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DOXY 100- doxycycline injection, powder, lyophilized, for solution


  1. Doxycycline For Injection, Usp
  2. Description
  3. Clinical Pharmacology
  4. Indications And Usage
  5. Contraindications
  6. Warnings
  7. Precautions
  8. Adverse Reactions
  9. Dosage And Administration
  10. Preparation Of Solution
  11. How Supplied
  12. References
  13. Boxed Warning
  14. Description
  15. Indications & Usage
  16. Dosage & Administration
  17. Sample Package Label
  18. Description:
  19. Clinical Pharmacology:
  20. Indications And Usage:
  21. Contraindications:
  22. Warnings:
  23. Precautions:
  24. Adverse Reactions:
  25. Dosage And Administration:
  26. Preparation Of Solution:
  27. How Supplied:
  28. References:
  29. Doxy 100 Doxycycline For Injection, Usp
  30. Description:
  31. Clinical Pharmacology:
  32. Indications And Usage:
  33. Contraindications:
  34. Warnings:
  35. Precautions:
  36. Adverse Reactions:
  37. Dosage And Administration:
  38. Preparation Of Solution:
  39. How Supplied:
  40. Principal Display Panel Doxy 100 100 Mg Per Vial Tray Panel
  41. Principal Display Panel Doxy 100 100 Mg Per Vial Label

Doxycycline For Injection, Usp 

FOR IV INFUSION ONLY

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 bacteria.

Description 

Doxycycline for Injection, USP is a sterile, lyophilized powder prepared from a solution of doxycycline hyclate, ascorbic acid and mannitol in Water for Injection. Doxycycline hyclate is a broad spectrum antibiotic derived from oxytetracycline. It is meant for INTRAVENOUS use only after reconstitution. Doxycycline hyclate is a yellowish crystalline powder which is chemically designated 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-de monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. It has the following structural formula:

structure

Doxycycline hyclate is soluble in water and chars at 201 C without melting. The base doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum.

Each 100 mg vial contains: Doxycycline hyclate equivalent to 100 mg doxycycline; ascorbic acid 480 mg; mannitol 300 mg. pH of the reconstituted solution (10 mg/mL) is between 1.8 and 3.3.

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 3.6 mcg/mL.

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.

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. Cross resistance with other tetracyclines is common.

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).

Gram-Negative Bacteria

Acinetobacter species

Bartonella bacilliformis

Brucella species

Calymmatobacterium granulomatis

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

Gram-Positive Bacteria

Bacillus anthracis

Streptococcus pneumoniae

Anaerobes

Clostridium species

Fusobacterium fusiforme

Propionibacterium acnes

Other Bacteria

Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema 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 Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar).1,2,4 The MIC values should be interpreted according to the criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. Zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method.1,3,4 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 1.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method5. The MIC values obtained should be interpreted according to the criteria provided in Table 1.

Table1.jpg

Table1.jpg

A report of Susceptible (S) indicates that antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies interpretation. A report of Resistant (R) indicates that the pathogen is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site: other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3,4,5,6,7. Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria in Table 2 should be achieved.

Table2.jpg

Table2.jpg

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 (PPLO, Eaton Agent).
  • Agents of psittacosis and ornithosis.
  • Agents of lymphogranuloma venereum and granuloma inguinale.
  • The spirochetal agent of relapsing fever ( Borelia recurrentis).

The following gram-negative microorganisms:

  • Haemophilus ducreyi (chancroid).
  • Yersinia pestis (formerly Pasteurella pestis) and Francisella tularensis (formerly Pasturella tularensis).
  • Bartonella bacilliformis.
  • Bacteroides species.
  • Vibrio cholerae (formerly Vibrio comma) and Campylobacter fetus (formerly Vibrio fetus).
  • Brucella species (in conjunction with streptomycin).

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 (formerly Aerobacter aerogenes).
  • Shigella species.
  • Acinetobacter species (formerly Mima species and Herellea species).
  • Haemophilus influenzae (respiratory infections).
  • Klebsiella species (respiratory and urinary infections).

Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug:

  • Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
  • Streptococcus species:

Up to 44% of strains of Streptococcus pyogenes and 74% of Enterococcus faecalis (formerly Streptococcus faecalis) have been found to be resistant to tetracycline drugs. Therefore, tetracyclines should not be used for streptococcal disease unless the organism has been demonstrated to be sensitive.

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 (formerly Diplococcus pneumoniae).
  • Staphylococcus aureus, respiratory, skin and soft tissue infections. Tetracyclines are not the drugs of choice in the treatment of any type of staphylococcal infections.

When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of infections due to:

  • Neisseria gonorrhoeae and N. meningitidis.
  • Treponema pallidum and Treponema pertenue (syphilis and yaws).
  • Listeria monocytogenes.
  • Clostridium species.
  • Fusobacterium fusiforme (Vincent s infection).
  • Actinomyces species.

