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Doxycycline Monohydrate

Dosage Form: capsule

Doxycycline Monohydrate Description

Doxycycline, USP   is   a   broad - spectrum   antibacterial   synthetically   derived   from   oxytetracycline.   Doxycycline  monohydrate  capsules  USP,   100   mg  and   75   mg  contain    doxycycline   monohydrate   equivalent   to   100   mg  and  75   mg  of   doxycycline   for   oral   administration.  The   chemical   designation   of   the   light  yellow   to  pale  yellow  powder  is  alpha- 6- deoxy- 5- oxytetracycline.



Structural    formula:


C22H24N2O8 •  H2O          M.W. =  462.45

Doxycycline   has   a   high   degree   of   lipid   solubility   and   a   low   affinity   for   calcium   binding.   It  is  highly   stable   in   normal   human  serum.   Doxycycline   will   not   degrade    into   an   epianhydro   form.
 

Inert  ingredients:   microcrystalline   cellulose; sodium   starch   glycolate;  povidone;  colloidal   silicon   dioxide;   magnesium  stearate;  and  a  hard  gelatin  capsule  which  contains  iron  oxide  black,  iron  oxide  red,  iron  oxide  yellow,  titanium dioxide,  gelatin  and  sodium  lauryl  sulphate.   The  capsule  shells  of  75  mg  are  printed  with  edible  black  ink  containing  shellac,  propylene  glycol,  iron  oxide  black  and  potassium  hydroxide.  The  cap  of  100  mg  capsule  shells  is  printed  with  edible  white  ink  containing  shellac,  propylene  glycol,  potassium  hydroxide  and  titanium  dioxide.   The  body  of  100  mg  capsule  shells  is  printed  with  edible  and  brown  ink  containing  shellac,  propylene  glycol,  potassium  hydroxide,  iron  oxide  brown  and  iron  oxide  black.


Doxycycline Monohydrate - Clinical Pharmacology

Tetracyclines  are  readily  absorbed  and  are  bound  to  plasma  proteins  in  varying  degrees.  They  are  concentrated   by  the  liver  in the  bile  and  excreted  in  the  urine  and  feces  at  high  concentrations  in  a  biologically  active  form.  Doxycycline  is  virtually completely  absorbed  after  oral  administration.


Following  a  200  mg  dose  of  doxycycline  monohydrate,  24  normal  adult  volunteers  averaged  the  following  serum concentration  values:


Time (hr): 0.5
1
1.5
2
3
4
8
12
24
48
72
Conc. 1.02
2.26
2.67
3.01
3.16
3.03
2.03
1.62
0.95
0.37
0.15 (μg/mL) 

Average Observed  Values


Maximum Concentration                                3.61 μg/mL (± 0.9  sd)

Time of Maximum  Concentration                   2.6 hr (± 1.1  sd)

Elimination Rate Constant                              0.049  per  hr  (±  0.03  sd)

Half-Life                                                         16.33 hr (± 4.53  sd)


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.
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.  

Antimocrobial 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 

Campylobacter  fetus 

Enterobacter  aerogenes 

Escherichia  coli  

Francisella  tularensis 

Haemophilus  ducreyi 

Haemophilus  influenza

Klebsiella granulomatis 

Klebsiella  species 

Neisseria  gonorrhoeae 

Shigella  species 

Vibrio  cholerae  

Yersinia  pestis

 

Gram-Positive  Bacteria 

Bacillus  anthracis

Listeria monocytogenes 

Streptococcus  pneumoniae 

 

Anaerobic  Bacteria 

Clostridium  species 

Fusobacterium  fusiforme 

Propionibacterium  acnes

Other  Bacteria 

Nocardiae and other Actinomyces  species 

Borrelia  recurrentis 

Chlamydophila  psittaci 

Chlamydia  trachomatis 

Mycoplasma  pneumoniae 

Rickettsiae 

Treponema  pallidum 

Treponema  pallidum subspecies pertenue  

Ureaplasma  urealyticum 

 

Parasites 

Balantidium  coli  

Entamoeba  species

Susceptibility Testing  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 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).1,2,4,6,7  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  method.1,5  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* 
Minimal Inhibitory  Concentration (mcg per   mL) 
Zone Diameter   (mm) 
Agar Dilution (mcg per   mL) 
S
I
R
S
I
R
S
I
R
Acinetobacter  spp. 
Doxycycline   Tetracycline 
 
