Doxycycline (1113)

CATEGORIES, DRUG CLASSES, BRAND NAMES & COST OF THERAPY

Subgingival Application

Microbiology

Doxycycline is a broad-spectrum semisynthetic tetracycyline. 1

Doxycycline is bacteriostatic, inhibiting bacterial protein synthesis due to disruption of transfer RNA and messenger RNA at ribosomal sites. ¹ In vitro testing has shown that Porphyromonas gingivalis, Prevotella intermedia, Campylobacter rectus, and Fusobacterium nucleatum, which are associated with periodontal disease, are susceptible to doxycycline at concentrations ≤6.0 μg/ml. ² A single-center, single-blind, randomized, clinical study in 45 subjects with periodontal disease demonstrated that a single treatment with doxycycline hyclate resulted in the reduction in the numbers of P. gingivalis, P. intermedia, C. rectus, F. nucleatum, Bacteroides forsythus, and E. corrodens in subgingival plaque samples. Levels of aerobic and anaerobic bacteria were also reduced after treatment with doxycycline hyclate. The clinical significance of these findings, however, is not known. During these studies, no overgrowth of opportunistic organisms such as gram-negative bacilli and yeast were observed. However, as with other antibiotic preparations, doxycycline hyclate therapy may result in the overgrowth of nonsusceptible organisms including fungi. (See PRECAUTIONS.)

Pharmacokinetics

In a clinical pharmacokinetic study, subjects were randomized to receive either doxycycline hyclate covered with Coe-Pak periodontal dressing (n=13), doxycycline hyclate covered with Octyldent periodontal adhesive (n=13), or oral doxycycline (n=5) (according to package dosing instructions). The doxycycline release characteristics in gingival crevicular fluid (GCF), saliva, and serum were evaluated.

Doxycycline levels in GCF peaked (∼1500 μg/ml and ∼2000 μg/ml for Coe-Pak and Octyldent groups, respectively) 2 hours following treatment with doxycycline hyclate. These levels remained above 1000 μg/ml through 18 hours, at which time the levels began to decline gradually. However, local levels of doxycycline remained well above the minimum inhibitory concentration (MIC₉₀) for periodontal pathogens (≤6.0 μg/ml) ² through Day 7. In contrast, subjects receiving oral doxycycline had peak GCF levels of ∼2.5 μg/ml at 12 hours following the initial oral dosing with levels declining at ∼0.2 μg/ml by Day 7. High variability was observed for doxycycline levels in GCF for both oral and doxycycline hyclate subgingival application treatment groups.

The maximum concentration of doxycycline in saliva was achieved at 2 hours after both treatments with doxycycline hyclate, with means of 4.05 μg/ml and 8.78 μg/ml and decreased to 0.36 μg/ml and 0.23 μg/ml at Day 7 for the Coe-Pak group and the Octyldent group, respectively.

Capsules

After oral administration, doxycycline hyclate is rapidly and nearly completely absorbed from the gastrointestinal tract. Doxycycline is eliminated with a half-life of approximately 18 hours by renal and fecal excretion of unchanged drug.

Mechanism of Action

Doxycycline has been shown to inhibit collagenase activity in vitro. ¹ Additional studies have shown that doxycycline reduces the elevated collagenase activity in the gingival crevicular fluid of patients with adult periodontitis. ^2,3 The clinical significance of these findings is not known.

Microbiology

Doxycycline is a member of the tetracycline class of antibiotics. The dosage of doxycycline achieved with this product during administration is well below the concentration required to inhibit microorganisms commonly associated with adult periodontitis. Clinical studies with this product demonstrated no effect on total anaerobic and facultative bacteria in plaque samples from patients administered this dose regimen for 9-18 months. This product should not be used for reducing the numbers of or eliminating those microorganisms associated with periodontitis.

Pharmacokinetics

The pharmacokinetics of doxycycline following oral administration of doxycycline hyclate were investigated in 3 volunteer studies involving 87 adults. Additionally, doxycycline pharmacokinetics have been characterized in numerous scientific publications. ⁴ Pharmacokinetic parameters for doxycycline hyclate following single oral doses and at steady-state in healthy subjects are presented in TABLE 1.

TABLE 1 Pharmacokinetic Parameters for Doxycycline Hyclate Capsules     Cmax Tmax Cl/F T½   n (ng/ml) (h) (L/h) (h) Single dose 20 mg 42 400 ± 142 1.5 (0.5−4.0) 3.80 ± 0.85 18.4 ± 5.38 Steady-state 20 mg bid 30 790 ± 285 2 (0.98−12.0) 3.76 ± 1.06 Not determined

Absorption

Doxycycline is virtually completely absorbed after oral administration. Following 20 mg doxycycline, twice a day, in healthy volunteers, the mean peak concentration in plasma was 790 ng/ml and the average steady-state concentration was 482 ng/ml. The effect of food on the absorption of doxycycline from doxycycline hyclate has not been studied.

