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Interaction between Tadalafil and Itraconazole

Authors:
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 tadalafilitraconazole 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
tadalafilitraconazole 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 icaPoliclinico Universitario
Via Consolare ValeriaGazzi
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 citrateassociated 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 patients 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 patients 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
The Annals of Pharmacotherapy
2005 January, Volume 39
www.theannals.com
... Only few case reports/series [28][29][30][31][32][33][34][35][36] of priapism have been described in the literature in patients taking PDE5Is. It is unlikely that prescribed PDE5Is alone can cause ischaemic priapism events [37], with most anecdotal published reports relating instead to specific conditions which may represent additional risk factors for ischaemic priapism. ...
... PDE5Is are mainly metabolised by the cytochrome P450 3A4 hepatic isoenzyme [38]. Pharmacokinetic interactions in patients taking concomitantly PDE5Is with other drugs which are known to increase the PDE5I steady-state concentrations, including cytochrome P450 3A4 inhibitors (e.g., itraconazole [32], cannabis [38]), were considered responsible for priapism events in some of these cases. Remaining PDE5I-related prolonged erections/manifest priapism events have been reported in: children following an accidental ingestion [30]; in a patient of with a sickle cells' trait [33]; and, in subjects taking large/massive dosages of PDE5Is for self-poisoning purposes [34]. ...
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A range of drugs have a direct role in triggering ischaemic priapism. We aimed at identifying: a) which medications are associated with most priapism-reports; and, b) within these medications, comparing their potential to elicit priapism through a disproportionality analysis. The FDA Adverse Event Reporting System (FAERS) database was queried to identify those drugs associated the most with priapism reports over the last 5 years. Only those drugs being associated with a minimum of 30 priapism reports were considered. The Proportional Reporting Ratios (PRRs), and their 95% confidence intervals were computed. Out of the whole 2015–2020 database, 1233 priapism reports were identified, 933 of which (75.7%) were associated with 11 medications with a minimum of 30 priapism-reports each. Trazodone, olanzapine and tadalafil showed levels of disproportionate reporting, with a PRR of 9.04 (CI95%: 7.73–10.58), 1.55 (CI95%: 1.27–1.89), and 1.42 (CI95%: 1.10–1.43), respectively. Most (57.5%) of the reports associated with the phosphodiesterase type 5 inhibitors (PDE5Is) were related with concomitant priapism-eliciting drugs taken at the same time and/or inappropriate intake/excessive dosage. Patients taking trazodone and/or antipsychotics need to be aware of the priapism-risk; awareness among prescribers would help in reducing priapism-related detrimental sequelae; PDE5I-intake is not responsible for priapism by itself, when appropriate medical supervision is provided.
... Only few case reports/series [28][29][30][31][32][33][34][35][36] of priapism have been described in the literature in patients taking 253 ...
... PDE5Is 257 are mainly metabolized by the cytochrome P450 3A4 hepatic isoenzyme [38]. Pharmacokinetic 258 interactions in patients taking concomitantly PDE5Is with other drugs which are known to increase the 259 PDE5I steady-state concentrations, including cytochrome P450 3A4 inhibitors (e.g., itraconazole [32], 260 cannabis [38]), were considered responsible for priapism events in some of these cases. Remaining 261 PDE5I-related prolonged erections/manifest priapism events have been reported in: children following 262 an accidental ingestion [30]; in a patient of with a sickle cells" trait [33]; and, in subjects taking 263 large/massive dosages of PDE5Is for self-poisoning purposes [34]. ...
... While there are no straightforward guidelines for adjusting medications in men who have previously experienced priapism, data suggested that increasing dosage, restarting treatment after an abstinence period, or switching to another class of antipsychotic drug may facilitate the occurrence of priapism [52]. Additionally, oral phosphodiesterase type 5 inhibitors (PDE5 inhibitors) themselves rarely cause priapism [53], but combining them with cytochrome P450 3A4 inhibitor medications may be responsible for priapic events [54]. ...
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