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DRUG RECORD

 

MINOCYCLINE

OVERVIEW
Minocycline

 

Minocycline is a tetracycline antibiotic with excellent absorption and tissue penetration that is used for several bacterial infections as well as treatment of acne.   Minocycline can cause both an acute hepatitis like syndrome occurring within 1 to 3 months of starting therapy or a more insidious chronic hepatitis with autoimmune features typically after long-term treatment.

 

Background

Minocycline (min" oh sye' kleen) is a semisynthetic derivative of tetracycline that has excellent oral absorption and wide tissue penetration. Like other tetracyclines, minocycline is believed to act by binding to bacterial ribosomes and inhibiting protein synthesis.  Minocycline has a broad spectrum of activity against both gram positive and gram negative organisms.  Minocycline was approved for use in the United States in 1971 and it continues in wide use with more than 4 million prescriptions being filled yearly.  Current indications are for therapy of susceptible infections, including gonorrhea, syphilis, non-gonococcal urethritis, Chlamydial infections, cholera, leprosy, and the meningococcal carrier state. Perhaps the major use of minocycline is chronic use for treatment of acne and suppression of staphylococcal bacterial flora that contribute to it. Minocycline is available in multiple generic forms as capsules or tablets of 50, 75 or 100 mg. For acute infections, minocycline is recommended in doses of 100 mg every 12 hours for 5 to 15 days, often after an initial loading dose of 200 mg. For therapy of acne, doses of 50 mg once to three times daily are recommended. Minocycline is also available in extended release formulations for daily dosing and as a solution or powder for intravenous use. Commercial names of minocycline include Minocin, Dynacin, Myrac, and Apo-, Novo- and PMS-Minocycline. Common side effects include nausea, diarrhea, gastrointestinal upset, headache, dizziness, visual blurring, skin rash and hypersensitivity reactions. 

 

Hepatotoxicity

Minocycline therapy is associated with two forms of clinically apparent liver injury, an acute hepatitis-like syndrome that arises within 1 to 3 months of starting therapy and a chronic hepatitis-like syndrome typically with autoimmune features that occurs with longterm therapy, sometimes after several years of use.  There is some overlap between these two presentations of minocycline hepatotoxicity, both are associated with a hepatocellular pattern of serum enzyme elevations and both can be associated with autoantibodies and immunological features.

 

Minocycline has been linked to cases of an acute hepatitis with jaundice that typically arises within a few weeks or months of starting therapy.  The enzyme elevations are typically hepatocellular and resemble acute viral hepatitis.  Immunoallergic features are common and may be prominent with fever, rash and eosinophilia and some cases with facial edema, lymphoadenopathy and lymphocytosis that may resemble acute mononucleosis.  The liver injury is usually self limited with complete resolution within 1 to 2 months of stopping. Some patients have autoimmune markers and these also improve upon stopping minocycline. 

 

Minocycline has also been linked to cases of chronic hepatitis with or without jaundice that typically arise during longterm therapy, sometimes after years of use.  The most common presentation is with an autoimmune hepatitis like syndrome that can be severe and even fatal, particularly if minocycline is not stopped promptly. Patients can present acutely with jaundice and fatigue or chronically with insidious onset of fatigue, joint aches and jaundice, usually after 6 months to many years of therapy. A hepatocellular pattern of enzyme elevations is typical with ALT levels ranging from 3 to 20 fold elevated depending upon the severity and duration of the injury. Autoantibodies are usually present, typically antinuclear antibody (ANA) at titers of >1:160. In some cases, ANA may initially be negative, arising later as the disease progresses or starts to improve. Immunoglobulins are also usually elevated and liver biopsy demonstrates changes typical of autoimmune hepatitis with active interface hepatitis, spotty eosinophilic necrosis and portal infiltrates rich in lymphocytes and plasma cells. Fibrosis is uncommon but can occur, particularly if the disease is prolonged and minocycline continued in the face of hepatic injury. The condition will resolve spontaneously if minocycline is withdrawn, but corticosteroids are often used. In long-term follow up after stopping minocycline, chronic injury is rare if it occurs at all and generally all symptoms and laboratory test abnormalities resolve within 6 to 12 months of stopping, although patients may continue to have low titers of ANA.

