Doxycycline Hyclate

INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate 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 Chlamydia 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 (formerly Pasteurella pestis ). Tularemia due to Francisella tularensis (formerly Pasteurella tularensis ). Cholera caused by Vibrio cholerae (formerly Vibrio comma ). Campylobacter fetus infections caused by Campylobacter fetus (formerly Vibrio fetus ). Brucellosis due to Brucella species (in conjunction with streptomycin). Bartonellosis due to Bartonella bacilliformis . Granuloma inguinale caused by Calymmatobacterium 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 microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug: Escherichia coli. Enterobacter aerogenes (formerly Aerobacter aerogenes ). Shigella species. Acinetobacter species (formerly Mima species and Herellea 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 (formerly Diplococcus 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 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 sec …

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. Doxycycline for Oral Suspension Mixing Directions Tap bottle lightly to loosen powder. Add 47.6 mL of water to the bottle to make a total volume of 60 mL. Sh …

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

ADVERSE REACTIONS Due to oral doxycycline's virtually complete absorption, side effects of 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 rarely. 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 Error! Hyperlink reference not valid. .) Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of the drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See Error! Hyperlink reference not valid. .) Skin: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, skin hyperpigmentation, maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See Error! Hyperlink reference not valid. .) Renal toxicity: Rise in BUN has been reported and is apparently dose related. (See Error! Hyperlink reference not valid. .) Immune: Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, exacerbation of systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS), and Jarisch-Herxheimer reaction has been reported in the setting of spirochete infections treated with doxycycline. Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Other: Bulging fontanels in infants and intracranial hypertension in adults. (See Error! Hyperlink reference not valid. ) When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function studies are known to occur. To report SUSPECTED ADVERSE REACTIONS, contact Viona Pharmaceuticals Inc. at 1-888-304-5011 at 1-888-304-5011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

DRUG INTERACTIONS Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. Absorption of tetracyclines is impaired by bismuth subsalicylate. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and Penthrane® (methoxyflurane) has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective. Drug/Laboratory Test Interactions False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test. 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 antibacterial drugs, 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 antibacterial drugs (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. Pregnancy Teratogenic Effects. 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. 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 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. 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 Error! Hyperlink reference not valid. .) Labor and Delivery The effect of tetracyclines on labor and delivery is unknown. Nursing Mothers 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. 4 Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nur …

Mechanism of Action 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 with other 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 as described in the INDICATIONS AND USAGE section of the package insert for Doxycycline Hyclate Capsules. Gram-Negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Klebsiella species Klebsiella granulomatis Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Neisseria gonorrhoeae Shigella species Vibrio cholera e Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Anaerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Nocardiae 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.

DESCRIPTION Doxycycline is an antibacterial drug synthetically derived from oxytetracycline, and is available as Doxycycline Hyclate Tablets and Capsules and Doxycycline for Oral Suspension; for oral administration. The structural formula of doxycycline monohydrate is with a molecular formula of C 22 H 24 N 2 O 8 ∙H 2 O and a molecular weight of 462.46. The chemical designation for doxycycline 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 monohydrate. The molecular formula for doxycycline hydrochloride hemiethanolate hemihydrate is (C 22 H 24 N 2 O 8 ∙HCl) 2 ∙C 2 H 6 O∙H 2 O 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. Inactive ingredients in the capsule formulations are: colloidal silicon dioxide, lactose anhydrous, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and stearic acid. 50 mg gelatin capsule shell contains: FD&C Blue #1, D&C Yellow #10, titanium dioxide and gelatin. 100 mg gelatin capsule shell contains: FD&C Blue #1, titanium dioxide and gelatin. Black ink contains shellac glaze in SD-45, black iron oxide, propylene glycol, FD&C Blue #2, FD&C Red # 40, FD&C Blue # 1, D&C Yellow # 10, butyl alcohol, denatured alcohol. Each capsule, for oral administration, contains doxycycline hyclate equivalent to 50 mg or 100 mg of doxycycline. Inactive ingredients for the oral suspension formulation are: confectioner's sugar, D&C red #27 aluminum lake, methylparaben, microcrystalline cellulose/ sodium carboxymethylcellulose, natural raspberry flavor; propylparaben, simethicone and sucrose. When reconstituted, each teaspoonful (5 mL) doxycycline suspension, for oral administration, contains doxycycline monohydrate equivalent to 25 mg of doxycycline. Inactive ingredients for the tablet formulation are: anhydrous lactose, colloidal silicon dioxide, FD&C Red No. 40, FD&C Yellow No. 6, hypromellose, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, stearic acid, and titanium dioxide. Each tablet, for oral administration, contains doxycycline hyclate equivalent to 50 mg or 100 mg doxycycline. Doxycycline Hyclate Tablets, USP meets USP Dissolution test 3. "Image Description"

