Colchicine Interactions with Other Drugs Can Be Life-Threatening

Patients taking the commonly used drug colchicine (COLCRYS, GLOPERBA, MITIGARE) should be aware that using it in combination with any one of numerous other drugs may lead to serious adverse interactions, some of which could be fatal.

FDA-approved uses and dosage

Colchicine is approved by the Food and Drug Administration (FDA) for the prevention and treatment of acute gout attacks (flares).[1] Gout develops in some patients who have high blood levels of the bodily waste product uric acid, which can be caused by the body producing too much uric acid or by the kidneys removing too little of it.

Acute gout attacks occur when uric acid crystals form in joints and surrounding tissues, resulting in severe joint pain, swelling and redness. Gout attacks usually affect a single joint, such as the big toe, ankle or knee; last several days; and occur intermittently. Standard treatments for acute gout attacks include nonsteroidal anti-inflammatory drugs (for example, ibuprofen [ADVIL, IBU-TAB, MOTRIN]), colchicine and injection of steroids into the affected joint.[2]

According to the FDA-approved drug labeling, the recommended dosage of colchicine for prevention of gout attacks for adults and adolescents older than 16 years of age is one tablet (0.6 milligrams [mg]) once or twice daily. The maximum recommended total daily dose for prevention of gout attacks is two tablets (1.2 mg). The recommended dose of colchicine for treatment of an acute gout attack is two tablets (1.2 mg) at the first sign of an attack followed by one tablet (0.6 mg) one hour later.

Colchicine also is approved by the FDA for treating a hereditary condition called familial Mediterranean fever,[3] which causes recurring episodes of painful inflammation in the abdomen, chest or joints, usually in combination with a fever.[4] The disease primarily affects people of Arab, Armenian, Jewish or Turkish ancestry, occurring in up to 0.5 percent of such individuals. The recommended dosage of colchicine for familial Mediterranean fever in adults is two to four tablets (1.2 mg to 2.4 mg) daily.

Importantly, the dosage of colchicine generally needs to be reduced in patients who have either moderate-to-severe impairment of kidney function or severe impairment of liver function.[5]

Drugs that increase colchicine levels

Like many drugs, colchicine is metabolized (broken down or chemically modified) by substances in the liver called enzymes. One important liver enzyme, known as CYP3A4, breaks down colchicine.[6] The most common way that other drugs can increase colchicine blood levels is by inhibiting this key liver enzyme.[7]

Other drugs can increase colchicine levels by blocking the effect of P-glycoprotein,[8] a substance that exists naturally in the intestines, kidneys and other organs.[9] P-glycoprotein in the intestines and kidneys normally removes colchicine from the body by excreting it into the stool and urine, respectively, thereby lowering blood levels of the drug.[10] When taken with colchicine, drugs that inhibit P-glycoprotein activity reduce the elimination of colchicine by the intestines and kidneys, thus increasing the risk of colchicine toxicity.

The Table below lists 15 oral drugs that, when taken concomitantly (simultaneously) with colchicine, may increase colchicine in the blood to toxic levels. The list includes antibiotics, antifungal drugs, antiviral drugs, calcium channel blockers used to treat high blood pressure, and immunosuppressive drugs routinely prescribed following organ transplantation.

Colchicine toxicity typically causes gastrointestinal symptoms, including abdominal pain, nausea, vomiting and diarrhea.[11] It also can cause muscle pain and weakness and impair the bone marrow's ability to make red and white blood cells, resulting in severe anemia and increasing the risk of serious infections, respectively. In extreme cases, colchicine toxicity can progress to failure of multiple vital organs and death.

Examples of Oral Drugs That Increase the Risk of Colchicine Toxicity[12],[13]

†Combination drug that contains other active ingrediants not listed
*Designated as Limited Use
**Designated as Do Not Use except for serious fungal infections
***Designated as Do Not Use

The antibiotic clarithromycin (generic only) is one of the strongest inhibitors of CYP3A4. One study showed that concomitant use of colchicine and clarithromycin for one week resulted in a more than 280-percent increase in colchicine blood levels compared with taking colchicine alone.[14]

Another study conducted by researchers in Hong Kong identified 116 patients who had been treated with both colchicine and clarithromycin following admission to the hospital.[15] The researchers compared the clinical outcomes of patients who took the two drugs simultaneously with those who were treated with the drugs sequentially, having had a course of one drug started only after the course of therapy with the other drug had been completed. In the 88 patients who received the two drugs together, nine (10 percent) died. In contrast, only one (3.6 percent) of the 28 patients who received the two drugs sequentially died. Furthermore, the risk of death from the concomitant use of colchicine and clarithromycin was much greater in those who had impaired kidney function.

