My collection of paper (letters, e-mail, abstracts, reprints,
package inserts, working notes, etc.) about tolcapone (Tasmar)
now weighs about a pound, and the end is not in sight.
Notwithstanding my wish to quit the subject, new twists and
turns keep popping up, and my insatiable curiosity drives me
on...(I'm NOT playing Cassandra; We have heard from some of the
best authorities in the business that Tasmar is safe to use,
if precautions, including biweekly blood tests of liver enzymes,
are carefully followed).
The latest conundrum is rhabdomyolysis, a term which I first
met in the revised, FDA-approved, Package Insert for Tasmar,
with its new prominent boxed "WARNING" and a very comprehensive
Patient Consent form. From a respected textbook on muscle
disease: "Rhabdomyolysis is not a disease. Rather, it is the
consequence of any cause of muscle necrosis [death of tissue].
Although [it] is most commonly associated with severe muscle
injury, it may be caused by a variety of conditions [Table,
with about a dozen]...The most threatening complication of
rhabdomyolysis is acute tubular necrosis. [kidney failure by
death of kidney tissue]" Here is the discussion pertinent to
rhabdomyolysis, in the revised Package Insert. These revisions
are baffling to me, so I only quote them as closely as I can:
OLD (BOTH) NEW
(Hepatic Enzyme Abnormalities: In Phase 3 controlled trials,
increases to more than 3 times the upper limit of normal in ALT
or AST occurred in approximately 1% of patients at 100 mg tid
and 3% of patients at 200 mg tid. Increases to more than 8 times
the upper limit of normal in liver enzymes occurred in 0.3% at
100 mg tid and 0.7% at 200 mg tid. Elevations usually occurred
within 6 weeks to 6 months of starting treatment. In about half
the cases with elevated liver enzymes, enzyme levels returned to
baseline values within 1 to 3 months while patients continued
TASMAR treatment. When treatment was discontinued, enzymes
generally declined within 2 to 3 weeks but in some cases took as
long as 1 to 2 months to return to normal.)
One patient, a 55-year-old woman |Rhabdomyolysis:cases of severe
who had received treatment with |rhabdomyolysis, with one case
tolcapone 200mg tid for 53 days, |of multiorgan system failure
had the onset of diarrhea |rapidly progressing to death,
followed 4 days later by |have been reported. The
yellowing of the skin and eyes. |complicated nature of these
She died 7 days after the onset |cases makes it impossible to
of the diarrhea. No liver |determine what role, if any,
function tests were performed |TASMAR played in their patho-
after the onset of symptoms. |genesis. Severe prolonged
|motor activity including
|dyskinesia may account for
|rhabdomyolysis. Some cases,
|however, included fever,
|alteration of consciousness
|and muscular rigidity. It is
|possible, therefore, that the
|rhabdomyolysis may be a result
|of the syndrome described in
|Hyperpyrexia and Confusion.
(more)
Withdrawal Emergent | P. 2 of 2
(Hyperpyrexia and Confusion:)
|In clinical trials,
(Four cases of a symptom complex
resembling the neuroleptic malignant syndrome (characterized by
elevated temperature, muscular rigidity, and altered conscious-
ness), similar to that reported in association with the rapid
dose reduction or withdrawal of other dopaminergic drugs, have
been reported in association with the abrupt withdrawal or the
lowering of the dose of tolcapone. In 3 of these cases, CPK* was
elevated as well. One patient died, and the other 3 patients
recovered over periods of 2, 4, and 6 weeks.)
|Rare cases of this system
|complex have been reported
|during marketed use. These
|cases are [complicated by
|presence of other factors
|...so it is difficult to
|determine the role of TASMAR]
*CPK = Creatine phosphokinase, an improper term for creatine
kinase (CK), an enzyme which is a prominent indicator of muscle
disease such as myocardial infarct (death of heart muscle).
Cheers,
Joe
--
J. R. Bruman (818) 789-3694
3527 Cody Road
Sherman Oaks, CA 91403-5013
