Doxycycline Hyclate

6 ADVERSE REACTIONS Adverse reactions observed in patients receiving tetracyclines include anorexia, nausea, vomiting, diarrhea, rash, photosensitivity, urticaria, and hemolytic anemia. (6) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience The safety and efficacy of Doxycycline hyclate delayed-release tablets, 200 mg as a single daily dose was evaluated in a multicenter, randomized, double-blind, active-controlled study. Doxycycline hyclate delayed-release tablets, 200 mg was given orally once-a-day for 7 days and compared to doxycycline hyclate capsules 100 mg given orally twice daily for 7 days for the treatment of men and women with uncomplicated urogenital C. trachomatis infection. Adverse events in the Safety Population were reported by 99 (40.2%) subjects in the doxycycline hyclate delayed-release tablets, 200 mg treatment group and 132 (53.2%) subjects in the doxycycline hyclate capsules reference treatment group. Most AEs were mild in intensity. The most commonly reported adverse events in both treatment groups were nausea, vomiting, diarrhea, and bacterial vaginitis, Table 1. Table 1: Adverse Reactions Reported in Greater than or Equal to 2% of Subjects Doxycycline Hyclate Delayed-Release Tablets, 200 mg N = 246 Preferred Term n (%) Subjects with anyAE 99 (40.2) Nausea 33 (13.4) Vomiting 20 (8.1) Headache 5 (2) Diarrhea 8 (3.3) Abdominal Pain Upper 5 (2) VaginitisBacterial 8 (3.3) Vulvovaginal Mycotic Infection 5 (2) Because clinical trials are conducted under prescribed conditions, adverse reaction rates observed in the clinical trial may not always reflect the rates observed in practice. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of doxycycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate a causal relationship to drug exposure. Due to oral doxycycline’s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines: Gastrointestinal : Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, inflammatory lesions (with monilial overgrowth) in the anogenital region and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development [See Warnings and Precautions (5.1)] . Esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline-class. Most of these patients took medications immediately before going to bed [see Dosage and Administration (2.1)]. Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, and erythema multiforme have been reported. Photosensitivity is discussed above [see Warnings and Precautions (5.3)]. Renal: Rise in BUN has been reported and is apparently dose-related [see Warnings and Precautions (5.8)]. Hypersensitivity reactions: Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus, and drug reaction with eosinophilia and systemic symptoms (DRESS). Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported. Intracranial Hypertension: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracycline [see Warnings and Precautions (5.6)]. Thyroid Gland Changes: When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function are known to occur.

4 CONTRAINDICATIONS The drug is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. Doxycycline hyclate delayed-release tablets are contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. (4)

11 DESCRIPTION Doxycycline hyclate delayed-release tablets, USP for oral administration, contain specially coated pellets of doxycycline hyclate, USP, a broad-spectrum antibacterial synthetically derived from oxytetracycline, in a delayed-release formulation for oral administration. The structural formula for doxycycline hyclate, USP is: with a molecular formula of C 22 H 24 N 2 O 8 , HCl, ½ C 2 H 6 O, ½ H 2 O 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-6-methyl-1,11-deoxonaphthacene-2-carboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate, USP is a yellow to light yellow powder, freely soluble in water and in methanol; sparingly soluble in alcohol; practically insoluble in chloroform and in ether. It dissolves in aqueous 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: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, sodium chloride, povidone (K-30), hypromellose, talc, hypromellose phthalate, triethyl citrate, polyethylene glycol 6000, corn starch, lactose anhydrous, low substituted hydroxypropyl cellulose, crospovidone, colloidal silicon dioxide and magnesium stearate. This drug product meets USP Dissolution Test 5. doxycycline-structure.jpg