Distribution

Doxycycline is greater than 90% bound to plasma proteins. Its apparent volume of distribution is variously reported as between 52.6 and 134 L. 4,6

Metabolism

Major metabolites of doxycycline have not been identified. However, enzyme inducers such as barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline.

Excretion

Doxycycline is excreted in the urine and feces as unchanged drug. It is variously reported that between 29% and 55.4% of an administered dose can be accounted for in the urine by 72 hours. ^5,6 Half-life averaged 18 hours in subjects receiving a single 20 mg doxycycline dose.

Special Populations

Geriatric

Doxycycline pharmacokinetics have not been evaluated in geriatric patients.

Pediatric

Doxycycline pharmacokinetics have not been evaluated in pediatric patients (see WARNINGS).

Gender

A study was conducted in 42 subjects where doxycycline pharmacokinetics were compared in men and women. It was observed that C_max was approximately 1.7-fold higher in women than in men. There were no apparent differences in other pharmacokinetic parameters.

Race

Differences in doxycycline pharmacokinetics among racial groups have not been evaluated.

Renal Insufficiency

Studies have shown no significant difference in serum half-life of doxycycline in patients with normal and severely impaired renal function. Hemodialysis does not alter the half-life of doxycycline.

Hepatic Insufficiency

Doxycycline pharmacokinetics have not been evaluated in patients with hepatic insufficiency.

Drug Interactions

See DRUG INTERACTIONS.

Subgingival Application

In two well-controlled, multicenter, parallel-design, 9 month clinical trials, 831 patients (Study 1 = 411; Study 2 = 420) with chronic adult periodontitis characterized by a mean probing depth of 5.9-6.0 mm were enrolled. Subjects received 1 of 4 treatments: (1) doxycycline hyclate, (2) scaling and root planing, (3) vehicle control, or (4) oral hygiene. Treatment was administered to sites with probing depths 5 mm or greater that bled on probing. Subjects with detectable subgingival calculus on greater than 80% of all tooth surfaces were excluded from enrollment. All subjects received a second administration of the initially randomized treatment 4 months after their Baseline treatment. Changes in the efficacy parameters, attachment level, pocket depth, and bleeding on probing, between Baseline and month 9 showed that: (1) doxycycline hyclate was superior to vehicle control and oral hygiene, and (2) doxycycline hyclate met the decision rule of being at least 75% as good as scaling and root planing (SRP) (the standard of at least 75% as good as SRP is required for any product approved as a stand alone therapy for periodontitis). Clinicians should note that the studies were of 9 months duration. Additional research would be necessary to establish long term comparability to SRP.

A third clinical trial was conducted to determine whether the product can be left in the pocket to bioabsorb or be expelled naturally and achieve comparable clinical results. In this study the product was retained with Octyldent dental adhesive rather than Coe-Pak periodontal dressing as in the previously mentioned studies. This was a 3-arm, randomized, controlled, parallel group, single blind trial that enrolled 605 subjects. The patient population studied and study design were comparable to that in Studies 1 and 2. Subjects received 1 of 3 treatments: (1) doxycycline hyclate with Coe-Pak removed after 7 days as in the pivotal trials (2) doxycycline hyclate, retained with Octyldent and left to bioabsorb or be expelled naturally or (3) Vehicle Control with Octyldent left to bioabsorb or be expelled naturally. Changes in the efficacy parameters, attachment level, pocket depth and bleeding on probing were equivalent to those observed in Studies 1 and 2. The results of the third study support the use of doxycycline hyclate retained with Octyldent and left to bioabsorb or be expelled naturally.

Capsules

In a randomized, multi-centered, double-blind, 9 month Phase 3 study involving 190 adult patients with periodontal disease [at least 2 probing sites per quadrant of between 5 and 9 mm pocket depth (PD) and attachment level (ALv)], the effects of oral administration of 20 mg twice a day of doxycycline hyclate plus scaling and root planing (SRP) were compared to placebo control plus SRP. Both treatment groups were administered a course of scaling and root planing in 2 quadrants at Baseline. Measurements of ALv, PD and bleeding on probing (BOP) were obtained at Baseline, 3, 6, and 9 months from each site about each tooth in the 2 quadrants that received SRP using the UNC-15 manual probe. Each tooth site was categorized into 1 of 3 strata based on Baseline PD: 0-3 mm (no disease), 4-6 mm (mild/moderate disease), ≥7 mm (severe disease). For each stratum and treatment group, the following were calculated at month 3, 6, and 9: mean change in ALv from baseline, mean change in PD from baseline, mean percentage of tooth sites per patient exhibiting attachment loss of ≥2 mm from baseline, and percentage of tooth sites with bleeding on probing. The results are summarized in TABLE 2.