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.

Contraindications 

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

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. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POST-EXPOSURE), UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline for injection, USP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C.difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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.

Usage in Pregnancy

(See above WARNINGS about use during tooth development).

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 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 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. (See above WARNINGS about use during tooth development).

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 six 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.

Precautions 

Prescribing doxycycline in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

In venereal diseases when coexistent syphilis is suspected, a dark field examination should be done before treatment is started and the blood serology repeated monthly for at least four months.

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies should be performed.

All infections due to group A beta_hemolytic streptococci should be treated for at least 10 days.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin.

Pregnancy: Teratogenic Effects: Pregnancy Category D

There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for treatment of anthrax exposure. An expert review of published data on experiences with doxycycline us during pregnancy by TERIS-the Teratogen Information System-concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1

A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. (Sixty-three(0.19%) of the controls and 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

Nursing Mothers

Tetracycline are excreted in human milk, however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated: however, the effects of prolonged exposure to doxycycline in breast milk are unknown.4 Because of the potential for 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).

Information for Patients

Patients should be counseled that antibacterial drugs including doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline 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 or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, 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 the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Adverse Reactions 

Gastrointestinal

Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines.

Skin

Maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (see WARNINGS)

Renal Toxicity

Rise in BUN has been reported and is apparently dose related (see WARNINGS)

Hypersensitivity Reactions

Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis and exacerbation of systemic lupus erythematosus.

Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving full therapeutic dosages. These conditions disappeared rapidly when the drug was discontinued.

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.

Dosage And Administration 

NOTE: Rapid administration is to be avoided. Parenteral therapy is indicated only when oral therapy is not indicated. Oral therapy should be instituted as soon as possible. If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result.

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 the antibiotic in patients with renal impairment.

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.

For Children Above Eight Years of Age

The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions. Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection. For children over 100 pounds the usual adult dose should be used (see WARNINGS , Usage in Children).

In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (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.

General

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.

Preparation Of Solution 

To prepare a solution containing 10 mg/mL, the contents of the vial should be reconstituted with 10 mL 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.

  1. Sodium Chloride Injection, USP
  2. 5% Dextrose Injection, USP
  3. Ringer s Injection, USP
  4. Invert Sugar, 10% in Water
  5. Lactated Ringer s Injection, USP
  6. Dextrose 5% in Lactated Ringer s
  7. Normosol-M in D5-W
  8. Normosol-R in D5-W
  9. Plasma-Lyte 56 in 5% Dextrose
  10. Plasma-Lyte 148 in 5% Dextrose

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.

Stability

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, to a concentration between 1 mg/mL and 0.1 mg/mL, must be completely infused within 12 hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. 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.

Diluted solutions (0.1 to 1 mg/mL) prepared using Normosol-M in D5-W; Normosol-R in D5-W; Plasma-Lyte 56 in 5% Dextrose; or Plasma-Lyte 148 in 5% Dextrose may also be stored up to 12 hours prior to start of infusion, if refrigerated and protected from sunlight and artificial light. The infusion must be completed within 12 hours. Solutions must be used within these time periods or discarded.

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 20 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How Supplied 

Table3.jpg

Table3.jpg

Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature].

PROTECT FROM LIGHT.

Retain in carton until time of use.

References 

  1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI document M100-S25. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
  2. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - 10th ed. CLSI document M07-A10, CLSI, Wayne, PA, 2015.
  3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard -12th ed. CLSI document M02-A12, CLSI, Wayne, PA, 2015.
  4. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline - Second Edition. CLSI document M45-A2. Clinical and Laboratory Standards Institute, Wayne, Pennsylvania, 2010.
  5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
  6. Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard - Second Edition. CLSI document M24-A2. Clinical and Laboratory Standards Institute, Wayne, Pennsylvania, 2011.
  7. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A. Clinical and Laboratory Standards Institute, Wayne, Pennsylvania, 2011.

Fresenius Kabi USA, LLC

Lake Zurich, IL 60047

www.fresenius-kabi.us

458241I

Revised: October 2015

Boxed Warning 

FOR INTRAVENOUS INFUSION ONLY

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 bacteria.

Description  

Doxycycline for Injection, USP is a sterile, lyophilized powder prepared from a solution of doxycycline hyclate, ascorbic acid and mannitol in Water for Injection. Doxycycline hyclate is a broad spectrum antibiotic derived from oxytetracycline. It is meant for INTRAVENOUS use only after reconstitution. Doxycycline hyclate is a yellowish crystalline powder which is chemically designated 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-de monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. It has the following structural formula:

Formula1.jpg

Formula1.jpg

Doxycycline hyclate is soluble in water and chars at 201 C without melting. The base doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum.

Each 100 mg vial contains: Doxycycline hyclate equivalent to 100 mg doxycycline; ascorbic acid 480 mg; mannitol 300 mg. pH of the reconstituted solution (10 mg/mL) is between 1.8 and 3.3.

