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Doxycycline Injection

Generic Name: doxycycline hyclate
Dosage Form: injection, powder, lyophilized, for solution

Medically reviewed on Oct 1, 2017

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.

Doxycycline Injection Description

See also: Orencia

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 yellow to light yellow 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- dioxo-2-naphthacenecarboxamide, monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. It has the following structural formula:

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.

Doxycycline Injection - 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. Doxycycline is virtually completely absorbed after oral administration.

Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours, decreasing to 1.45 mcg/mL at 24 hours. Excretion of doxycycline by the kidney is about 40 %/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1 to 5 %/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 serum half-life.

Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.

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 as described in the INDICATIONS AND USAGE section of the package insert for Doxycycline for injection.

Gram-Negative Bacteria 

Acinetobacter species

Bartonella bacilliformis

Brucella species

Klebsiella species

Klebsiella granulomatis

Campylobacter fetus

Enterobacter aerogenes

Escherichia coli

Francisella tularensis

Haemophilus ducreyi

Haemophilus influenzae

Neisseria gonorrhoeae

Shigella species

Vibrio cholerae

Yersinia pestis

Gram-Positive Bacteria 

Bacillus anthracis

Listeria monocytogenes

Streptococcus pneumoniae 

Anaerobic Bacteria

Clostridium species

Fusobacterium fusiforme 

Propionibacterium acnes 

Other Bacteria 

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 Test Methods

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas 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 method1,2,4 (broth or agar). The MIC values should be interpreted according to 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. The zone size should be determined using a standardized  test method.1,3,4 This procedure uses paper disks impregnated with 30 mcg doxycycline to test the susceptibility of  microorganisms 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 l.

Table 1
Susceptibility Test Interpretive Criteria for Doxycycline and Tetracycline
Bacteriaa
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
-
-
Nocardiae and other aerobic
Actinomyces speciesb
    Doxycycline
≤ 1
2 to 4
≥ 8
-
-
-
-
-
-
Neisseria gonorrhoeaec
    Tetracycline
-
-
-
≥ 38
31 to 37
≤ 30
≤ 0.25
0.5 to 1
≥ 2
Streptococcus pneumoniae
    Doxycycline
    Tetracycline
≤ 0.25
≤1
0.5
2
≥ 1
≥ 4
≥ 28
≥ 28
25 to 27
25 to 27
≤ 24
≤ 24
-
-
-
-
-
-
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 the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism 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 in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the microorganism if the antimicrobial drug 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 the 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 noted in Table 2 should be achieved.

Table 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
-
-
Eggerthella lenta ATCC 43055



    Doxycycline
2 to 16
-
-
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
-
-
0.12 to 0.5
Bacteroides thetaiotaomicron ATCC 29741



    Doxycycline
    Tetracycline
2 to 8
-
-
-
-
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 for Doxycycline Injection

To reduce the development of drug-resistant bacteria and maintain 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.

Treatment:

Doxycycline is indicated for the treatment of the following infections:

  • Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae.
  • Respiratory tract infections caused by Mycoplasma pneumoniae .
  • Lymphogranuloma venereum caused by Chlamydia trachomatis .
  • Psittacosis (ornithosis) caused by Chlamydophila psittaci .
  • Trachoma caused by Chlamydia trachomatis , although the infectious agent is not always eliminated, as judged by immunofluorescence.
  • Inclusion conjunctivitis caused by Chlamydia trachomatis .
  • Uncomplicated urethral, endocervical, or rectal infections in adults caused by Chlamydia trachomatis .
  • Nongonococcal urethritis caused by Ureaplasma urealyticum .
  • Relapsing fever due to Borrelia recurrentis .

Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms:

  •   Chancroid caused by Haemophilus ducreyi .
  •   Plague due to Yersinia pestis .
  •   Tularemia due to Francisella tularensis .
  •   Cholera caused by Vibrio cholerae .
  •   Campylobacter fetus infections caused by Campylobacter fetus .
  •   Brucellosis due to Brucella species (in conjunction with streptomycin).
  •   Bartonellosis due to Bartonella bacilliformis .
  •   Granuloma inguinale caused by Klebsiella granulomatis .

Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended.

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

  • Escherichia coli.
  • Enterobacter aerogenes.
  • Shigella species.
  • Acinetobacter species.
  • Respiratory tract infections caused by Haemophilus influenzae.
  • Respiratory tract and urinary tract infections caused by Klebsiella species.

