do not substitute DORYX for other oral doxycyclines on a mg per mg basis because of differing bioavailability.
  • Do not chew or crush tablets [see Dosage and Administration (2.4)] .
  • The recommended dosage, frequency of administration and weight-based dosage recommendations of DORYX differ from that of the other tetracyclines [see Dosage and Administration (2.2, 2.3, 2.4)] . Exceeding the recommended dosage may result in an increased incidence of adverse reactions.
  • Administer DORYX with an adequate amount of fluid to wash down the drug and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)] .
  • If gastric irritation occurs, DORYX may be given with food or milk [see Clinical Pharmacology (12.3)] .

2.2Switching from DORYX to DORYX MPC


When switching from DORYX to DORYX MPC:
  • A 60 mg dose of DORYX MPC will replace a 50 mg dose of DORYX
  • A 120 mg dose of DORYX MPC will replace a 100 mg dose of DORYX

2.3Dosage in Adult Patients

  • The usual dosage of DORYX is 200 mg on the first day of treatment (administered 100 mg every 12 hours), followed by a maintenance dose of 100 mg daily.
  • 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 certain selected specific indications, the recommended duration or dosage and duration of DORYX MPC in adult patients are as follows:
    • Streptococcal infections, therapy should be continued for 10 days.
    • Uncomplicated urethral, endocervical, or rectal infection caused by C. trachomatis: 100 mg, by mouth, twice-a-day for 7 days.
    • 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 followed in one hour by a second 300 mg dose.
    • Nongonococcal urethritis (NGU) caused by U. urealyticum: 100 mg, by mouth, twice-a-day for 7 days.
    • Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 120 mg, by mouth, twice-a-day for 2 weeks.
    • Syphilis of more than one year's duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice-a-day for 4 weeks.
    • Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg, by mouth, twice-a-day for at least 10 days.
    • Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice-a-day for at least 10 days

2.4Dosage in Pediatric Patients

  • For all pediatric patients weighing less than 45 kg with severe or life threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage of doxycycline is 2.2 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose [see Warnings and Precautions (5.1)] .
  • For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of doxycycline is 4.4 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used.

2.5Dosage for Prophylaxis of Malaria


For adults, the recommended dose of DORYX is 100 mg daily. For pediatric patients 8 years of age and older, the recommended dose is 2 mg/kg administered once daily up to the adult dose. Pediatric patients weighing 45 kg or more should receive the adult dose.

Prophylaxis should begin 1 or 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area.

2.6Dosage for Inhalational Anthrax (Post-Exposure)


For adults the recommended dosage is 100 mg of DORYX, by mouth, twice-a-day for 60 days.

For pediatric patients weighing less than 45 kg, the recommended dosage of DORYX is 2.2 mg/kg of body weight, by mouth, twice-a-day for 60 days. Pediatric patients weighing 45 kg or more should receive the adult dose.

2.7Sprinkling the Tablet Over Applesauce


DORYX may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed-release pellets) on a spoonful of applesauce. The delayed-release pellets must not be crushed or damaged when breaking up the tablet. Any loss of pellets in the transfer would prevent using the dose. The applesauce/DORYX mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/DORYX mixture cannot be taken immediately, the mixture should be discarded and not stored for later use.

3 Dosage Forms And Strengths


DORYX (doxycycline hyclate delayed-release tablets, USP), 50 mg are white, oval tablets containing yellow pellets and debossed with "DV" on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 50 mg of doxycycline.

DORYX (doxycycline hyclate delayed-release tablets, USP) 80 mg are white, oval scored tablets containing yellow pellets and debossed with "D|8" on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 80 mg of doxycycline.

DORYX (doxycycline hyclate delayed-release tablets), 200 mg are white, oval scored tablets containing yellow pellets and debossed with "D|D" on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 200 mg of doxycycline.


DORYX Delayed-Release Tablets: 50 mg, 80 mg, and 200 mg ( 3)

4 Contraindications


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


DORYX is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. ( 4 )

5 Warnings And Precautions


  • 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). ( 5.1)
  • Clostridioides difficile-associated diarrhea (CDAD) has been reported: Evaluate patients if diarrhea occurs. ( 5.2)
  • Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Limit sun exposure. ( 5.3)
  • Overgrowth of non-susceptible organisms, including fungi, may occur. If such infections occur, discontinue use and institute appropriate therapy. ( 5.4)

5.1Tooth Development


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 it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use DORYX in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies.

