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July 9, 2001

Dear Healthcare Professional:

The purpose of this letter is to bring to your attention the recent addition to the Precautions
Section of the Carnitor ® (levocarnitine) Injection, Tablets and Oral Solution labeling a statement
regarding the use of oral formulations of levocarnitine in End Stage Renal Disease (ESRD)
patients on dialysis and patients with severely compromised renal function.

The basis for the labeling change arises from reports of the unapproved use of oral formulations
of levocarnitine in ESRD patients. Only the intravenous form has been approved for use in this
patient population.

Sigma-Tau Pharmaceuticals, Inc., received approval on December 15, 1999 from the U.S. Food
and Drug Administration (FDA) to market Carnitor Injection for the prevention and treatment of
carnitine deficiency in patients with ESRD who are undergoing dialysis.

The statement added to the Precautions Section of all dosage forms is as follows:

Administration of high doses of the oral formulations of levocarnitine for long
periods of time is not recommended in patients with severely compromised renal
function or in ESRD patients on dialysis due to the fact that major metabolites formed
following oral administration (trimethylamine [TMA] and trimethylamine-N-oxide
[TMAO]) will accumulate since they can not be efficiently removed by the kidneys.
This does not occur to the same extent following intravenous administration. TMA
accumulation is not desirable since it increases the amount of nitrogenous waste to be
removed in the dialysis procedure. In addition, increased levels of TMA in dialysis
patients have been reported to be associated with possible neurophysiologic effects.
Also, the inefficient removal of TMA may result in the development of ‘fishy odor’
syndrome. Only the intravenous form of levocarnitine is indicated for use in ESRD
patients on hemodialysis.

Adverse events reported with Carnitor use include nausea, vomiting, body odor, gastritis and
seizures. An incidence for these reactions is difficult to estimate due to the confounding effects
of the underlying pathology. There are no reported contraindications or warnings.

Sigma-Tau does not promote or recommend the use of oral Carnitor in ESRD patients on
dialysis.

The attached package insert for Carnitor Injection highlights this important new information,
which is also included in the labeling for Carnitor Oral Solution and Tablets.

Further information may be obtained by calling 1-800-447-0169.

Sincerely,

C. Kenneth Mehrling
Chief Operating Officer

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