doxycycline

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline and other antibacterial drugs, doxycycline 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. Treatment: Doxycycline is indicated for the treatment of the following infections: • Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. • Respiratory tract infections caused by Mycoplasma pneumoniae . • Lymphogranuloma venereum caused by Chlamydia trachomatis . • Psittacosis (ornithosis) caused by Chlamydophila psittaci . • Trachoma caused by Chlamydia trachomatis , although the infectious agent is not always eliminated, as judged by immunofluorescence. • Inclusion conjunctivitis caused by Chlamydia trachomatis . • Uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis . • Nongonococcal urethritis caused by Ureaplasma urealyticum . • Relapsing fever due to Borrelia recurrentis . Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms: • Chancroid caused by Haemophilus ducreyi . • 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 . • Granuloma inguinale caused by Klebsiella granulomatis . 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 bacteria, when bacteriologic testing indicates appropriate susceptibility to the drug: • Escherichia coli . • Enterobacter aerogenes . • Shigella species. • Acinetobacter species. • Respiratory tract infections caused by Haemophilus influenzae . • Respiratory tract and urinary tract infections caused by Klebsiella species. Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: • Upper respiratory infections caused by Streptococcus pneumoniae . • Anthrax due to Bacillus anthracis , including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis . When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: • Uncomplicated gonorrhea caused by Neisseria gonorrhoeae . • Syphilis caused by Treponema pallidum . • Yaws caused by Treponema pallidum subspecies pertenue . • Listeriosis due to Listeria monocytogenes . • Vincent's infection caused by Fusobacterium fusiforme . • Actinomycosis caused by Actinomyces israelii . • Infections caused by Clostridium species. In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy. Prophylaxis: Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (< 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. (See DOSAGE AND ADMINISTRATION section and Information for Patients subsection of the PRECAUTIONS section.)

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/day. 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 is 2.2 mg/kg of body weight administered every 12 hours. Children 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 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. 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. 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. Children weighing 45 kg or more should receive the adult dose.

3 DOSAGE FORMS AND STRENGTHS Doxycycline capsules, 40 mg are light yellow to pale yellow colored and light to dark beige colored pellets filled in capsule shell with white opaque colored cap imprinted with “DOX” and white opaque colored body imprinted with “40” with black ink. Free from physical defects. 40 mg capsule. ( 3 )

4 CONTRAINDICATIONS This drug is contraindicated in persons who have shown hypersensitivity to doxycycline or any other tetracyclines. Doxycycline capsules are contraindicated in persons who have shown hypersensitivity to doxycycline or other tetracyclines. ( 4 )