2 DOSAGE AND ADMINISTRATION • Adults: o The usual dosage is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg daily. (2.1) o In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. (2.1) • Pediatric Patients: o For all pediatric patients weighing less than 45 kg with severe or life -threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dose 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. (2.1) o For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dose 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 two doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. (2.1) 2.1 Usual Dosage and Administration The usual dosage and frequency of administration of doxycycline differs from that of the other tetracyclines. Exceeding the recommended dosage may result in an increased incidence of side effects. Adults: The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours), followed by a maintenance dose of 100 mg daily. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. Pediatric patients: For all pediatric patients weighing less than 45 kg with severe or life threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage of doxycycline is 2.2 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose [see Warnings and Precautions (5.1)]. For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of doxycycline is 4.4 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline-class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)]. If gastric irritation occurs, doxycycline may be given with food or milk [see Clinical Pharmacology (12)]. When used in streptococcal infections, therapy should be continued for 10 days. Uncomplicated urethral, endocervical, or rectal infection caused by Chlamydia trachomatis : 100 mg by mouth twice a day for 7 days. As an alternate dosing regimen for uncomplicated urethral or endocervical infection caused by Chlamydia trachomatis , administer 200 mg by mouth once-a-day for 7 days. Uncomplicated gonococcal infections in adults (except anorectal infections in men): 100 mg, by mouth, twice-a-day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose. Nongonococcal urethritis (NGU) caused by U. urealyticum : 100 mg by mouth twice-a-day for 7 days. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 2 weeks. Syphilis of more than one year’s duration: Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice-a-day for 4 weeks. Acute epididymo-orchitis caused by C. trachomatis : 100 mg, by mouth, twice-a-day for at least 10 days. 2.2 For Prophylaxis of Malaria For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1 or 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area. 2.3 Inhalational Anthrax (post-exposure) Adults: 100 mg, of doxycycline, by mouth, twice-a-day for 60 days. Children: weighing less than 45 kg, 2.2 mg/kg of body weight, by mouth, twice-a-day for 60 days. Children weighing 45 kg or more should receive the adult dose. 2.4 Sprinkling the Tablet Over Applesauce Doxycycline hyclate delayed-release tablets may also be administered by carefully breaking up the tablet and sprinkling the tablet contents (delayed-release pellets) on a spoonful of applesauce. The delayed-release pellets must not be crushed or damaged when breaking up the tablet. Any loss of pellets in the transfer would prevent using the dose. The applesauce/doxycycline hyclate delayed-release tablets mixture should be swallowed immediately without chewing and may be followed by a glass of water if desired. The applesauce should not be hot, and it should be soft enough to be swallowed without chewing. In the event that a prepared dose of applesauce/doxycycline hyclate delayed-release tablets cannot be taken immediately, the mixture should be discarded and not stored for later use.

1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate delayed-release tablets and other antibacterial drugs, doxycycline hyclate delayed-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Doxycycline is a tetracycline-class antibacterial indicated in the following conditions or disease. Doxycycline hyclate delayed-release tablets are a tetracycline-class drug indicated for: • Rickettsial infections (1.1) • Sexually transmitted infections (1.2) • Respiratory tract infections (1.3) • Specific bacterial infections (1.4) • Ophthalmic infections (1.5) • Anthrax, including inhalational anthrax (post-exposure) (1.6) • Alternative treatment for selected infections when penicillin is contraindicated (1.7) • Adjunctive therapy in acute intestinal amebiasis and severe acne (1.8) • Prophylaxis of malaria (1.9) To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate delayed-release tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1) 1.1 Rickettsial Infections Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae . 1.2 Sexually Transmitted Infections Uncomplicated urethral, endocervical or rectal infections caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum. Lymphogranuloma venereum caused by Chlamydia trachomatis. Granuloma inguinale caused by Klebsiella granulomatis. Uncomplicated gonorrhea caused by Neisseria gonorrhoeae. Chancroid caused by Haemophilus ducreyi. 1.3 Respiratory Tract Infections Respiratory tract infections caused by Mycoplasma pneumoniae. Psittacosis (ornithosis) caused by Chlamydophila psittaci. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Respiratory tract infections caused by Haemophilus influenzae . Respiratory tract infections caused by Klebsiella species. Upper respiratory infections caused by Streptococcus pneumonia. 1.4 Specific Bacterial Infections Relapsing fever due to Borrelia recurrentis . Plague due to Yersinia pestis. Tularemia due to Francisella tularensis. Cholera caused by Vibrio cholerae. Campylobacter fetus infections caused by Campylobacter fetus. Brucellosis due to Brucella species (in conjunction with streptomycin). Bartonellosis due to Bartonella bacilliformis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella species Acinetobacter species Urinary tract infections caused by Klebsiella species. 1.5 Ophthalmic Infections Trachoma caused by Chlamydia trachomatis , although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis . 1.6 Anthrax including Inhalational Anthrax (post-exposure) Anthrax due to Bacillus anthracis , including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis . 1.7 Alternative Treatment for Selected Infections when Penicillin is Contraindicated When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Syphilis caused by Treponema pallidum. Yaws caused by Treponema pallidum subspecies pertenue . Vincent’s infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii . Infections caused by Clostridium species. 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy. 1.9 Prophylaxis of Malaria Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (less than 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains [see Dosage and Administration (2.2) and Patient Counseling Information (17)].

