Italian Generic Clopidogrel Worse Than Brand Name at Suppressing Platelets


A generic version of the standard antiplatelet agent clopidogrel used in Italy may do a worse job of suppressing platelet reactivity than the brand-name form of the drug, according to lab data from an Italian center published online December 12, 2012, ahead of print in the Journal of the American College of Cardiology.

Since October 2011, the Careggi Hospital (Florence, Italy) has received clopidogrel base (generic) instead of the pre-generic version clopidogrel hydrogen sulfate at the University Hospital. The generic version is the parent metabolite of the drug and is not chemically identical to the earlier version.

To compare the 2 forms, Rossella Marcucci, MD, PhD, and colleagues at the University of Florence (Florence, Italy), looked at rates of high platelet reactivity in 1,579 ACS patients at their institution who received clopidogrel from October 2011 through March 2012 or during the same period the previous year prior to the availability of the generic version. By 2 out of 3 assay methods, more patients who received clopidogrel base showed high platelet reactivity compared with patients who received clopidogrel hydrogen sulfate (table 1).

Table 1. Platelet Reactivity by Light Transmission Aggregometry (LTA)

 

Clopidogrel Hydrogen Sulfate
(Oct 2010 - Mar 2011;
n = 838)

Clopidogrel Base
(Oct 2011 - Mar 2012;
n = 741)

P Value

High Platelet Reactivitya

25.4%

42.4%

< 0.0001

LTA, 1 mmol/L AA

17%

18%

0.715

LTA, 2 µg/mL Collagen

33.5%

36.7%

< 0.001

a Defined as presence of 10 µmol/L ADP LTA ≥ 70%.

After adjustment for age, sex, classic cardiovascular risk factors, and STEMI/NSTEMI status, the prevalence of high platelet reactivity by ADP remained higher in the clopidogrel base group compared with the clopidogrel hydrogen sulfate group. And on a month by month comparison, the difference in platelet reactivity between clopidogrel versions remained consistent, with the exception of 1 month that showed a strong trend (table 2).

Table 2. High Platelet Reactivity: Month-to-Month Comparison

 

Clopidogrel Hydrogen Sulfate
(Oct 2010 - Mar 2011)

Clopidogrel Base
(Oct 2011 - Mar 2012)

P Value

October

27%

40%

< 0.05

November

30%

42%

< 0.05

December

29%

38%

0.06

January

30%

44%

< 0.05

February

24%

44%

< 0.05

March

13%

45%

< 0.005


Other than the change in the chemical structure of clopidogrel, the researchers could identify no significant variation in clinical characteristics of the patients or in the interventional procedures which could have accounted for the higher prevalence of high platelet reactivity.

Dr. Marcucci and colleagues stress that “this finding only represents the descriptive analysis of laboratory data produced in our department in relation to the shift to the new preparation of clopidogrel and cannot be applied to the several other generic forms of clopidogrel now available.”

Still, they add, an adequate randomized trial comparing the 2 forms of the drug is warranted, as is “accurate post-marketing surveillance of generic forms of a drug such as clopidogrel for which the lack of effective platelet inhibition is associated with a documented ischemic risk.”

According to Dr. Marcucci, who communicated with TCTMD via e-mail, Dr. Reddy’s Laboratories (Hyderabad, India) is the manufacturer of the generic clopidogrel used in the study. A company press release reports that Dr. Reddy’s launched bioequivalent generic clopidogrel tablets, 75 mg and 300 mg, in the United States on May 18, 2012. The US version appears to be clopidogrel bisulphate, and not the base form. The company has not responded to an e-mail inquiry.

‘People Should Not Panic’

In a telephone interview with TCMD, Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), called the high platelet reactivity results using the LTA ADP test “dramatically different even for this kind of testing. . . . [I]t’s disturbing in Italy but may not apply to the United States, and we don’t have any outcomes to see if it’s clinically important.”

Dr. Bates added that after trials such as GRAVITAS and ARCTIC, it is questionable as to “whether we can believe anything on platelet aggregation.”

Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), agreed that the results are “concerning.” But “the bottom line is people should not panic,” he told TCTMD in a telephone interview.

He noted that there are a few possibilities to explain the results. “Either it’s a chance finding, or they had a bad batch, or it wasn’t stored properly, or it’s a different patient group,” Dr. Kleiman said.

Regardless, “somebody’s got to verify this quickly,” he added. “We in the community who research this stuff ought to get off our butts and do something.”

Clopidogrel at Home and Abroad

Dr. Kleiman noted that the European Medicines Agency (EMEA) is charged with approving generics that prove bioequivalence to brand name compounds, and in the case of clopidogrel, he wondered why the generic version was chemically different than the original version, which is a salt. “Clopidogrel base is the parent compound. It’s the acid,” he said. “I don’t understand why they don’t just duplicate the same salt as the brand name compound unless it’s just a lot more expensive.”

In June 2009, the EMEA gave the go-ahead to 6 generic versions of clopidogrel bisulfate and the drug is now available in several European countries. On June 2, 2010, the EMEA approved the generic version clopidogrel base, stating that 75-mg tablets possess adequate quality and benefit/risk ratio and are comparable to the reference clopidogrel product.

The US Food and Drug Administration (FDA) approved generic versions of clopidogrel on May 17, 2012, noting in a press statement that “generic drugs approved by FDA are of the same high quality and strength as brand-name drugs. The generic manufacturing and packaging sites must pass the same quality standards as those for brand-name drugs.”

Dr. Reddy's Laboratories, Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals have gained FDA approval for 300-mg clopidogrel. Apotex Corporation, Aurobindo Pharma, Mylan Pharmaceuticals, Roxane Laboratories, Sun Pharma, Teva Pharmaceuticals, and Torrent Pharmaceuticals have received approval for 75-mg clopidogrel.

 


Source:
Marcucci R, Paniccia R, Gori AM, et al. Bioequivalence in the real world is a complex challenge: The case of clopidogrel [research correspondence]. J Am Coll Cardiol. 2012;Epub ahead of print.

 

 

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Disclosures
  • Dr. Marcucci reports receiving lecture fees from Eli Lilly and Merck Sharp and Dohme.
  • Dr. Bates reports serving on advisory boards for AstraZeneca, Daiichi Sankyo/Eli Lilly, and Sanofi.
  • Dr. Kleiman reports serving on an advisory board for Eli Lilly and receiving honoraria from AstraZeneca and Sanofi.

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