Doxy 100

Fresenius Kabi USA, LLC

Doxycycline for Injection USP

FULL PRESCRIBING INFORMATION: CONTENTS*

• DOXY 100 DESCRIPTION
• CLINICAL PHARMACOLOGY
  • Susceptibility Plate Testing
• DOXY 100 INDICATIONS AND USAGE
• DOXY 100 CONTRAINDICATIONS
• WARNINGS
  • Usage in Pregnancy
  • Usage in Children
• PRECAUTIONS
  • PregnancyTeratogenic Effects: Pregnancy Category D
  • Nursing Mothers
  • Information for Patients
• DOXY 100 ADVERSE REACTIONS
  • Gastrointestinal
  • Skin
  • Renal Toxicity
  • Hypersensitivity Reactions
  • Blood
• DOXY 100 DOSAGE AND ADMINISTRATION
  • Adults
  • For Children Above Eight Years of Age
  • General
• PREPARATION OF SOLUTION
  • Stability
• HOW SUPPLIED
• REFERENCES

FULL PRESCRIBING INFORMATION

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.

DOXY 100 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:

(C₂₂H₂₄N₂ O₈ • HCl)₂ • C₂H₆O • H₂O             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

Doxycycline is primarily bacteriostatic and thought to exert its antimicrobial effect by the inhibition of protein synthesis.  Doxycycline is active against a wide range of gram-positive and gram-negative organisms.

The drugs in the tetracycline class have closely similar antimicrobial spectra and cross resistance among them is common.  Microorganisms may be considered susceptible to doxycycline (likely to respond to doxycycline therapy) if the minimum inhibitory concentration (MIC) is not more than 4 mcg/mL.  Microorganisms may be considered intermediate (harboring partial resistance) if the MIC is 4 to 12.5 mcg/mL and resistant (not likely to respond to therapy) if the MIC is greater than 12.5 mcg/mL.

Susceptibility Plate Testing

If the Kirby-Bauer method of disc susceptibility testing is used, a 30 mcg doxycycline disc should give a zone of at least 16 mm when tested against a doxycycline-susceptible bacterial strain.  A tetracycline disc may be used to determine microbial susceptibility.  If the Kirby-Bauer method of disc susceptibility testing is used, a 30 mcg tetracycline disc should give a zone of at least 19 mm when tested against a tetracycline-susceptible bacterial strain.

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.

DOXY 100 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).
• 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 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 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.

DOXY 100 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.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including doxycycline, and may range in severity from mild to life-threatening.  Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia.  Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis.”

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated.  Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone.  In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

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.

PregnancyTeratogenic 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.

DOXY 100 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.

DOXY 100 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 1000 mL of the intravenous solutions listed below.

• Sodium Chloride Injection, USP
• 5% Dextrose Injection, USP
• Ringer’s Injection, USP
• Invert Sugar, 10% in Water
• Lactated Ringer’s Injection, USP
• Dextrose 5% in Lactated Ringer’s
• Normosol-M^® in D5-W
• Normosol-R^® in D5-W
• Plasma-Lyte^® 56 in 5% Dextrose
• 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

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

• Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press: 2000; 149-195.
• Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528.
• Horne HW Jr. and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25:315-317.
• 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.

Novation and NOVAPLUS are registered trademarks of Novation, LLC.

Manufactured by:

451295

Issued: July 2012

PACKAGE LABEL - PRINCIPAL DISPLAY - Doxycycline 100 mg Vial Label

NDC 63323-130-13

NP1311

Doxy 100™

Doxycycline for Injection, USP

equivalent to

100 mg Doxycycline

For IV Infusion Only.

Must Dilute Reconstituted Solution.

Rx only

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 Doxycycline

For IV Infusion Only.

Must Dilute Reconstituted Solution.

10 vials

Rx only