5.2 -Associated Diarrhea


Clostridioides difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including DORYX Tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C . difficile , and surgical evaluation should be instituted as clinically indicated.

5.3Photosensitivity


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.

5.4Potential for Microbial Overgrowth


DORYX may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, the antibacterial should be discontinued and appropriate therapy instituted.

5.5Severe Skin Reactions


Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline [see Adverse Reactions (6)] . If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.

5.6Intracranial Hypertension


Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline including DORYX. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Avoid concomitant use of isotretinoin and DORYX because isotretinoin is also known to cause pseudotumor cerebri.

Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.

5.7Skeletal Development


All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every six 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 embryotoxicity also 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.

5.8Antianabolic Action


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.

5.9Malaria


Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains.

Doxycycline does not suppress P. falciparum's sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.

5.10Development of Drug-Resistant Bacteria


Prescribing DORYX 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.

5.11Laboratory Monitoring for Long-Term Therapy


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

6 Adverse Reactions



Adverse reactions observed in patients receiving tetracyclines include anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience


The safety and efficacy of DORYX Tablets, 200 mg as a single daily dose was evaluated in a multicenter, randomized, double-blind, active-controlled study. DORYX Tablets, 200 mg was given orally once-a-day for 7 days and compared to doxycycline hyclate capsules 100 mg given orally twice daily for 7 days for the treatment of men and women with uncomplicated urogenital C. trachomatis infection.

Adverse reactions in the Safety Population were reported by 99 (40.2%) subjects in the DORYX Tablets, 200 mg treatment group and 132 (53.2%) subjects in the doxycycline hyclate capsules reference treatment group. Most adverse reactions were mild in intensity. The most commonly reported adverse reactions in both treatment groups were nausea, vomiting, diarrhea, and bacterial vaginitis, Table 1.
Table 1: Adverse Reactions Reported in Greater than or Equal to 2% of Subjects
Adverse Reactions DORYX Tablets, 200 mg N = 246
n (%)
Subjects with any AE 99 (40.2)
Nausea 33 (13.4)
Vomiting 20 (8.1)
Headache 5 (2.0)
Diarrhea 8 (3.3)
Abdominal Pain Upper 5 (2.0)
Vaginitis Bacterial 8 (3.3)
Vulvovaginal Mycotic Infection 5 (2.0)

Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trial may not always reflect the rates observed in practice.

6.2Postmarketing Experience


The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate a causal relationship to drug exposure.

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, inflammatory lesions (with monilial overgrowth) in the anogenital region and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development [see Warnings and Precautions (5.1)] . 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 (2.1) ].

Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above [ see Warnings and Precautions (5.3) ].

Renal: Rise in BUN has been reported and is apparently dose-related [ see Warnings and Precautions (5.8) ].

Hypersensitivity reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus, and drug reaction with eosinophilia and systemic symptoms (DRESS).

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

Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline [ see Warnings and Precautions (5.6) ]

Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur.

7 Drug Interactions


  • Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage ( 7.1)
  • Avoid co-administration of tetracyclines with penicillin ( 7.2)
  • Absorption of tetracyclines, including DORYX, is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations ( 7.3)
  • Concurrent use of tetracyclines, including DORYX, may render oral contraceptives less effective ( 7.4)
  • Barbiturates, carbamazepine and phenytoin decrease the half-life of doxycycline ( 7.5)

7.1Anticoagulant Drugs


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

7.2Penicillin


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

7.3Antacids and Iron Preparations


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

7.4Oral Contraceptives


Concurrent use of tetracycline may render oral contraceptives less effective.

7.5Barbiturates and Anti-Epileptics


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

7.6Penthrane


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

7.7Drug/Laboratory Test Interactions


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

8 Use In Specific Populations


  • Tetracycline-class drugs can cause fetal harm when administered to a pregnant woman, but data for doxycycline are limited. ( 5.6, 8.1)
  • Tetracyclines are excreted in human milk; however, the extent of absorption of doxycycline in the breastfed infant is not known. DORYX use during nursing should be avoided if possible. (8.3)

8.1 Pregnancy


Risk Summary

There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is 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 the 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 risk (see Data) . 1

In the US general population the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.


