Newly-Published Colchicine Safety Data Provide First Evidence-Based Dosing Guidance to Avoid Potentially Serious Interactions With Commonly Prescribed Drugs

- Paper Published in August Issue of Arthritis & Rheumatism Highlights Several Previously Unknown Drug-Drug Interactions

- Colchicine Dose Reductions Necessary in Presence of Certain CYP3A4 or P-gp Inhibitors

- Studies Supported URL Pharma Clinical Research Program that Led to FDA Approval of Colcrys®

PHILADELPHIA, Aug. 11, 2011 /PRNewswire/ -- Newly-published results from a series of colchicine safety studies provide physicians with the first evidence-based dosing guidance for colchicine when co-administered with certain commonly prescribed drugs, helping doctors and patients avoid serious and potentially life-threatening drug-drug interactions.

The study results, published in a paper titled "Evidence Basis of a Novel Colchicine Dose Reduction Algorithm to Predict and Prevent Colchicine Toxicity in the Presence of P-gp/CYP450 3A4 Inhibitors," appear in the August issue of Arthritis & Rheumatism, the journal of the American College of Rheumatology. The paper recommends colchicine dose reductions when used with medications such as immunosuppressants, antibiotics, hypertension drugs, anti-fungals and protease inhibitors.

The seven studies highlighted in the paper formed part of the basis for URL Pharma's New Drug Application (NDA) for Colcrys® (colchicine, USP). Colcrys is the only single-ingredient colchicine product to be reviewed and approved by the U.S. Food and Drug Administration, and is indicated for the prophylaxis and treatment of gout flares, and for the treatment of Familial Mediterranean Fever (FMF).

The studies assessed cyclosporine, an immunosuppressant; clarithromycin and azithromycin, two antibiotics; diltiazem and verapamil, two hypertension drugs; ketoconazole, an anti-fungal drug; and ritonavir, a protease inhibitor. Each of these drugs is known to inhibit cytochrome P450 3A4 (CYP3A4) and/or P-glycoprotein (P-gp).

Each of these drugs, except for azithromycin, was found to interact significantly with standard colchicine dosing regimens, in some cases more than doubling levels of colchicine in the blood and increasing the risk of serious toxicities. Cyclosporine and clarithromycin in particular increased peak colchicine blood levels by nearly 300 percent. The authors recommended that colchicine doses be reduced between one-third and two-thirds for acute flares, and by 50 to 75 percent for flare prophylaxis, when used as concomitant therapy with six of the seven drugs studied. No colchicine dose adjustments were necessary when used with azithromycin.

In the case of ritonavir, the discovery of serious interactions with colchicine prompted the FDA on May 5, 2010 to require that the new dosing recommendations be included in the prescribing information of all protease inhibitors.

"Despite the fact that colchicine has been used for decades in the prevention and treatment of gout flares and for FMF, the pharmacokinetics and metabolism of colchicine have not been extensively studied, until now," said Robert A. Terkeltaub, M.D., Interim Division Chief and Professor of Medicine at the University of California San Diego and the VA Medical Center, and the paper's lead author. "The results of these studies form the foundation of evidence-based dosing guidance for colchicine in the presence of CYP3A4 or P-gp inhibitors that help achieve optimal therapeutic benefit while avoiding dangerous and unnecessary safety risks."

Safety issues resulting from the concurrent use of colchicine with CYP3A4 or P-gp inhibitors have been documented in the past. At least 60 deaths have been linked to colchicine in patients who were also taking clarithromycin, but there have been no published studies characterizing these interactions, nor any suggestions or recommendations to modify colchicine dosing, according to the authors.

"The need to understand, and avoid, colchicine drug-drug interactions is greater than ever, especially in people with gout," said Matthew W. Davis, M.D., R.Ph., Chief Medical Officer, URL Pharma and a co-author of the paper. "Many gout patients struggle with obesity and have multiple co-morbid conditions, including hypertension, diabetes, metabolic syndrome and renal insufficiency, which may require patients to be on multiple medications. These studies are part of our continued investigation of the pharmacokinetics of colchicine, and reflect our ongoing commitment to making the necessary research investments to advance colchicine science."