 
≤4
≤4
 
 


 
 
≥16
≥16
 
 
≥13
≥15
 
 
10 to 12 
12 to 14 
 
 
≤9
≤11
 
 


 
 


 
 


Anaerobes   Tetracycline 
 
-
 
-
 
-
 
-
 
-
 
-
 
≤4
 

 
≥16
Bacillus  anthracis Doxycycline Tetracycline
 
≤1
≤1
 


 


 


 


 


 


 


 


Brucella  species  Doxycycline Tetracycline
 
≤1
≤1
 


 


 


 


 


 


 


 


Enterobacteriaceae  Doxycycline Tetracycline 
 
≤4
≤4
 


 
≥16
≥16
 
≥14
≥15
 
11 to 13 
12 to 14 
 
≤10
≤11
 


 


 


Franciscella  tularensis Doxycycline Tetracycline
 
 
≤4
≤4
 
 


 
 


 
 


 
 


 
 


 
 


 
 


 
 


Haemophilus  influenzae 
Tetracycline 
 
 
≤2
 
 

 
 
≥8
 

≥29
 
-
26 to 28 
 

≤25
 
 

 
 

 
 

Mycoplasma  pneumoniae Tetracycline
 
 

 
 

 
 

 
 

 
 

 
 

 
 
≤2
 
 

 
 

Neisseria  gonorrhoeae Tetracycline
 
 

 
 

 
 

 
 
≥38
 
 
31 to 37 
 
 
≤30
 
 
≤0.25
 
 
0.5 to 1 
 
 
≥2
Norcardiae and other  aerobic Actinomyces   speciesDoxycycline
 
 
 
≤1
 
 
 
2 to 4 
 
 
 
≥8
 
 
 

 
 
 

 
 
 

 
 
 

 
 
 

 
 
 

Streptococcus  pneumonia
Doxycycline 
Tetracycline 
 
 
<0.25
≤1
 
 
0.5

 
 
≥1 
≥4
 
 
≥28 
≥28
 
 
25 to 27
25 to 27 
 
 
<24
≤24
 
 
-

 
 
-

 
 
-

Vibrio  cholerae 
Doxycycline 
Tetracycline 
 
≤4
≤4
 


 
≥16
≥16
 


 


 


 


 


 


Yersinia  pestis 
Doxycycline 
Tetracycline 
 
≤4
≤4
 


 
≥16
≥16
 


 


 


 


 


 


Ureaplasma  urealyticum 
Tetracycline 
 
 

 
 

 
 

 
 

 
 

 
 

 
 
≤1
 
 

 
 
≥2

*  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. 

 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.

 Gonococci  with  30  mcg  tetracycline  disk  zone  diameters  of  less  than  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 per   mL).


A  report  of  Susceptible  (S) indicates  that  the  antimicrobial  is  likely  to inhibit  growth  of  the  microorganism if  the  antimicrobial  drug reaches  the  concentrations  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  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 or 30 mcg tetracycline disk, the  criteria  noted  in  should  be  achieved.


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

 

QC Strain 
Minimal Inhibitory  Concentration (mcg per   mL) 
Zone Diameter   (mm) 
Agar Dilution (mcg per   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 ATCC43055
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
 
 

 
 

 
 
0.125 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

* ATCC is the American Type Culture Collection

INDICATIONS  AND  USAGE

To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline capsules, USP and other antibacterial drugs, doxycycline capsules, 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 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 microorganisms, 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.



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, including doxycycline, 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 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. 


Clostridium  difficile  associated  diarrhea  (CDAD)  has  been  reported   with  use  of  nearly  all antibacterial  agents,  including doxycycline capsules,  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.


Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including doxycycline capsules. 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 capsules 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  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.


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  embryo  toxicity  has  been  noted  in animals  treated  early  in  pregnancy.  If  any  tetracycline  is  used  during  pregnancy  or  if  the  patient  becomes  pregnant  while taking  these  drugs,  the  patient  should  be  apprised  of  the  potential  hazard  to  the  fetus.


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 preparations, use of this drug may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, doxycycline  capsules 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 Monohydrate capsules 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:

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 eruptions, 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.)
–not to use outdated or poorly stored doxycycline.
–that the use of doxycycline might increase the incidence of vaginal candidiasis.
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.

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

Laboratory Tests:

In venereal disease 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.

In long-term therapy, periodic laboratory evaluations 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.