TABLE 2 Clinical Results at 9 Months as an Adjunct to SRP   Baseline Pocket Depth   0-3 mm 4-6 mm ≥7 mm Parameter n=90 n=90 n=79 Mean Gain in ALv   Doxycycline hyclate 20 mg bid 0.25 mm 1.03 mm* 1.55 mm*   Placebo 0.20 mm 0.86 mm 1.17 mm Mean Decrease in PD   Doxycycline hyclate 20 mg bid 0.16 mm† 0.95 mm† 1.68 mm†   Placebo 0.05 mm 0.69 mm 1.20 mm % of Sites With Loss of ALv ≥2 mm   Doxycycline hyclate 20 mg bid 1.9% 1.3% 0.3%*   Placebo 2.2% 2.4% 3.6% % of Sites With BOP   Doxycycline hyclate 20 mg bid 39%† 64%* 75%   Placebo 46% 70% 80%

* p <0.050 versus the placebo control group.

† p <0.010 versus the placebo control group.

Subgingival Application

General

Doxycycline hyclate has not been clinically tested in pregnant women.

Doxycycline hyclate has not been clinically evaluated in patients with conditions involving extremely severe periodontal defects with very little remaining periodontium.

Doxycycline hyclate has not been clinically tested for use in the regeneration of alveolar bone, either in preparation for or in conjunction with the placement of endosseous (dental) implants or in the treatment of failing implants.

Doxycycline hyclate has not been clinically tested in immunocompromised patients (such as patients immunocompromised by diabetes, chemotherapy, radiation therapy, or infection with HIV).

As with other antibiotic preparations, doxycycline hyclate therapy may result in overgrowth of nonsusceptible organisms, including fungi. 1 The effects of prolonged treatment, greater than 6 months, have not been studied.

Doxycycline hyclate should be used with caution in patients with a history of or predisposition to oral candidiasis. The safety and effectiveness of doxycycline hyclate have not been established for the treatment of periodontitis in patients with coexistent oral candidiasis.

Information for the Patient

Mechanical oral hygiene procedures (i.e., tooth brushing, flossing) should be avoided on any treated areas for 7 days.

Avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline.

Doxycycline may decrease the effectiveness of birth control pills.

Carcinogenesis, Mutagenesis, and 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 antibiotics, 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 antibiotics (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 Category D

See WARNINGS.

Nursing Mothers

Tetracycylines appear in breast milk following oral administration. It is not known whether doxycycline is excreted in human milk following use of doxycycline hyclate. 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

The safety and effectiveness of doxycycline hyclate in pediatric patients have not been established. Oral doses of doxycycline in children up to 8 years of age have caused permanent discoloration of teeth.

Capsules

While no overgrowth by opportunistic microorganisms such as yeast were noted during clinical studies, as with other antimicrobials, doxycycline hyclate therapy may result in overgrowth of nonsusceptible microorganisms including fungi.

The use of tetracyclines may increase the incidence of vaginal candidiasis.

Doxycycline hyclate should be used with caution in patients with a history or predisposition to oral candidiasis. The safety and effectiveness of doxycycline hyclate has not been established for the treatment of periodontitis in patients with coexistent oral candidiasis.

If superinfection is suspected, appropriate measures should be taken.

Laboratory Tests

In long term therapy, periodic laboratory evaluations of organ systems, including hematopoietic, renal, and hepatic studies should be performed.

Drug/Laboratory Test Interactions

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

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Doxycycline hyclate has not been evaluated for carcinogenic potential in long-term animal studies. Evidence of oncogenic activity was obtained in studies with related compounds (i.e., oxytetracycline [adrenal and pituitary tumors] and minocycline [thyroid tumors]).

Doxycycline hyclate 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 assay with CHO cells for potential to cause chromosomal aberrations suggest that doxycycline hyclate is a weak clastogen.

Oral administration of doxycycline hyclate 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 hyclate 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 10 times the amount of doxycycline hyclate contained in the recommended daily dose of doxycycline hyclate for a 60 kg human when compared on the basis of body surface area estimates (mg/m²). Although doxycycline impairs the fertility of rats when administered at sufficient dosage, the effect of doxycycline hyclate on human fertility is unknown.

Pregnancy, Teratogenic Effects, Pregnancy Category D

(See WARNINGS.) Results from animal studies indicate that doxycycline crosses the placenta and is found in fetal tissues.

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. Because of the potential for serious adverse reactions in nursing infants from doxycycline, the use of doxycycline hyclate in nursing mothers is contraindicated. (See WARNINGS.)