6 ADVERSE REACTIONS Some of the most common adverse reactions (incidence >2% and more common than with placebo) are nasopharyngitis, sinusitis, diarrhea, hypertension and aspartate aminotransferase increase. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE 1-855-361-3993; email drugsafety@avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials of Doxycycline Capsules: In controlled clinical trials of adult subjects with mild to moderate rosacea, 537 subjects received doxycycline capsules or placebo over a 16-week period. The following table summarizes selected adverse reactions that occurred in the clinical trials at a rate of ≥ 1% for the active arm: Table 1. Incidence (%) of Selected Adverse Reactions in Clinical Trials of Doxycycline Capsules (n=269) vs. Placebo (n=268) Doxycycline capsules Placebo Nasopharyngitis 13 (5) 9 (3) Pharyngolaryngeal Pain 3 (1) 2 (1) Sinusitis 7 (3) 2 (1) Nasal Congestion 4 (2) 2 (1) Fungal Infection 5 (2) 1 (0) Influenza 5 (2) 3 (1) Diarrhea 12 (5) 7 (3) Abdominal Pain Upper 5 (2) 1 (0) Abdominal Distention 3 (1) 1 (0) Abdominal Pain 3 (1) 1 (0) Stomach Discomfort 3 (1) 2 (1) Dry Mouth 3 (1) 0 (0) Hypertension 8 (3) 2 (1) Blood Pressure Increase 4 (2) 1 (0) Aspartate Aminotransferase Increase 6 (2) 2 (1) Blood Lactate Dehydrogenase Increase 4 (2) 1 (0) Blood Glucose Increase 3 (1) 0 (0) Anxiety 4 (2) 0 (0) Pain 4 (2) 1 (0) Back Pain 3 (1) 0 (0) Sinus Headache 3 (1) 0 (0) Note: Percentages based on total number of study participants in each treatment group. Adverse Reactions for Tetracyclines: The following adverse reactions have been observed in patients receiving tetracyclines at higher, antimicrobial doses: Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital region. Hepatotoxicity. Esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the drugs in the tetracycline-class. Most of the patients experiencing esophagitis and/or esophageal ulceration took their medication immediately before lying down [see Dosage and Administration ( 2 )]. Renal toxicity: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions ( 5.4 )]. Skin: maculopapular and erythematous rashes. Exfoliative dermatitis. Photosensitivity is discussed above [see Warnings and Precautions ( 5.5 )] . Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia. 6.2 Postmarketing Adverse Reactions Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of doxycycline capsules. Nervous system: Pseudotumor cerebri (benign intracranial hypertension), headache. Skin: fixed drug eruption Psychiatric: depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination To report SUSPECTED ADVERSE REACTIONS, contact AvKARE 1-855-361-3993; email drugsafety@avkare.com or FDA at 1-800- FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Click here to enter Drug Interactions • Patients on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. ( 7.1 ) • Some bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin. ( 7.2 ) • The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. ( 7.3 ) 7.1 Anticoagulants 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 tetracycline-class drugs in conjunction with penicillin. 7.3 Methoxyflurane The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. 7.4 Antacids and Iron Preparations Absorption of tetracyclines is impaired by bismuth subsalicylate, proton pump inhibitors, antacids containing aluminum, calcium or magnesium and iron-containing preparations. 7.5 Oral Retinoids There have been reports of pseudotumor cerebri (benign intracranial hypertension) associated with the concomitant use of isotretinoin and tetracyclines. Since both oral retinoids, including isotretinoin and acitretin, and the tetracyclines, primarily minocycline, can cause increased intracranial pressure, the concurrent use of an oral retinoid and a tetracycline should be avoided. 7.6 Barbiturates and Anti-epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. 7.7 Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

8 USE IN SPECIFIC POPULATIONS Click here to enter Use in Specific Populations Lactation: Breastfeeding is not recommended ( 8.2 ) 8.1 Pregnancy Risk Summary Doxycycline may cause reversible inhibition of bone growth and permanent discoloration of deciduous teeth when administered during the second and third trimesters of pregnancy [see Warnings and Precautions ( 5.1 and 5.2 )]. Available data from published studies have not shown a difference in major birth defect risk with doxycycline exposure in the first trimester of pregnancy compared to unexposed pregnancies. Avoid use of doxycycline capsules during the second and third trimester of pregnancy. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Published studies, including epidemiological and observational studies, with use of doxycycline during the first trimester of pregnancy have not identified drug-related increases in major birth defects. The use of tetracycline during tooth development (second and third trimester of pregnancy) may cause permanent discoloration of deciduous teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drug but has been observed following repeated short- term courses. Animal Data Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues. 8.2 Lactation Risk Summary Based on available published data, doxycycline is likely to be present in human breast milk but the specific concentration in breastmilk is not clear. There is no information on the effects of doxycycline on the breastfed infant or the effects on milk production. Because there are other antibacterial drug options available to treat rosacea in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with doxycycline capsules and for 5 days after the last dose. 8.4 Pediatric Use Doxycycline capsules should not be used in infants and children less than 8 years of age [ see Warnings and Precautions ( 5.1 ) ]. Doxycycline capsules have not been studied in children of any age with regard to safety or efficacy, therefore use in children is not recommended. 8.5 Geriatric Use Clinical studies of doxycycline capsules 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant disease or other drug therapy.