Each 200 mg vial contains: Doxycycline hyclate equivalent to doxycycline 200 mg; ascorbic acid 960 mg; mannitol 600 mg. pH of the reconstituted solution (10 mg/mL) is between 1.8 and 3.3.

Indications & Usage 

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Doxy-cycline for Injection, USP and other antibacterial drugs, Dooxycycline 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 (PPLO, Eaton Agent).
  • Agents of psittacosis and ornithosis.
  • Agents of lymphogranuloma venereum and granuloma inguinale.
  • The spirochetal agent of relapsing fever (Borelia recurrentis).

The following gram-negative microorganisms:

  • Haemophilus ducreyi (chancroid).
  • Pasteurella pestis and Pasteurella tularensis.
  • Bartonella bacilliformis.
  • Bacteroides species
  • Vibrio comma and Vibrio fetus.
  • Brucella species (in conjunction with streptomycin).

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 (formerly Aerobacter aerogenes).
  • Shigella species.
  • Mima species and Herellea species.
  • Haemophilus influenzae (respiratory infections).
  • Klebsiella species (respiratory and urinary infections).

Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug:

  • Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
  • Streptococcus species:

Up to 44% of strains of Streptococcus pyogenes and 74% of Streptococcus pyogenes and 74% of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracyclines should not be used for streptococcal disease unless the organism has been demonstrated to be sensitive.

For upper respiratory infections due to group A beta-hemolytic streptococci, penicillin is the usual drug of choice, including prophylaxis of rheumatic fever.

  • Diplococcus pneumoniae.
  • Staphylococcus aureus, respiratory, skin and soft tissue infections. Tetracyclines are not the drugs of choice in the treatment of any type of staphylococcal infections.

When penicillin is contraindicated, doxycycline is and alternative drug in the treatment of infections due to:

  • Neisseria gonorrhoeae and N. meningitidis.
  • Treponema pallidum and Treponema pertenue (syphilis and yaws).
  • Listeria monocytogenes.
  • Clostridium species.
  • Fusobacterium fusiforme (Vincent's infection).
  • Actinomyces species.

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 & Administration 

NOTE: Rapid administration is to be avoided. Parenteral therapy is indicated only when oral therapy is not indicated. Oral therapy should be instituted as soon as possible. If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result.

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 the antibiotic in patients with renal impairment.

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.

For Children Above Eight Years of Age

The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions. Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection. For children over 100 pounds the usual adult dose should be used (see WARNINGS-Usage in Children)

In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighting less than 100 lb (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 continued for a total of 60 days.

General

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.

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 1000 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 2000mL of the following intravenous solutions:

1. Sodium Chloride Injection, USP

2. 5% Dextrose Injection, USP

3. Ringer's Injection, USP

4. Invert Sugar, 10% in Water

5. Lactated Ringer's Injection, USP

6. Dextrose 5% in Lactated Ringer's

7. Normosol-M in D5-W (Abbott)

8. Normosol-R in D5-W (Abbott)

9. Plasma-Lyte 56 in 5% Dextrose (Baxter)

10. Plasma-Lyte 148 in 5% Dextrose (Baxter)

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.

Stability

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 degrees 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 periods or discarded.

Doxycycline, when diluted with Ringer's Injection, USP, or Invert Sugar, 10% in Water, to a concentration between 1 mg/mL and 0.1 mg/mL, must be completely infused within 12 hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. 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.

Diluted solutions (0.1 to 1 mg/mL) prepared using Normosol-M in D5-W (Abbott); Normosol-R in D5-W (Abbott); plasma-Lyte 56 in 5% Dextrose (Baxter); or Plasma-Lyte 148 in 5% Dextrose (Baxter) may also be stored up to 12 hours prior to start of infusion, if refrigerated and protected from sunlight and artificial light. The infusion must be completed within 12 hours. Solutions must be used within these time periods or discarded.

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 - 20 degrees 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Sample Package Label 

Label1.jpg

DOXY 100
doxycycline injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:52584-028(NDC:63323-130)
Route of Administration INTRAVENOUS
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Doxycycline Hyclate (UNII: 19XTS3T51U) (Doxycycline Anhydrous - UNII:334895S862) Doxycycline Anhydrous 100 mg in 10 mL
Inactive Ingredients
Ingredient Name Strength
ASCORBIC ACID (UNII: PQ6CK8PD0R) 480 mg in 10 mL
MANNITOL (UNII: 3OWL53L36A) 300 mg in 10 mL
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:52584-028-11 1 in 1 BAG 08/03/2018
1 10 mL in 1 VIAL; Type 0: Not a Combination Product
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA062475 02/22/2012
Labeler - General Injectables & Vaccines, Inc (108250663)

Revised: 11/2018 General Injectables & Vaccines, Inc

Description: 

Doxycycline for Injection, USP is a sterile, lyophilized powder prepared from a solution of doxycycline hyclate, ascorbic acid and mannitol in Water for Injection. Doxycycline hyclate is a broad spectrum antibiotic derived from oxytetracycline. It is meant for INTRAVENOUS use only after reconstitution. Doxycycline hyclate is a yellowish crystalline powder which is chemically designated 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-de monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. It has the following structural formula:

structure

(C 22H 24N 2O 8 HCl) 2 C 2H 6O H 2O M.W. 1025.89

Doxycycline hyclate is soluble in water and chars at 201 C without melting. The base doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum.

