DOXYCYCLINE HYCLATE- doxycycline hyclate_powder, for solution

CLINICAL PHARMACOLOGY
Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form. Following a single 100 mg dose administered in a concentration of 0. 4 mg/mL in a one-hour infusion, normal adult volunteers averaged a peak of 2. 5 mcg/mL, while 200 mg of a concentration of 0. 4 mg/mL administered over two hours averaged a peak of 3. Excretion of doxycycline by the kidney is about 40 percent/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage of excretion may fall as low as 1 to 5 percent/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min). Studies have shown no significant difference in serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter this serum half-life of doxycycline. Population pharmacokinetic analysis of sparse concentration-time data of doxycycline following standard of care intravenous and oral dosing in 44 pediatric patients (2-18 years of age) showed that allometrically-scaled clearance (CL) of doxycycline in pediatric patients >=2 to <=8 years of age (median [range] 3. 82] L/h/70 kg, N=11) did not differ significantly from pediatric patients ˃8 to 18 years of age (3. 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. 202] L/kg/h, N=10) did not differ significantly from those ˃8 to 18 years of age (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 of age (0. 050 L/kg/h, N=1) and those ˃8 to 18 years of age (0. 121] L/kg/h, N=25). No clinically significant difference in CL between oral and IV dosing was observed in the small cohort of pediatric patients who received the oral (N=19) or IV (N=21) formulation alone. 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. Cross resistance with other tetracyclines is common. Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro INDICATIONS AND USAGE Acinetobacter Bartonella bacilliformis Brucella Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella Neisseria gonorrhoeae Shigella species Vibrio cholerae Campylobacter fetus Yersinia pestis Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae Clostridium Fusobacterium fusiforme Propionibacterium Nocardiae Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum pertenue Ureaplasma urealyticum Balantidium coli Entamoeba Plasmodium falciparum *Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum P. falciparum 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.
Microbiology
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. Cross resistance with other tetracyclines is common. Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro INDICATIONS AND USAGE.
Gram-Positive Bacteria
Bacillus anthracis Listeria monocytogenes Streptococcus pneumoniae
Anaerobic Bacteria
Clostridium Fusobacterium fusiforme Propionibacterium

Gram-Negative Bacteria
Acinetobacter Bartonella bacilliformis Brucella Enterobacter aerogenes Escherichia coli Francisella tularensis Haemophilus ducreyi Haemophilus influenzae Klebsiella granulomatis Klebsiella Neisseria gonorrhoeae Shigella species Vibrio cholerae Campylobacter fetus Yersinia pestis
INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Doxycycline for Injection, USP and other antibacterial drugs, Doxycycline for Injection, USP 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 for Injection, USP is indicated in infections caused by the following microorganisms: Rickettsiae (Rocky Mountain spotted fever, typhus fever, and the typhus group, Q fever, rickettsial pox and tick fevers). Mycoplasma pneumoniae Agents of psittacosis and ornithosis. Agents of lymphogranuloma venereum and granuloma inguinale. The spirochetal agent of relapsing fever ( Borrelia recurrentis The following gram-negative microorganisms: Haemophilus ducreyi Yersinia pestis. Francisella tularensis Bartonella bacilliformis Bacteroides Vibrio cholerae. Campylobacter fetus Brucella Because many strains of the following groups of microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Escherichia coli Enterobacter aerogenes Shigella Acinetobacter Haemophilus influenzae Klebsiella Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Streptococcus Up to 44 percent of strains of Streptococcus pyogenes Enterococcus faecalis For upper respiratory infections due to group A beta-hemolytic streptococci, penicillin is the usual drug of choice, including prophylaxis of rheumatic fever. Streptococcus pneumoniae Staphylococcus aureus Anthrax due to Bacillus anthracis Bacillus anthracis When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of infections due to: Neisseria gonorrhoeae N. meningitidis Treponema pallidum Treponema pertenue Listeria monocytogenes. Clostridium Fusobacterium fusiforme Actinomyces In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. Doxycycline is indicated in the treatment of trachoma, although the infectious agent is not always eliminated, as judged by immunofluorescence.