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.

Doxycycline Hyclate Capsules, USP, are an antibacterial drug synthetically derived from oxytetracycline. The structural formula of doxycycline monohydrate is: [structural formula of doxycycline monohydrate] with a molecular formula of C22H24N2O8•H2O and a molecular weight of 462.46. The chemical designation for doxycycline is 4­ (Dimethylamino)­1,4,4a,5,5a,6,11,12a­octahydro­3,5,10,12,12a­pentahydroxy­6­methyl­1,11­dioxo­2­naphthacenecarboxamide monohydrate. The molecular formula for doxycycline hydrochloride hemiethanolate hemihydrate is (C22H24N2O8•HCl)2•C2H6O•H2O and the molecular weight is 1025.89. Doxycycline is a light yellow crystalline powder. Doxycycline hyclate is soluble in water, while doxycycline monohydrate is very slightly soluble in water. Doxycycline has a high degree of lipoid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Each capsule for oral administration contains doxycycline hyclate equivalent to 100 mg of doxycycline (anhydrous). Inactive ingredients: lactose monohydrate, microcrystalline cellulose, magnesium stearate. The 100 mg capsule shell contains: gelatin, diacetylated monoglycerides, sucrose fatty acid esters, glacial acetic acid, sodium lauryl sulfate, colloidal silicon dioxide, FD&C Blue #1 and titanium dioxide. The printing ink may contain: Shellac Glaze, Iron Oxide Black, N­Butyl Alcohol, Propylene Glycol, SDA 3A Alcohol, FD&C Blue #2, FD&C Red #40, FD&C Blue #1, D&C Yellow #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.

HOW SUPPLIED Doxycycline Capsules USP, 50 mg are light yellow to yellow powder filled in hard gelatin capsule shell having an opaque yellow cap and an opaque white body printed with 782 on cap with black ink and are supplied as follows: NDC 68382-782-06 in bottle of 30 capsules with child-resistant closure NDC 68382-782-18 in bottle of 50 capsules with child-resistant closure NDC 68382-782-16 in bottle of 90 capsules with child-resistant closure NDC 68382-782-01 in bottle of 100 capsules NDC 68382-782-05 in bottle of 500 capsules NDC 68382-782-10 in bottle of 1000 capsules NDC 68382-782-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose capsules Doxycycline Capsules USP, 75 mg are light yellow to yellow powder filled in hard gelatin capsule shells having an opaque orange cap and an opaque white body printed with 706 on cap in black ink and are supplied as follows: NDC 68382-706-06 in bottle of 30 capsules with child-resistant closure NDC 68382-706-18 in bottle of 50 capsules with child-resistant closure NDC 68382-706-16 in bottle of 90 capsules with child-resistant closure NDC 68382-706-01 in bottle of 100 capsules NDC 68382-706-05 in bottle of 500 capsules NDC 68382-706-10 in bottle of 1000 capsules NDC 68382-706-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose capsules Doxycycline Capsules USP, 100 mg are light yellow to yellow powder filled in hard gelatin capsule shells having an opaque yellow cap and an opaque orange body printed with 707 on cap in black ink and are supplied as follows: NDC 68382-707-06 in bottle of 30 capsules with child-resistant closure NDC 68382-707-18 in bottle of 50 capsules with child-resistant closure NDC 68382-707-16 in bottle of 90 capsules with child-resistant closure NDC 68382-707-01 in bottle of 100 capsules NDC 68382-707-21 in bottle of 250 capsules NDC 68382-707-05 in bottle of 500 capsules NDC 68382-707-10 in bottle of 1000 capsules NDC 68382-707-77 in unit-dose blister cartons of 100 (10 x 10) unit-dose capsules Storage Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO 4 , and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO 4 , and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline. Minocycline, tetracycline PO 4 , methacycline, doxycycline, tetracycline base, oxytetracycline HCl and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet. Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline), in chickens (chlortetracycline) and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.