Clinical Considerations


Embryo/Fetal Risk

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 embryotoxicity also 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 [see Warnings and Precautions (5.1, 5.6)].


Data


Human Data

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 (that is, in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases. 2

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 1 year of age. 3

8.2 Lactation



Risk Summary

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. The effects of prolonged exposure to doxycycline in breast milk production and breast fed neonates, infants and children are unknown 4. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for DORYX and any potential adverse effects on the breast fed child from DORYX or from the underlying maternal condition [see Warnings and Precautions (5.1, 5.6)] .

8.4 Pediatric use


Because of the effects of drugs of the tetracycline-class on tooth development and growth, use DORYX in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly, when there are no alternative therapies [ see Dosage and Administration (2.1, 2.3) and Warnings and Precautions (5.1, 5.6) ].

8.5 Geriatric use


Clinical studies of DORYX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

DORYX 50 mg tablets contain 3 mg (0.131 mEq) of sodium.

DORYX 80 mg tablets contain 4.8 mg (0.209 mEq) of sodium.

DORYX 200 mg tablets contain 12 mg (0.522 mEq) of sodium.

10 Overdosage


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

11 Description


DORYX (doxycycline hyclate delayed-release tablets), contain specially coated pellets of doxycycline hyclate, a tetracycline class drug synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration.

The structural formula for doxycycline hyclate is:



with a molecular formula of C 22H 24N 2O 8, HCl, ½ C 2H 6O, ½ H 2O and a molecular weight of 512.9. The chemical name for doxycycline hyclate is [4S(4aR,5S,5aR,6R,12aS)]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6- methyl-1,11-deoxonaphthacene-2-carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. Doxycycline 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.

Each tablet contains doxycycline 50 mg, 80 mg or 200 mg (equivalent to doxycycline hyclate 57.7 mg, 92.3 mg or 230.8 mg). Inactive ingredients in the tablet formulation are: lactose monohydrate; microcrystalline cellulose; sodium lauryl sulfate; sodium chloride; talc; anhydrous lactose; corn starch; crospovidone; magnesium stearate; cellulosic polymer coating.

Each DORYX 50 mg tablet contains 3 mg (0.131 mEq) of sodium, each DORYX 80 mg tablet contains 4.8 mg (0.209 mEq) of sodium, and each DORYX 200 mg tablet contains 12 mg (0.522 mEq) of sodium.

12 Clinical Pharmacology


12.1 Mechanism of Action


Doxycycline is a tetracycline-class antimicrobial drug [ see Microbiology (12.4) ].

12.3 Pharmacokinetics


Following single and multiple-dose administration of DORYX Tablets, 200 mg to adult volunteers, average peak plasma doxycycline concentration (C max) was 4.6 mcg/mL and 6.3 mcg/mL, respectively with median t max of 3 hours; the corresponding mean plasma concentration values 24 hours after single and multiple doses were 1.5 mcg/mL and 2.3 mcg/mL, respectively.


Absorption

Doxycycline is virtually completely absorbed after oral administration.


Effect of Food

The mean C max and AUC 0-∞ of doxycycline are 24% and 13% lower, respectively, following single dose administration of DORYX Tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean C max of doxycycline is 19% lower and the AUC 0-∞ is unchanged following single dose administration of DORYX Tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown. Doxycycline bioavailability from DORYX Tablets, 200 mg was not affected by food, but the incidence of nausea was higher in fasted subjects. The 200 mg tablets may be administered without regard to meals.

When DORYX Tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly.


Elimination

Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1-5%/72 hours in individuals with a creatinine clearance below 10 mL/min.


Specific Populations


Patients with Renal Impairment

Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life.


Pediatric Patients

Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 children (2-18 years of age) showed that allometrically-scaled clearance of doxycycline in children ≥2 to ≤8 years of age (median [range] 3.58 [2.27-10.82] L/h/70 kg, N=11) did not differ significantly from children >8 to 18 years of age (3.27 [1.11-8.12] L/h/70 kg, N=33). For pediatric patients weighing ≤45 kg, body weight normalized doxycycline CL in those ≥2 to ≤8 years of age (median [range] 0.071 [0.041-0.202] L/kg/h, N=l0) did not differ significantly from those >8 to 18 years of age (0.081 [0.035-0.126] L/kg/h, N=8). In pediatric patients weighing >45 kg no clinically significant differences in body weight normalized doxycycline CL were observed between those ≥2 to ≤8 years (0.050 L/kg/h, N=l) and those >8 years of age (0.044 [0.014-0.121] L/kg/h, N=25). No clinically significant difference in CL differences between oral and IV were observed in the small cohort of pediatric patients who received the oral (N=l9) or IV (N=21) formulation alone.