Dosing Recommendations

Seven separate drug-drug interaction (DDI) studies were conducted with single-dose Colcrys® to understand the effect of administering colchicine concomitantly with medications that are known inhibitors of CYP3A4 or P-gp. Six of the seven drugs caused significant increases in mean peak colchicine concentrations and mean peak total colchicine exposure (AUC(0-t)). Dosing recommendations are summarized as follows:


 
 

Drug

Acute Flare Dosing Recommendations

Flare Prophylaxis Dosing Recommendations

FMF Dosing Recommendations

 

Cyclosporine

0.6mg (1 tablet) X 1 dose

0.3mg once a day, or 0.3 mg every other day

Maximum daily dose of 0.6 mg (or 0.3mg twice a day)

 

Clarithromycin, Ketoconazole, Ritonavir

0.6mg (1 tablet) X 1 dose, followed by 0.3mg (half tablet) 1 hour later

0.3mg once a day, or 0.3mg every other day

Maximum daily dose of 0.6mg (or 0.3mg twice a day)

 

Diltiazem, Verapamil

1.2mg (2 tablets) X 1 dose

0.3mg twice a day (or 0.6mg once a day), or 0.3mg once a day

Maximum daily dose of 1.2mg (or 0.6mg twice a day)

 

Azithromycin

No dose reduction required

No dose reduction required

No dose reduction required

 

 
 
       


 

The studies were among the 17 clinical trials conducted by URL Pharma that led to the FDA approval of Colcrys. URL Pharma also conducted AGREE (Acute Gout Flare Receiving Colchicine Evaluation), the first placebo-controlled comparison of low-dose and high-dose colchicine in the treatment of acute gout flares. AGREE was published in Arthritis & Rheumatism in April 2010.

About Gout and Painful Gout Flares

Gout is a painful form of arthritis that affects an estimated 8 million Americans, most commonly adult men. It occurs when excess uric acid in the body is deposited as needle-like crystals, or tophi, in the joints or soft tissues, which cause inflammatory arthritis and can lead to gout flares typically lasting three to 10 days.

Gout flares are characterized by intermittent swelling, redness, heat, joint stiffness and pain, which are often excruciating and can be debilitating enough to significantly interfere with work, social activities and daily living. For many people, gout initially affects the joint of the big toe, though it can also affect other joint areas such as the ankles, heels, knees, wrists, fingers and elbows.

About Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is a rare, inherited inflammatory disorder generally found in people of Mediterranean origin and characterized by recurrent fevers and painful inflammation of the abdomen, lungs and joints. Colchicine has been used to treat FMF since 1972 and is considered the "gold standard" in the treatment of the disease.  Although the mechanism is not yet fully understood, Colcrys appears to be effective in FMF by blocking both inflammation and a condition known as amyloidosis.

Important Safety Information

COLCRYS® (colchicine, USP) tablets are indicated for prophylaxis and the treatment of gout flares.

COLCRYS is contraindicated in patients with renal or hepatic impairment who are concurrently prescribed P-gp inhibitors or strong inhibitors of CYP3A4 as life-threatening or fatal toxicity has been reported. Dose adjustments of COLCRYS may be required when co-administered with P-gp or CYP3A4 inhibitors. The most common adverse events in clinical trials for the prophylaxis and treatment of gout were diarrhea and pharyngolaryngeal pain. Rarely, myelosuppression, thrombo-cytopenia, and leukopenia have been reported in patients taking colchicine. Rhabdomyolysis has been occasionally observed, especially when colchicine is prescribed in combination with other drugs known to cause this effect. Monitoring is recommended for patients with a history of blood dyscrasias or rhabdomyolysis.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1.800.FDA.1088.

You may also report negative side effects to the manufacturer of COLCRYS by calling 1.888.351.3786.

Please see www.colcrys.com for full Prescribing Information.

About URL Pharma

URL Pharma, Inc., headquartered in Philadelphia, PA, is a leading specialty pharmaceutical company with fully integrated technology development, product development, manufacturing, and commercialization capabilities. After a long history of generic pharmaceutical research, development, and manufacturing, the Company has successfully transitioned to a technology-driven, specialty pharmaceutical business. The Company seeks to develop and commercialize scientifically and medically innovative products that address unmet medical needs for improvements in safety and efficacy. For additional information about the company, please visit www.urlpharma.com.  For further information, please call 215-697-1900 or media@urlpharma.com.

SOURCE URL Pharma, Inc.

Web Site: http://www.urlpharma.com

Posted: August 2011

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