Pediatric Use

The use of doxycycline hyclate in infancy and childhood is contraindicated. (See WARNINGS.)

Subgingival Application

In clinical trials involving a total of 1436 patients, adverse experiences from all causalities were monitored across treatment groups.

In the Circulatory System category, 10 subjects (1.6%) in the doxycycline hyclate group were reported as having “unspecified essential hypertension”. Only 1 subject (0.2%) in the Vehicle group, and none in the Scaling and Root Planing or Oral Hygiene groups were reported to have “unspecified essential hypertension”. In all cases, the event occurred anywhere from 13-134 days post treatment. There is no known association of oral administration of doxycycline with essential hypertension.

Two patients in the polymer vehicle group and none in the doxycycline hyclate group (0.2% for both groups combined) reported adverse events consistent with a localized allergic response.

Sex, age, race and smoking status did not appear to be correlated with adverse events.

TABLE 3 lists the incidence of treatment-emergent adverse events from all-causalities, across all treatment groups, occurring in ≥1% of the entire study population.

TABLE 3   Doxycycline Vehicle OH SRP Body System Verbatim Terms n=609 n=413 n=204 n=210 Circulatory   High blood pressure 1.6% 0.2% 0.0% 0.0% Digestive   Gum discomfort, pain or soreness; loss of attachment; increased pocket depth 18.1% 23.0% 20.1% 21.0%   Toothache, pressure sensitivity 14.3% 14.3% 10.3% 18.1%   Periodontal abscess, exudate, infection, drainage, extreme mobility, suppuration 9.9% 10.9% 10.3% 8.6%   Thermal tooth sensitivity 7.7% 8.5% 4.4% 6.7%   Gum inflammation, swelling, sensitivity 4.1% 5.8% 5.4% 5.7%   Soft tissue erythema, sore mouth, unspecified pain 4.3% 5.3% 2.7% 6.2%   Indigestion, upset stomach, stomach ache 3.6% 4.1% 2.9% 3.8%   Diarrhea 3.3% 2.4% 1.0% 1.0%   Tooth mobility, bone loss 2.0% 0.7% 0.5% 2.4%   Periapical abscess, lesion 1.5% 1.9% 1.0% 0.5%   Aphthous ulcer, canker sores 0.7% 1.7% 1.0% 1.4%   Fistula 0.8% 1.5% 1.5% 1.0%   Endodontic abscess, pulpitis 1.5% 1.5% 0.0% 0.5%   Jaw pain 1.1% 0.5% 1.0% 1.9%   Tooth loss 0.8% 1.5% 1.5% 0.0%   Bleeding gums 1.0% 0.7% 0.0% 2.4% Genitourinary   Premenstrual tension syndrome 4.4% 3.1% 2.5% 3.3% Ill-Defined Conditions   Headache 27.3% 28.1% 23.5% 23.8%   Cough 3.6% 6.1% 2.9% 2.4%   Sleeplessness 3.4% 1.5% 2.0% 2.9%   Body aches, soreness 1.6% 1.2% 1.5% 1.4%   Nausea and vomiting 1.8% 0.7% 2.5% 0.5%   Fever 1.0% 1.9% 1.0% 1.9% Injury & Poisoning   Broken tooth 5.1% 4.1% 4.9% 5.7% Mental   Tension headache 1.8% 0.7% 0.0% 1.0% Musculoskeletal   Muscle aches 6.4% 4.6% 4.9% 3.3%   Backaches 3.6% 5.3% 2.5% 6.2%   Pain in arms or legs 1.5% 2.2% 2.0% 2.4%   Lower back pain 1.6% 1.7% 0.5% 2.9%   Neck pain 1.3% 1.7% 1.0% 1.9%   Shoulder pain 1.0% 1.0% 1.5% 1.0% Nervous System   Ear infection 1.6% 1.9% 2.0% 0.0% Respiratory   Common cold 25.5% 25.2% 18.1% 16.7%   Flu, respiratory 6.1% 9.0% 3.9% 6.7%   Stuffy head, post nasal drip, congestion 5.6% 7.7% 2.9% 4.8%   Sore throat 5.7% 6.5% 2.0% 3.3%   Sinus infection 5.3% 2.7% 1.0% 1.9%   Flu 2.8% 2.9% 2.9% 3.3%   Bronchitis 2.3% 1.9% 1.5% 1.0%   Allergies 1.0% 1.0% 1.0% 1.9% Skin & Subcutaneous Tissue   Skin infection or inflammation 1.3% 1.0% 1.0% 1.0%

Capsules

Adverse Reactions in Clinical Trials of Doxycycline Hyclate

In clinical trials of adult patients with periodontal disease 213 patients received doxycycline hyclate 20 mg bid over a 9-12 month period. The most frequent adverse reactions occurring in studies involving treatment with doxycycline hyclate or placebo are listed in TABLE 4.

