Included as part of the PRECAUTIONS section.
ORACEA should not be used during pregnancy. Doxycycline,
like other tetracycline-class antibiotics, can cause fetal harm when
administered to a pregnant woman. If any tetracycline is used during pregnancy
or if the patient becomes pregnant while taking these drugs, the patient should
be informed of the potential hazard to the fetus and treatment stopped
The use of drugs of the tetracycline-class during tooth
development (last half of pregnancy, infancy, and childhood up 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 drug but has been
observed following repeated short-term courses. Enamel hypoplasia has also been
reported. Tetracycline drugs, therefore, should not be used during tooth
development unless other drugs are not likely to be effective or are
All tetracyclines form a stable calcium complex in any
bone-forming tissue. A decrease in fibula growth rate has been observed in
premature human infants 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 cause retardation of skeletal development on
the developing fetus. Evidence of embryotoxicity has been noted in animals
treated early in pregnancy.
Clostridium difficile associated diarrhea (CDAD) has been
reported with nearly all antibacterial agents, including doxycycline, and may
range in severity from mild 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.
The anti-anabolic action of the tetracyclines may cause
an increase in BUN. While this is not a problem in those with normal renal
function, in patients with significantly impaired function, higher serum levels
of tetracycline-class antibiotics may lead to azotemia, hyperphosphatemia, and
acidosis. If renal impairment exists, even usual oral or parenteral doses may
lead to excessive systemic accumulations of the drug and possible liver
toxicity. Under such conditions, lower than usual total doses are indicated,
and if therapy is prolonged, serum level determinations of the drug may be
Photosensitivity manifested by an exaggerated sunburn
reaction has been observed in some individuals taking tetracyclines. Although
this was not observed during the duration of the clinical studies with ORACEA,
patients should minimize or avoid exposure to natural or artificial sunlight
(tanning beds or UVA/B treatment) while using ORACEA. If patients need to be outdoors
while using ORACEA, they should wear loose-fitting clothes that protect skin
from sun exposure and discuss other sun protection measures with their
Tetracyclines have been associated with the development
of autoimmune syndromes. Symptoms may be manifested by fever, rash, arthralgia,
and malaise. In symptomatic patients, liver function tests, ANA, CBC, and other
appropriate tests should be performed to evaluate the patients. Use of all tetracycline-class
drugs should be discontinued immediately.
Tetracycline-class drugs are known to cause
hyperpigmentation. Tetracycline therapy may induce hyperpigmentation in many
organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral
cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral
pigmentation has been reported to occur independently of time or amount of drug
administration, whereas other pigmentation has been reported to occur upon
prolonged administration. Skin pigmentation includes diffuse pigmentation as
well as over sites of scars or injury.
Pseudotumor cerebri (benign intracranial hypertension) in
adults has been associated with the use of tetracyclines. The usual clinical
manifestations are headache and blurred vision. Bulging fontanels have been
associated with the use of tetracyclines in infants. While both of these conditions
and related symptoms usually resolve after discontinuation of the tetracycline,
the possibility for permanent sequelae exists. Patients should be questioned
for visual disturbances prior to initiation of treatment with tetracyclines and
should be routinely checked for papiledema while on treatment.
Development of Drug Resistant Bacteria
Bacterial resistance to tetracyclines may develop in
patients using ORACEA. Because of the potential for drug-resistant bacteria to
develop during the use of ORACEA, it should only be used as indicated.
As with other antibiotic preparations, use of ORACEA may
result in overgrowth of non-susceptible microorganisms, including fungi. If
superinfection occurs, ORACEA should be discontinued and appropriate therapy
instituted. Although not observed in clinical trials with ORACEA, the use of
tetracyclines may increase the incidence of vaginal candidiasis. ORACEA should
be used with caution in patients with a history of or predisposition to Candida
Periodic laboratory evaluations of organ systems,
including hematopoietic, renal and hepatic studies should be performed.
Appropriate tests for autoimmune syndromes should be performed as indicated.
Patient Counseling Information
See FDA-approved patient
labeling (PATIENT INFORMATION)
Patients taking ORACEA Capsules 40 mg should receive the
following information and instructions:
- It is recommended that ORACEA not be used by individuals
of either gender who are attempting to conceive a child
- It is recommended that ORACEA not be used by pregnant or
breast feeding women
- Patients should be advised that pseudomembranous colitis
can occur with doxycycline therapy. If patients develop watery or bloody
stools, they should seek medical attention.