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

The concurrent use of tetracycline and 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 the carcinogenic potential of doxycycline have not been conducted. However, there has been evidence of oncogenic activity in rats in studies with related antibacterial, 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 (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.
Pregnancy Category   D:
 

There are no adequate and well-controlled studies on the use of doxycycline in pregnant 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.8

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.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

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 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

Due to oral doxycycline’s virtually complete absorption, side effects to the lower bowel, particularly diarrhea, have been infrequent. The following adverse reactions have been observed in patients receiving tetracyclines.

Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region, and pancreatitis. Hepatotoxicity has been reported. These reactions have been caused by both the oral and parenteral administration of tetracyclines. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving capsule and tablet forms of drugs in the tetracycline class. Most of these patients took medications immediately before going to bed. (See DOSAGE AND ADMINISTRATION.)

Skin: Maculopapular and erythematous rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported. 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, serum sickness, pericarditis, and exacerbation of systemic lupus erythematosus.

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

Other: Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines. (See PRECAUTIONS-General.)

When given over prolonged periods, tetracyclines have been reported to produce brown-black microscopic discoloration of the thyroid gland. No abnormalities of thyroid function 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 it would not be of benefit in treating cases of overdosage.

Doxycycline Monohydrate Dosage and Administration

THE  USUAL  DOSAGE  AND  FREQUENCY  OF  ADMINISTRATION  OF  DOXYCYCLINE  DIFFERS  FROM  THAT  OF THE  OTHER  TETRACYCLINES.  EXCEEDING  THE  RECOMMENDED  DOSAGE  MAY  RESULT  IN   AN INCREASED INCIDENCE OF SIDE  EFFECTS.


Adults:  The  usual  dose  of  oral doxycycline  is  200  mg  on  the  first  day  of  treatment  (administered  100   mg every  12  hours   or 50 mg every 6 hours) followed by a maintenance dose of 100 mg/day. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended.


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 per kg of body weight divided into two doses on the first day of treatment, followed by a maintenance dose of 2.2 mg per kg of body weight (given as a single daily dose or divided into twice daily doses). For pediatric patients weighing over 45 kg, the usual adult dose should be used.


The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.


When used in streptococcal infections, therapy should be continued for 10 days.


Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS)


If gastric irritation occurs, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk.


Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of doxycycline in patients with renal impairment. 


Uncomplicated gonococcal infections in adults (except anorectal infections in men): 100 mg, by mouth, twice a day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose.


Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg, by mouth, twice a day for at least 10 days.

Primary and secondary syphilis: 300 mg a day in divided doses for at least 10 days.


Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis: 100 mg, by mouth, twice a day for at least 7 days.


Nongonococcal urethritis caused by C. trachomatis and U. urealyticum: 100 mg, by mouth, twice a day for at least 7 days.


Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice a day for at least 10 days.


Inhalational anthrax (post-exposure): ADULTS: 100 mg of doxycycline, by mouth, twice a day for 60 days. CHILDREN: weighing less than 45 kg; 2.2 mg/kg of body weight, by mouth, twice a day for 60 days. Children weighing 45 kg or more should receive the adult dose.

How is Doxycycline Monohydrate Supplied

Doxycycline capsules USP, 75   mg   are opaque brown cap/opaque white body hard gelatin capsules size “2” having imprinting “A” on cap with black ink and “241” on body with black ink filled with yellow to brown granular powder. Each   capsule   contains   doxycycline   monohydrate    equivalent   to   75   mg   doxycycline.


NDC   46708-249-30    bottle   of    30  capsules

NDC   46708-249-31    bottle   of    100  capsules


Doxycycline  capsules USP, 100   mg   are opaque brown cap/opaque yellow body hard gelatin capsules size “1” having imprinting “A” on cap with white ink and “242” on body with brown ink filled with yellow to brown granular powder. Each   capsule   contains   doxycycline   monohydrate   equivalent  to   100   mg  doxycycline.


NDC   46708-250-30    bottle   of    30   capsules

NDC   46708-250-50    bottles   of    50   capsules

NDC   46708-250-60    bottle  of     60   capsules

NDC   46708-250-61    bottle   of    250   capsules


Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Dispense  in a  tight  light- resistant   container   as  defined   in   the  USP/NF. 

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.

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

REFERENCES

1.      Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility  Testing; Twenty-Seventh Informational Supplement, CLSI document M100-S27 [2017]. CLSI document M100S23, Clinical  Laboratory Standards  Institute,  950 West  Valley  Road,  Suite  2500,  Wayne  Pennsylvania  19087,  USA. 