Each 100 mg vial contains: Doxycycline hyclate equivalent to 100 mg doxycycline; ascorbic acid 480 mg; mannitol 300 mg. pH of the reconstituted solution (10 mg/mL) is between 1.8 and 3.3.

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 3.6 mcg/mL.

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.

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. Cross resistance with other tetracyclines is common.

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).

Gram-Negative Bacteria

Acinetobacter species

Bartonella bacilliformis

Brucella species

Calymmatobacterium granulomatis

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

Gram-Positive Bacteria

Bacillus anthracis

Streptococcus pneumoniae

Anaerobes

Clostridium species

Fusobacterium fusiforme

Propionibacterium acnes

Other Bacteria

Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema 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 Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting the most effective antimicrobial.


Dilution Techniques


Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar). 1,2,4 The MIC values should be interpreted according to the criteria provided in Table 1.


Diffusion Techniques


Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. Zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standard test method. 1,3,4 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of bacteria to doxycycline. The disk diffusion interpretive criteria are provided in Table 1.


Anaerobic Techniques


For anaerobic bacteria, the susceptibility to doxycycline can be determined by a standardized test method 5. The MIC values obtained should be interpreted according to the criteria provided in Table 1.



Table 1: Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline



Bacteria a

Minimal

Inhibitory Concentration (mcg/mL)





Zone Diameter

(mm)





Agar Dilution

(mcg/mL)




S



I



R



S



I



R



S



I



R


Acinetobacter spp.
Doxycycline
Tetracycline



4

4





8

8





16

16





13

15





10 to 12

12 to 14





9

11





-

-





-

-





-

-


Anaerobes
Tetracycline



-





-





-





-





-





-





4





8





16


Bacillus anthracisb
Doxycycline
Tetracycline



1

1





-

-





-

-





-

-





-

-





-

-





-

-





-

-





-

-


Brucella speciesb
Doxycycline
Tetracycline



1

1





-

-





-

-





-

-





-

-





-

-





-

-





-

-





-

-


Enterobacteriaceae
Doxycycline
Tetracycline



4

4





8

8





16

16





14

15





11 to 13

12 to 14





10

11





-

-





-

-





-

-


Franciscella tularensisb
Doxycycline
Tetracycline



4

4





-

-





-

-





-

-





-

-





-

-





-

-





-

-





-

-


Haemophilus influenzae
Tetracycline



2





4





8





29





26 to 28





25





-





-





-


Mycoplasma pneumoniaeb
Tetracycline



-





-





-





-





-





-





2





-





-


Neisseria gonorrhoeaec
Tetracycline



-





-





-





38





31 to 37





30





0.25





0.5 to 1





2


Nocardiae and other aerobic
Actinomyces species
Doxycycline



1





2 to 4





8





-





-





-





-





-





-


Streptococcus pneumoniae
Tetracycline



2





4





8





23





19 to 22





18





-





-





-


Vibrio cholerae
Doxycycline
Tetracycline



4

4





8

8





16

16





-

-





-

-





-

-





-

-





-

-





-

-


Yersinia pestis
Doxycycline
Tetracycline



4

4





8

8





16

16





-

-





-

-





-

-





-

-





-

-





-

-


Ureaplasma urealyticum
Tetracycline



-





-





-





-





-





-





1





-





2


a Organisms susceptible to tetracycline are also considered susceptible to doxycycline. However, some organisms
that are intermediate or resistant to tetracycline may be susceptible to doxycycline.
b The current absence of resistance isolates precludes defining any results other than Susceptible . If isolates
yielding MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.
c Gonococci with 30 mcg tetracycline disk zone diameters of < 19 mm usually indicate a plasmid-mediated
tetracycline resistant Neisseria gonorrhoeae isolate. Resistance in these strains should be confirmed by a dilution
test (MIC 16 mcg/mL).

A report of Susceptible (S) indicates that antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the bacteria is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug product is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies interpretation. A report of Resistant (R) indicates that the pathogen is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site: other therapy should be selected.


Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test 1,2,3,4,5,6,7. Standard doxycycline and tetracycline powders should provide the following range of MIC values noted in Table 2. For the diffusion technique using the 30 mcg doxycycline disk the criteria in Table 2 should be achieved.