TABLE 4 Incidence (%) of Adverse Reactions in Doxycycline Hyclate Capsules Clinical Trials   Doxycycline Hyclate 20 mg bid Placebo Adverse Reaction (n=213) (n=215) Headache 55 (26%) 56 (26%) Common cold 47 (22%) 46 (21%) Flu symptoms 24 (11%) 40 (19%) Tooth ache 14 (7%) 28 (13%) Periodontal abscess 8 (4%) 21 (10%) Tooth disorder 13 (6%) 19 (9%) Nausea 17 (8%) 12 (6%) Sinusitis 7 (3%) 18 (8%) Injury 11 (5%) 18 (8%) Dyspepsia 13 (6%) 5 (2%) Sore throat 11 (5%) 13 (6%) Joint pain 12 (6%) 8 (4%) Diarrhea 12 (6%) 8 (4%) Sinus congestion 11 (5%) 11 (5%) Coughing 9 (4%) 11 (5%) Sinus headache 8 (4%) 8 (4%) Rash 8 (4%) 6 (3%) Back pain 7 (3%) 8 (4%) Back ache 4 (2%) 9 (4%) Menstrual cramp 9 (4%) 5 (2%) Acid indigestion 8 (4%) 7 (3%) Pain 8 (4%) 5 (2%) Infection 4 (2%) 6 (3%) Gum pain 1 (1%) 6 (3%) Bronchitis 7 (3%) 5 (2%) Muscle pain 2 (1%) 6 (3%)

Note: Percentages are based on total number of study participants in each treatment group.

Adverse Reactions for Tetracyclines

The following adverse reactions have been observed in patients receiving tetracyclines:

Gastrointestinal:  Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with vaginal candidiasis) in the anogenital region. Hepatoxicity has been reported rarely. Rare instances of esophagitis and esophageal ulcerations have been reported in patients receiving the capsule forms of the 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. Exfoliative dermatitis has been reported but is uncommon. (For information concerning photosensitivity, 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.

Subgingival Application

Preparation for Use

1. Remove the pouched product from refrigeration at least 15 minutes prior to mixing.

2. Couple Syringe A (liquid delivery system) and Syringe B (drug powder).

3. Inject the liquid contents of Syringe A (indicated by purple stripe) into Syringe B (doxycycline powder) and then push the contents back into Syringe A. This entire operation is 1 mixing cycle.

4. Complete 100 mixing cycles at a pace of 1 cycle/second using brisk strokes. If immediate use is desired, skip to step 7.

5. If necessary, the coupled syringes can be stored in the resealable pouch at room temperature for a maximum of 3 days.

6. After storage, perform an additional 10 mixing cycles just prior to use. Continue with immediate use instructions.

7. The contents will be in Syringe A (indicated by purple stripe). Hold the coupled syringes vertically with Syringe A at the bottom. Pull back on the Syringe A plunger and allow the contents to flow down the barrel for several seconds.

8. Uncouple the 2 syringes and attach the blunt cannula to Syringe A. Product is now ready for application.

Product Administration

Doxycycline hyclate does not require local anesthesia for placement. Bend the cannula to resemble a periodontal probe and explore the periodontal pocket in a manner similar to periodontal probing. Keeping the cannula tip near the base of the pocket, express the product into the pocket until the formulation reaches the top of the gingival margin. Withdraw the cannula tip from the pocket. In order to separate the tip from the formulation, turn the tip of the cannula towards the tooth, press the tip against the tooth surface, and pinch the string of formulation from the tip of the cannula. Variations on this technique may be needed to achieve separation between doxycycline hyclate and cannula.

If desired, using an appropriate dental instrument, doxycycline hyclate may be packed into the pocket. Dipping the edge of the instrument in water before packing will help keep doxycycline hyclate from sticking to the instrument, and will help speed coagulation of doxycycline hyclate. A few drops of water dripped onto the surface of doxycycline hyclate once in the pocket will also aid in coagulation. If necessary, add more doxycycline hyclate as described above and pack it into the pocket until the pocket is full.

Cover the pockets containing doxycycline hyclate with either Coe-Pak periodontal dressing or Octyldent dental adhesive.

Application of doxycycline hyclate may be repeated 4 months after initial treatment.

Capsules

THE DOSAGE OF DOXYCYCLINE HYCLATE CAPSULES DIFFERS FROM THAT OF DOXYCYCLINE USED TO TREAT INFECTIONS. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS INCLUDING THE DEVELOPMENT OF RESISTANT MICROORGANISMS.

