DORYX MPC

6 ADVERSE REACTIONS 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 their frequency or establish 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. 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. 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. 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 Mayne Pharma at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS DORYX MPC is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. Doxycycline is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines. ( 4 )

11 DESCRIPTION Doryx MPC (doxycycline hyclate delayed-release tablets) for oral use, contain doxycycline hyclate, a tetracycline class drug synthetically derived from oxytetracycline, in a delayed-release formulation consisting of pellets with a modified polymer enteric coat that has increased acid resistance. The structural formula for doxycycline hyclate 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 name 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 is a yellow crystalline powder soluble in water and in solutions of alkali hydroxides and carbonates. Doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Each tablet contains doxycycline 60 mg (equivalent to doxycycline hyclate 69.4 mg) or doxycycline 120 mg (equivalent to doxycycline hyclate 138.8 mg). Inactive ingredients in the tablet formulation are: lactose monohydrate; microcrystalline cellulose; sodium lauryl sulfate; sodium chloride; talc; anhydrous lactose; corn starch; crospovidone; magnesium stearate; cellulosic polymer coating. Each DORYX MPC 60 mg Tablet contains 3.6 mg (0.157 mEq) of sodium. Each DORYX MPC 120 mg Tablet contains 7.2 mg (0.313 mEq) of sodium. Chemical Structure

2 DOSAGE AND ADMINISTRATION Important Dosage and Administration Instructions: DORYX MPC is not substitutable on a mg per mg basis with other oral doxycyclines. ( 2.1 ) Do not chew or crush tablets. ( 2.1 ) Dosage in Adult Patients The usual dosage of DORYX MPC is 240 mg on the first day of treatment (administered 120 mg every 12 hours) followed by a maintenance dose of 120 mg daily. ( 2.3 ) In the management of more severe infections (particularly chronic infections of the urinary tract), 120 mg every 12 hours is recommended. ( 2.3 ) Dosage in 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 DORYX MPC is 2.6 mg per kg of body weight administered every 12 hours. Pediatric patients weighing 45 kg or more should receive the adult dose. ( 2.4 ) For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule of DORYX MPC is 5.3 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.6 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. ( 2.4 ) See Full Prescribing Information for additional indication specific dosage information and important administration instructions for DORYX MPC. ( 2.2 , 2.5 , 2.6 ) 2.1 Important Dosage and Administration Instructions DORYX MPC is not substitutable on a mg per mg basis with other oral doxycyclines. To avoid prescribing errors, do not substitute DORYX MPC for other oral doxycyclines on a mg per mg basis because of differing bioavailability. Do not chew or crush tablets. The recommended dosage, frequency of administration and weight-based dosage recommendations of DORYX MPC differ from that of the other tetracyclines [ see Dosage and Administration (2.2 , 2.3 , 2.4) ] . Exceeding the recommended dosage may result in an increased incidence of adverse reactions. Administer DORYX MPC with an adequate amount of fluid to wash down the drug and reduce the risk of esophageal irritation and ulceration [ see Adverse Reactions (6) ]. If gastric irritation occurs, DORYX MPC may be given with food or milk [see Clinical Pharmacology (12.3) ] . 2.2 Switching from DORYX to DORYX MPC When switching from DORYX to DORYX MPC : A 60 mg dose of DORYX MPC will replace a 50 mg dose of DORYX A 120 mg dose of DORYX MPC will replace a 100 mg dose of DORYX 2.3 Dosage in Adult Patients The usual dosage of DORYX MPC is 240 mg on the first day of treatment (administered 120 mg every 12 hours) followed by a maintenance dose of 120 mg daily. The maintenance dose may be administered as a single dose or as 60 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 120 mg every 12 hours is recommended. For certain selected specific indications, the recommended duration or dosage and duration of DORYX MPC in adult patients are as follows: Streptococcal infections, therapy should be continued for 10 days. Uncomplicated urethral, endocervical, or rectal infection caused by C. trachomatis : 120 mg, by mouth, twice-a-day for 7 days. Uncomplicated gonococcal infections in adults (except anorectal infections in men): 120 mg, by mouth, twice-a-day for 7 days. As an alternate single visit dose, administer 360 mg followed in one hour by a second 360 mg dose. Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum : 120 mg, by mouth, twice-a-day for 7 days. Syphilis – early: Patients who are allergic to penicillin should be treated with doxycycline 120 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 120 mg, by mouth, twice-a-day for 4 weeks. Acute epididymo-orchitis caused by N. gonorrhoeae : 120 mg, by mouth, twice-a-day for at least 10 days. Acute epididymo-orchitis caused by C. trachomatis : 120 mg, by mouth, twice-a-day for at least 10 days 2.4 Dosage in 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 DORYX MPC is 2.6 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 DORYX MPC is 5.3 mg per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.6 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. 2.5 Dosage for Prophylaxis of Malaria For adults, the recommended dose of DORYX MPC is 120 mg daily. For pediatric patients 8 years of age and older, the recommended dosage of DORYX MPC is 2.4 mg per kg of body weight administered once daily. Pediatric patients weighing 45 kg or more should receive 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. 2.6 Dosage for Inhalational Anthrax (Post-Exposure) For adults, the recommended dosage is 120 mg, of DORYX MPC, by mouth, twice-a-day for 60 days. For pediatric patients weighing less than 45 kg, the recommended dosage of DORYX MPC is 2.6 mg per kg of body weight, by mouth, twice-a-day for 60 days. Pediatric patients weighing 45 kg or more should receive the adult dose.