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.

7 DRUG INTERACTIONS Patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage (7.1) Avoid co-administration of tetracyclines with penicillin (7.2) Absorption of tetracyclines, including doxycycline hyclate delayed-release tablets, is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations (7.3) Concurrent use of tetracyclines, including doxycycline hyclate delayed-release tablets, may render oral contraceptives less effective (7.4) Barbiturates, carbamazepine and phenytoin decrease the half-life of doxycycline (7.5) 7.1 Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 7.2 Penicillin Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. 7.3 Antacids and Iron Preparations Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. 7.4 Oral Contraceptives Concurrent use of tetracycline may render oral contraceptives less effective. 7.5 Barbiturates and Anti-epileptics Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. 7.6 Penthrane The concurrent use of tetracycline and Penthrane ® (methoxyflurane) has been reported to result in fatal renal toxicity. 7.7 Drug/Laboratory Test Interactions False elevations of urinary catecholamines may occur due to interference with the fluorescence test.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Doxycycline is an antibacterial drug [see Microbiology (12.4)]. 12.3 Pharmacokinetics Following single and multiple-dose administration of doxycycline hyclate delayed-release tablets, 200 mg to adult volunteers, average peak plasma doxycycline concentration (C max ) was 4.6 mcg/mL and 6.3 mcg/mL, respectively with median t max of 3 hours; the corresponding mean plasma concentration values 24 hours after single and multiple doses were 1.5 mcg/mL and 2.3 mcg/mL, respectively. Absorption Doxycycline is virtually completely absorbed after oral administration. Effect of Food The mean C max and AUC 0-∞ of doxycycline are 24% and 13% lower, respectively, following single dose administration of doxycycline hyclate delayed-release tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean C max of doxycycline is 19% lower and the AUC 0-∞ is unchanged following single dose administration of doxycycline hyclate delayed-release tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown. Doxycycline bioavailability from doxycycline hyclate delayed-release tablets, 200 mg was not affected by food, but the incidence of nausea was higher in fasted subjects. The 200 mg tablets may be administered without regard to meals. When doxycycline hyclate delayed-release tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly. Elimination Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1 to 5%/72 hours in individuals with a creatinine clearance below 10 mL/min. Specific Populations Patients with Renal Impairment Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life. Pediatric Patients Population pharmacokinetic analysis of sparse concentration-time data of doxycycline. following standard of care intravenous and oral dosing in 44 children (2 to18 years of age) showed that allometrically-scaled clearance of doxycycline in children ≥2 to ≤8 years of age (median [range] 3.58 [2.27 to 10.82] L/h/70 kg, N=11) did not differ significantly from children >8 to 18 years of age (3.27 [1.11 to 8.12] L/h/70 kg, N=33). For pediatric patients weighing ≤45 kg, body weight normalized doxycycline CL in those ≥2 to ≤8 years of age (median [range] 0.071 [0.041 to 0.202] L/kg/h, N=l0) did not differ significantly from those >8 to 18 years of age (0.081 [0.035 to 0.126] L/kg/h, N=8). In pediatric patients weighing >45 kg no clinically significant differences in body weight normalized doxycycline CL were observed between those ≥2 to ≤8 years (0.05 L/kg/h, N=l) and those >8 years of age (0.044 [0.014 to 0.121] L/kg/h, N=25). No clinically significant difference in CL differences between oral and IV were observed in the small cohort of pediatric patients who received the oral (N=l9) or IV (N=21) formulation alone. 12.4 Microbiology Mechanism of Action Doxycycline inhibits bacterial protein synthesis by binding to the 30S ribosomal subunit. Doxycycline has bacteriostatic activity against a broad range of Gram-positive and Gram-negative bacteria. Resistance Cross-resistance between tetracyclines is common. Antimicrobial Activity Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1)]. Gram-Negative Bacteria Acinetobacter species Bartonella bacilliformis Brucella species Campylobacter fetus Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella species Neisseria gonorrhoeae Shigella species Vibrio cholerae Yersinia pestis Gram-Positive Bacteria Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Anaerobic Bacteria Clostridium species Fusobacterium fusiforme Propionibacterium acnes Other Bacteria Norcardiae and other aerobic Actinomyces species Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum subspecies pertenue Ureaplasma urealyticum Parasites Balantidium coli Entamoeba species Plasmodium falciparum * * Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum . The precise mechanism of action of the drug is not known. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: http://www.fda.gov/STIC.