Doxycycline hyclate 20 mg twice daily as an adjunct following scaling and root planing may be administered for up to 9 months. Safety beyond 12 months and efficacy beyond 9 months have not been established.

Doxycycline hyclate should be administered at least 1 hour prior to morning and evening meals.

Administration of adequate amounts of fluid along with the capsules is recommended to wash down the drug and reduce the risk of esophageal irritation and ulceration. (See ADVERSE REACTIONS.)

References

Subgingival Application

1. Stratton C.W., Lorian V.: Mechanisms of Action for Antimicrobial Agents: General Principles and Mechanisms for Selected Classes of Antibiotics. Antibiotics in Laboratory Medicine, 4^th edition, Williams and Wilkins, Baltimore, MD, 1996.

2. Slots J., Rams T.E. Antibiotics in periodontal therapy: advantages and disadvantages. J Clin Periodontol 1990; 17:479-493.

Capsules

1. Golub L.M., Sorsa T., Lee H-M., Ciancio S., Sorbi D., Ramamurthy N.S., Gruber B., Salo T., Konttinen Y.T.: Doxycycline Inhibits Neutrophil (PMN)-type Matrix Metalloproteinases in Human Adult Periodontitis Gingiva. J. Clin. Periodontol 1995; 22: 100-109.

2. Golub L.M., Ciancio S., Ramamurthy N.S., Leung M., McNamara T.F.: Low-dose Doxycycline Therapy: Effect on Gingival and Crevicular Fluid Collagenase Activity in Humans. J. Periodont Res 1990; 25: 321-330.

3. Golub L.M., Lee H.M., Greenwald R.A., Ryan M.E., Salo T., Giannobile W.V.: A Matrix Metalloproteinase Inhibitor Reduces Bone-type Collagen Degradation Fragments and SpecificCollegenases in Gingival Crevicular Fluid During Adult Periodontitis. Inflammation Research 1997; 46: 310-319.

4. Saivain S., Houin G.: Clinical Pharmacokinetics of Doxycycline and Minocycline. Clin. Pharmacokinetics 1988; 15; 355-366.

5. Schach von Wittenau M., Twomey T.: The Disposition of Doxycycline by Man and Dog. Chemotherapy 1971; 16: 217-228.

6. Campistron G., Coulais Y., Caillard C., Mosser J., Pontagnier H., Houin G.: Pharmacokinetics and Bioavailability of Doxycycline in Humans. Arzneimittel Forschung 1986; 36: 1705-1707.

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN). This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POST-EXPOSURE), UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED.

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light, should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

The 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.

Use in Pregnancy

(See above WARNINGS about use during tooth development.)

Doxycycline hyclate for injection has not been studied in pregnant patients. It should not be used in pregnant women unless, in the judgment of the physician, it is essential for the welfare of the patient.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy.

Use in Children

The use of doxycycline hyclate for injection in children under 8 years is not recommended because safe conditions for its use have not been established.

(See above WARNINGS about use during tooth development.)

As with other tetracyclines, doxycycline forms a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued.

Tetracyclines are present in the milk of lactating women who are taking a drug in this class.

Gastrointestinal:  Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, and inflammatory lesions (with monilial overgrowth) in the anogenital region. Hepatotoxicity has been reported rarely. These reactions have been caused by both the oral and parenteral administration of tetracyclines.

Skin:  Maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is uncommon. Photosensitivity is discussed above. (See WARNINGS.)

Renal Toxicity:  Rise in BUN has been reported and is apparently dose related. (See WARNINGS.)

Hypersensitivity Reactions:  Urticaria, angioneurotic edema, anaphylaxis, anaphylactoid purpura, pericarditis and exacerbation of systemic lupus erythematosus.

Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving full therapeutic dosages. These conditions disappeared rapidly when the drug was discontinued.

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

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

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 VIBRAMYCIN IV (100-200 mg/day) DIFFERS FROM THAT OF THE OTHER TETRACYCLINES (1-2 g/day). EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS.

Studies to date have indicated that doxycycline 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 hyclate for injection is 200 mg on the first day of treatment administered in 1 or 2 infusions. Subsequent daily dosage is 100-200 mg depending upon the severity of infection, with 200 mg administered in 1 or 2 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 8 Years of Age

The recommended dosage schedule for children weighing 100 lb or less is 2 mg/lb of body weight on the first day of treatment, administered in 1 or 2 infusions. Subsequent daily dosage is 1-2 mg/lb of body weight given as 1 or 2 infusions, depending on the severity of the infection. For children over 100 lb the usual adult dose should be used (see WARNINGS, Use in Children).

In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (45 kg). Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time. Oral therapy should be instituted as soon as possible. Therapy must continue for a total of 60 days.