1 INDICATIONS AND USAGE DORYX MPC is 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 ) Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of doxycycline hyclate and other antibacterial drugs, DORYX MPC Tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. ( 1.10 ) 1.1 Rickettsial Infections DORYX MPC is indicated for treatment of Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae . 1.2 Sexually Transmitted Infections DORYX MPC is indicated for treatment of the following sexually transmitted infections: Uncomplicated urethral, endocervical or rectal infections in adults 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 DORYX MPC is indicated for treatment of the following respiratory tract infections: Respiratory tract infections caused by Mycoplasma pneumoniae . Psittacosis (ornithosis) caused by Chlamydophila psittaci . Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following microorganisms, when bacteriological testing indicates appropriate susceptibility to the drug: – Respiratory tract infections caused by Haemophilus influenzae . – Respiratory tract infections caused by Klebsiella species. – Upper respiratory infections caused by Streptococcus pneumoniae . 1.4 Specific Bacterial Infections DORYX MPC is indicated for treatment of the following 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. DORYX MPC 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 DORYX MPC is indicated for treatment of the following 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) DORYX MPC is indicated for treatment of 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 DORYX MPC is indicated as an alternative treatment for the following selected infections when penicillin is contraindicated: 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. 1.8 Adjunctive Therapy for Acute Intestinal Amebiasis and Severe Acne In acute intestinal amebiasis, DORYX MPC may be a useful adjunct to amebicides. In severe acne, DORYX MPC may be useful adjunctive therapy. 1.9 Prophylaxis of Malaria DORYX MPC 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) ]. 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORYX MPC and other antibacterial drugs, DORYX MPC 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.

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 DORYX MPC is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate and iron-containing preparations ( 7.3 ) Concurrent use of tetracyclines, including DORYX MPC 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, including DORYX MPC in conjunction with penicillin. 7.3 Antacids and Iron Preparations Absorption of tetracyclines including DORYX MPC is impaired by antacids containing aluminum, calcium, or magnesium, bismuth subsalicylate, and iron-containing preparations. 7.4 Oral Contraceptives Concurrent use of tetracyclines, including DORYX MPC 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 a tetracycline-class antimicrobial drug [ see Microbiology (12.4) ]. 12.3 Pharmacokinetics Effect of Food Following administration of a single dose of DORYX MPC under fasting conditions, the AUC inf and C max were 26.7 mcg-h/mL and 1.6 mcg/mL, respectively. The Tmax was 2.8 hours. In a single-dose study to evaluate the relative bioavailability in healthy adult subjects under fasted conditions, DORYX MPC 120 mg Tablets were found to be bioequivalent to Doryx 100 mg Tablets. When a single dose of DORYX MPC 120 mg Tablet was administered with a standardized high-fat high-calorie meal, (937kcal consisting of approximately 55% fat, 30% carbohydrate and 15% protein), the C max was approximately 30% lower, but there was no significant difference in the AUC inf compared to administration under fasting conditions [see Dosage and Administration (2.1) ] . Absorption Doxycycline is virtually completely absorbed after oral administration. 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 1-5%/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 (2-18 years of age) showed that allometrically-scaled clearance of doxycycline in children ≥2 to ≤8 years of age (median [range] 3.58 [2.27-10.82] L/h/70 kg, N=11) did not differ significantly from children >8 to 18 years of age (3.27 [1.11-8.12] 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 [0.041-0.202] L/kg/h, N=l0) did not differ significantly from those >8 to 18 years of age (0.081 [0.035-0.126] 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 (0.050 L/kg/h, N=l) and those >8 years of age (0.044 [0.014-0. 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 bacteria, 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 pneumonia 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: https://www.fda.gov/STIC.

12.1 Mechanism of Action Doxycycline is a tetracycline-class antimicrobial drug [ see Microbiology (12.4) ].

12.3 Pharmacokinetics Effect of Food Following administration of a single dose of DORYX MPC under fasting conditions, the AUC inf and C max were 26.7 mcg-h/mL and 1.6 mcg/mL, respectively. The Tmax was 2.8 hours. In a single-dose study to evaluate the relative bioavailability in healthy adult subjects under fasted conditions, DORYX MPC 120 mg Tablets were found to be bioequivalent to Doryx 100 mg Tablets. When a single dose of DORYX MPC 120 mg Tablet was administered with a standardized high-fat high-calorie meal, (937kcal consisting of approximately 55% fat, 30% carbohydrate and 15% protein), the C max was approximately 30% lower, but there was no significant difference in the AUC inf compared to administration under fasting conditions [see Dosage and Administration (2.1) ] . Absorption Doxycycline is virtually completely absorbed after oral administration. 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 1-5%/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 (2-18 years of age) showed that allometrically-scaled clearance of doxycycline in children ≥2 to ≤8 years of age (median [range] 3.58 [2.27-10.82] L/h/70 kg, N=11) did not differ significantly from children >8 to 18 years of age (3.27 [1.11-8.12] 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 [0.041-0.202] L/kg/h, N=l0) did not differ significantly from those >8 to 18 years of age (0.081 [0.035-0.126] 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 (0.050 L/kg/h, N=l) and those >8 years of age (0.044 [0.014-0. 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.