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 Manufactured for Chartwell RX, LLC. Congers, NY 10920 Doxycycline Hyclate Capsules, USP 50 mg are available as a blue and white capsule filled with yellow powder, imprinted with " 2984 ", containing doxycycline hyclate, equivalent to 50 mg doxycycline. NDC 62135-984-50 Bottles of 50 capsules NDC 62135-984-05 Bottles of 500 capsules Doxycycline Hyclate Capsules, USP 100 mg are available as a light blue capsule filled with yellow powder imprinted with " 2985 " containing doxycycline hyclate, equivalent to 100 mg of doxycycline. NDC 62135-985-50 Bottles of 50 capsules NDC 62135-985-01 Bottles of 100 capsules NDC 62135-985-05 Bottles of 500 capsules NDC 62135-985-10 Bottles of 1000 capsules Doxycycline Hyclate Tablets, USP equivalent to 50 mg doxycycline: Round, orange, film-coated tablet de-bossed with " CE over 30 " on one side, and plain on the other side. NDC 62135-625-60 Bottles of 60 tablets Doxycycline Hyclate Tablets, USP equivalent to 100 mg doxycycline: Round, orange film-coated tablet engraved with " 3626 " on one side, and plain on the other side. NDC 62135-626-20 Bottles of 20 tablets NDC 62135-626-28 Bottles of 28 tablets NDC 62135-626-50 Bottles of 50 tablets NDC 62135-626-01 Bottles of 100 tablets NDC 62135-626-12 Bottles of 120 tablets NDC 62135-626-23 Bottles of 210 tablets NDC 62135-626-31 Bottles of 300 tablets NDC 62135-626-40 Bottles of 400 tablets NDC 62135-626-05 Bottles of 500 tablets NDC 62135-626-10 Bottles of 1000 tablets NDC 62135-626-96 Bottles of 2000 tablets Doxycycline for Oral Suspension USP is available as a raspberry-flavored, pink dry powder for oral suspension. When reconstituted, each teaspoonful (5 mL) contains doxycycline monohydrate equivalent to 25 mg of doxycycline in a 2 oz (60 mL) bottle. NDC 62135-417-46 NDC 62135-877-46 Manufactured for Chartwell Governmental & Specialty RX, LLC. Congers, NY 10920 Doxycycline Hyclate Capsules, USP 50 mg are available as a blue and white capsule filled with yellow powder, imprinted with " 2984 ", containing doxycycline hyclate, equivalent to 50 mg doxycycline. NDC 68999-984-50 Bottles of 50 capsules Doxycycline Hyclate Capsules, USP 100 mg are available as a light blue capsule filled with yellow powder imprinted with " 2985 " containing doxycycline hyclate, equivalent to 100 mg of doxycycline. NDC 68999-985-50 Bottles of 50 capsules NDC 68999-985-01 Bottles of 100 capsules NDC 68999-985-05 Bottles of 500 capsules NDC 68999-985-10 Bottles of 1000 capsules Doxycycline Hyclate Tablets, USP equivalent to 50 mg doxycycline: Round, orange, film-coated tablet de-bossed with " CE over 30 " on one side, and plain on the other side. NDC 68999-625-60 Bottles of 60 tablets Doxycycline Hyclate Tablets, USP equivalent to 100 mg doxycycline: Round, orange film-coated tablet engraved with " 3626 " on one side, and plain on the other side. NDC 68999-626-02 Bottles of 20 tablets NDC 68999-626-28 Bottles of 28 tablets NDC 68999-626-30 Bottles of 30 tablets NDC 68999-626-50 Bottles of 50 tablets NDC 68999-626-06 Bottles of 100 tablets NDC 68999-626-12 Bottles of 120 tablets NDC 68999-626-23 Bottles of 210 tablets NDC 68999-626-31 Bottles of 300 tablets NDC 68999-626-40 Bottles of 400 tablets NDC 68999-626-05 Bottles of 500 tablets NDC 68999-626-10 Bottles of 1000 tablets NDC 68999-626-96 Bottles of 2000 tablets Doxycycline for Oral Suspension USP is available as a raspberry-flavored, pink dry powder for oral suspension. When reconstituted, each teaspoonful (5 mL) contains doxycycline monohydrate equivalent to 25 mg of doxycycline in a 2 oz (60 mL) bottle. NDC 68999-417-46 Dispense in a tight, light-resistant container as defined in the USP. Use child-resistant closure (as required). Store at 20° to 25° C (68° to 77° F) (see USP controlled room temperature)