DOSAGE AND ADMINISTRATION
NOTE: The usual dosage and frequency of administration of Doxycycline for Injection (100 to 200 mg/day) differs from that of the other tetracyclines (1 to 2 g/day). Exceeding the recommended dosage may result in an increased incidence of side effects. Studies to date have indicated that doxycycline hyclate at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment. The usual dosage of doxycycline for injection is 200 mg on the first day of treatment administered in one or two infusions. Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions. In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days. In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day. Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time. Oral therapy should be instituted as soon as possible. Therapy must continue for a total of 60 days. For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e. , anthrax, Rocky Mountain spotted fever), the recommended dosage is 2. 2 mg/kg of body weight administered every 12 hours. Children weighing 45 kg or more should receive the adult dose (see WARNINGS PRECAUTIONS For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule is 4. 4 mg/kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2. 2 mg/kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. In the treatment of inhalational anthrax (post-exposure) the recommended dose is 2. 2 mg/kg of body weight, twice a day in children weighing less than 45 kg. The duration of infusion may vary with the dose (100 to 200 mg/day), but is usually one to four hours. A recommended minimum infusion time for 100 mg of a 0. 5 mg/mL solution is one hour. Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided. The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage. Intravenous solutions should not be injected intramuscularly or subcutaneously. Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue. To prepare a solution containing 10 mg/mL, the contents of the vial should be reconstituted with 10 mL (for the 100 mg/vial container) or 20 mL (for the 200 mg/vial container) of Sterile Water for Injection or any of the 10 intravenous infusion solutions listed below. Each 100 mg of doxycycline for injection (i. , withdraw entire solution from the 100 mg vial) is further diluted with 100 mL to 1,000 mL of the intravenous solutions listed below. Each 200 mg of doxycycline for injection (i. , withdraw entire solution from the 200 mg vial) is further diluted with 200 mL to 2,000 mL of the following intravenous solutions: Sodium Chloride Injection, USP 5% Dextrose Injection, USP Ringer''s Injection, USP Invert Sugar, 10% in Water Lactated Ringer''s Injection, USP Dextrose 5% in Lactated Ringer''s Normosol-M registered Normosol-R registered Plasma-Lyte registered Plasma-Lyte registered This will result in desired concentrations of 0. 1 to 1 mg/mL. Concentrations lower than 0. 1 mg/mL or higher than 1 mg/mL are not recommended. Doxycycline is stable for 48 hours in solution when diluted with Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to concentrations between 1 mg/mL and 0. 1 mg/mL and stored at 25°C. Doxycycline in these solutions is stable under fluorescent light for 48 hours, but must be protected from direct sunlight during storage and infusion. Reconstituted solutions (1 to 0. 1 mg/mL) may be stored up to 72 hours prior to start of infusion if refrigerated and protected from sunlight and artificial light. Infusion must then be completed within 12 hours. Solutions must be used within these time periods or discarded. Doxycycline, when diluted with Ringer''s Injection, USP, or Invert Sugar, 10% in Water, or Normosol-M registered registered registered registered When diluted with Lactated Ringer''s Injection, USP, or Dextrose 5% in Lactated Ringer''s, infusion of the solution (ca. 1 mg/mL) or lower concentrations (not less than 0. 1 mg/mL) must be completed within six hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. Solutions must be used within this time period or discarded. Solutions of doxycycline for injection, at a concentration of 10 mg/mL in Sterile Water for Injection, when frozen immediately after reconstitution are stable for eight weeks when stored at en dash20°C. If the product is warmed, care should be taken to avoid heating it after the thawing is complete. Once thawed the solution should not be refrozen.
Adults
The usual dosage of doxycycline for injection is 200 mg on the first day of treatment administered in one or two infusions. Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions. In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days. In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day. Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time. Oral therapy should be instituted as soon as possible. Therapy must continue for a total of 60 days.

ADVERSE REACTIONS
Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis and inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development (see WARNINGS Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, and fixed drug eruption have been reported. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (see WARNINGS Rise in BUN has been reported and is apparently dose related (see WARNINGS Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis and exacerbation of systemic lupus erythematosus, and drug reaction with eosinophilia and systemic symptoms (DRESS). Bulging fontanels in infants and intracranial hypertension in adults (see WARNINGS Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been reported. When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur. Depression, anxiety, suicidal ideation, insomnia, abnormal dreams, hallucination.
Gastrointestinal
Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis and inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Superficial discoloration of the adult permanent dentition, reversible upon drug discontinuation and professional dental cleaning has been reported. Permanent tooth discoloration and enamel hypoplasia may occur with drugs of the tetracycline class when used during tooth development (see WARNINGS
Skin
Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme, and fixed drug eruption have been reported. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (see WARNINGS
Immune
Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, 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. When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of thyroid glands. No abnormalities of thyroid function studies are known to occur.

