Doxycycline Hyclate (Doxycycline Hyclate Delayed-release Tablets ): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Doxycycline Hyclate

Doxycycline Hyclate Delayed-Release Tablets, for oral administration, contain specially coated pellets 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:

with a molecular formula of C₂₂H₂₄N₂O₈, HCl, ½ C₂H₆O, ½ H₂O and a molecular weight of 512.9. The chemical designation 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-6methyl-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. 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.

Uses for Doxycycline Hyclate

To reduce the development ofdrug-resistant bacteria and maintain the effectiveness of Doxycycline HyclateDelayed-Release Tablets and other antibacterial drugs, Doxycycline HyclateDelayed-Release Tablets should be used only to treat or prevent infections thatare proven or strongly suspected to be caused by susceptible bacteria. Whenculture and susceptibility information are available, they should be consideredin selecting or modifying antibacterial therapy. In the absence of such data,local epidemiology and susceptibility patterns may contribute to the empiricselection of therapy.

Doxycycline is a tetracycline-class antibacterial indicated in the following conditions ordiseases:

Rickettsial Infections

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

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.

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.

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 infectionscaused by the following gram-negative microorganisms, when bacteriologicaltesting indicates appropriate susceptibility to the drug:

Escherichia coli
Enterobacter aerogenes
Shigella species
Acinetobacter species
Urinary tract infections caused by Klebsiella species.

Ophthalmic Infections

Trachoma caused by Chlamydia trachomatis, althoughthe infectious agent is not always eliminated as judged by immunofluorescence.

Inclusion conjunctivitis caused by Chlamydiatrachomatis.

Anthrax Including Inhalational Anthrax (post-exposure)

Anthrax due to Bacillus anthracis, includinginhalational anthrax (post-exposure): to reduce the incidence or progression ofdisease following exposure to aerosolized Bacillus anthracis.

Alternative Treatment For Selected Infections When Penicillin Is Contraindicated

When penicillin is contraindicated, doxycycline is analternative 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.

Adjunctive Therapy For Acute Intestinal Amebiasis And Severe Acne

In acute intestinal amebiasis, doxycycline may be auseful adjunct to amebicides. In severe acne, doxycycline may be usefuladjunctive therapy.

Prophylaxis Of Malaria

Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistantstrains [see DOSAGE AND ADMINISTRATION and PATIENT INFORMATION].

Dosage for Doxycycline Hyclate

Usual Dosage And Administration

The usual dosage and frequency of administration ofdoxycycline differs from that of the other tetracyclines. Exceeding therecommended 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].
• 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 withcapsule and tablet forms of drugs in the tetracycline-class is recommended towash down the drugs and reduce the risk of esophageal irritation and ulceration [see ADVERSE REACTIONS].

If gastric irritation occurs, doxycycline may be givenwith food or milk [see CLINICAL PHARMACOLOGY].

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

Uncomplicated urethral, endocervical, or rectal infectioncaused by Chlamydia trachomatis: 100 mg by mouth twice a day for 7 days. As analternate dosing regimen for uncomplicated urethral or endocervical infectioncaused by Chlamydia trachomatis, administer 200 mg by mouth once-a-day for 7days.

Uncomplicated gonococcal infections in adults (exceptanorectal infections in men): 100 mg, by mouth, twice-a-day for 7 days. As analternate single visit dose, administer 300 mg stat followed in one hour by asecond 300 mg dose.

Nongonococcal urethritis (NGU) caused by U. urealyticum:100 mg by mouth twice-aday for 7 days.

Syphilis – early: Patients who are allergic topenicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2weeks.

Syphilis of more than one year's duration: Patients whoare allergic to penicillin should be treated with doxycycline 100 mg by mouthtwice-a-day for 4 weeks.

Acute epididymo-orchitis caused by C. trachomatis:100 mg, by mouth, twice-a-day for at least 10 days.

For Prophylaxis Of Malaria

For adults, the recommended dose is 100 mg daily. Forchildren over 8 years of age, the recommended dose is 2 mg/kg given once dailyup to the adult dose. Prophylaxis should begin 1 or 2 days before travel to themalarious area. Prophylaxis should be continued daily during travel in themalarious area and for 4 weeks after the traveler leaves the malarious area.

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 bodyweight, by mouth, twice-a-day for 60 days. Children weighing 45 kg or moreshould receive the adult dose.