- Patients should be advised that
pseudotumor cerebri can occur with doxycycline therapy.
If patients experience headache or blurred vision they should seek medical
- Photosensitivity manifested by
an exaggerated sunburn reaction has been observed in some individuals taking
tetracyclines, including doxycycline. Patients should minimize or avoid exposure to natural or artificial
sunlight (tanning beds or UVA/B treatment) while using doxycycline. If patients
need to be outdoors while using doxycycline, they should wear loose-fitting
clothes that protect skin from sun exposure and discuss other sun protection
measures with their physician. Treatment should be discontinued at the first
evidence of sunburn.
- Concurrent use of doxycycline
may render oral contraceptives less effective.
- Autoimmune syndromes, including drug-induced lupus-like
syndrome, autoimmune hepatitis, vasculitis and serum sickness have been
observed with tetracycline-class drugs, including doxycycline. Symptoms may be
manifested by arthralgia, fever, rash and malaise. Patients who experience such
symptoms should be cautioned to stop the drug immediately and seek medical
- Patients should be counseled
about discoloration of skin, scars, teeth or gums that can arise from
- Take ORACEA exactly as
directed. Increasing doses beyond 40 mg every
morning may increase the likelihood that bacteria will develop resistance and
will not be treatable by other antibacterial drugs in the future.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Doxycycline was assessed for potential to induce
carcinogenesis in a study in which the compound was administered to
Sprague-Dawley rats by gavage at dosages of 20, 75, and 200 mg/kg/day for two
years. An increased incidence of uterine polyps was observed in female rats
that received 200 mg/kg/day, a dosage that resulted in a systemic exposure to
doxycycline approximately 12.2 times that observed in female humans who use
ORACEA [exposure comparison based upon area under the curve (AUC) values]. No
impact upon tumor incidence was observed in male rats up to at 200 mg/kg/day,
or in females at the lower dosages studied.
Doxycyline was assessed for potential to induce
carcinogenesis in CD-1 mice by gavage at dosages 20, 75, and 150 mg/kg/day in
males and at dosages of 20, 100, and 300 mg/kg/day in females. No impact upon
tumor incidence was observed in male and female mice at systemic exposures
approximately 4.2 and 8.3 times that observed in humans, respectively.
Doxycycline demonstrated no potential to cause genetic
toxicity in an in vitro point mutation study with mammalian cells (CHO/HGPRT
forward mutation assay) or in an in vivo micronucleus assay conducted in CD-1
mice. However, data from an in vitro mammalian chromosomal aberration assay
conducted with CHO cells suggest that doxycycline is a weak clastogen. Oral
administration of doxycycline to male and female Sprague-Dawley rats adversely
affected fertility and reproductive performance, as evidenced by increased time
for mating to occur, reduced sperm motility, velocity, and concentration,
abnormal sperm morphology, and increased pre-and post-implantation losses.
Doxycycline induced reproductive toxicity at all dosages that were examined in
this study, as even the lowest dosage tested (50 mg/kg/day) induced a
statistically significant reduction in sperm velocity. Note that 50 mg/kg/day
is approximately 3.6 times the amount of doxycycline contained in the
recommended daily dose of ORACEA when compared on the basis of AUC estimates.
Although doxycycline impairs the fertility of rats when administered at sufficient
dosage, the effect of ORACEA on human fertility is unknown.
Use In Specific Populations
Pregnancy Category D [see WARNINGS
AND PRECAUTIONS]. Results from animal studies indicate that
doxycycline crosses the placenta and is found in fetal tissues.
Tetracyclines are excreted in human milk. Because of the
potential for serious adverse reactions in infants from doxycycline, ORACEA
should not be used in mothers who breastfeed.
ORACEA should not be used in infants and children less
than 8 years of age [see WARNINGS AND PRECAUTIONS].
ORACEA has not been studied in children of any age with regard to safety or
efficacy, therefore use in children is not recommended.
Clinical studies of ORACEA did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. Other reported clinical experience has not
identified differences in responses between elderly and younger patients. In
general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and concomitant disease or
other drug therapy.