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

Usage in Pregnancy
(See WARNINGS Doxycycline for Injection has not been studied in pregnant patients. It should not be used in pregnant women unless, in the judgment of the physician, it is essential for the welfare of the patient. Results of animal studies indicate that tetracycline cross the placenta, are found in fetal tissues and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy.
Usage in Children
The use of Doxycycline for Injection in children under 8 years is not recommended because safe conditions for its use have not been established. Because of the effects of drugs of the tetracycline-class on tooth development and growth, use of doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies (see WARNINGS DOSAGE AND ADMINISTRATION As with other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Tetracyclines are present in the milk of lactating women who are taking a drug in this class.
Pediatric Patients
For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage is 2.2 mg/kg of body weight administered every 12 hours. Children weighing 45 kg or more should receive the adult dose (see WARNINGS PRECAUTIONS For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg/kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used. In the treatment of inhalational anthrax (post-exposure) the recommended dose is 2.2 mg/kg of body weight, twice a day in children weighing less than 45 kg. Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time. Oral therapy should be instituted as soon as possible. Therapy must continue for a total of 60 days.

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and Penthrane registered Concurrent use of tetracycline may render oral contraceptives less effective.

Doxycycline is stable for 48 hours in solution when diluted with Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to concentrations between 1 mg/mL and 0.1 mg/mL and stored at 25°C. Doxycycline in these solutions is stable under fluorescent light for 48 hours, but must be protected from direct sunlight during storage and infusion. Reconstituted solutions (1 to 0.1 mg/mL) may be stored up to 72 hours prior to start of infusion if refrigerated and protected from sunlight and artificial light. Infusion must then be completed within 12 hours. Solutions must be used within these time periods or discarded. Doxycycline, when diluted with Ringer's Injection, USP, or Invert Sugar, 10% in Water, or Normosol-M registered registered registered registered When diluted with Lactated Ringer's Injection, USP, or Dextrose 5% in Lactated Ringer's, infusion of the solution (ca. 1 mg/mL) or lower concentrations (not less than 0.1 mg/mL) must be completed within six hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. Solutions must be used within this time period or discarded. Solutions of doxycycline for injection, at a concentration of 10 mg/mL in Sterile Water for Injection, when frozen immediately after reconstitution are stable for eight weeks when stored at en dash20°C. If the product is warmed, care should be taken to avoid heating it after the thawing is complete. Once thawed the solution should not be refrozen.

Other Bacteria
Nocardiae Actinomyces Borrelia recurrentis Chlamydophila psittaci Chlamydia trachomatis Mycoplasma pneumoniae Rickettsiae Treponema pallidum Treponema pallidum pertenue Ureaplasma urealyticum
Parasites
Balantidium coli Entamoeba Plasmodium falciparum *Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum P. falciparum
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.
WARNINGS
The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Use doxycycline in pediatric patients 8 years of age or less only when the potential benefits are expected to outweigh the risks in severe or life-threatening conditions (e.g., anthrax, Rocky Mountain spotted fever), particularly when there are no alternative therapies. Clostridium difficile C. difficile C. difficile C. difficile If CDAD is suspected or confirmed, ongoing use of antibacterial drugs not directed against C. difficile C. difficile Severe skin reactions, such as exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients receiving doxycycline. Fixed drug eruptions have occurred with doxycycline and have been associated with worsening severity upon subsequent administrations, including generalized bullous fixed drug eruption (see ADVERSE REACTIONS Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and doxycycline should be avoided because isotretinoin is also known to cause pseudotumor cerebri. Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light, should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema. The anti-anabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function.
Other
Bulging fontanels in infants and intracranial hypertension in adults (see WARNINGS
Preparation of Solution
To prepare a solution containing 10 mg/mL, the contents of the vial should be reconstituted with 10 mL (for the 100 mg/vial container) or 20 mL (for the 200 mg/vial container) of Sterile Water for Injection or any of the 10 intravenous infusion solutions listed below. Each 100 mg of doxycycline for injection (i.e., withdraw entire solution from the 100 mg vial) is further diluted with 100 mL to 1,000 mL of the intravenous solutions listed below. Each 200 mg of doxycycline for injection (i.e., withdraw entire solution from the 200 mg vial) is further diluted with 200 mL to 2,000 mL of the following intravenous solutions: Sodium Chloride Injection, USP 5% Dextrose Injection, USP Ringer''s Injection, USP Invert Sugar, 10% in Water Lactated Ringer''s Injection, USP Dextrose 5% in Lactated Ringer''s Normosol-M registered Normosol-R registered Plasma-Lyte registered Plasma-Lyte registered This will result in desired concentrations of 0.1 to 1 mg/mL. Concentrations lower than 0.1 mg/mL or higher than 1 mg/mL are not recommended.

Slate Run Pharmaceuticals, LLC

DOXYCYCLINE HYCLATE- doxycycline hyclate_powder, for solution Product manual source documgent