Sprinkling The Tablet Over Applesauce

Doxycycline Hyclate Delayed-Release Tablets may also beadministered by carefully breaking up the tablet and sprinkling the tabletcontents (delayed-release pellets) on a spoonful of applesauce. Thedelayed-release pellets must not be crushed or damaged when breaking up thetablet. Any loss of pellets in the transfer would prevent using the dose. Theapplesauce/Doxycycline Hyclate Delayed-Release Tablets mixture should beswallowed immediately without chewing and may be followed by a glass of waterif desired. The applesauce should not be hot, and it should be soft enough tobe swallowed without chewing. In the event that a prepared dose ofapplesauce/Doxycycline Hyclate Delayed-Release Tablets cannot be takenimmediately, the mixture should be discarded and not stored for later use.

HOW SUPPLIED

Dosage Forms And Strengths

Doxycycline Hyclate Delayed-Release Tablets, 75 mg arewhite, oval, scored tablets containing yellow pellets and debossed with “D|5”on one face and plain on the other. Each tablet contains specially coatedpellets of doxycycline hyclate equivalent to 75 mg of doxycycline.

Doxycycline Hyclate Delayed-Release Tablets, 100 mg arewhite, oval, scored tablets containing yellow pellets and debossed with “D|0”on one face and plain on the other. Each tablet contains specially coatedpellets of doxycycline hyclate equivalent to 100 mg of doxycycline.

Doxycycline Hyclate Delayed-Release Tablets, 150 mg arewhite, rectangular, dual scored tablets containing yellow pellets and debossedwith “D|I|I” on one face and plain on the other. Each tablet contains speciallycoated pellets of doxycycline hyclate equivalent to 150 mg of doxycycline.

Doxycycline Hyclate Delayed-Release Tablets, 200 mg arewhite, oval, scored tablets containing yellow pellets and debossed with “D|D”on one face and plain on the other. Each tablet contains specially coatedpellets of doxycycline hyclate equivalent to 200 mg of doxycycline.

Storage And Handling

Doxycycline HyclateDelayed-Release Tablets, 75 mg are white, oval, scored tablets containingyellow pellets and debossed with “D|5” on one face and plain on the other. Eachtablet contains specially coated pellets of doxycycline hyclate equivalent to75 mg of doxycycline.

Bottles of 60 tablets NDC68308-775-60

Doxycycline Hyclate Delayed-Release Tablets, 100 mg arewhite, oval, scored tablets containing yellow pellets and debossed with “D|0”on one face and plain on the other. Each tablet contains specially coatedpellets of doxycycline hyclate equivalent to 100 mg of doxycycline.

Bottles of 100 tablets NDC 68308-710-10

Doxycycline Hyclate Delayed-Release Tablets, 150 mg arewhite, rectangular, dual scored tablets containing yellow pellets and debossedwith “D|I|I” on one face and plain on the other. Each tablet contains speciallycoated pellets of doxycycline hyclate equivalent to 150 mg of doxycycline.

Bottles of 100 tablets NDC 68308-715-10

Doxycycline Hyclate Delayed-Release Tablets, 200 mg arewhite, oval, scored tablets containing yellow pellets and debossed with “D|D”on one face and plain on the other. Each tablet contains specially coatedpellets of doxycycline hyclate equivalent to 200 mg of doxycycline.

Bottles of 60 tablets NDC 68308-716-60

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

Distributed by: Mayne Pharma, Greenville, NC 278341-844-825-8500. Manufactured by: Mayne Pharma International Pty Ltd, SalisburySouth, SA 5106 Australia. Revised: Apr 2016

Side Effects for Doxycycline Hyclate

Clinical Trial Experience

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

Adverse events in the Safety Population were reported by99 (40.2%) subjects in the Doxycycline Hyclate Delayed-Release Tablets, 200 mgtreatment group and 132 (53.2%) subjects in the doxycyclinehyclate capsules referencetreatment group. Most AEs were mild in intensity. The most commonly reportedadverse events in both treatment groups were nausea, vomiting, diarrhea, andbacterial vaginitis, Table 1.

Table 1: Adverse Reactions Reported in Greater than orEqual to 2% of Subjects

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

Postmarketing Experience

The following adverse reactionshave been identified during post-approval use of doxycycline. Because thesereactions are reported voluntarily from a population of uncertain size, it isnot always possible to reliably estimate a causal relationship to drugexposure.