 

Other immunologically mediated syndromes associated with minocycline use include a serum sickness like syndrome (generally within 3 to 12 weeks of starting), a lupus-like syndrome and hemolytic anemia (the latter two with chronic therapy). Liver injury can accompany these other autoimmune conditions, but is generally anicteric, mild and rapidly reversible.    The pattern of serum enzyme elevations is typically hepatocellular and autoantibodies are common.

 

Mechanism of Injury

The cause of the liver injury associated with minocycline use is probably immunological, mediated by autoimmune reactions against liver cells or minocycline adducts present in the liver.

 

Outcome and Management

The acute liver injury attributed to minocycline is usually self-limited in course, although fatal examples have been reported.  In addition, the autoimmune hepatitis like syndrome caused by minocycline can be severe, and fatal outcomes have been described. Most cases, however, resolve slowly with withdrawal of the agent. Corticosteroids are often used to treat minocycline-induced liver injury, largely because it resembles spontaneous autoimmune hepatitis that responds rapidly to immunosuppressive therapy. The effectiveness of corticosteroids in speeding recovery from minocycline-induced autoimmune hepatitis has not been proven, but anecdotal cases suggest a fairly dramatic effect. If corticosteroids are used, the dose should be rapidly reduced and the medication should be discontinued within 3 to 6 months. Furthermore, patients should be followed carefully after withdrawal of corticosteriods. Recurrence of hepatitis after withdrawal should suggest that the autoimmune hepatitis was unrelated to the minocycline or that the minocycline brought out the autoimmune diathesis that is self-sustaining. Autoimmune hepatitis not caused by medications usually requires long-term if not life-long immunosuppressive therapy. There is no information about possible cross-sensitivity to hepatic injury among the various tetracyclines.  Interestingly, doxycycline which resembles minocycline structurally, has been associated with a short latency acute hepatitis with immunoallergic features, but has not been associated definitively with the longer latency autoimmune hepatitis-like syndrome. 

 

References

References to minocycline-induced liver injury are provided in the introductory overview section on the tetracyclines.

 

Drug Class: Tetracyclines

 

 

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CASE REPORT
Minocycline

 

Case 1. Chronic hepatitis with autoimmune features caused by minocycline.
[Modified from a case in the database of the Drug-Induced Liver Injury Network]

 

A 20 year old woman had been taking minocycline for acne for one and a half years when she developed joint pains in the hands, wrists, hips and ankles. She stopped minocycline and began to feel better but was found to have markedly elevated serum enzymes on routine evaluation of the joint symptoms a few weeks later. She denied significant past medical history and had no risk factors for viral hepatitis. She took no other medications except oral contraceptives and did not drink alcohol regularly. Initially, serum ALT and AST were 15- to 20-fold elevated but alkaline phosphatase and serum bilirubin were normal. Tests for hepatitis A, B, and C and for infectious mononucleosis were negative. Autoantibody testing showed a positive antinuclear antibody (1:160), but negative tests for smooth muscle and liver-kidney microsomal antibodies. Serum globulins were elevated as was IgG (1960 mg/dL, normal < 1520).  Ceruloplasmin was low normal. An ultrasound of the abdomen showed normal gallbladder and no enlargement of bile ducts. A liver biopsy showed changes suggestive of autoimmune hepatitis with marked interface hepatitis, portal inflammation with lymphocytes and plasma cells but no fibrosis. She was started on prednisone and laboratory test abnormalities improved rapidly.