12.1 Mechanism of Action Doxycycline is an antibacterial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics Following single and multiple-dose administration of doxycycline hyclate delayed-release tablets, 200 mg to adult volunteers, average peak plasma doxycycline concentration (C max ) was 4.6 mcg/mL and 6.3 mcg/mL, respectively with median t max of 3 hours; the corresponding mean plasma concentration values 24 hours after single and multiple doses were 1.5 mcg/mL and 2.3 mcg/mL, respectively. Absorption Doxycycline is virtually completely absorbed after oral administration. Effect of Food The mean C max and AUC 0-∞ of doxycycline are 24% and 13% lower, respectively, following single dose administration of doxycycline hyclate delayed-release tablets, 100 mg with a high fat meal (including milk) compared to fasted conditions. The mean C max of doxycycline is 19% lower and the AUC 0-∞ is unchanged following single dose administration of doxycycline hyclate delayed-release tablets, 150 mg with a high fat meal (including milk) compared to fasted conditions. The clinical significance of these decreases is unknown. Doxycycline bioavailability from doxycycline hyclate delayed-release tablets, 200 mg was not affected by food, but the incidence of nausea was higher in fasted subjects. The 200 mg tablets may be administered without regard to meals. When doxycycline hyclate delayed-release tablets are sprinkled over applesauce and taken with or without water, the extent of doxycycline absorption is unchanged, but the rate of absorption is increased slightly. Elimination Tetracyclines are concentrated in bile by the liver and excreted in the urine and feces at high concentrations and in a biologically active form. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with a creatinine clearance of about 75 mL/min. This percentage may fall as low as 1 to 5%/72 hours in individuals with a creatinine clearance below 10 mL/min. Specific Populations Patients with Renal Impairment Studies have shown no significant difference in the serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter the serum half-life. Pediatric Patients Population pharmacokinetic analysis of sparse concentration-time data of doxycycline. following standard of care intravenous and oral dosing in 44 children (2 to18 years of age) showed that allometrically-scaled clearance of doxycycline in children ≥2 to ≤8 years of age (median [range] 3.58 [2.27 to 10.82] L/h/70 kg, N=11) did not differ significantly from children >8 to 18 years of age (3.27 [1.11 to 8.12] L/h/70 kg, N=33). For pediatric patients weighing ≤45 kg, body weight normalized doxycycline CL in those ≥2 to ≤8 years of age (median [range] 0.071 [0.041 to 0.202] L/kg/h, N=l0) did not differ significantly from those >8 to 18 years of age (0.081 [0.035 to 0.126] L/kg/h, N=8). In pediatric patients weighing >45 kg no clinically significant differences in body weight normalized doxycycline CL were observed between those ≥2 to ≤8 years (0.05 L/kg/h, N=l) and those >8 years of age (0.044 [0.014 to 0.121] L/kg/h, N=25). No clinically significant difference in CL differences between oral and IV were observed in the small cohort of pediatric patients who received the oral (N=l9) or IV (N=21) formulation alone.

