AHFS Class:

• Antibacterials 52:04.04

Generic Name(s):

• Doxycycline Hyclate

Doxycycline is a semisynthetic tetracycline antibiotic derived from oxytetracycline.1,14

Periodontitis

Doxycycline hyclate is used orally (as tablets containing 20 mg of doxycycline)14 or subgingivally (as an extended-release preparation)1 in the treatment of adult periodontitis.1,14

Oral Administration

Oral doxycycline hyclate is used as an adjunct to scaling and root planing to promote attachment-level gain and reduce pocket depth in adults with periodontitis.14,15,16

Safety and efficacy of oral doxycycline (20 mg twice daily) as an adjunct to scaling and root planing were evaluated in a randomized, placebo-controlled study in 190 adults with periodontal disease (at least 2 probing sites per quadrant with 5-9 mm pocket depths and attachment levels).14 At 9 months after initiation of treatment, the mean decrease in pocket depth in pockets with baseline depths up to 3 mm was 0.16 mm in those receiving oral doxycycline and 0.05 mm in those receiving placebo.14 The mean decrease in pocket depth in pockets with baseline depths of 4-6 mm or 7 mm or greater was 0.95 or 1.68 mm, respectively, in those receiving oral doxycycline and 0.69 or 1.2 mm, respectively, in those receiving placebo.14 In addition, the percentage of sites with loss of attachment level of 2 mm or greater was 0.3-1.9% in those receiving oral doxycycline compared with 2.2-3.6% in those receiving placebo.14

Subgingival Administration

Doxycycline hyclate, as a subgingival extended-release preparation containing the drug incorporated into a bioabsorbable polymer (doxycycline hyclate polymer), is used in the treatment of chronic periodontitis in adults for reduction of pocket depth, gain in clinical attachment level, and reduction in bleeding associated with probing.1,2,3,4,5,7,10,11

Safety and efficacy of the subgingival preparation of doxycycline hyclate were established in 2 controlled clinical studies in 831 adults with moderate to severe periodontitis.1,4 Patients were randomized to receive one of the following treatments: doxycycline hyclate polymer for subgingival administration, scaling and root planing, subgingival vehicle control, or oral hygiene.1,4 All periodontal pocket sites that bled on probing and had a probing depth of 5 mm or greater at baseline were treated initially and again at 4 months with the assigned treatment.1,4 At 9 months after initiation of therapy, patients treated with subgingival doxycycline hyclate polymer had greater reductions in pocket depth, greater gains in attachment level, and less bleeding on probing than did patients treated with vehicle control or oral hygiene; improvements in these parameters (e.g., pocket depth, attachment level, and bleeding on probing) were similar in patients receiving subgingival doxycycline hyclate polymer or scaling and root planing.1,4,12 Following treatment with doxycycline hyclate polymer for subgingival administration, both deeper (exceeding 7 mm) and shallower (5-6 mm) periodontal pockets showed substantial reductions in pocket depth and gains in attachment level throughout both studies.4 Smokers, nonsmokers, and former smokers receiving doxycycline hyclate polymer generally achieved similar reductions in pocket depth and gains in attachment level over a period of 9 months.9 Additional clinical studies have reported that subgingival doxycycline hyclate polymer is effective in the treatment of adult periodontitis.1,5

For systemic uses of doxycycline, see Doxycycline 8:12.24.

Reconstitution and Administration

Oral Administration

Doxycycline hyclate tablets containing 20 mg of doxycycline are administered orally.14

Doses should be taken at least 1 hour prior to or 2 hours after meals.14 In addition, to reduce the risk of esophageal irritation and ulceration, the tablets should be administered with adequate amounts of fluids.14

Subgingival Administration

Doxycycline hyclate polymer is inserted subgingivally into periodontal pockets by a dental health-care provider.1

Commercially available doxycycline hyclate for subgingival administration is provided in a kit that includes a syringe containing the liquid polymeric delivery system (syringe A), a syringe containing doxycycline hyclate powder (syringe B), and a blunt cannula.1 The contents of the 2 syringes must be mixed together prior to administration.1 The kit should be stored at 2-30°C.1 If stored in a refrigerator, it must be removed from the refrigerator at least 15 minutes prior to preparing the drug for subgingival administration.1

Subgingival administration does not require local anesthesia.1

Reconstitution

To mix the components to prepare the drug for subgingival administration, the 2 syringes should be coupled together and the liquid contents of syringe A injected into the powder in syringe B and then back into syringe A to complete 1 mixing cycle.1 A total of 100 mixing cycles should be performed using brisk strokes (approximately 1 mixing cycle per second).1 The final mixture appears as a pale yellow to yellow viscous liquid.1 After subgingival administration into periodontal pockets, the liquid solidifies and then results in controlled release of doxycycline over a period of 7 days.1,8 (See Pharmacokinetics.)