 

Key Points

 

Medication: Minocycline (100 mg daily)
Pattern: Hepatocellular (elevations in ALT only)
Severity: 1+ (No jaundice)
Latency: 1.5 Years
Recovery: 8 Months on prednisone
Other medications:Oral contraceptives, rare use of ibuprofen

 

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
1.5 years 1 month 607 87 0.2
1.5 months 965 86 0.4
2.2 years 9 months 216 88 0.3 Biopsy
  10 months 135 90 0.4 Prednisone started
  11 months 41 55 0.3
2.5 years 12 months 27 .. 0.3
  15 months 55 57 .. Prednisone stopped
3 years 18 months 45 62 0.3
4 years 30 months 23   Normal
Normal Values <35 <130 < 1.2

Comment

The major symptoms were arthralgias, suggesting that the reaction to minocycline therapy was a lupus-like syndrome. These symptoms, however, abated and the patient was found to have a fairly significant anicteric hepatitis which was slow to resolve. Ultimately, a liver biopsy was done that suggested autoimmune hepatitis. Thereupon, prednisone was started with prompt improvement in serum aminotransferase levels. The dose of prednisone was gradually decreased and stopped within 6 months.   She had no further symptoms but serum ALT levels were mildly abnormal. 

 

Case 2. Severe acute hepatitis with autoimmune features caused by minocycline.
[Modified from a case in the database of the Drug-Induced Liver Injury Network]

A 21 year old man was started on minocycline for acne and two months later developed fatigue, dark urine and weight loss and stopped therapy. A week later he was admitted to the hospital because of jaundice. He denied a previous history of liver disease or risk factors for viral hepatitis. He drank alcohol rarely. Serum bilirubin was elevated as were serum aminotransferase levels. Tests for hepatitis A, B, and C and for infectious mononucleosis were negative. Autoantibody testing showed a positive antinuclear antibody (1:1280), but negative tests for smooth muscle and liver-kidney microsomal antibodies. A liver biopsy was done which showed changes suggestive of autoimmune hepatitis with marked activity. He was started on prednisone and rapidly improved. Therapy was gradually reduced and then discontinued several months later without relapse of symptoms or recurrence of laboratory abnormalities.

 

Key Points

 

Medication:Minocycline (100 mg daily for 9 weeks)
Pattern: Hepatocellular (elevations in ALT only)
Severity: 3+ (Jaundice and hospitalization)
Latency: 8 Weeks
Recovery: 2 Months on prednisone
Other medications:None

 

Laboratory Values

Time After Starting Time After Stopping ALT (U/L) Alk P (U/L) Bilirubin (mg/dL) Other
10 weeks 1 week 1343 783 5.7
11 weeks 2 weeks 1649 638 4.8 Liver biopsy
Prednisone (60 mg daily) started
14 weeks 5 weeks 83 145 1.1
Normal Values <35 <130 <1.2

Comment

Minocycline can cause either an acute or a chronic hepatitis, but both are characterized by a hepatocellular pattern of serum enzyme elevations, the presence of autoantibodies and a liver biopsy showing changes typical of autoimmune hepatitis. Spontaneous recovery with stopping minocycline is the rule, but recovery can be prolonged, and prednisone therapy may speed the process. Whether prednisone actually improves ultimate outcome has not been proven. Nevertheless, both drug-induced and spontaneous autoimmune hepatitis can be severe and even fatal, and prednisone therapy may provide rapid relief. Most important, however, is to limit the dose and duration of therapy, carefully monitoring patients after stopping for evidence of recurrence.

 

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PRODUCT INFORMATION
Minocycline

 

REPRESENTATIVE TRADE NAMES
Minocycline – Dynacin®, Minocin®

 

DRUG CLASS
Anti-Infective Agents

 

COMPLETE LABELING

FDA product labeling at DailyMed, National Library of Medicine, NIH
Minocin® (minocycline hydrochloride) Product Labeling, Triax Pharmaceuticals.

 

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DRUG CAS REGISTRY NO MOLECULAR FORMULA STRUCTURE
Minocycline Hydrochloride
13614-98-7 C23-H27-N3-O7.Cl-H Minocycline  chemical structure

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OTHER REFERENCE LINKS
Minocycline

 

  1. PubMed logoRecent References on Minocycline

  2. Clinical Trials logoTrials on Minocycline

  3. TOXLINE logoTOXLINE Citations on Minocycline
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