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

  • Upper respiratory infections caused by Streptococcus pneumoniae .
  • 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 the following infections:

  • Uncomplicated gonorrhea caused by Neisseria gonorrhoeae .
  • Syphilis caused by Treponema pallidum .
  • Yaws caused by Treponema pallidum subspecies pertenue .
  • Listeriosis due to Listeria monocytogenes .
  • Vincent's infection caused by Fusobacterium fusiforme .
  • Actinomycosis caused by Actinomyces israelii .
  • Infections caused by Clostridium species .

In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides.

In severe acne, doxycycline may be useful adjunctive therapy.

Prophylaxis:

Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (< 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. (See DOSAGE AND ADMINISTRATION section and Information for Patients subsection of the PRECAUTIONS section.)

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 it 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, 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 the use of antibacterial drugs. 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 use of antibacterial drugs not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial 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.

All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in 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.

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. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

The antianabolic 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.

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.

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.

Doxycycline offers substantial but not complete suppression of the asexual blood stages of Plasmodium strains.

Doxycycline does not suppress P. falciparum's sexual blood stage gametocytes. Subjects completing this prophylactic regimen may still transmit the infection to mosquitoes outside endemic areas.

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.

Information For Patients

Patients taking doxycycline for malaria prophylaxis should be advised:

—  that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria.

—  to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (e.g., staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent).

—  that doxycycline prophylaxis:

     should begin 1–2 days before travel to the malarious area,

     should be continued daily while in the malarious area and after leaving the malarious area,

     should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area,

     should not exceed 4 months.

All patients taking doxycycline should be advised:

—  to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered. (See WARNINGS.)

—  to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS.)

—  that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. (See DRUG INTERACTIONS.)

—  that the absorption of tetracyclines is reduced when taking bismuth subsalicylate. (See DRUG INTERACTIONS.)

—  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 disease, when co-existent syphilis is suspected, dark field examinations 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 tetracyclines in conjunction with penicillin.

Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations.

Absorption of tetracyclines is impaired by bismuth subsalicylate.

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.

Drug/Laboratory Test Interactions

False elevations of urinary catecholamine levels may occur due to interference with the fluorescence test.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies in animals to evaluate carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with the related antibacterial drugs, oxytetracycline (adrenal and pituitary tumors), and minocycline (thyroid tumors).

Likewise, although mutagenicity studies of doxycycline have not been conducted, positive results in in vitro mammalian cell assays have been reported for related antibacterial drugs (tetracycline, oxytetracycline).

Doxycycline administered orally at dosage levels as high as 250 mg/kg/day had no apparent effect on the fertility of female rats. Effect on male fertility has not been studied.

Pregnancy:

Teratogenic Effects.

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.8A 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 fifty-six (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.9

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.10

Nonteratogenic Effects: (See WARNINGS.)

Labor and Delivery

The effect of tetracyclines on labor and delivery is unknown.

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.11 Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. (See WARNINGS.)

Pediatric Use

Because of the effects of drugs of the tetracycline-class on tooth development and growth, 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. (See WARNINGS and DOSAGE AND ADMINISTRATION.)

Adverse Reactions

Gastrointestinal: anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, 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: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, 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, serum sickness, pericarditis, exacerbation of systemic lupus erythematosus, and drug reaction with eosinophilia and systemic symptoms (DRESS).

Blood: Hemolytic anemia, thrombocytopenia, neutropenia, and eosinophilia have been reported.

Other: Bulging fontanels in infants and intracranial hypertension in adults. (See WARNINGS.)

When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function studies are known to occur.

Overdosage

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

Doxycycline Injection 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.

For prophylaxis of malaria: For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1 to 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area.

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 ten 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 2000 mL 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 (Travenol)
  10. Plasma-Lyte® 148 in 5% Dextrose (Travenol)

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 for injection 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 for injection 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 for injection, when diluted with Ringer's Injection, USP, or Invert Sugar, 10% in Water, or Normosol-M® in D5-W (Abbott), or Normosol-R® in D5-W (Abbott), or Plasma-Lyte® 56 in 5% Dextrose (Travenol), or Plasma-Lyte® 148 in 5% Dextrose (Travenol) 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.

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 hyclate 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.

How is Doxycycline Injection Supplied

NDC 

68382-910-10     
Doxycycline for Injection, USP (equivalent to 100 mg Doxycycline with 480 mg ascorbic acid and 300 mg mannitol), lyophilized in a flip-top vial, in packages of 10.
68382-911-01    
Doxycycline for Injection, USP (equivalent to 200 mg Doxycycline with 960 mg ascorbic acid and 600 mg mannitol), lyophilized in a flip-top vial, packaged individually.

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.