20230609

12

3 DOSAGE FORMS AND STRENGTHS DORYX MPC (doxycycline hyclate delayed-release tablets), 60 mg are white, oval tablets containing yellow pellets and debossed with "D6" on one face and plain on the other. Each tablet contains doxycycline 60 mg (equivalent to doxycycline hyclate 69.4 mg). DORYX MPC Delayed-Release Tablets 60 mg ( 3 )

DORYX MPC doxycycline hyclate Doxycycline Hyclate Doxycycline Anhydrous Lactose Monohydrate Microcrystalline Cellulose Sodium Lauryl Sulfate Sodium Chloride Talc Anhydrous Lactose Starch, Corn CROSPOVIDONE (120 .MU.M) Magnesium Stearate containing yellow pellets D;6 DORYX MPC Doxycycline Hyclate Doxycycline Hyclate Doxycycline Anhydrous Lactose Monohydrate Microcrystalline Cellulose Sodium Lauryl Sulfate Sodium Chloride Talc Anhydrous Lactose Starch, Corn CROSPOVIDONE (120 .MU.M) Magnesium Stearate containing yellow pellets D;C

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 antibiotics, 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 antibiotics, 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.

NDA050795

DORYX MPC

doxycycline hyclate

51862-560

HUMAN PRESCRIPTION DRUG

ORAL

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 bacteria, 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 pneumonia 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: https://www.fda.gov/STIC.

PRINCIPAL DISPLAY PANEL - 60 mg Tablet Bottle Label NDC 51862-560-12 Doryx ® MPC (Doxycycline Hyclate Delayed-Release Tablets) 60 mg Do not chew or crush tablets. Rx Only 120 Tablets mayne pharma PRINCIPAL DISPLAY PANEL - 60 mg Tablet Bottle Label

Distributed by: Mayne Pharma Raleigh, NC 27609 61596

17 PATIENT COUNSELING INFORMATION Advise patients taking DORYX MPC for malaria prophylaxis: 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. Advise all patients taking DORYX MPC: 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 DORYX MPC to reduce the risk of esophageal irritation and ulceration [ see Adverse Reactions (6) ] that the absorption of tetracyclines is reduced when taken with foods, especially those that contain calcium. [ see Drug Interactions (7.3) ] that if gastric irritation occurs, DORYX MPC may be given with food or milk [ see Clinical Pharmacology (12.3) ] 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. Advise patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterial drugs, 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 DORYX MPC should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When DORYX MPC 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 DORYX MPC or other antibacterial drugs in the future.

15 REFERENCES Friedman JM, Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS) . Baltimore, MD: The Johns Hopkins University Press: 2000: 149-195. The TERIS (Teratogen Information System) is available at: http://www.micromedexsolutions.com/ (cited: 2016 Jan). 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 DORYX MPC 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. DORYX MPC Tablets each contain less than 10 mg of sodium.

8.4 Pediatric Use Because of the effects of drugs of the tetracycline-class on tooth development and growth, use DORYX MPC 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 , 2.4) ].

8.1 Pregnancy Risk Summary There are no adequate 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 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 [ see Data ]. Clinical Considerations Embryo/Fetal Risk Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. [ see Warnings and Precautions (5.1 , 5.6) ]. 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 (0.30%) 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

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. DORYX MPC use during nursing should be avoided if possible. ( 8.2 ) 8.1 Pregnancy Risk Summary There are no adequate 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 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 [ see Data ]. Clinical Considerations Embryo/Fetal Risk Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. [ see Warnings and Precautions (5.1 , 5.6) ]. 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 (0.30%) 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 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 contraindicated. The effects of prolonged exposure to doxycycline on breast milk production and breast fed neonates, infants and children are unknown. 4 The developmental and health benefits of breast feeding should be considered along with the mother's clinical need for DORYX MPC and any potential adverse effects on the breast fed child from DORYX MPC or from the underlying maternal condition [ 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 DORYX MPC 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 , 2.4) ]. 8.5 Geriatric Use Clinical studies of DORYX MPC 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. DORYX MPC Tablets each contain less than 10 mg of sodium.

16 HOW SUPPLIED/STORAGE AND HANDLING DORYX MPC (doxycycline hyclate delayed-release tablets), 60 mg are white, oval tablets containing yellow pellets and debossed with "D6" on one face and plain on the other. Each tablet contains doxycycline 60 mg (equivalent to doxycycline hyclate 69.4 mg). The 60 mg tablet is supplied in bottles of 60 tablets (NDC 51862-560-60) and 120 tablets (NDC 51862-560-12). Store at 25° C (77° F); excursions permitted to 15°C to 30° C (59°F to 86° F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container (USP).

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