T able 2: Acceptable Quality Control Ranges for Susceptibility Testing for Doxycycline and Tetracycline





QC Strain



Minimal

Inhibitory Concentration

(mcg/mL)



Zone Diameter (mm)



Agar Dilution (mcg/mL)



Enterococcus faecalis ATCC 29212

Doxycycline

Tetracycline





2 to 8

8 to 32



-

-



-

-



Escherichia coli ATCC 25922

Doxycycline

Tetracycline





0.5 to 2

0.5 to 2





18 to 24

18 to 25





-

-



Haemophilus influenzae ATCC 49247

Tetracycline





4 to 32





14 to 22





-



Neisseria gonorrhoeae ATCC 49226

Tetracycline





-





30 to 42





0.25 to 1



Staphylococcus aureus ATCC 25923

Doxycycline

Tetracycline





-

-





23 to 29

24 to 30





-

-



Staphylococcus aureus ATCC 29213

Doxycycline

Tetracycline



0.12 to 0.5

0.12 to 1





-

-





-

-



Streptococcus pneumoniae ATCC 49619

Doxycycline

Tetracycline





0.015 to 0.12

0.06 to 0.5





25 to 34

27 to 31





-

-



Bacteroides fragilis ATCC 25285

Tetracycline





-





-





0.125 to 0.5



Bacteroides thetaiotaomicron ATCC 29741

Tetracycline





-





-





8 to 32



Mycoplasma pneumoniae ATCC 29342

Tetracycline





0.06 to 0.5





-





0.06 to 0.5



Ureaplasma urealyticum ATCC 33175

Tetracycline





-





-





8


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 (PPLO, Eaton Agent).
  • Agents of psittacosis and ornithosis.
  • Agents of lymphogranuloma venereum and granuloma inguinale.
  • The spirochetal agent of relapsing fever (Borelia recurrentis).

The following gram-negative microorganisms:

  • Haemophilus ducreyi (chancroid).
  • Yersinia pestis (formerly Pasteurella pestis) and Francisella tularensis (formerly Pasturella tularensis).
  • Bartonella bacilliformis.
  • Bacteroides species.
  • Vibrio cholerae (formerly Vibrio comma) and Campylobacter fetus (formerly Vibrio fetus).
  • Brucella species (in conjunction with streptomycin).

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 (formerly Aerobacter aerogenes).
  • Shigella species.
  • Acinetobacter species (formerly Mima species and Herellea species).
  • Haemophilus influenzae (respiratory infections).
  • Klebsiella species (respiratory and urinary infections).

Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug:

  • Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
  • Streptococcus species:

Up to 44% of strains of Streptococcus pyogenes and 74% of Enterococcus faecalis (formerly Streptococcus faecalis) have been found to be resistant to tetracycline drugs. Therefore, tetracyclines should not be used for streptococcal disease unless the organism has been demonstrated to be sensitive.

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 (formerly Diplococcus pneumoniae).
  • Staphylococcus aureus, respiratory, skin and soft tissue infections. Tetracyclines are not the drugs of choice in the treatment of any type of staphylococcal infections.

When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of infections due to:

  • Neisseria gonorrhoeae and N. meningitidis.
  • Treponema pallidum and Treponema pertenue (syphilis and yaws).
  • Listeria monocytogenes.
  • Clostridium species.
  • Fusobacterium fusiforme (Vincent s infection).
  • Actinomyces species.

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.

Contraindications: 

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

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. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POST-EXPOSURE), UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline for injection, USP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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.

Usage in Pregnancy

(See above WARNINGS about use during tooth development).

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 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 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. (See above WARNINGS about use during tooth development).

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 six 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.

Precautions: 

Prescribing doxycycline in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

In venereal diseases when coexistent syphilis is suspected, a dark field examination should be done before treatment is started and the blood serology repeated monthly for at least four months.

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal and hepatic studies should be performed.

All infections due to group A beta-hemolytic streptococci should be treated for at least 10 days.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin.

Pregnancy

Teratogenic Effects: Pregnancy Category D
There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS the Teratogen Information System concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no risk. 1

A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. (Sixty-three (0.19%) of the controls and 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 (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

Nursing Mothers

Tetracyclines are excreted in human milk, however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknown. 4 Because of the potential for 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).

Information for Patients

Patients should be counseled that antibacterial drugs including doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline 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 or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, 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 the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Adverse Reactions: 

Gastrointestinal

Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines.

Skin

Maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (see WARNINGS).

Renal Toxicity

Rise in BUN has been reported and is apparently dose related (see WARNINGS).

Hypersensitivity Reactions

Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis and exacerbation of systemic lupus erythematosus.

Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving full therapeutic dosages. These conditions disappeared rapidly when the drug was discontinued.

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.

Dosage And Administration: 

NOTE: Rapid administration is to be avoided. Parenteral therapy is indicated only when oral therapy is not indicated. Oral therapy should be instituted as soon as possible. If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result.