After the doxycycline hyclate polymer is mixed, the coupled syringes should be held vertically with syringe A (indicated by a red stripe) at the bottom.1 After pulling down on the plunger of syringe A, the contents should be allowed to flow down the barrel for several seconds into syringe A.1 For immediate administration, the syringes should then be uncoupled and the blunt cannula that is supplied in the kit should be attached to syringe A.1

If the drug is not administered immediately after mixing, the coupled syringes may be stored in the resealable pouch (or an airtight container) at room temperature for up to 3 days.1 After such storage, an additional 10 mixing cycles must be performed just prior to administration.1 Each pair of syringes is intended for single use only.1

Subgingival Administration Technique

The final doxycycline hyclate polymer mixture should be administered subgingivally using the syringe with the cannula bent similarly to a periodontal probe; the tip of the cannula should be positioned near the base of the periodontal pocket and the doxycycline hyclate polymer administered into the pocket until the mixture reaches the top of the gingival margin.1 The cannula is then withdrawn from the pocket.1

If desired, the doxycycline hyclate polymer may be packed into the periodontal pocket using an appropriate dental instrument.1 The edge of the dental instrument should be dipped in water before packing to keep the doxycycline hyclate polymer from sticking to the instrument and to speed coagulation of the polymer.1 Once the preparation is in the periodontal pocket, a few drops of water dripped onto its surface can also aid in coagulation of the polymer.1 If necessary, more doxycycline hyclate polymer can be added and packed into the periodontal pocket until it is full.1

Following subgingival administration of doxycycline hyclate polymer, treated periodontal pockets should be covered with a periodontal dressing (Coe-Pak^®) or cyanoacrylate dental adhesive.1

Results of clinical trials demonstrate that doxycycline hyclate polymer retained with Coe-Pak^® periodontal dressing or Octyldent^® dental adhesive (no longer commercially available in the US) will be bioabsorbed or expelled naturally and does not need to be manually removed.1,4,13

The manufacturer's literature should be consulted for additional information regarding the preparation and subgingival administration of doxycycline hyclate polymer.1

Dosage

Dosage of doxycycline hyclate is expressed in terms of doxycycline.1,14

Oral Dosage

The usual adult dosage of oral doxycycline for the adjunctive treatment of periodontitis is 20 mg twice daily.14 Daily doses should be taken at 12-hour intervals, usually in the morning and evening, at least 1 hour prior to or 2 hours after meals.14

The manufacturers state that safety of oral doxycycline for the adjunctive treatment of periodontitis has not been established beyond 12 months and efficacy has not been established beyond 9 months of therapy.14

Subgingival Dosage

The usual adult dosage of doxycycline hyclate polymer for subgingival administration varies depending on the size, shape, and number of periodontal pockets treated.1 Treatment with subgingival doxycycline hyclate polymer may be repeated 4 months after the initial treatment.1

After doxycycline hyclate polymer is prepared as directed (see Reconstitution under Reconstitution and Administration: Subgingival Administration, in Dosage and Administration), the mixture in the syringe contains 50 mg of doxycycline hyclate (equivalent to 42.5 mg of doxycycline).1

Special Populations

No special population dosage recommendations.1 Doxycycline plasma half-life in patients with severely impaired renal function is similar to that in those with normal renal function.14

Contraindications

Oral doxycycline hyclate and doxycycline hyclate for subgingival administration are contraindicated in patients hypersensitive to doxycycline or other tetracyclines.1,14

Warnings/Precautions

Warnings

Dental and Bone Effects

Tetracyclines should not be used during tooth development (e.g., pregnancy, infancy, childhood up to 8 years of age) because the drugs may cause permanent discoloration of teeth (yellow-gray-brown).1,14 This adverse effect is most common with long-term tetracycline use, but has been reported following repeated short-term use.1,14 Enamel hypoplasia also has been reported.1,14