20230410

2

3 DOSAGE FORMS AND STRENGTHS Doxycycline hyclate delayed-release tablets USP, 75 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L241” on one side and score line on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 75 mg of doxycycline. Doxycycline hyclate delayed-release tablets USP, 100 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L242” on one side and score line on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 100 mg of doxycycline. Doxycycline hyclate delayed-release tablets USP, 150 mg having functional scoring are white, rectangular tablets containing yellow specks. Tablets have two parallel score lines on both side, debossed with “2|4|3” on one side and “|L|” on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 150 mg of doxycycline. Doxycycline hyclate delayed-release tablets USP, 200 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L594” on one side and score line on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 200 mg of doxycycline. Tablets having functional scoring: 75 mg, 100 mg, 150 mg and 200 mg (3)

Doxycycline Hyclate Doxycycline Hyclate DOXYCYCLINE HYCLATE DOXYCYCLINE ANHYDROUS MICROCRYSTALLINE CELLULOSE LACTOSE MONOHYDRATE CROSCARMELLOSE SODIUM SODIUM CHLORIDE POVIDONE K30 HYPROMELLOSE, UNSPECIFIED TALC TRIETHYL CITRATE POLYETHYLENE GLYCOL 6000 HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED CROSPOVIDONE SILICON DIOXIDE STARCH, CORN HYPROMELLOSE PHTHALATE (24% PHTHALATE, 55 CST) MAGNESIUM STEARATE ANHYDROUS LACTOSE containing yellow specks L241 Doxycycline Hyclate Doxycycline Hyclate DOXYCYCLINE HYCLATE DOXYCYCLINE ANHYDROUS MICROCRYSTALLINE CELLULOSE LACTOSE MONOHYDRATE CROSCARMELLOSE SODIUM SODIUM CHLORIDE POVIDONE K30 HYPROMELLOSE, UNSPECIFIED TALC TRIETHYL CITRATE POLYETHYLENE GLYCOL 6000 HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED CROSPOVIDONE SILICON DIOXIDE STARCH, CORN HYPROMELLOSE PHTHALATE (24% PHTHALATE, 55 CST) MAGNESIUM STEARATE ANHYDROUS LACTOSE containing yellow specks L242 Doxycycline Hyclate Doxycycline Hyclate DOXYCYCLINE HYCLATE DOXYCYCLINE ANHYDROUS MICROCRYSTALLINE CELLULOSE CROSCARMELLOSE SODIUM SODIUM CHLORIDE POVIDONE K30 HYPROMELLOSE, UNSPECIFIED TALC TRIETHYL CITRATE POLYETHYLENE GLYCOL 6000 HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED CROSPOVIDONE SILICON DIOXIDE STARCH, CORN HYPROMELLOSE PHTHALATE (24% PHTHALATE, 55 CST) MAGNESIUM STEARATE ANHYDROUS LACTOSE LACTOSE MONOHYDRATE containing yellow specks 2;4;3;L Doxycycline Hyclate Doxycycline Hyclate DOXYCYCLINE HYCLATE DOXYCYCLINE ANHYDROUS MICROCRYSTALLINE CELLULOSE LACTOSE MONOHYDRATE CROSCARMELLOSE SODIUM SODIUM CHLORIDE POVIDONE K30 HYPROMELLOSE, UNSPECIFIED TALC TRIETHYL CITRATE POLYETHYLENE GLYCOL 6000 HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED CROSPOVIDONE SILICON DIOXIDE STARCH, CORN HYPROMELLOSE PHTHALATE (24% PHTHALATE, 55 CST) MAGNESIUM STEARATE ANHYDROUS LACTOSE containing yellow specks L594

13.2 Animal Toxicology and/or Pharmacology Hyperpigmentation of the thyroid has been produced by members of the tetracycline- class in the following species: in rats by oxytetracycline, doxycycline, tetracycline 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. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterials, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterials (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterials, oxytetracycline (adrenal and pituitary tumors) and minocycline (thyroid tumors). Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterials (tetracycline, oxytetracycline). Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied. 13.2 Animal Toxicology and/or Pharmacology Hyperpigmentation of the thyroid has been produced by members of the tetracycline- class in the following species: in rats by oxytetracycline, doxycycline, tetracycline 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. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.