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 receivingtetracyclines:

Gastrointestinal: Anorexia, nausea, vomiting,diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilialovergrowth) in the anogenital region. Hepatotoxicity has been reported. Thesereactions have been caused by both the oral and parenteral administration oftetracyclines. Esophagitis and esophageal ulcerations have been reported inpatients receiving capsule and tablet forms of drugs in the tetracycline-class.Most of these patients took medications immediately before going to bed [seeDOSAGE AND ADMINISTRATION].

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].

Renal: Rise in BUN has been reported and isapparently dose-related [see WARNINGS AND PRECAUTIONS].

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

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

Intracranial Hypertension: Intracranialhypertension (IH, pseudotumor cerebri) has been associated with the use oftetracycline [see WARNINGS AND PRECAUTIONS]

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

Drug Interactions for Doxycycline Hyclate

Anticoagulant Drugs

Because tetracyclines have been shown to depress plasmaprothrombin activity, patients who are on anticoagulant therapy may requiredownward adjustment of their anticoagulant dosage.

Penicillin

Since bacteriostatic drugs may interfere with the bactericidalaction of penicillin, it is advisable to avoid giving tetracyclines inconjunction with penicillin.

Antacids And Iron Preparations

Absorption of tetracyclines is impaired by antacidscontaining aluminum, calcium, or magnesium, bismuth subsalicylate, andiron-containing preparations.

Oral Contraceptives

Concurrent use of tetracycline may render oralcontraceptives less effective.

Barbiturates And Anti-Epileptics

Barbiturates, carbamazepine, and phenytoin decrease thehalf-life of doxycycline.

Penthrane

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

Drug/Laboratory Test Interactions

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

Warnings for Doxycycline Hyclate

Included as part of the PRECAUTIONS section.

Precautions for Doxycycline Hyclate

Tooth Development

The use of drugs of the tetracycline-class during toothdevelopment (last half of pregnancy, infancy and childhood to the age of 8years) may cause permanent discoloration of the teeth (yellow-gray-brown). Thisadverse reaction is more common during long-term use of the drugs but it hasbeen observed following repeated short-term courses. Enamel hypoplasia has alsobeen reported. Use Doxycycline Hyclate Delayed-Release Tablets in pediatricpatients 8 years of age or less only when the potential benefits are expectedto outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternativetherapies.

Clostridium Difficile Associated Diarrhea

Clostridium 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 whichcontribute to the development of CDAD. Hypertoxin producing strains of C.difficile cause increased morbidity and mortality, as these infections canbe refractory to antimicrobial therapy and may require colectomy. CDAD must beconsidered in all patients who present with diarrhea following antibacterialuse. Careful medical history is necessary since CDAD has been reported to occurover two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterialuse 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 shouldbe instituted as clinically indicated.

Photosensitivity

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

Superinfection

As with other antibacterial preparations, use ofDoxycycline Hyclate Delayed-Release Tablets may result in overgrowth ofnon-susceptible organisms, including fungi. If superinfection occurs, theantibacterial should be discontinued and appropriate therapy instituted.

Intracranial Hypertension

Intracranial hypertension (IH, pseudotumor cerebri) hasbeen associated with the use of tetracycline including Doxycycline HyclateDelayed-Release Tablets. Clinical manifestations of IH include headache,blurred vision, diplopia, and vision loss; papilledema can be found onfundoscopy. Women of childbearing age who are overweight or have a history ofIH are at greater risk for developing tetracycline associated IH. Avoidconcomitant use of isotretinoin and Doxycycline Hyclate Delayed-Release Tabletsbecause isotretinoin is also known to cause pseudotumor cerebri. Although IHtypically resolves after discontinuation of treatment, the possibility forpermanent visual loss exists. If visual disturbance occurs during treatment,prompt ophthalmologic evaluation is warranted. Since intracranial pressure canremain elevated for weeks after drug cessation patients should be monitoreduntil they stabilize.

Skeletal Development

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

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

Antianabolic Action

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

Malaria

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

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

Development Of Drug-Resistant Bacteria

Prescribing Doxycycline Hyclate Delayed-Release Tabletsin the absence of a proven or strongly suspected bacterial infection or aprophylactic indication is unlikely to provide benefit to the patient andincreases the risk of the development of drug-resistant bacteria.

Laboratory Monitoring For Long-Term Therapy

In long-term therapy, periodic laboratory evaluation oforgan systems, including hematopoietic, renal, and hepatic studies should beperformed.

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].
• to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration [see ADVERSE REACTIONS].
• 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].
• 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].
• that the use of doxycycline might increase the incidence of vagin*l candidiasis.

