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4. Grose JH, Gbeassor FM, Lebel M. Differential effects of diuretics on
eicosanoid biosynthesis. Prostaglandin Leukot Med 1986;24:103-9.
DOI 10.1016/0262-1746(86)90118-6
5. Iakovlev VM, Sokolov GS. [The possibilities of arifon in the combined
therapy of unstable stenocardia in persons with arterial hypertension]
Russian. Ter Arkh 1997;69(6):53-5.
Interaction between tadalafil and itraconazole
TO THE EDITOR: Erectile dysfunction (ED) is a common medical condi-
tion affecting millions of men worldwide.
1
Sildenafil citrate, an inhibitor
of phosphodiesterase type-5 enzyme (PDE5), is the first and most widely
prescribed oral agent for ED. Tadalafil and vardenafil are newer PDE5
inhibitors approved for marketing. We describe priapism and increased
duration of tadalafil action in a patient treated for ED in addition to itra-
conazole for onychomycosis.
Case Report. A 56-year-old white man with no concomitant illness had been
using sildenafil 100 mg as needed for ED from 1999 to April 2003 without any
known adverse events. He then switched to tadalafil 10 mg, hoping to achieve bet-
ter and longer efficacy. He was not taking other drugs and did not complain of any
undesirable effects. In September 2003, because of recurrent onychomycosis of
the foot, he was prescribed itraconazole 400 mg/day for 7 days monthly. He had
previously taken itraconazole, even while taking sildenafil, without experiencing
adverse effects.
During the first day of monthly (October) itraconazole therapy, the patient took
tadalafil. Within a few hours, priapism occurred, lasting >4 hours, without impedi-
ment of urinary flow. In November (still during itraconazole weekly treatment),
the patient took the same dose of tadalafil and the same symptom occurred, with
analogous onset and duration. This time he reported the reaction to his physician,
adding that painful erections had occurred repeatedly over 72 hours. During the
following 7 months, the patient did not use tadalafil, and the adverse effect did not
recur when he resumed use of sildenafil during itraconazole therapy.
Discussion. As of November 19, 2004, priapism has not been associated
with tadalafil.
2,3
Tadalafil is primarily metabolized through CYP3A4. Ke-
toconazole, a CYP3A4 inhibitor, at doses of 200 mg/day has increased
tadalafil (10 mg) AUC and maximum concentration 2 times and 15%,
respectively, relative to the values of the same dose of tadalafil alone.
3
Therefore, although no studies of possible interaction have been performed,
caution is required when tadalafil is given with other potent CYP3A4 in-
hibitors, such as itraconazole.
In our patient, the tadalafil–itraconazole interaction, leading to pri-
apism, was confirmed by positive rechallenge, absence of concomitant
medications and conditions and by the absence of adverse effects with
tadalafil alone. Based on the Naranjo probability scale, the event/drug re-
lationship was probable.
4
Surprisingly, this adverse effect never occurred in the patient during
concurrent use of itraconazole and sildenafil, which is a substrate not
only of CYP3A4 but also of CYP2C9. Furthermore, one sildenafil circu-
lating metabolite may contribute to approximately 20% of the net phar-
macologic effect of the drug.
5
On the contrary, the tadalafil main metabo-
lite is 13 000 times less potent than tadalafil.
3
In the absence of other observations, we assume that the pharmacoki-
netic interaction between tadalafil and itraconazole could have produced
priapism in our patient. To our knowledge, this is the first report of a
tadalafil–itraconazole interaction leading to priapism; this case indicates that
prescribers should monitor tadalafil closely for the risk of drug interactions.
Laura Galatti PharmD
Resident in Clinical Pharmacology
Department of Clinical and Experimental Medicine and Pharmacology
University of Messina
Torre Bi olog ica—Policlinico Universitario
Via Consolare Valeria—Gazzi
98100 Messina, Italy
fax 39 090 2213300
lgalatti@unime.it
Antonio Fioravanti MD
General Practitioner
Fano Asur
Marche, Italy
Francesco Salvo MD
Resident in Clinical Pharmacology
Department of Clinical and Experimental Medicine and Pharmacology
University of Messina
Giovanni Polimeni PharmD
Resident in Clinical Pharmacology
Department of Clinical and Experimental Medicine and Pharmacology
University of Messina
Saffi E Giustini MD
General Practitioner
Head
Pharmacovigilance Network of Italian College of General Practitioners
Florence, Italy
Published Online, 30 Nov 2004, www.theannals.com
DOI 10.1345/aph.1E383
REFERENCES
1. Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erec-
tile dysfunction between 1995 and 2025 and some possible policy conse-
quence. BJU Int 1999;84:50-6.