ANDA213075

Doxycycline Hyclate

Doxycycline Hyclate

46708-481

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-75 mg NDC 46708-481-60 Doxycycline Hyclate Delayed-Release Tablets, USP 75 mg Do not chew or crush tablets. Rx only 60 Tablets Alembic doxycycline-75mg.jpg

17 PATIENT COUNSELING INFORMATION Patients taking doxycycline for malaria prophylaxis should be advised: • that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. • to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (for example, staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). • that doxycycline prophylaxis: should begin 1 to 2 days before travel to the malarious area, should be continued daily while in the malarious area and after leaving the malarious area, should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area, should not exceed 4 months. All patients taking doxycycline should be advised: • to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (for example, skin eruptions, etc.) occurs. Sunscreen or sunblock should be considered [see Warnings and Precautions (5.3)]. • to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration [see Adverse Reactions (6.1)]. • that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk [see Drug Interactions (7.3)]. • that the absorption of tetracyclines is reduced when taken with antacids containing aluminum, calcium or magnesium, bismuth subsalicylate, and iron-containing preparations [see Drug Interactions (7.3)]. • that the use of doxycycline might increase the incidence of vaginal candidiasis. Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of antibacterial. If this occurs, patients should contact their physician as soon as possible. Patients should be counseled that antibacterial drugs including doxycycline hyclate delayed-release tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When doxycycline hyclate delayed-release tablets is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Doxycycline hyclate delayed-release tablets or other antibacterial drugs in the future. 17.1 Instructions for Breaking the 150 mg Doxycycline Hyclate Delayed-Release 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 tablet is held between the thumbs and index fingers close to the appropriate score line. Then, with the score line facing the patient, enough pressure is applied to snap the tablet segments apart (segments that do not break along the score line should not be used). doxycycline-full-150mg tablet.jpg doxycycline-two-third tablet.jpg doxycycline-one-third tablet.jpg

14 CLINICAL STUDIES This was a randomized, double-blind, active-controlled, multicenter trial which enrolled 495 subjects, between 19 to 45 years of age with a confirmed diagnosis of urogenital C. trachomatis infection less than 14 days prior to enrollment, or partner(s) of a subject with a known positive test for urogenital C. trachomatis infection. The primary purpose of this study was to evaluate the efficacy and safety of doxycycline hyclate delayed-release tablets, 200 mg once daily versus doxycycline hyclate capsules, 100 mg twice daily for seven days for the treatment of uncomplicated urogenital C. trachomatis infection. The primary efficacy objective was to demonstrate non-inferiority of the doxycycline hyclate delayed-release tablets, 200 mg once daily treatment regimen versus the doxycycline 100 mg twice daily treatment regimen for the indication using a negative nucleic acid amplification test (NAAT) at the test of cure visit (day 28) in the mITT population (subjects who were positive at baseline and took at least one day of study drug). Table 2: Prim ary Efficacy Outcome – Microbiological Cure of C.trachomatis at Day 28 mITT Population Doxycycline Hyclate Delayed-Release Tablets, 200 mg once daily Cure Rate (%) Doxycycline Hyclate Capsules, 100 mg twice daily Cure Rate (%) Difference (%) N 188 190 Microbiological Cure, n (%) 163 (86.7) 171 (90) -3.3% 95% Confidence Interval for Cure Rate -10.3, 3.7

15 REFERENCES Friedman JM, Polifka JE. Teratogenic Effects of Drug s. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000:149-195. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317. Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); [Last Revision Date 2015 March 10; cited 2016 Jan]. Doxycycline; LactMed Record Number: 100; [about 3 screens]. Available from: http://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm.