General

The duration of infusion may vary with the dose (100-200 mg/day), but is usually 1-4 hours. A recommended minimum infusion time for 100 mg of a 0.5 mg/ml solution is 1 hour. Therapy should be continued for at least 24-48 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 10 intravenous infusion solutions listed below. Each 100 mg of doxycycline hyclate for injection (i.e., withdraw entire solution from the 100 mg vial) is further diluted with 100-1000 ml of the intravenous solutions listed below. Each 200 mg of doxycycline hyclate for injection (i.e., withdraw entire solution from the 200 mg vial) is further diluted with 200-2000 ml of the following intravenous solutions:

Sodium chloride injection

5% Dextrose injection

Ringer's injection

Invert sugar, 10% in water

Lactated Ringer's injection

Dextrose 5% in lactated Ringer's

Normosol-M in D5-W (Abbott)

Normosol-R in D5-W (Abbott)

Plasma-Lyte 56 in 5% dextrose (Travenol)

Plasma-Lyte 148 in 5% dextrose (Travenol)

This will result in desired concentrations of 0.1-1.0 mg/ml. Concentrations lower than 0.1 mg/ml or higher than 1.0 mg/ml are not recommended.

Stability

Doxycycline hyclate for injection is stable for 48 hours in solution when diluted with sodium chloride injection, or 5% dextrose injection, to concentrations between 1.0 mg/ml and 0.1 mg/ml and stored at 25°C. Doxycycline hyclate 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 (1.0 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 hyclate for injection, when diluted with Ringer's injection, 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 1.0 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 (1.0 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, or dextrose 5% in lactated Ringer's, infusion of the solution (ca. 1.0 mg/ml) or lower concentrations (not less than 0.1 mg/ml) must be completed within 6 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 8 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.

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 μg/ml of doxycycline at 2 hours decreasing to 1.45 μg/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 1-5%/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 18-22 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

The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including doxycycline, have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance of these organisms to tetracyclines is common.

Gram-Negative Bacteria

Neisseria gonorrhoeae

Calymmatobacterium granulomatis

Haemophilus ducreyi

Haemophilus influenzae

Yersinia pestis (formerly Pasteurella pestis)

Francisella tularensis (formerly Pasteurella tularensis)

Vibrio cholerae (formerly Vibrio comma)

Bartonella bacilliformis

Brucella species

Because many strains of the following groups of gram-negative microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended:

Escherichia coli

Klebsiella species

Enterobacter aerogenes

Shigella species

Acinetobacter species (formerly Mima species and Herellea species)

Bacteroides species

Gram-Positive Bacteria

Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracycline, culture and susceptibility testing are recommended. Up to 44% of strains of Streptococcus pyogenes and 74% of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracycline should not be used for streptococcal disease unless the organism has been demonstrated to be susceptible.

Streptococcus pyogenes

Streptococcus pneumoniae

Enterococcus group (Streptococcus faecalis and Streptococcus faecium)

Alpha-hemolytic streptococci (viridans group)

Other Microorganisms

Rickettsiae

Clostridium species

Chlamydia psittaci

Fusobacterium fusiforme

Chlamydia trachomatis

Actinomyces species

Mycoplasma pneumoniae

Bacillus anthracis

Ureaplasma urealyticum

Propionbacterium acnes

Borrelia recurrentis

Entamoeba species

Treponema pallidum

Balantidium coli

Treponema pertenue

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 Testing

Diffusion Techniques

Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedure 1 which has been recommended for use with disks to test susceptibility of organisms to doxycycline uses the 30 μg tetracycline-class disk or the 30 μg doxycycline disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for tetracycline or doxycycline, respectively.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30 μg tetracycline-class disk or the 30 μg doxycycline disk should be interpreted according to the criteria in TABLE 9.

TABLE 9 Zone Diameter   Tetracycline Doxycycline Interpretation ≥19 mm ≥16 mm Susceptible 15-18 mm 13-15 mm Intermediate ≤14 mm ≤12 mm Resistant

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of "Intermediate" suggests that the organism would be susceptible if a high dosage is used or if the infection is confined to tissues and fluids in which high antimicrobial levels are attained. A report of "Resistant" indicates that achievable concentrations are unlikely to be inhibitory, and other therapy should be selected.

Standardized procedures require the use of laboratory control organisms. The 30 μg tetracycline-class disk or the 30 μg doxycycline disk should give the zone diameters in TABLE 10.

TABLE 10   Zone Diameter Organism Tetracycline Doxycycline E. coli ATCC 25922 18-25 mm 18-24 mm S. aureus ATCC 25923 19-28 mm 23-29 mm

Dilution Techniques

Use a standardized dilution method 2 (broth, agar, microdilution) or equivalent with tetracycline powder. The MIC values obtained should be interpreted according to the criteria found in TABLE 11.