Diarrhea is a common problem caused by antibacterialswhich usually ends when the antibacterial is discontinued. Sometimes afterstarting treatment with antibacterials, patients can develop watery and bloodystools (with or without stomach cramps and fever) even as late as two or moremonths 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 drugsincluding Doxycycline Hyclate Delayed-Release Tablets should only be used totreat bacterial infections. They do not treat viral infections (for example,the common cold). When Doxycycline Hyclate Delayed-Release Tablets isprescribed to treat a bacterial infection, patients should be told thatalthough it is common to feel better early in the course of therapy, the medicationshould be taken exactly as directed. Skipping doses or not completing the fullcourse of therapy may (1) decrease the effectiveness of the immediate treatmentand (2) increase the likelihood that bacteria will develop resistance and willnot be treatable by Doxycycline Hyclate Delayed-Release Tablets or otherantibacterial drugs in the future.

Instructions For Breaking The 150 mg Doxycycline Hyclate Delayed-Release Tablets Dual-Scored Tablet

The tablet is marked with separation lines (score lines)and may be broken at these score lines to provide any of the following doses.

• 150 mg treatment (the entire tablet is taken)

• 100 mg treatment (two thirds of the tablet or two 50 mg tablet segments are taken)

• 50 mg treatment (one third of the tablet is taken)

To break the tablet, the tabletis held between the thumbs and index fingers close to the appropriate scoreline. Then, with the score line facing the patient, enough pressure is appliedto snap the tablet segments apart (segments that do not break along the scoreline should not be used).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals toevaluate carcinogenic potential of doxycycline have not been conducted.However, there has been evidence of oncogenic activity in rats in studies withthe related antibacterials, oxytetracycline (adrenal and pituitary tumors) andminocycline (thyroid tumors). Likewise, although mutagenicity studies ofdoxycycline have not been conducted, positive results in in vitro mammaliancell assays have been reported for related antibacterials (tetracycline,oxytetracycline).

Doxycycline administered orallyat dosage levels as high as 250 mg/kg/day had no apparent effect on thefertility of female rats. Effect on male fertility has not been studied.

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category D: There are no adequate andwell-controlled studies on the use of doxycycline in pregnant women. The vastmajority of reported experience with doxycycline during human pregnancy isshort-term, first trimester exposure. There are no human data available toassess the effects of long-term therapy of doxycycline in pregnant women suchas that proposed for the treatment of anthrax exposure. An expert review ofpublished data on experiences with doxycycline use during pregnancy by TERIS-the Teratogen Information System -concluded that therapeutic doses duringpregnancy are unlikely to pose a substantial teratogenic risk (the quantity andquality of data were assessed as limited to fair), but the data areinsufficient to state that there is no risk.¹

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 totalmalformations and use of doxycycline anytime during pregnancy. Sixty-three(0.19%) of the controls and 56 (0.30%) of the cases were treated withdoxycycline. This association was not seen when the analysis was confined tomaternal treatment during the period of organogenesis (that is, in the secondand third months of gestation), with the exception of a marginal relationshipwith neural tube defect based on only two-exposed cases.²

A small prospective study of 81 pregnancies describes 43pregnant women treated for 10 days with doxycycline during early firsttrimester. All mothers reported their exposed infants were normal at 1 year ofa*ge.³

Nonteratogenic effects: [see WARNINGS AND PRECAUTIONS].

Nursing Mothers

Tetracyclines are excreted in human milk, however, theextent of absorption of tetracyclines including doxycycline, by the breastfedinfant is not known. Short-term use by lactating women is not necessarilycontraindicated. The effects of prolonged exposure to doxycycline in breastmilk are unknown⁴. Because of the potential for serious adversereactions in nursing infants from doxycycline, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into accountthe importance of the drug to the mother [see WARNINGS AND PRECAUTIONS].

Pediatric Use

Because of the effects of drugs of the tetracycline-classon tooth development and growth, use Doxycycline Hyclate Delayed-ReleaseTablets in pediatric patients 8 years of age or less only when the potentialbenefits are expected to outweigh the risks in severe or life-threateningconditions (e.g., anthrax, Rocky Mountain spotted fever), particularly, whenthere are no alternative therapies Doxycycline Hyclate Delayed-Release Tablets[seeWARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Geriatric Use

Clinical studies of Doxycycline Hyclate Delayed-ReleaseTablets did not include sufficient numbers of subjects aged 65 and over todetermine whether they respond differently from younger subjects. Otherreported clinical experience has not identified differences in responsesbetween the elderly and younger patients.