2. Sur RL, Kane CJ. Sildenafil citrate–associated priapism. Urology 2000;
55:950.
3. Product information. Cialis (tadalafil). Sesto Fiorentino (FI), Italy: Eli
Lilly, January 2004.
4. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A
method for estimating the probability of adverse drug reactions. Clin
Pharmacol Ther 1981;30:239- 45.
5. Warrington JS, Shader RI, Von Moltke LL, Greenblatt DJ. In vitro bio-
transformation of sildenafil (Viagra): identification of human cytochromes
and potential drug interactions. Drug Metab Dispos 2000;28:392-7.
Aripiprazole-associated dyskinesia
TO THE EDITOR: Aripiprazole, a dopamine-2 (D
2
) receptor partial ago-
nist, has been associated with a placebo-level incidence of extrapyrami-
dal symptoms and treatment-emergent dyskinesia.
1
The incidence of
dyskinesia is similar to that reported for risperidone and olanzapine.
2
One case report documented improvement of antipsychotic-induced tar-
dive dyskinesia with aripiprazole
3
; it has not been documented to pro-
duce de novo dyskinesias. We report a case of new-onset aripiprazole-
associated lingual dyskinesia.
Case Report. A 35-year-old man had a 22-year history of schizoaffective dis-
order that had been largely untreated. He had minimal intermittent antipsychotic
exposure prior to admission to our hospital. Medication history included less than
one-month trials of desipramine, fluoxetine, sertraline, olanzapine, and trifluoper-
azine at various times, with no reported movement disorder symptoms. His medi-
cal history was noncontributory; he had never undergone neuroimaging. He had
not taken any antipsychotics for 5 months prior to or 4 months after hospital ad-
mission for acute psychotic exacerbation (July 2003).
On November 25, 2003 (day 1), abnormal movements were absent, and oral
olanzapine 5 mg was initiated. The dose was increased to 10 mg daily on day 15
due to persistent symptoms. The patient’s total Abnormal Involuntary Movement
Scale (AIMS) score on day 10 was zero. After one month, he requested a medica-
tion change due to concern over weight gain; therefore, on day 34, aripiprazole
was started at 10 mg/day. The aripiprazole dose was increased to 20 mg/day on
day 55 due to continued psychosis, and olanzapine was discontinued.
On day 105, after 7 weeks of monotherapy with aripiprazole, the patient report-
ed that his tongue felt large, slow, thick, and uncoordinated. These symptoms had
emerged over a few days; he was noted to be talking with a lisp. The dyskinesia of
his tongue manifested as rolling/writhing movements, exacerbated by purposeful
movements (eg, finger tapping), and interfered with his sleep. He experienced
episodic quivering of the upper lip; examination did not detect any other dyskinet-
ic movements. The AIMS total score on day 105 was 8. Aripiprazole was discon-
tinued and, within a day, the patient noted mild improvement. Within 10 days (day
115), the dyskinesia had resolved and the AIMS score on day 127 was zero. At the
time of writing, the patient remained hospitalized. He was subsequently titrated
onto quetiapine 500 mg/day and, after 2 months of therapy, had no recurrence of
lingual dyskinesia.
Discussion. This report describes the emergence of lingual dyskinesia
with aripiprazole monotherapy. The absence of abnormal movements
before starting this agent, the lack of concurrent therapy, and prompt res-
olution upon drug discontinuation suggest that aripiprazole may have
produced the abnormal movements. The Naranjo probability scale indi-
cated a probable relationship.
4
It is doubtful that this reaction represented
withdrawal dyskinesia given the short, low-dose olanzapine trial prior to
aripiprazole, and the dyskinesia did not emerge until many weeks after
olanzapine was discontinued. The patient’s history of intermittent an-
tipsychotic exposure, albeit limited, may have rendered him vulnerable
to dyskinesias. It is notable that he did not experience similar symptoms
in the setting of treatment with D
2
receptor antagonists. This suggests
200
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The Annals of Pharmacotherapy
■
2005 January, Volume 39
www.theannals.com