Tetracyclines form a stable calcium complex in any bone-forming tissue.14 Reversible decrease in fibula growth rate has occurred in premature infants receiving oral tetracyclines.14

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, anaphylactoid purpura, serum sickness, urticaria, angioedema, pericarditis, and exacerbation of systemic lupus erythematosus, have been reported in patients receiving tetracyclines.14

Photosensitivity Reactions

Photosensitivity, manifested as an exaggerated sunburn reaction on areas of the body exposed to direct sunlight or ultraviolet light, has occurred in some patients receiving tetracyclines.1,14

Oral or subgingival doxycycline should be discontinued at the first sign of skin erythema.13,14

Other Warnings/Precautions

Precautions Related to Oral Doxycycline

Dosage of oral doxycycline used in the adjunctive treatment of periodontitis differs from that used for the treatment of infections.14 An increased incidence of adverse effects, including development of resistant organisms, may occur if higher than recommended dosage is used in patients with periodontitis.14

Dosage of oral doxycycline used in the adjunctive treatment of periodontitis does not provide drug concentrations high enough to inhibit organisms commonly associated with adult periodontitis.14 The 20-mg tablets of the drug used in the treatment of periodontitis should not be used in an attempt to reduce or eliminate such organisms.14

Precautions Related to Subgingival Doxycycline

Doxycycline hyclate polymer for subgingival administration has not been studied in patients with extremely severe periodontal defects with little remaining periodontium.1

The subgingival preparation of doxycycline hyclate has not been studied for use in the regeneration of alveolar bone, either in preparation for or in conjunction with placement of endosseous (dental) implants or in the treatment of failing implants.1

The subgingival preparation of doxycycline hyclate has not been studied in immunocompromised patients (e.g., those with diabetes mellitus or human immunodeficiency virus [HIV] infection, those receiving chemotherapy or radiation therapy).1

Superinfection/Candidiasis

Overgrowth of opportunistic microorganisms, such as yeast, was not reported in clinical studies evaluating oral doxycycline in adults with periodontitis.14 However, as with other anti-infectives, use of oral or subgingival doxycycline may result in overgrowth of nonsusceptible organisms, including fungi.1,14 If superinfection occurs, appropriate measures should be initiated.14

Tetracyclines may increase the incidence of vaginal candidiasis.14

Oral and subgingival doxycycline should be used with caution in patients with a history of or predisposition to oral candidiasis.1,14 Safety and efficacy of oral or subgingival doxycycline have not been established for the treatment of periodontitis in patients with concomitant oral candidiasis.1,14

Specific Populations

Pregnancy

Results from animal studies indicate that doxycycline crosses the placenta, is found in fetal tissues, and can cause toxic effects on developing fetuses (often related to retardation of skeletal development).1,14

Doxycycline can cause fetal harm if administered to pregnant women.14 The effects of tetracyclines on labor and delivery are unknown.14

Doxycycline hyclate polymer for subgingival administration has not been evaluated in pregnant women.1

Tetracyclines should not be used during pregnancy.1,14 If a tetracycline is used during pregnancy, the patient should be apprised of potential hazards to the fetus.1,14

Lactation

Tetracyclines are distributed into milk following oral administration.1,14 It is not known whether doxycycline is distributed into milk following subgingival administration.1

Doxycycline is contraindicated in nursing women.14 Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or doxycycline, taking into account the importance of the drug to the woman.1

Pediatric Use

Oral doxycycline should not be used in children younger than 8 years of age.14 (See Dental and Bone Effects under Warnings/Precautions: Warnings, in Cautions.)

Safety and efficacy of subgingival doxycycline have not been established in pediatric patients younger than 18 years of age.1,2,13

Common Adverse Effects

Adverse effects reported in 6% of more of patients receiving oral doxycycline hyclate tablets (containing 20 mg of doxycycline) include headache, common cold, flu symptoms, toothache or tooth disorder, GI symptoms (diarrhea, nausea, dyspepsia), and joint pain.14

Adverse effects occurring in 7% or more of patients receiving doxycycline hyclate polymer via subgingival administration include headache; common cold; gum discomfort, pain or soreness, loss of attachment, or increased pocket depth; toothache or pressure sensitivity; periodontal abscess, exudate, infection, drainage, extreme mobility, or suppuration; and thermal tooth sensitivity.1

The following drug interactions involve oral doxycycline.14 No formal drug interaction studies have been performed with doxycycline hyclate polymer for subgingival administration.1

