Subantimicrobial Dose Doxycycline for Acne and Rosacea

Joseph B. Bikowski, MD

Disclosures

Skinmed. 2003;2(4) 

In This Article

Adverse Events Associated With Acne Therapy

GI disturbances (nausea, vomiting, and diarrhea) are the most common side effects associated with all the tetracyclines. All tetracycline antimicrobials carry warnings of phototoxicity reactions, manifested as an exaggerated sunburn reaction. To date, there have been no double-blind, controlled studies showing that tetracycline HCl is a photosensitizer. Minocycline is generally regarded as the least photosensitizing of the tetracycline derivatives at the commonly administered dose.[30]

Prescribing information for all tetracyclines warns that they can cross the placenta and have shown evidence of embryotoxicity with toxic effects on the developing fetus. Minocycline has been shown to have a carcinogenic metabolite, although the clinical relevance of this finding is unknown.[31]

Tetracycline HCl has been implicated in an increased incidence of esophageal ulceration,[32] particularly when administered in capsule form. The use of tetracycline HCl has also been associated with the development of pseudotumor cerebri in adult and pediatric patients[33] and in patients receiving concomitant isotretinoin therapy.[34]

Esophageal irritation has been seen with doxycycline hyclate, which dissolves at a pH of 2-3. In contrast, the pH on dissolution of the newer salt, doxycycline monohydrate, is 5-6, resulting in no esophageal irritation and less GI upset.[15]

Photosensitivity can be seen with doxycycline therapy. The relationship is dose dependent, and phototoxicity occurs in 3% of patients taking 100 mg/day. This can be a problem clinically because patients who do not respond to standard doses may be taking maintenance therapy doses in excess of 100 mg/day, which greatly increases the potential for phototoxic eruptions (20% at 150 mg and 42% at 200 mg/day).[35]

Because these drugs are given long-term for acne and rosacea, the possibility for carcinogenic potential is also of concern. Recently, during the development of a SD of doxycycline as a chronic, adjunctive therapy for the treatment of adult periodontitis, this issue was systematically addressed for the first time. The labeling for this drug (Periostat) states that the carcinogenic potential of doxycycline has been investigated with no findings of changes indicating a direct carcinogenic effect. Increases in benign fibroadenomas of the breast, polyps of the uterus, and adenoma of the thyroid, which are consistent with a hormonal effect, were observed in treated women. Doxycycline has shown no mutagenic activity and no convincing evidence of clastogenic activity.[36]

The vestibular side effects of lightheadedness, loss of balance, dizziness, or true vertigo in patients taking minocycline are well known and occur more often in women.[37,38] These effects arise because the lipophilicity of minocycline results in some degree of blood-brain barrier penetration.

Hyperpigmentation or a blue/black skin or mucous membrane discoloration has been found with long-term use of minocycline.[39,40] In rare cases, such hyperpigmentation may occur within 1 month of minocycline therapy. There are two types: localized pigmentation occurring at the site of previous inflammation, and a more generalized diffuse pigmentation.[41]

Although rare, a variety of drug-induced syndromes have been described in patients taking minocycline for acne. Drug-induced lupus and hepatitis are the most common reactions and except for serum sickness (mean time to occur-rence: 16 days); these syndromes typically present after prolonged use (mean time to occur-rence: 25.3 months).[42,43] Coexistent minocycline-induced lupus erythematosus and autoimmune hepatitis after long-term use (4-120 months) occurred at dose ranges of 50-200 mg/day.[44] Hepatitis with minocycline use is most often associated with hypersensitivity syndromes or delayed autoimmune hepatitis.[44,45]

Case reports of pneumonitis,[46] lymphadenopathy, and an infectious mononucleosis-type reaction[47] have been reported. Rare cases of pseudotumor cerebri (idiopathic intracranial hypertension)[48] associated with long-term minocycline treatment (4 weeks-18 months) have occurred.[41,49] Long-term administration in rat studies resulted in evidence of thyroid tumor production and thyroid hyperplasia in rats and dogs.[31] Based on reports of adverse drug reactions, Gough et al.[50] recommended that safer alternatives than minocycline should be considered for treating acne.

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