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 the antibiotic in patients with renal impairment.

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.

For Children Above Eight Years of Age

The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions. Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection. For children over 100 pounds the usual adult dose should be used (see WARNINGS, Usage in Children).

In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (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.

General

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.

Preparation Of Solution: 

To prepare a solution containing 10 mg/mL, the contents of the vial should be reconstituted with 10 mL 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.

  1. Sodium Chloride Injection, USP
  2. 5% Dextrose Injection, USP
  3. Ringer s Injection, USP
  4. Invert Sugar, 10% in Water
  5. Lactated Ringer s Injection, USP
  6. Dextrose 5% in Lactated Ringer s
  7. Normosol-M in D5-W
  8. Normosol-R in D5-W
  9. Plasma-Lyte 56 in 5% Dextrose
  10. Plasma-Lyte 148 in 5% Dextrose

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.

Stability

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, to a concentration between 1 mg/mL and 0.1 mg/mL, must be completely infused within 12 hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. 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.

Diluted solutions (0.1 to 1 mg/mL) prepared using Normosol-M in D5-W; Normosol-R in D5-W; Plasma-Lyte 56 in 5% Dextrose; or Plasma-Lyte 148 in 5% Dextrose may also be stored up to 12 hours prior to start of infusion, if refrigerated and protected from sunlight and artificial light. The infusion must be completed within 12 hours. Solutions must be used within these time periods or discarded.

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 20 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How Supplied: 

Product
No.
NDC
No .

NP1311
63323-130-13
Doxycycline for Injection, USP (equivalent to 100 mg Doxycycline with 480 mg ascorbic acid and 300 mg mannitol per vial), lyophilized in a flip-top 20 mL vial, in packages of 10.

Store at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature].

PROTECT FROM LIGHT.

Retain in carton until time of use.

References: 


  1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement. CLSI document M100-S23. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013.
  2. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - 9th ed. CLSI document M07-A9, CLSI, Wayne, PA, 2012.
  3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard -11th ed. CLSI document M02-A11, CLSI, Wayne, PA, 2012.
  4. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline - Second Edition. CLSI document M45-A2. Clinical and Laboratory Standards Institute, Wayne, Pennsylvania, 2010.
  5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012.
  6. Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard - Second Edition. CLSI document M24-A2. Clinical and Laboratory Standards Institute, Wayne, Pennsylvania, 2011.
  7. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A. Clinical and Laboratory Standards Institute, Wayne, Pennsylvania, 2011.
  8. Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000; 149-195.
  9. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528.
  10. Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25:315-317.
  11. Hale T. Medications and Mothers Milk. 9th edition. Amarillo, TX: Pharmasoft Publishing 2000; 225-226.

The brand names mentioned in this document are the trademarks of their respective owners.

N+ and NOVAPLUS are registered trademarks of Novation, LLC.


Manufactured by:

Fresenius Kabi USA, LLC

Lake Zurich, IL 60047

451295A

Revised: February 2014

logo

PACKAGE LABEL - PRINCIPAL DISPLAY - Doxycycline 100 mg Vial Label

NDC 63323-130-13

NP1311

Doxy 100

Doxycycline for Injection, USP

equivalent to

100 mg per vial Doxycycline

For IV Infusion Only.

Must Dilute Reconstituted Solution.

Rx only

np1311-vial

PACKAGE LABEL - PRINCIPAL DISPLAY - Doxycycline 100 mg Vial Tray Label

NDC 63323-130-13

NP1311

Doxy 100

Doxycycline for Injection, USP

equivalent to

100 mg per vial Doxycycline

For IV Infusion Only.

Must Dilute Reconstituted Solution.

10 vials

Rx only

np1311-tray





DOXY 100
doxycycline injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63323-130
Route of Administration INTRAVENOUS
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE HYCLATE (UNII: 19XTS3T51U) (DOXYCYCLINE ANHYDROUS - UNII:334895S862) DOXYCYCLINE ANHYDROUS 100 mg in 10 mL
Inactive Ingredients
Ingredient Name Strength
ASCORBIC ACID (UNII: PQ6CK8PD0R) 480 mg in 10 mL
MANNITOL (UNII: 3OWL53L36A) 300 mg in 10 mL
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:63323-130-13 10 in 1 TRAY 10/17/2000
1 10 mL in 1 VIAL; Type 0: Not a Combination Product
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA062475 10/17/2000
Labeler - Fresenius Kabi USA, LLC (608775388)
Establishment
Name Address ID/FEI Business Operations
Fresenius Kabi USA, LLC 023648251 manufacture(63323-130)
Establishment
Name Address ID/FEI Business Operations
Fresenius Kabi USA, LLC 840771732 manufacture(63323-130)

Revised: 10/2019 Fresenius Kabi USA, LLC

Doxy 100 Doxycycline For Injection, Usp  

FOR INTRAVENOUS INFUSION ONLY

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 bacteria.

