Included as part of the "PRECAUTIONS" Section
Tooth Discoloration And Enamel Hypoplasia
The use of LYMEPAK 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 of the tetracycline class, but
it has been observed following repeated short-term courses. Enamel hypoplasia has also been
reported with drugs of the tetracycline class. Advise the patient of the potential risk to the fetus if
LYMEPAK is used during the second or third trimester of pregnancy [see Use In Specific Populations].
Inhibition Of Bone Growth
The use of LYMEPAK during the second and third trimester of pregnancy, infancy and
childhood up to the age of 8 years may cause reversible inhibition of bone growth. All
tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula
growth rate has been observed in premature 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. Advise
the patient of the potential risk to the fetus if LYMEPAK is used during the second or third
trimester of pregnancy [see Use In Specific Populations ].
Clostridium Difficile Associated Diarrhea
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all
antibacterial agents, including LYMEPAK, 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.
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 LYMEPAK, and treatment should be
discontinued at the first evidence of skin erythema.
Severe Skin Reactions
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, discontinue LYMEPAK immediately and initiate
The Jarisch-Herxheimer reaction is a self-limiting systemic reaction that has been reported after
the initiation of doxycycline therapy in up to 30% of patients with early Lyme disease. The
reaction begins one to two hours after initiation of therapy and disappears within 12 to 24 hours.
It is characterized by fever, chills, myalgias, headache, exacerbation of cutaneous lesions,
tachycardia, hyperventilation, vasodilation with flushing, and mild hypotension. The
pathogenesis of the Jarisch-Herxheimer reaction is unknown, but thought to be due to the release
of spirochetal heat-stable pyrogen. Advise the patient of this reaction before starting LYMEPAK.
Administer fluids and antipyretics to alleviate symptoms and duration of the reaction if severe.
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 LYMEPAK should be avoided
because isotretinoin is also known to cause pseudotumor cerebri.
Although IH may improve 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.
The antianabolic action of the tetracyclines, including LYMEPAK may cause an increase in
BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients
with renal impairment.
Development Of Drug Resistant Bacteria
Prescribing LYMEPAK in the absence of a proven or strongly suspected bacterial infection or a
prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the
development of drug-resistant bacteria
Potential For Microbial Overgrowth
As with other antibacterial drugs, use of LYMEPAK may result in overgrowth of nonsusceptible
organisms, including fungi. If such infections occur, discontinue doxycycline and
institute appropriate therapy.
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
Likewise, although mutagenicity studies of doxycycline have not been conducted, positive
results using in vitro mammalian cell assays have been reported for related antibacterial drugs
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.
Use In Specific Populations
LYMEPAK, like other tetracycline-class antibacterial drugs, may cause discoloration of
deciduous teeth and reversible inhibition of bone growth when administered during the second
and third trimester of pregnancy [see WARNINGS AND PRECAUTIONS, Data, Pediatric Use]. Available data from published studies over decades have not shown a
difference in major birth defect risk compared to unexposed pregnancies with doxycycline
exposure in the first trimester of pregnancy (see Data). There are no available data on the risk of
miscarriage following exposure to doxycycline in pregnancy.
The estimated background risk of major birth defects and miscarriage for the indicated
population is unknown. All pregnancies have a background risk of birth defect, loss, or other
adverse outcomes. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
A retrospective cohort study of 1,690 pregnant patients who received doxycycline prescriptions
in the first trimester of pregnancy compared to an unexposed pregnant cohort showed no
difference in the major malformation rate. There is no information on the dose or duration of
treatment, or if the patients actually ingested the doxycycline that was prescribed.
Other published studies on exposure to doxycycline in the first trimester of pregnancy have small
sample sizes; however, these studies have not shown an increased risk of major malformations.
The use of tetracyclines during tooth development (second and third trimester of pregnancy) 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
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 also has been noted in animals treated early in
pregnancy [see WARNINGS AND PRECAUTIONS].
Based on available published data, doxycycline is present in human milk. There are no data that
inform the levels of doxycycline in breastmilk, the effects on the breastfed infant, or the effects
on milk production. Because there are other antibacterial drug options available to treat Lyme
disease in lactating women and because of the potential for serious adverse reactions, including
tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not
recommended during treatment with LYMEPAK and for 5 days after the last dose.
The safety and efficacy of LYMEPAK has been established in pediatric patients 8 years of age
and older, weighing 45 kg and greater.
Because of the effects of the tetracycline-class of drugs on tooth development and growth, use of
LYMEPAK in pediatric patients younger than 8 years of age, weighing less than 45 kg is not
recommended [see WARNINGS AND PRECAUTIONS].
Clinical studies of LYMEPAK did not report specific treatment outcomes of patients aged 65
and over to determine whether they respond differently from younger subjects.
The use of tetracyclines has been associated with hepatotoxicity.
Studies have shown no significant difference in the serum half-life of doxycycline [see CLINICAL PHARMACOLOGY]. No dosage adjustment is warranted in patients with renal impairment.