Doxycycline Hyclate Delayed-Release Tablets 75 mg tabletscontain 3 mg (0.196 mEq) of sodium

Doxycycline Hyclate Delayed-Release Tablets 100 mgtablets contain 3 mg (0.261 mEq) of sodium

Doxycycline Hyclate Delayed-Release Tablets 150 mgtablets contain 9 mg (0.392 mEq) of sodium

Doxycycline Hyclate Delayed-Release Tablets 200 mgtablets contain 12 mg (0.522 mEq) of sodium.

REFERENCES

1. Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Recredit for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins UniversityPress: 2000: 149-195.

2. Cziezel AE and Rockenbauer M. Teratogenic study ofdoxycycline. 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. Hale T. Medications and Mothers Milk. 9^th edition. Amarillo, TX: Pharmasoft Publishing 2000; 225-226.

Overdose Information for Doxycycline Hyclate

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

Contraindications for Doxycycline Hyclate

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

Clinical Pharmacology for Doxycycline Hyclate

Mechanism Of Action

Doxycycline is an antibacterial drug [see Microbiology].

Pharmaco*kinetics

Doxycycline is virtuallycompletely absorbed after oral administration. Following single andmultiple-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; thecorresponding mean plasma concentration values 24 hours after single andmultiple doses were 1.5 mcg/mL and 2.3 mcg/mL, respectively. The mean Cmax andAUC 0-∞ of doxycycline are 24% and 13% lower, respectively, followingsingle dose administration of Doxycycline Hyclate Delayed-Release Tablets, 100mg with a high fat meal (including milk) compared to fasted conditions. Themean Cmax of doxycycline is 19% lower and the AUC 0-∞ is unchangedfollowing single dose administration of Doxycycline Hyclate Delayed-ReleaseTablets, 150 mg with a high fat meal (including milk) compared to fastedconditions. 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 infasted subjects. The 200 mg tablets may be administered without regard to meals.

When Doxycycline HyclateDelayed-Release Tablets are sprinkled over applesauce and taken with or withoutwater, the extent of doxycycline absorption is unchanged, but the rate ofabsorption is increased slightly.

Tetracyclines are concentrated in bile by the liver andexcreted in the urine and feces at high concentrations and in a biologicallyactive form. Excretion of doxycycline by the kidney is about 40%/72 hours inindividuals with a creatinine clearance of about 75 mL/min. This percentage mayfall as low as 1-5%/72 hours in individuals with a creatinine clearance below10 mL/min.

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

Microbiology

Mechanism Of Action

Doxycycline inhibits bacterial protein synthesis bybinding to the 30S ribosomal subunit.

Doxycycline has bacteriostatic activity against a broadrange of Gram-positive and Gram-negative bacteria. Cross-resistance betweentetracyclines is common.

Doxycycline has been shown to be active against mostisolates of the following microorganisms, both in vitro and in clinicalinfections as described in the INDICATIONS AND USAGE section of the packageinsert for Doxycycline Hyclate Delayed-Release Tablets [see INDICATIONS ANDUSAGE].

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 Streptococcus pneumoniae

Anerobic Bacteria

Clostridium species
Fusobacterium fusiforme
Propionibacterium acnes

Other Bacteria

Borrelia recurrentis
Chlamydophila psittaci
Chlamydia trachomatis
Mycoplasma pneumoniae
Norcardiae and other aerobic
Actinomyces species
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 thedrug is not known.

Susceptibility Test Methods

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

Dilution Techniques

Quantitative methods are used to determine antimicrobialminimum inhibitory concentrations (MICs). These MICs provide estimates of thesusceptibility of bacteria to antimicrobial compounds. The MICs should bedetermined using a standardized test method (broth and/or agar)^5,6,8.The MIC values should be interpreted according to the criteria provided inTable 2.

Diffusion Techniques

Quantitative methods that require measurement of zonediameters can also provide reproducible estimates of the susceptibility ofbacteria to antimicrobial compounds. Zone size provides an estimate of thesusceptibility of bacteria to antimicrobial compounds. The zone size should bedetermined using a standard test method^5,7,8. This procedure usespaper disks impregnated with 30 mcg doxycycline to test the susceptibility ofbacteria to doxycycline. The disk diffusion interpretive criteria are providedin Table 2.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doxycyclinecan be determined by a standardized test method⁹. The MIC valuesobtained should be interpreted according to the criteria provided in Table 2.