8.5 Geriatric Use Clinical studies of doxycycline hyclate delayed-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Doxycycline hyclate delayed-release tablets 75 mg contain 4.7 mg (0.204 mEq) of sodium. Doxycycline hyclate delayed-release tablets 100 mg contain 6.3 mg (0.274 mEq) of sodium. Doxycycline hyclate delayed-release tablets 150 mg contain 9.4 mg (0.409 mEq) of sodium. Doxycycline hyclate delayed-release tablets 200 mg contain 12.6 mg (0.548 mEq) of sodium.

8.4 Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline hyclate delayed-release tablets in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly, when there are no alternative therapies [see Warnings and Precautions (5.1, 5.6) and Dosage and Administration (2.1, 2.3)].

8.1 Pregnancy Teratogenic Effects . Pregnancy Category D: Risk Summary There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1 Data Human Data A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.3%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (that is, in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases. 2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age. 3 Nonteratogenic effects: [see Warnings and Precautions (5.1, 5.6)].

8 USE IN SPECIFIC POPULATIONS Tetracycline-class drugs can cause fetal harm when administered to a pregnant woman, but data for doxycycline are limited. (5.6, 8.1) Tetracyclines are excreted in human milk; however, the extent of absorption of doxycycline in the breastfed infant is not known. Doxycycline hyclate delayed-release tablets use during nursing should be avoided if possible. (8.2) 8.1 Pregnancy Teratogenic Effects . Pregnancy Category D: Risk Summary There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for the treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1 Data Human Data A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.3%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (that is, in the second and third months of gestation), with the exception of a marginal relationship with neural tube defect based on only two-exposed cases. 2 A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of age. 3 Nonteratogenic effects: [see Warnings and Precautions (5.1, 5.6)]. 8.2 Lactation Risk Summary Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated. The effects of prolonged exposure to doxycycline in breast milk are unknown 4 . Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.1, 5.6)]. 8.4 Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use doxycycline hyclate delayed-release tablets in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly, when there are no alternative therapies [see Warnings and Precautions (5.1, 5.6) and Dosage and Administration (2.1, 2.3)]. 8.5 Geriatric Use Clinical studies of doxycycline hyclate delayed-release tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Doxycycline hyclate delayed-release tablets 75 mg contain 4.7 mg (0.204 mEq) of sodium. Doxycycline hyclate delayed-release tablets 100 mg contain 6.3 mg (0.274 mEq) of sodium. Doxycycline hyclate delayed-release tablets 150 mg contain 9.4 mg (0.409 mEq) of sodium. Doxycycline hyclate delayed-release tablets 200 mg contain 12.6 mg (0.548 mEq) of sodium.

16 HOW SUPPLIED/STORAGE AND HANDLING Doxycycline hyclate delayed-release tablets USP, 75 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L241” on one side and score line on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 75 mg of doxycycline. NDC 46708-481-60 bottle of 60 tablets NDC 46708-481-31 bottle of 100 tablets NDC 46708-481-91 bottle of 1000 tablets Doxycycline hyclate delayed-release tablets USP, 100 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L242” on one side and score line on the other side.Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 100 mg of doxycycline. NDC 46708-482-60 bottle of 60 tablets NDC 46708-482-31 bottle of 100 tablets NDC 46708-482-91 bottle of 1000 tablets Doxycycline hyclate delayed-release tablets USP, 150 mg having functional scoring are white, rectangular tablets containing yellow specks. Tablets have two parallel score lines on both side, debossed with “2|4|3” on one side and “|L|” on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 150 mg of doxycycline. NDC 46708-483-30 bottle of 30 tablets NDC 46708-483-60 bottle of 60 tablets NDC 46708-483-31 bottle of 100 tablets NDC 46708-483-71 bottle of 500 tablets Doxycycline hyclate delayed-release tablets USP, 200 mg having functional scoring are white, oval tablets containing yellow specks, debossed with “L594” on one side and score line on the other side. Each tablet contains specially coated pellets of doxycycline hyclate USP equivalent to 200 mg of doxycycline. NDC 46708-484-30 bottle of 30 tablets NDC 46708-484-60 bottle of 60 tablets NDC 46708-484-31 bottle of 100 tablets NDC 46708-484-71 bottle of 500 tablets Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container (USP).