Description:  

Doxycycline for Injection, USP is a sterile, lyophilized powder prepared from a solution of doxycycline hyclate, ascorbic acid and mannitol in Water for Injection. Doxycycline hyclate is a broad spectrum antibiotic derived from oxytetracycline. It is meant for INTRAVENOUS use only after reconstitution. Doxycycline hyclate is a yellowish crystalline powder which is chemically designated 4-(Dimethylamino)-1,4,4a,5,5a,6,11, 12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-de monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. It has the following structural formula:

Structural Formula
(C22H24N2O8 HCl)2 C2H6O H2O M.W. 1025.89

Doxycycline hyclate is soluble in water and chars at 201 C without melting. The base doxycycline has a high degree of lipid solubility and a low affinity for calcium binding. It is highly stable in normal human serum.

Each 100 mg vial contains: Doxycycline hyclate equivalent to 100 mg doxycycline; ascorbic acid 480 mg; mannitol 300 mg. pH of the reconstituted solution (10 mg/mL) is between 1.8 and 3.3.

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 3.6 mcg/mL.

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.

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 with other tetracyclines is common.

Antimicrobial Activity

Doxycycline has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections (see INDICATIONS AND USAGE).

Gram-Negative Bacteria

Acinetobacter species

Bartonella bacilliformis

Brucella species

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Klebsiella granulomatis

Klebsiella species

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Campylobacter fetus

Yersinia pestis

Gram-Positive Bacteria

Bacillus anthracis

Listeria monocytogenes

Streptococcus pneumoniae

Anaerobic Bacteria

Clostridium species

Fusobacterium fusiforme

Propionibacterium acnes

Other Bacteria

Nocardiae and other aerobic Actinomyces species

Borrelia recurrentis

Chlamydophila psittaci

Chlamydia trachomatis

Mycoplasma pneumoniae

Rickettsiae

Treponema pallidum

Treponema pallidum subspecies pertenue

Ureaplasma urealyticum

Parasites

Balantidium coli

Entamoeba species

Plasmodium falciparum*

*Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.

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.

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 (PPLO, Eaton Agent).
  • 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 (chancroid).
  • Yersinia pestis (formerly Pasteurella pestis) and Francisella tularensis (formerly Pasteurella tularensis).
  • Bartonella bacilliformis.
  • Bacteroides species.
  • Vibrio cholerae (formerly Vibrio comma) and Campylobacter fetus (formerly Vibrio fetus).
  • Brucella species (in conjunction with streptomycin).

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 (formerly Aerobacter aerogenes).
  • Shigella species.
  • Acinetobacter species (formerly Mima species and Herellea species).
  • Haemophilus influenzae (respiratory infections).
  • Klebsiella species (respiratory and urinary infections).

Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug:

  • Streptococcus species:

Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Enterococcus faecalis (formerly Streptococcus faecalis) have been found to be resistant to tetracycline drugs. Therefore, tetracyclines should not be used for streptococcal disease unless the organism has been demonstrated to be sensitive.

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 (formerly Diplococcus pneumoniae).
  • Staphylococcus aureus, respiratory, skin and soft tissue infections. Tetracyclines are not the drugs of choice in the treatment of any type of staphylococcal infections.
  • Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.

When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of infections due to:

  • Neisseria gonorrhoeae and N. meningitidis.
  • Treponema pallidum and Treponema pertenue (syphilis and yaws).
  • Listeria monocytogenes.
  • Clostridium species.
  • Fusobacterium fusiforme (Vincent's infection).
  • Actinomyces species.

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.

Contraindications:  

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

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 associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline for injection, USP, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

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 (see ADVERSE REACTIONS). If severe skin reactions occur, doxycycline should be discontinued immediately and appropriate therapy should be instituted.

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.

Precautions:  

General

As with other antibacterial drugs, use of doxycycline may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, doxycycline should be discontinued and appropriate therapy instituted.

Incision and drainage or other surgical procedures should be performed in conjunction with antibacterial therapy, when indicated.

Prescribing doxycycline in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

All infections due to group A beta-hemolytic streptococci should be treated for at least 10 days.

Information for Patients

Patients taking doxycycline should be advised:

  • to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered. (See WARNINGS.)
  • that the use of doxycycline might increase the incidence of vaginal candidiasis.

Patients should be counseled that antibacterial drugs, including doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline 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 or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibacterial drugs, which usually ends when the antibacterials are 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 the antibacterial drug. If this occurs, patients should contact their physician as soon as possible.

Laboratory Tests

In venereal diseases when coexistent syphilis is suspected, a dark field examination should be done before treatment is started and the blood serology repeated monthly for at least 4 months.

In long-term therapy, periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic studies should be performed.

Drug Interactions

Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline in conjunction with penicillin.

Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

The concurrent use of tetracycline and Penthrane (methoxyflurane) has been reported to result in fatal renal toxicity.

