DOTUR

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline.

It is a second-generation tetracycline that was first discovered in 1967.

Second-generation tetracyclines exhibit lesser toxicity than first-generation tetracyclines.

Doxycycline is used to treat a wide variety of gram-positive and gram-negative bacterial infections.

It is also used to treat acne and malaria.

Doxycycline is indicated for the treatment of various infections by gram-positive and gram-negative bacteria, aerobes and anaerobes, as well other types of bacteria, including: Early Lyme disease (as evidenced by erythema migraines) due to Borrelia burgdorferi in adults and pediatric patients 8 years of age and older weighing 45 kg and above 12 Rickettsial infections, 11 such as Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers 13 Sexually transmitted infections 11 Respiratory tract infections 11 caused by Mycoplasma pneumoniae and Haemophilus influenzae 13 Specific bacterial infections 11 after indicative bacteriologic testing.

These include infections caused by

Escherichia coli, Enterobacter aerogenes, Shigella species, Acinetobacter species, and Klebsiella species 13 Ophthalmic infections, 11 such as inclusion conjunctivitis caused by Chlamydia trachomatis 13 Anthrax, including inhalational anthrax (post-exposure) 11 Alternative treatment for selected infections when penicillin is contraindicated 11 Adjunctive therapy in acute intestinal amebiasis and severe acne 11, 13 Lymphogranuloma venereum caused by Chlamydia trachomatis 13 Psittacosis (ornithosis) caused by Chlamydophila psittaci 13 Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated, as judged by immunofluorescence 13 Uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis 13 Nongonococcal urethritis caused by Ureaplasma urealyticum 13 Relapsing fever due to Borrelia recurrentis 13 Prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (<4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains 11, 13 It is also used to treat infections caused by the following gram-negative microorganisms: Chancroid caused by Haemophilus ducreyi 13 Plague due to Yersinia pestis 13 Tularemia due to Francisella tularensis 13 Cholera caused by Vibrio cholerae 13 Campylobacter fetus infections caused by Campylobacter fetus 13 Brucellosis due to Brucella species (in conjunction with streptomycin ) 13 Bartonellosis due to Bartonella bacilliformis 13 Granuloma inguinale caused by Klebsiella granulomatis

Doxycycline and other tetracyclines are mainly bacteriostatic and are thought to exert antimicrobial effects by the inhibition of protein synthesis.

They suppress the growth of bacteria or keep them in the stationary phase of growth.

Tetracyclines have antimicrobial spectrum of activity against a variety of gram-positive and gram-negative microorganisms.

Cross-resistance of these microorganisms to tetracyclines is a common occurrence.

As it is a highly lipophilic drug, doxycycline crosses multiple membranes of target molecules.

Doxycycline shows favorable intra-cellular penetration, with bacteriostatic activity against a wide range of bacteria.

Doxycycline also exhibits antiparasitic properties 1, 2, 3 and anti-inflammatory actions. 4, 8 Its anti-inflammatory effects were investigated in various inflammatory skin conditions, such as bullous dermatoses and rosacea. 4, 8.

30S ribosomal protein Inhibitor.

Doxycycline is virtually completely absorbed after oral administration with a bioavailability of ranging from 73-95%.

Following an oral dose of 500 mg, the C max of 15.3 mg/L was reached in four hours.

Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours, decreasing to 1.45 mcg/mL at 24 hours.

While a high-fat meal lowers

C max and the rate of absorption, the effect is not clinically significant.

There is limited information available.

Tetracyclines, including doxycycline, 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.

Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 pediatric patients two to 18 years of age showed allometrically -scaled clearance (CL) ranging from 3.27-3.58 L/h/70 kg.

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LD is 2000 mg/kg in rats, 1870 mg/kg in mice, and 500 mg/kg in dog.

In case of overdosage, doxycycline should be discontinued and symptomatic and supportive treatment should be initiated.

Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

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 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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline, 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 the use of antibacterial drugs.

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 use of antibacterial drugs 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.

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. If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.

Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline.

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.

Concomitant use of isotretinoin and doxycycline should be avoided because isotretinoin is also known to cause pseudotumor cerebri.

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.

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 6 hours.

This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development).

Evidence of embryotoxicity has also been noted in animals treated early in pregnancy.

If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

The antianabolic action of the tetracyclines may cause an increase in BUN.

Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines.

Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

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

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.

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/day. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended.

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 is 2.2 mg/kg of body weight administered every 12 hours.

Children weighing 45 kg or more should receive the adult dose.

For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg/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.

The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

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

Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration. See ADVERSE REACTIONS. If gastric irritation occurs, it is recommended that doxycycline be given with food or milk.

The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk.

Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment.

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.

The dose may be administered with food, including milk or carbonated beverage, as required.

Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis: 100 mg, by mouth twice a day for 7 days.

Nongonococcal urethritis (NGU) caused by C. trachomatis or 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

N. gonorrhoeae: 100 mg, by mouth, twice a day for at least 10 days.

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.

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 1-2 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.

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.

Capsules, USP are light blue, and imprinted with "186" on the body and "CY" on the cap.

Each capsule contains doxycycline hyclate equivalent to: 100 mg doxycycline NDC 60760-721-60 BOTTLES OF 60 All products are to be stored at 20° to 25°C (68° to 77°F) and dispensed in tight, light-resistant containers with a child-resistant closure.

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 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.

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 fifty-six (0.30%) of the cases were treated with doxycycline.

This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed cases.

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.

Effects See WARNINGS..

Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known.

Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown.

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..

Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline 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 DOSAGE AND ADMINISTRATION..