Table 2: Susceptibility Test Interpretive Criteria forDoxycycline and Tetracycline

A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if theantimicrobial drug reaches the concentrations usually achievable at the site ofinfection. A report of Intermediate (I) indicates that the result shouldbe considered equivocal, and, if the bacteria is not fully susceptible toalternative, clinically feasible drugs, the test should be repeated. Thiscategory implies possible clinical applicability in body sites where the drugis physiologically concentrated or in situations where high dosage of drug canbe used. This category also provides a buffer zone that prevents smalluncontrolled technical factors from causing major discrepancies ininterpretation. A report of Resistant (R) indicates that theantimicrobial is not likely to inhibit growth of the pathogen if theantimicrobial drug reaches the concentrations usually achievable at theinfection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require theuse of laboratory controls to monitor and ensure the accuracy and precision ofthe supplies and reagents used in the assay, and the techniques of theindividuals performing the test^{5,6,7,8,9,10,11}. Standard doxycyclineand tetracycline powders should provide the following range of MIC values notedin Table 3. For the diffusion technique using the 30 mcg doxycycline disk thecriteria noted in Table 3 should be achieved.

Table 3: Acceptable Quality Control Ranges forSusceptiblity Testing for Doxycycline and Tetracycline

Animal Toxicology And/Or Pharmacology

Hyperpigmentation of the thyroid has been produced bymembers of the tetracycline-class in the following species: in rats byoxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigsby doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs bydoxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO4, methacycline, doxycycline,tetracycline base, oxytetracycline HCl, and tetracycline HCl, were goitrogenicin 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 ofdrugs has also resulted in the induction of thyroid hyperplasia in thefollowing: in rats and dogs (minocycline); in chickens (chlortetracycline); andin rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observedin goats and rats treated with oxytetracycline.

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

Clinical Studies

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

The primary purpose of this study was to evaluate theefficacy and safety of Doxycycline Hyclate Delayed-Release Tablets, 200 mg oncedaily versus doxycycline hyclate capsules, 100 mg twice daily for seven daysfor the treatment of uncomplicated urogenital C. trachomatis infection.The primary efficacy objective was to demonstrate non-inferiority of theDoxycycline Hyclate Delayed-Release Tablets 200 mg once daily treatment regimenversus the doxycycline 100 mg twice daily treatment regimen for the indicationusing a negative nucleic acid amplification test (NAAT) at the test of curevisit (day 28) in the mITT population (subjects who were positive at baselineand took at least one day of study drug).

Table 4: Primary Efficacy Outcome – MicrobiologicalCure of C. trachomatis at Day 28

REFERENCES

5. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement, CLSI document M100-S24. Clinical Laboratory Standards Institute,950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2014.

6. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Ninth Edition. CLSI document M07-A9, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, WaynePennsylvania 19087, USA, 2012.

7. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition. CLSI document M02-A11, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania19087, USA, 2012.

8. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline – Second Edition CLSI document M45-A2, Clinical Laboratory Standards Institute, 950 West Valley Road,Suite 2500, Wayne Pennsylvania 19087, USA, 2010.

9. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard – Eighth Edition. CLSI document M11-A8, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA,2012.

10. Clinical and Laboratory Standards Institute (CLSI). Methods for Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard – Second Edition. CLSI document M24-A2, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA,2011.

11. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A, Clinical Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne Pennsylvania 19087, USA, 2011.

Patient Information for Doxycycline Hyclate

Doxycycline Hyclate
Delayed-Release Tablets, 75 mg, 100 mg, 150 mg and 200 mg

Instructions for Breaking the 150 mg Doxycycline Hyclate Delayed-Release Tablets Dual-Scored Tablet

Your doctor may find itnecessary to adjust your dosage of Doxycycline Hyclate Delayed-Release Tabletsto obtain the proper treatment response. The tablet is marked with separationlines (score lines) and may be broken at these score lines to provide any ofthe following doses.

If your doctor prescribed:

• 150 mg treatment (taken the entire tablet)

• 100 mg treatment (two thirds of the tablet or two 50 mg tablet segments are taken)

• 50 mg treatment (one third of the tablet is taken)

To break the tablet, hold thetablet between your thumbs and index fingers close to the appropriate scoreline. Then, with the score line facing you, apply enough pressure to snap thetablet segments apart (do not use segments that do not break along the scoreline).