ANIMAL PHARMACOLOGY AND ANIMAL TOXICOLOGY

Hyperpigmentation of the thyroid has been produced by members of the tetracycline class in the following species: in rats by oxytetracycline, doxycycline, tetracycline PO4, and methacycline; in minipigs by doxycycline, minocycline, tetracycline PO4, and methacycline; in dogs by doxycycline and minocycline; in monkeys by minocycline.

Minocycline, tetracycline PO4, methacycline, doxycycline, tetracycline base, oxytetracycline HCl, and tetracycline HCl were goitrogenic in rats fed a low iodine diet. This goitrogenic effect was accompanied by high radioactive iodine uptake. Administration of minocycline also produced a large goiter with high radioiodine uptake in rats fed a relatively high iodine diet.

Treatment of various animal species with this class of drugs has also resulted in the induction of thyroid hyperplasia in the following: in rats and dogs (minocycline); in chickens (chlortetracycline); and in rats and mice (oxytetracycline). Adrenal gland hyperplasia has been observed in goats and rats treated with oxytetracycline.

REFERENCES

  1. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Sixth Informational Supplement, CLSI document M100-S26 [2016], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087.
  2. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-A10 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
  3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard Twelfth Edition. CLSI document M02-A12 [2015], Clinical and Laboratory Standards Institute, 950West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
  4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline Third Edition. CLSI document M45-A3 [2015],  Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
  5. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eighth Edition. CLSI document M11-A8 [2012]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA.
  6. Clinical and Laboratory Standards Institute. Susceptibility Testing of Mycobacteria, Nocardiae, and Other Aerobic Actinomycetes; Approved Standard Second Edition. CLSI document M24-A2 [2011].  Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA.
  7. Clinical and Laboratory Standards Institute. Methods for Antimicrobial Susceptibility Testing for Human Mycoplasmas; Approved Guideline. CLSI document M43-A [2011]. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA.
  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.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Manufactured by:

Cadila Healthcare Limited.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev: 08/17

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL – DOXYCYCLINE 100 MG CONTAINER LABEL

NDC 68382-910-01

Doxycycline for Injection, USP

100 mg per vial

For Intravenous Infusion

MUST DILUTE RECONSTITUTED SOLUTION

Single-dose vial

Rx only

Zydus Pharmaceuticals

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - DOXYCYCLINE 100 MG CARTON LABEL

NDC 68382-910-10

Doxycycline for Injection, USP

100 mg per vial

For Intravenous Infusion

MUST DILUTE RECONSTITUTED SOLUTION

10 x Single-dose vials

Rx only

Zydus Pharmaceuticals

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL – DOXYCYCLINE 200 MG CONTAINER LABEL

NDC 68382-911-01

Doxycycline for Injection, USP

200 mg per vial

For Intravenous Infusion

MUST DILUTE RECONSTITUTED SOLUTION

Single-dose vial

Rx only

Zydus Pharmaceuticals

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - DOXYCYCLINE 200 MG CARTON LABEL

NDC 68382-911-01

Doxycycline for Injection, USP

200 mg per vial

For Intravenous Infusion

MUST DILUTE RECONSTITUTED SOLUTION

Single-dose vial

Rx only

Zydus Pharmaceuticals

DOXYCYCLINE 
Doxycycline Injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:68382-910
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE HYCLATE (DOXYCYCLINE ANHYDROUS) DOXYCYCLINE ANHYDROUS 100 mg  in 10 mL
Inactive Ingredients
Ingredient Name Strength
ASCORBIC ACID 480 mg  in 10 mL
MANNITOL 300 mg  in 10 mL
Packaging
# Item Code Package Description
1 NDC:68382-910-10 10 VIAL in 1 CARTON
1 10 mL in 1 VIAL
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA207757 02/01/2018
DOXYCYCLINE 
Doxycycline Injection, powder, lyophilized, for solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:68382-911
Route of Administration INTRAVENOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE HYCLATE (DOXYCYCLINE ANHYDROUS) DOXYCYCLINE ANHYDROUS 200 mg  in 20 mL
Inactive Ingredients
Ingredient Name Strength
ASCORBIC ACID 960 mg  in 20 mL
MANNITOL 600 mg  in 20 mL
Packaging
# Item Code Package Description
1 NDC:68382-911-01 1 VIAL in 1 CARTON
1 20 mL in 1 VIAL
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA207757 02/01/2018
Labeler - Zydus Pharmaceuticals (USA) Inc. (156861945)
Registrant - Zydus Pharmaceuticals (USA) Inc. (156861945)
Establishment
Name Address ID/FEI Operations
Cadila Healthcare Limited 918596198 ANALYSIS(68382-910, 68382-911), MANUFACTURE(68382-910, 68382-911)
 
Zydus Pharmaceuticals (USA) Inc.
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