Antacids

Pharmacokinetic interaction with antacids containing aluminum, calcium, or magnesium (decreased absorption of doxycycline).14

Anticoagulants

Potential pharmacologic interaction with oral anticoagulants (decreased plasma prothrombin activity); anticoagulant dosage may need to be adjusted in patients receiving doxycycline.14

Anticonvulsants

Potential pharmacokinetic interaction with barbiturates, carbamazepine, or phenytoin (decreased doxycycline half-life).14

Bismuth Subsalicylate

Potential pharmacokinetic interaction with bismuth subsalicylate (decreased absorption of doxycycline).14

Hormonal Contraceptives

Potential pharmacologic interaction (decreased effectiveness of oral contraceptive).1,13,14

Iron

Potential pharmacokinetic interaction with iron-containing preparations (decreased absorption of doxycycline).14

Methoxyflurane

Concomitant use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity.14

Penicillins

Potential pharmacologic interaction (antagonism); avoid concomitant use.14

Pharmacokinetics

Absorption

Bioavailability

Following oral administration, doxycycline hyclate is rapidly and almost completely absorbed from the GI tract.14 In adults receiving doxycycline hyclate tablets containing 20 mg of doxycycline, peak serum doxycycline concentrations are attained within 1.4 hours after a single dose or within 2 hours after a dose at steady state.14 The rate and extent of absorption of oral doxycycline hyclate are decreased if the drug is administered with a high-fat, high-protein meal that includes dairy products.14

Following subgingival administration of doxycycline hyclate polymer (a mixture of doxycycline hyclate and a polymeric delivery system) into periodontal pockets and after contact with gingival crevicular fluid (GCF), the mixture solidifies and provides an extended-release preparation that allows controlled release of the drug for a period of 7 days.1,8 When the doxycycline hyclate polymer was administered subgingivally and covered with Coe-Pak^® periodontal dressing or Octyldent^® dental adhesive (no longer commercially available in the US), doxycycline concentrations in GCF peaked at 2 hours following administration and were approximately 1.5 or 2 mg/mL, respectively.1 GCF concentrations of doxycycline remained above 1 mg/mL through 18 hours and then declined gradually, but remained above the MIC₉₀ for periodontal pathogens (6 mcg/mL) through 7 days.1 After subgingival administration and use of the periodontal dressing or dental adhesive, mean peak doxycycline concentrations in saliva were 4.1 or 8.8 mcg/mL, respectively, at 2 hours and decreased to 0.4 or 0.2 mcg/mL, respectively, at day 7.1 Serum concentrations of doxycycline never exceeded 0.1 mcg/mL.1

Description

Doxycycline hyclate is a semisynthetic tetracycline antibiotic derived from oxytetracycline.1,14 For the treatment of periodontitis, doxycycline hyclate is commercially available as tablets containing 20 mg of doxycycline for oral administration14 and in a kit that includes the drug and a polymeric delivery system to provide an extended-release preparation for subgingival administration.1

The commercially available oral tablets containing 20 mg of doxycycline are used only for adjunctive treatment of periodontitis.14 The mechanisms of action of oral doxycycline in promoting attachment-level gain and reducing pocket depth in patients with adult periodontitis have not been elucidated.14 Although the clinical importance is unknown, doxycycline has been shown to inhibit collagenase activity in vitro and oral doxycycline has been shown to reduce the elevated collagenase activity in gingival crevicular fluid (GCF) of patients with adult periodontitis.14

After the components of the commercially available kit containing doxycycline hyclate and a polymeric delivery system are mixed together, the preparation for subgingival administration is a viscous liquid that contains 50 mg of doxycycline hyclate (42.5 mg of doxycycline) mixed with a bioabsorbable polymer.1 Following subgingival administration into periodontal pockets and contact with GCF, the mixture solidifies resulting in an extended-release preparation that allows controlled release of the drug for a period of 7 days.1,8 (See Pharmacokinetics.)

