DOXYCYCLINE HYCLATE tablet, delayed release

Doxycycline Hyclate by

Drug Labeling and Warnings

Doxycycline Hyclate by is a Prescription medication manufactured, distributed, or labeled by Mylan Pharmaceuticals Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate delayed-release tablets and other antibacterial drugs, doxycycline hyclate delayed-release 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 is a tetracycline-class antibacterial indicated in the following conditions or diseases:

    1.1 Rickettsial Infections

    Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.

    1.2 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

    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 microorganisms, 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

    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.

    Doxycycline 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

    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)

    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

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

    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, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy.

    1.9 Prophylaxis of Malaria

    Doxycycline 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)].

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Usual Dosage and Administration

    The usual dosage and frequency of administration of doxycycline 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 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.

    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.

    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 (6.1)].

    If gastric irritation occurs, doxycycline may be given with food or milk [see Clinical Pharmacology (12)].

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

    Uncomplicated Urethral, Endocervical, or Rectal Infection Caused by Chlamydia Trachomatis

    100 mg by mouth twice a day for 7 days. As an alternate dosing regimen for uncomplicated urethral or endocervical infection caused by Chlamydia trachomatis, administer 200 mg by mouth once-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 stat 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 100 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 C. Trachomatis

    100 mg, by mouth, twice-a-day for at least 10 days.

    2.2 For Prophylaxis of Malaria

    For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to 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.

    2.3 Inhalational Anthrax (Post-Exposure)

    Adults

    100 mg, of doxycycline, by mouth, twice-a-day for 60 days.

    Children

    weighing less than 45 kg, 2.2 mg/kg of body weight, by mouth, twice-a-day for 60 days. Children weighing 45 kg or more should receive the adult dose.

    2.4 Sprinkling the Tablet over Applesauce

    Doxycycline hyclate delayed-release tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed-release beads) on a spoonful of applesauce. The delayed-release beads must not be crushed or damaged when breaking up the tablet. Any loss of beads in the transfer would prevent using the dose. The applesauce/doxycycline hyclate delayed-release tablets 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/doxycycline hyclate delayed-release tablets cannot be taken immediately, the mixture should be discarded and not stored for later use.

  • 3 DOSAGE FORMS AND STRENGTHS

    Doxycycline Hyclate Delayed-Release Tablets, USP are available containing delayed-release beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline.

    • The 50 mg tablets are white, round, unscored tablets containing yellow beads debossed with M on one side of the tablet and D36 on the other side. Each tablet contains specially coated beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline.
  • 4 CONTRAINDICATIONS

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

  • 5 WARNINGS AND PRECAUTIONS

    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 doxycycline hyclate delayed-release tablets 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 doxycycline hyclate delayed-release 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

    As with other antibacterial preparations, use of doxycycline hyclate delayed-release tablets 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 doxycycline hyclate delayed-release tablets. 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 doxycycline hyclate delayed-release tablets 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 doxycycline hyclate delayed-release 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.

    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 ADVERSE REACTIONS

    6.1 Clinical Trial Experience

    The safety and efficacy of doxycycline hyclate delayed-release tablets, 200 mg as a single daily dose was evaluated in a multicenter, randomized, double-blind, active-controlled study. Doxycycline hyclate delayed-release 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 events in the Safety Population were reported by 99 (40.2%) subjects in the doxycycline hyclate delayed-release tablets, 200 mg treatment group and 132 (53.2%) subjects in the doxycycline hyclate capsules reference treatment group. Most AEs were mild in intensity. The most commonly reported adverse events 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

    Doxycycline Hyclate Delayed-Release Tablets, 200 mg

    N = 246

    Preferred Term

    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.

    6.2 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 DRUG INTERACTIONS

    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 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Teratogenic Effects. Pregnancy Category D

    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.1

    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

    Nonteratogenic Effects

    [See Warnings and Precautions (5.1, 5.6)].

    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 are unknown.4 Because of the potential for serious 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 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 doxycycline hyclate delayed-release tablets 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 Warnings and Precautions (5.1, 5.6) and Dosage and Administration (2.1, 2.3)].

    8.5 Geriatric Use

    Clinical studies of doxycycline hyclate delayed-release tablets 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.

    Doxycycline hyclate delayed-release 50 mg tablets contain 1.43 mg (0.06 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

    Doxycycline hyclate delayed-release tablets, USP, for oral administration, contain specially coated beads of doxycycline hyclate, a broad-spectrum antibacterial synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration.