For patients prescribed any of the drugs listed in the Table above, the dosage of colchicine needs to be reduced significantly to avoid dangerous colchicine blood levels.[16] Moreover, patients with impaired kidney or liver function should not take colchicine concomitantly with clarithromycin or other drugs that are strong inhibitors of either CYP3A4 or P-glycoprotein.

Other important drug interactions

Colchicine itself can cause myopathy (muscle damage) with long-term treatment at the recommended dosages.[17] Symptoms of myopathy include muscle pain and weakness. In severe cases, this condition can progress to rhabdomyolysis, a life-threatening, muscle-destroying condition that can lead to sudden kidney failure and death. Patients with impaired kidney function and elderly patients are at increased risk of myopathy and rhabdomyolysis.

Concomitant use of colchicine with any of the following drugs can increase the risk of developing myopathy or rhabdomyolysis: atorvastatin (CADUET, LIPITOR), fluvastatin (LESCOL XL), lovastatin (ALTOPREV), pravastatin (PRAVACHOL), simvastatin (FLOLIPID, VYTORIN, ZOCOR), fenofibrate (ANTARA, FENOGLIDE, LIPOFEN, TRICOR, TRIGLIDE), fenofibric acid (TRILIPIX), gemfibrozil (LOPID), cyclosporine (GENGRAF, NEORAL, SANDIMMUNE) and digoxin (LANOXIN).[18] Notably, all of these drugs, except digoxin and cyclosporine, themselves are associated with an increased risk of myopathy.

What You Can Do

These types of potentially dangerous drug interactions reinforce the importance of bringing all of the prescription and nonprescription drugs that you take each time you visit any doctor. Because many drugs, including others not listed in this article, may affect the blood levels of colchicine, you should find out from your doctor whether any other drugs that you are taking could interact with your colchicine treatment.

Before taking colchicine, tell your doctor about all your medical conditions, particularly if you have kidney or liver disease.

If you are taking colchicine and begin or end treatment with another drug that can increase colchicine blood levels or increase the risk of myopathy, speak with your doctor about whether you will need to adjust your colchicine dosage or whether there is an alternative drug that will not interact with colchicine. If you have significant kidney or liver disease, you should not take any drugs that are strong inhibitors of CYP3A4, like clarithromycin, or P-glycoprotein while taking colchicine.

You should seek immediate medical attention if you experience any of the following symptoms, which could indicate life-threatening colchicine toxicity:

• Severe diarrhea or vomiting
• Muscle weakness or pain
• Numbness or tingling in your fingers or toes
• Unusual bleeding or bruising
• Increased infections
• Feel weak or tired
• Pale or gray color to your lips, tongue or palms of your hands

Finally, keep colchicine out of the reach of children to prevent a potentially fatal accidental overdose.
 

References

[1] Takeda Pharmaceuticals America. Label: colchicine (COLCRYS). January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6adc880-5499-4691-93f3-27c87902d5fc. Accessed March 7, 2019.

[2] Becker MA. Treatment of gout flares. UpToDate. Updated February 11, 2019.

[3] Takeda Pharmaceuticals America. Label: colchicine (COLCRYS). January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6adc880-5499-4691-93f3-27c87902d5fc. Accessed March 7, 2019.

[4] U.S. National Library of Medicine. Familial Mediterranean fever. https://ghr.nlm.nih.gov/condition/familial-mediterranean-fever. Accessed March 7, 2019.

[5] Takeda Pharmaceuticals America. Label: colchicine (COLCRYS). January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6adc880-5499-4691-93f3-27c87902d5fc. Accessed March 7, 2019.

[6] Ibid.

[7] Ibid.

[8] Becker MA. Treatment of gout flares. UpToDate. Updated February 11, 2019.

[9] Ledwitch KV, Roberts AG. Cardiovascular ion channel inhibitor drug-drug interactions with P-glycoprotein. AAPS J. 2017;19(2):409-420.

[10] Becker MA. Treatment of gout flares. UpToDate. Updated February 11, 2019.

[11] Takeda Pharmaceuticals America. Label: colchicine (COLCRYS). January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6adc880-5499-4691-93f3-27c87902d5fc. Accessed March 7, 2019.

[12] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Accessed March 7, 2019.

[13] Takeda Pharmaceuticals America. Label: colchicine (COLCRYS). January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6adc880-5499-4691-93f3-27c87902d5fc. Accessed March 7, 2019.

[14] Takeda Pharmaceuticals America. Label: colchicine (COLCRYS). January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6adc880-5499-4691-93f3-27c87902d5fc. Accessed March 7, 2019.

[15] Hung IF, Wu AK, Cheng VC, et al. Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study. Clin Infect Dis. 2005;41(3):291-300.

[16] Takeda Pharmaceuticals America. Label: colchicine (COLCRYS). January 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d6adc880-5499-4691-93f3-27c87902d5fc. Accessed March 7, 2019.

[17] Ibid.

[18] Ibid.