TABLE 11 MIC Interpretation ≤4 μg/ml Susceptible 8 μg/ml Intermediate ≥16 μg/ml Resistant

As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard tetracycline powder should provide the MIC values found in TABLE 12.

TABLE 12 Organism MIC E. coli ATCC 25922 1.0-4.0 μg/ml S. aureus ATCC 29213 0.25-1.0 μg/ml E. faecalis ATCC 29212 8-32 μg/ml P. aeruginosa ATCC 27853 8-32 μg/ml

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 Chlamydia 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 (formerly Pasteurella pestis).

Tularemia due to Francisella tularensis (formerly Pasteurella tularensis).

Cholera caused by Vibrio cholerae (formerly Vibrio comma).

Campylobacter fetus infections caused by Campylobacter fetus (formerly Vibrio fetus).

Brucellosis due to Brucella species (in conjunction with streptomycin).

Bartonellosis due to Bartonella bacilliformis.

Granuloma inguinale caused by Calymmatobacterium 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 (formerly Aerobacter aerogenes).

Shigella species.

Acinetobacter species (formerly Mima species and Herellea 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 tract infections caused by Streptococcus pneumoniae (formerly Diplococcus 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 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 and PRECAUTIONS, Information for the Patient.

General

As with other antibiotic preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibiotic should be discontinued and appropriate therapy instituted.

Bulging fontanels in infants and benign intracranial hypertension in adults have been reported in individuals receiving tetracyclines. These conditions disappeared when the drug was discontinued.

Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic 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.

Information for the Patient

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.

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/Laboratory Test Interactions

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

Carcinogenesis, Mutagenesis, and 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 antibiotics, 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 antibiotics (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 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 ³ . 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 (0.30%) 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 2 exposed cases ⁴ .

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 ⁵ .

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 ⁶ . 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

See WARNINGS and DOSAGE AND ADMINISTRATION.

Due to oral doxycycline's virtually complete absorption, side effects of 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. Hepatotoxicity has been reported rarely. 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 the 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. 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.

Other:  Bulging fontanels in infants and intracranial hypertension in adults. 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 studies are known to occur.

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) 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.

For Children Above 8 Years of Age:  The recommended dosage schedule for children weighing 100 lb or less is 2 mg/lb of body weight divided into 2 doses on the first day of treatment, followed by 1 mg/lb of body weight given as a single daily dose or divided into 2 doses, on subsequent days. For more severe infections up to 2 mg/lb of body weight may be used. For children over 100 lb 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 the antibiotic 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 1 hour by a second 300 mg dose. The dose may be administered with food, including milk or carbonated beverage, as required.

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

Nongonococcal urethritis (NGU) caused by C. trachomatis or U. urealyticum:   100 mg by mouth twice a day for 7 days.

Syphilis — Early:  Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice a day for 2 weeks.

Syphilis of More Than 1 Year's Duration:  Patients who are allergic to penicillin should be treated with doxycycline 100 mg by mouth twice a day for 4 weeks.

Acute Epididymo-Orchitis Caused by N. gonorrhoeae:  100 mg, by mouth, twice a day for at least 10 days.

Acute Epididymo-Orchitis Caused by C. trachomatis:  100 mg, by mouth, twice a day for at least 10 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 1-2 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.

Inhalational Anthrax (post-exposure):

Adults:  100 mg of doxycycline, by mouth, twice a day for 60 days.

Children:  Weighing less than 100 lb (45 kg); 1 mg/lb (2.2 mg/kg) of body weight, by mouth, twice a day for 60 days. Children weighing 100 lb or more should receive the adult dose.

References

1. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests, Fourth Edition. Approved Standard NCCLS Document M2-A4, Vol. 10, No. 7 NCCLS, Villanova, PA, April 1990.

2. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically, Second Edition. Approved Standard NCCLS Document M7-A2, Vol. 10, No. 8 NCCLS, Villanova, PA, April 1990.

3. Friedman JM and Polifka JE. Teratogenic Effects of Drugs. A Resource for Clinicians (TERIS). Baltimore, MD: The Johns Hopkins University Press, 2000: 149-195.

4. Cziezel AE and Rockenbauer M. Teratogenic study of doxycycline. Obstet Gynecol 1997; 89: 524-528.

5. Horne HW Jr and Kundsin RB. The role of mycoplasma among 81 consecutive pregnancies: a prospective study. Int J Fertil 1980; 25: 315-317.

6. Hale T. Medications and Mothers Milk. 9^th edition. Amarillo, TX: Pharmasoft Publishing, 2000:225-226.