12.4Microbiology



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 between 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

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

Parasites

Balantidium coli Entamoeba species Plasmodium falciparum 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, associated test methods and quality control standards recognized by FDA for this drug, please see: https://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 have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterials, 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 antibacterials (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.

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.

14 Clinical Studies


This was a randomized, double-blind, active-controlled, multicenter trial which enrolled 495 subjects, between 19 to 45 years of age with a confirmed diagnosis of urogenital C. trachomatis infection less than 14 days prior to enrollment, or partner(s) of a subject with a known positive test for urogenital C. trachomatis infection.

The primary purpose of this study was to evaluate the efficacy and safety of DORYX Tablets, 200 mg once daily versus doxycycline hyclate capsules, 100 mg twice daily for seven days for the treatment of uncomplicated urogenital C. trachomatis infection. The primary efficacy objective was to demonstrate non-inferiority of the DORYX Tablets, 200 mg once daily treatment regimen versus the doxycycline 100 mg twice daily treatment regimen for the indication using a negative nucleic acid amplification test (NAAT) at the test of cure visit (day 28) in the mITT population (subjects who were positive at baseline and took at least one day of study drug).
Table 2: Primary Efficacy Outcome – Microbiological Cure of C. trachomatis at Day 28
mITT Population DORYX Tablets, 200 mg once daily Cure Rate (%) Doxycycline hyclate capsules, 100 mg twice daily Cure Rate (%) Difference (%)
N 188 190
Microbiological Cure, n (%) 163 (86.7) 171 (90.0) -3.3%
95% Confidence Interval for Cure Rate -10.3, 3.7

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 2015 March 10; cited 2016 Jan]. Doxycycline; LactMed Record Number: 100; [about 3 screens]. Available from: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm.

16 How Supplied/storage And Handling


DORYX ® (doxycycline hyclate delayed-release tablets), 50 mg are white, oval tablets containing yellow pellets and debossed with "DV" on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 50 mg of doxycycline.
Bottles of 120 tablets NDC 51862-557-12

DORYX ® (doxycycline hyclate delayed-release tablets), 80 mg are white, oval scored tablets containing yellow pellets and debossed with "D|8" on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 80 mg of doxycycline.
Bottles of 30 tablets NDC 51862-562-30

DORYX ® (doxycycline hyclate delayed-release tablets), 200 mg are white, oval scored tablets containing yellow pellets and debossed with "D|D" on one face and plain on the other. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 200 mg of doxycycline.
Bottles of 60 tablets NDC 51862-558-06

STORAGE AND HANDLING SECTION


Store at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container (USP).

17 Patient Counseling Information


Advise patients taking doxycycline 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 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:
  • 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 (5.3) ].
  • to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration [ see Adverse Reactions (6.1) ].
  • that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk [ see Drug Interactions (7.3) ].
  • 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.

Advise patients that diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, 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.

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


Distributed by: Mayne Pharma Greenville, NC 27834

61450

Principal Display Panel - 200 Mg Tablet Bottle Label


NDC 51862-558-06

DORYX ® (doxycycline hyclate delayed-release tablets)

200 mg

Do not chew or crush tablets Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 200 mg of doxycycline.

Rx Only

mayne pharma

60 Tablets

Principal Display Panel - 50 Mg Tablet Bottle Label


NDC 51862-557-12

DORYX ® (doxycycline hyclate delayed-release tablets)

50 mg

Do not chew or crush tablets. Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 50 mg of doxycycline.

Rx Only

mayne pharma

120 Tablets

Principal Display Panel - 80 Mg Tablet Bottle Label


NDC 51862-562-30

DORYX ® (doxycycline hyclate delayed-release tablets)

80 mg

Do not chew or crush tablets Each tablet contains specially coated pellets of doxycycline hyclate equivalent to 80 mg of doxycycline.

Rx Only

mayne pharma

30 Tablets

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