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  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  Laboratory  Standards Institute,  950 West  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  M45­A3 [2015],  Clinical  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  Laboratory  Standards  Institute,  950 West  Valley  Road,  Suite  2500,  Wayne  Pennsylvania  19087,  USA.


6.      Clinical  and  Laboratory  Standards  Institute  (CLSI).  Methods  for  Mycobacteria,  Nocardiae,  and  Other  Aerobic  Actinomycetes;  Approved  Standard  –  Second  Edition.  CLSI  document  M24-A2 [2011],  Clinical  Laboratory  Standards Institute,  950 West  Valley  Road,  Suite  2500,  Wayne  Pennsylvania  19087,  USA.


7.      Clinical  and  Laboratory  Standards  Institute  (CLSI).  Methods  for  Antimicrobial  Susceptibility  Testing  for  Human Mycoplasmas;  Approved  Guideline.  CLSI  document  M43-A [2011],  Clinical  Laboratory  Standards  Institute,  950  West Valley Road, Suite 2500, Wayne Pennsylvania 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. 


Manufactured by:

Alembic Pharmaceuticals Limited

(Formulation Division),

Village Panelav, P.O. Tajpura,
Near Baska, Taluka-Halol,
Panchmahal 389350, Gujarat, India 


  

Revised: 04/2017



PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 75 mg


Doxycycline Capsules, USP 75 mg (30's bottle pack)
Each capsule contains Doxycycline Monohydrate, equivalent to 75 mg of doxycycline USP .
46708-249-30



PACKAGE LABEL.PRINCIPAL DISPLAY PANEL 100 mg

Doxycycline Capsules, USP 100 mg (30's bottle pack)
Each capsule contains Doxycycline Monohydrate,  equivalent to 100 mg of doxycycline USP .
46708-250-30


DOXYCYCLINE 
doxycycline capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:46708-249
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE (DOXYCYCLINE ANHYDROUS) DOXYCYCLINE ANHYDROUS 75 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
POVIDONE  
SILICON DIOXIDE  
MAGNESIUM STEARATE  
FERROSOFERRIC OXIDE  
FERRIC OXIDE RED  
FERRIC OXIDE YELLOW  
TITANIUM DIOXIDE  
GELATIN  
SODIUM LAURYL SULFATE  
SHELLAC  
PROPYLENE GLYCOL  
POTASSIUM HYDROXIDE  
Product Characteristics
Color BROWN (opaque browncap opaque white body) Score no score
Shape CAPSULE Size 18mm
Flavor Imprint Code A;241
Contains     
Packaging
# Item Code Package Description
1 NDC:46708-249-30 30 CAPSULE in 1 BOTTLE
2 NDC:46708-249-31 100 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA209165 07/31/2017
DOXYCYCLINE 
doxycycline capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:46708-250
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
DOXYCYCLINE (DOXYCYCLINE ANHYDROUS) DOXYCYCLINE ANHYDROUS 100 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
POVIDONE  
SILICON DIOXIDE  
MAGNESIUM STEARATE  
FERROSOFERRIC OXIDE  
FERRIC OXIDE RED  
FERRIC OXIDE YELLOW  
TITANIUM DIOXIDE  
GELATIN  
SODIUM LAURYL SULFATE  
SHELLAC  
PROPYLENE GLYCOL  
POTASSIUM HYDROXIDE  
BROWN IRON OXIDE  
Product Characteristics
Color BROWN (opaque brown cap opaque yellow body) Score no score
Shape CAPSULE Size 20mm
Flavor Imprint Code A;242
Contains     
Packaging
# Item Code Package Description
1 NDC:46708-250-30 30 CAPSULE in 1 BOTTLE
2 NDC:46708-250-50 50 CAPSULE in 1 BOTTLE
3 NDC:46708-250-60 60 CAPSULE in 1 BOTTLE
4 NDC:46708-250-61 250 CAPSULE in 1 BOTTLE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA209165 07/31/2017
Labeler - Alembic Pharmaceuticals Limited (650574663)
Establishment
Name Address ID/FEI Operations
Alembic Pharmaceutical Limited (Formulation Division) 650574671 MANUFACTURE(46708-249, 46708-250)
Revised: 08/2017
 
Alembic Pharmaceuticals Limited
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