Important Drug Warning from the Manufacturer on MELLARIL
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This is a re-typed text of a letter from Novartis Pharmaceuticals
Canada, Inc. Contact the company for a copy of any referenced enclosures.
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July 31, 2000
Dear Doctor or Pharmacist:
This communication is to advise you of important prescribing information
applicable to Mellaril® (thioridazine HCl). Mellaril has
been shown to prolong the QTc interval in a dose related manner, and drugs
with this potential, including Mellaril, have been associated with torsade
de pointes-type arrhythmias and sudden death. Therefore, the following
major modifications to the use of Mellaril must be immediately implemented:
Mellaril is now indicated only for schizophrenic patients who
fail to show an acceptable response to adequate courses of treatment with
other antipsychotic drugs, either because of insufficient effectiveness
or the inability to achieve an effective dose due to intolerable adverse
effects. Notwithstanding, Mellaril has not been systematically evaluated
in controlled trials in treatment of refractory schizophrenic patients
and its efficacy in such patients is unknown.
Mellaril is now contraindicated with certain other drugs, including fluvoxamine,
propranolol, pindolol, any drug that inhibits the cytochrome P450 2D6
isozyme, e.g., fluoxetine and paroxetine, and agents known to prolong
the QTc interval; Mellaril is also contraindicated in patients known to
have reduced levels of the cytochrome P450 2D6 isozyme as well as in patients
with congenital long QT syndrome or a history of cardiac arrhythmias;
Patients being considered for treatment with Mellaril should have a baseline
ECG performed and serum potassium levels measured. Serum potassium should
be normalized before starting treatment and patients with a QTc interval
greater than 450 msec should not receive Mellaril. Periodic ECG's and
serum potassium levels during Mellaril treatment may be useful and Mellaril
should be discontinued in patients who are found to have a QTc interval
over 500 msec.
Treatment of Mellaril overdosage should entail immediate cardiovascular
monitoring, to include continuous electrocardiographic monitoring to detect
arrhythmias. Drugs that may produce additive QT-prolonging effects, such
as disopyramide, procainamide, and quinidine, should be avoided in the
treatment of Mellaril overdosage.
These changes to the use of the product are based primarily on the findings
reported in three published studies.
The first of these investigations, a randomized, double-blind, three-period
crossover study in nine healthy males following single dose exposure to
placebo or one of two thioridazine doses (10 mg or 50 mg), with a one
week or longer washout between treatment periods, showed cardiac effects
related to the plasma concentration of thioridazine and its metabolites.
Among these, this study reported a dose-related prolongation of the QTc
interval between 2 and 8 hours after thioridazine administration. Following
dosing with thioridazine 50 mg, the mean QTc increased from 388 (SD±18)
to 411 (SD±14) msec four hours post-dose, with a mean maximal increase
of 23 msec. This change was statistically significantly greater than that
for either placebo or thioridazine 10 mg (< 0.01 and < 0.05, respectively).1
The second recent study demonstrated altered pharmacokinetics and increased
serum levels of thioridazine in patients with a genetic defect resulting
in slow hydroxylation of debrisoquin. This genetic defect is present in
about 7% of the Caucasian population. This study examined results from
a single 25 mg oral dose of thioridazine in 19 healthy subjects: 6 slow
and 13 rapid hydroxylators of debrisoquin. The slow hydroxylators obtained
higher serum levels of thioridazine with a 2.4-fold higher Cmax and a
4.5-fold larger AUC associated with a twofold longer half-life compared
with that of the rapid hydroxylators.2
The rate of debrisoquin hydroxylation appears to depend on the activity
level of the cytochrome P450 2D6 isozyme. Thus, this study suggests that
the co-administration of Mellaril with drugs that inhibit this isozyme
and the use of Mellaril in patients with reduced levels of activity of
this isozyme will result in substantial elevation of thioridazine plasma
levels.
The third recent study evaluated the effect of fluvoxamine (25 mg bid
for one week) on thioridazine steady state concentration in 10 male inpatients
with schizophrenia. Concentrations of thioridazine and its two active
metabolites, mesoridazine and sulforidazine, increased three-fold following
co-administration of fluvoxamine.3
Prolongation of the QTc interval has been associated with torsade de
pointes-type arrhythmias and sudden death. There are several published
case reports of torsade de pointes and sudden death associated with thioridazine
treatment. A causal relationship between these events and thioridazine
therapy has not been established but, given the ability of thioridazine
to prolong the QTc interval, such a relationship is possible.
Since the degree of QTc interval prolongation appears to be related to
the dose of thioridazine, it is reasonable to assume that concomitant
medications or other factors, which produce elevations in thioridazine
plasma levels, will increase the degree of QTc prolongation and possibly
increase the risk of serious ventricular arrhythmias. In addition, the
co-administration of Mellaril with other drugs that prolong the QTc interval
is expected to produce additive prolongation of the QTc interval. Therefore,
the co-administration of Mellaril with inhibitors of cytochrome P450 2D6,
e.g., fluoxetine and paroxetine, drugs that prolong the QTc interval,
fluvoxamine, propranolol, or pindolol is now contraindicated. For the
same reason, Mellaril is also contraindicated in patients known to have
reduced levels of cytochrome P450 2D6.
Furthermore, patients with congenital long QT syndrome or a history of
cardiac arrhythmias may be at increased risk for cardiac arrhythmias in
the context of thioridazine- associated QTc interval prolongation. Thus,
Mellaril is contraindicated in such patients as well.
Patients currently being treated with Mellaril should be fully informed
of the above information. Switching to a different antipsychotic agent
should be considered and a decision regarding continuation of Mellaril
treatment should be based on a careful assessment of the potential benefits
and risks of Mellaril for each patient. Please note that mesoridazine,
the active ingredient of Serentil®, is the major active metabolite
of Mellaril and also appears to have the capacity to prolong the QTc interval.
Sincerely,
original signed by
Beat Sümegi, MD
Vice-President, Medical
original signed by
Guy Rousseau, PhD
Vice-President, Drug Regulatory Affairs
References
1 Hartigan-Go K, et al.
Concentration-related pharmacodynamic effects of thioridazine and its
metabolites in humans. Clin Pharmacol Ther 1996;60:543-553.
2 vonBahr C, et al. Plasma levels of thioridazine
and metabolites are influenced by the debrisoquin hydroxylation phenotype.
Clin Pharmacol Ther 1991:49(3):234-240.
3 Carillo JA, et al. Pharmacokinetic Interaction
of Fluvoxamine and Thioridazine in Schizophrenic Patients. J Clin Psychopharmacol
1999;19:494-499.
Novartis is committed to providing you with the most current product
information available for the management of patients receiving Mellaril.
You can further our understanding of adverse events by reporting all cases
to:
Novartis Pharmaceuticals Canada Inc., 385 Bouchard Boulevard, Dorval,
Quebec, H9S 1A9 by phone at (800) 363-8883 or by fax at (514) 636-3175.
You can also report adverse drug reactions to the: Adverse Reaction Review
and Information Unit, Adverse Reaction and Medication Error Assessment
Division, Bureau of Licensed Product Assessment, Therapeutic Products
Programme, Health Canada, Finance Building, Tunney's Pasture, Address
Locator 0201C2, Ottawa, Ontario K1A 1B9
ADR Report Forms can be found in: The Canadian
Compendium of Pharmaceutical and Specialties or by contacting the Adverse
Reaction Review and Information Unit at tel.: (613) 957-0337 or fax (613)
957-0335.
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