Concurrent use of tetracycline may render oral contraceptives less effective.

Usage in Pregnancy

(See WARNINGS about use during tooth development.)

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 and 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.

Adverse Reactions:  

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. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above (see WARNINGS).

Renal Toxicity

Rise in BUN has been reported and is apparently dose related (see WARNINGS).

Immune

Hypersensitivity reactions including urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis and exacerbation of systemic lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS).

Other

Bulging fontanels in infants and intracranial hypertension in adults (see WARNINGS).

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.

Dosage And Administration:  

NOTE: Rapid administration is to be avoided. Parenteral therapy is indicated only when oral therapy is not indicated. Oral therapy should be instituted as soon as possible. If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result.

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 the antibiotic in patients with renal impairment.

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.

Pediatric Patients

For all pediatric patients weighing less than 45 kg with severe or life-threatening infections (e.g., anthrax, Rocky Mountain spotted fever), the recommended dosage is 2.2 mg/kg of body weight administered every 12 hours. Children weighing 45 kg or more should receive the adult dose (see WARNINGS and PRECAUTIONS).

For pediatric patients with less severe disease (greater than 8 years of age and weighing less than 45 kg), the recommended dosage schedule is 4.4 mg/kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg/kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used.

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.

General

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.

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) 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:

  1. Sodium Chloride Injection, USP
  2. 5% Dextrose Injection, USP
  3. Ringer's Injection, USP
  4. Invert Sugar, 10% in Water
  5. Lactated Ringer's Injection, USP
  6. Dextrose 5% in Lactated Ringer's
  7. Normosol-M in D5-W
  8. Normosol-R in D5-W
  9. Plasma-Lyte 56 in 5% Dextrose
  10. Plasma-Lyte 148 in 5% Dextrose

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.

Stability

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, to a concentration between 1 mg/mL and 0.1 mg/mL, must be completely infused within 12 hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. 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.

Diluted solutions (0.1 to 1 mg/mL) prepared using Normosol-M in D5-W; Normosol-R in D5-W; Plasma-Lyte 56 in 5% Dextrose; or Plasma-Lyte 148 in 5% Dextrose may also be stored up to 12 hours prior to start of infusion, if refrigerated and protected from sunlight and artificial light. The infusion must be completed within 12 hours. Solutions must be used within these time periods or discarded.

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 20 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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

How Supplied:  

Doxycycline for Injection, USP, sterile powder, supplied as follows:

Product Code Unit of Sale Strength Each
1311 NDC 63323-130-11
Unit of 10
Doxycycline hyclate equivalent to
100 mg doxycycline
per vial
NDC 63323-130-02
20 mL Single Dose Vial

Store at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature].

PROTECT FROM LIGHT.

Retain in carton until time of use.

The brand names mentioned in this document are the trademarks of their respective owners.

Fresenius Kabi Logo

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

45824K

Revised: July 2019

Principal Display Panel Doxy 100 100 Mg Per Vial Tray Panel  

NDC 63323-130-11 1311

DOXY 100TM

Doxycycline for Injection, USP

equivalent to

100 mg per vial

Doxycycline

For intravenous infusion only.

MUST BE FURTHER DILUTED AFTER RECONSTITUTION.

Preservative free.

10 x Single Dose Vials Rx only

Principal Display Panel     Doxy 100    100 mg per Vial Tray Panel

Principal Display Panel Doxy 100 100 Mg Per Vial Label  

NDC 63323-130-02 1311

DOXY 100TM

Doxycycline for Injection, USP

equivalent to

100 mg per vial

Doxycycline

For intravenous infusion only.

MUST BE FURTHER DILUTED AFTER RECONSTITUTION.

Preservative free. Rx only

Principal Display Panel     Doxy 100    100 mg per Vial Label
DOXY 100
doxycycline injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63323-130
Route of Administration INTRAVENOUS
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE HYCLATE (UNII: 19XTS3T51U) (DOXYCYCLINE ANHYDROUS - UNII:334895S862) DOXYCYCLINE ANHYDROUS 100 mg in 10 mL
Inactive Ingredients
Ingredient Name Strength
ASCORBIC ACID (UNII: PQ6CK8PD0R) 480 mg in 10 mL
MANNITOL (UNII: 3OWL53L36A) 300 mg in 10 mL
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:63323-130-11 10 in 1 TRAY 10/17/2000
1 NDC:63323-130-02 10 mL in 1 VIAL; Type 0: Not a Combination Product
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA062475 10/17/2000
Labeler - Fresenius Kabi USA, LLC (608775388)
Establishment
Name Address ID/FEI Business Operations
Fresenius Kabi USA, LLC 023648251 manufacture(63323-130)
Establishment
Name Address ID/FEI Business Operations
Fresenius Kabi USA, LLC 840771732 manufacture(63323-130)

Revised: 9/2019 Fresenius Kabi USA, LLC



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