1.1 Rickettsial 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.

1.2 Sexually 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.

1.3 Respiratory 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.

1.4 Specific 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.

1.5 Ophthalmic 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.

1.6 Anthrax 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.

1.7 Alternative 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.

1.8 Adjunctive 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.

1.9 Prophylaxis 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)].

1.10 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 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.

2.1 Important 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)].

2.2 Switching 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

2.3 Dosage 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:
  1. Streptococcal infections, therapy should be continued for 10 days.
  2. Uncomplicated urethral, endocervical, or rectal infection caused by C. trachomatis: 100 mg, by mouth, twice-a-day for 7 days.
  3. 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.
  4. Nongonococcal urethritis (NGU) caused by U. urealyticum: 100 mg, by mouth, twice-a-day for 7 days.
  5. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 120 mg, by mouth, twice-a-day for 2 weeks.
  6. 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.
  7. Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg, by mouth, twice-a-day for at least 10 days.
  8. Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice-a-day for at least 10 days

2.4 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 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.

2.5 Dosage 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.

2.6 Dosage 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.

2.7 Sprinkling 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.

5.1 Tooth 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 Clostridioides difficile-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.

5.3 Photosensitivity

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.

5.4 Potential 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.

5.5 Severe 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.

5.6 Intracranial 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.

5.7 Skeletal 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.

5.8 Antianabolic 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.

5.9 Malaria

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.

5.10 Development 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.

5.11 Laboratory Monitoring for Long-Term Therapy

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

6.1 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.

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.

6.2 Postmarketing 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.

7.1 Anticoagulant 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.

7.2 Penicillin

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

7.3 Antacids and Iron Preparations

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

7.4 Oral Contraceptives

Concurrent use of tetracycline may render oral contraceptives less effective.

7.5 Barbiturates and Anti-Epileptics

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

7.6 Penthrane

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

7.7 Drug/Laboratory Test Interactions

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

8.1 Pregnancy

8.2 Lactation

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.

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 (Cmax) was 4.6 mcg/mL and 6.3 mcg/mL, respectively with median tmax 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.

12.4 Microbiology

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 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 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.

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).