    The structural formula for doxycycline hyclate is:

    Doxycycline Hyclate Structural Formula

    with a molecular formula of (C22H24N2O8HCl)2C2H6OH2O and a molecular weight of 1025.87. The chemical designation for doxycycline hyclate is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate, USP is a yellow to light 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. Inactive ingredients in the tablet formulation are: anhydrous lactose, colloidal silicon dioxide, crospovidone, hypromellose phthalate, lactose monohydrate, povidone, pregelatinized starch (corn), sodium chloride, sodium lauryl sulfate, stearic acid, talc, and triethyl citrate.

    The 50 mg tablet strength Meets USP Dissolution Test 5.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Doxycycline is an antibacterial drug [see Microbiology (12.4)].

    12.3 Pharmacokinetics

    Following single and multiple-dose administration of doxycycline hyclate delayed-release 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.

    Absorption

    Doxycycline is virtually completely absorbed after oral administration.

    Effect of Food

    The mean Cmax and AUC0-∞ of doxycycline are 24% and 13% lower, respectively, following single dose administration of doxycycline hyclate delayed-release tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean Cmax of doxycycline is 19% lower and the AUC0-∞ is unchanged following single dose administration of doxycycline hyclate delayed-release 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 doxycycline hyclate delayed-release 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 doxycycline hyclate delayed-release 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 = 10) 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.

    12.4 Microbiology

    Mechanism of Action

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

    Resistance

    Cross-resistance 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 Methods

    For specific information regarding susceptibility test interpretative criteria and 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 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.

  • 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 doxycycline hyclate delayed-release 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 doxycycline hyclate delayed-release 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

    Doxycycline Hyclate Delayed-Release 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

    Doxycycline Hyclate Delayed-Release Tablets, USP are available containing delayed-release beads of doxycycline hyclate, USP equivalent to 50 mg of doxycycline.

    The 50 mg tablets are white, round, unscored tablets containing yellow beads debossed with M on one side of the tablet and D36 on the other side. They are available as follows:

    NDC: 0378-4535-78
    bottles of 120 tablets

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

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

  • 17 PATIENT COUNSELING INFORMATION

    Patients taking doxycycline for malaria prophylaxis should be advised:

    • 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.

    All patients taking doxycycline should be advised:

    • 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.

    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 doxycycline hyclate delayed-release tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When doxycycline hyclate delayed-release tablets are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline hyclate delayed-release tablets or other antibacterial drugs in the future.

    The brands listed are trademarks of their respective owners.

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

    Revised: 2/2020
    DXYDR:R21

  • PRINCIPAL DISPLAY PANEL – 50 mg

    NDC: 0378-4535-78

    Doxycycline
    Hyclate
    Delayed-Release
    Tablets, USP
    50 mg*

    Do not chew or crush tablets.

    Rx only 120 Tablets

    *Each tablet contains delayed-release
    beads of doxycycline hyclate, USP
    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.]

    Usual Dosage: See accompanying
    prescribing information.

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

    Mylan.com

    RM4535DA1

    Doxycycline Hyclate Delayed-Release Tablets, USP 50 mg
  • INGREDIENTS AND APPEARANCE
    DOXYCYCLINE HYCLATE 
    doxycycline hyclate tablet, delayed release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0378-4535
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    DOXYCYCLINE HYCLATE (UNII: 19XTS3T51U) (DOXYCYCLINE ANHYDROUS - UNII:334895S862) DOXYCYCLINE ANHYDROUS50 mg
    Inactive Ingredients
    Ingredient NameStrength
    ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561)  
    HYPROMELLOSE PHTHALATE (24% PHTHALATE, 55 CST) (UNII: 87Y6436BKR)  
    LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)  
    POVIDONE, UNSPECIFIED (UNII: FZ989GH94E)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    SODIUM CHLORIDE (UNII: 451W47IQ8X)  
    SODIUM LAURYL SULFATE (UNII: 368GB5141J)  
    STEARIC ACID (UNII: 4ELV7Z65AP)  
    TALC (UNII: 7SEV7J4R1U)  
    TRIETHYL CITRATE (UNII: 8Z96QXD6UM)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeROUNDSize10mm
    FlavorImprint Code M;D36
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0378-4535-78120 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product05/23/2016
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA09043105/23/2016
    Labeler - Mylan Pharmaceuticals Inc. (059295980)
    • © 2024 FDA.report
    This site is not affiliated with or endorsed by the FDA.