Doxycycline is bacteriostatic in action and exerts its antimicrobial activity by inhibiting protein synthesis in susceptible bacteria through disruption of transfer RNA and messenger RNA at ribosomal sites.1 The drug is active in vitro against some organisms associated with periodontal disease.1 Porphyromonas gingivalis , Prevotella intermedia , Campylobacter rectus , and Fusobacterium nucleatum are inhibited in vitro by doxycycline concentrations of 6 mcg/mL or less.1 In one study, there was no evidence of emergence of doxycycline resistance in the anaerobic flora cultured from subgingival plaque or saliva of adults with periodontitis who were treated with subgingival doxycycline hyclate polymer.6

Advice to Patients

Advise patients taking doxycycline hyclate tablets of the importance of drinking sufficient amounts of fluids to reduce the risk of esophageal irritation and ulceration.14

Advise patients being treated with subgingival doxycycline of the importance of not using mechanical oral hygiene procedures (i.e., brushing teeth, flossing) around treated sites for 7 days following administration of the subgingival preparation.1

Advise patients receiving oral or subgingival doxycycline of the importance of avoiding exposure to direct sunlight or ultraviolet light and the importance of notifying a dental health-care professional and discontinuing therapy at the first sign of skin erythema.1,13,14

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant diseases.1,14

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,14 Advise patients that doxycycline may decrease effectiveness of oral contraceptives.1,14

Importance of informing patients of other important precautionary information.1,14 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Den-Mat Holdings, LLC. Atridox^® (doxycycline hyclate 10%) prescribing information. Lompoc, CA; 2016 Oct.

2. Wennström JL, Newman HN, MacNeill SR et al. Utilisation of locally delivered doxycycline in non-surgical treatment of chronic periodontitis. J Clin Periodontol . 2001; 28:753-761. [PubMed 11442735]

3. Garrett S, Adams DF, Bogle G et al. The effect of locally delivered controlled-release doxycycline or scaling and root planing on periodontal maintenance patients over 9 months. J Periodontol . 2000; 71:22-30. [PubMed 10695935]

4. Garrett S, Johnson L, Drisko CH et al. Two multi-center studies evaluating locally delivered doxycycline hyclate, placebo control, oral hygiene, and scaling and root planing in the treatment of periodontitis. J Periodontol . 1999; 70:490-503. [PubMed 10368053]

5. Drisko CH. The use of locally-delivered doxycycline in the treatment of periodontitis. Clinical results. J Clin Periodontol . 1998; 25:947-52. [PubMed 9839851]

6. Walker CB, Godowski KC, Borden L. The effects of sustained release doxycycline on anaerobic flora and antibiotic-resistant patterns in subgingival plaque and saliva. J Periodontol . 2000; 71:768-74. [PubMed 10872958]

7. Wolinsky LE, Camargo PM, Polson A et al. The significance of prior mechanical therapy for changes of periodontal status achieved by local delivery of a doxycycline-hyclate containing gel. J Clin Periodontol . 2001; 28:1115-20. [PubMed 11737508]

8. Stoller NH, Johnson LR, Trapnell S et al. The pharmacokinetic profile of a biodegradable controlled-release delivery system containing doxycycline compared to systemically delivered doxycycline in gingival crevicular fluid, saliva, and serum. J Periodontol . 1998; 69:1085-91. [PubMed 9802705]

9. Ryder MI, Pons B, Adams D et al. Effects of smoking on local delivery of controlled-release doxycycline as compared to scaling and root planing. J Clin Periodontol . 1999; 26:683-91. [PubMed 10522780]

10. Greenstein G, Tonetti M and the Research, Science et al. Position Paper. The role of controlled drug delivery for periodontitis. J Periodontol . 2000; 71:125-40. [PubMed 10695948]

11. Greenstein G, Polson A. The role of local drug delivery in the management of periodontal diseases: a comprehensive review. J Periodontol . 1998; 69:507-520. [PubMed 9623893]

12. Garrett S. Local delivery of doxycycline for the treatment of periodontitis. Compendium . 1999; 20:437-46. [PubMed 10650359]

13. CollaGenex Pharmaceuticals, Inc. Newtown, PA; Personal communication.

14. Lannett Company, Inc. Doxycycline hyclate tablets (equivalent to 20 mg doxycycline) prescribing information. Philadelphia, PA; 2017 Aug.

15. Greenstein G. The role of Periostat^® in the management of adult periodontitis: a critical assessment. Compend Contin Educ Dent . 1999; 20:664,666-8,670,672,574,676-8. [PubMed 10650384]

16. Caton JG. Evaluation of Periostat^® for patient management. Compend Contin Educ Dent . 1999; 20:451-2,454-6,458-63. [PubMed 10650360]