A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Cialis Side Effects, and Drug Interactions - Tadalafil
Cialis Side Effects, and Drug Interactions - Tadalafil
SIDE EFFECTS
Tadalafil was administered to over 5700 men (mean age 59, range
19 to 87 years) during clinical trials worldwide. Over 1000 patients were treated
for 1 year or longer and over 1300 patients were treated for 6 months or more.
In placebo-controlled Phase 3 clinical trials, the discontinuation rate due
to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared
to 1.4% in placebo-treated patients. When tadalafil was taken as recommended
in the placebo-controlled clinical trials, the following adverse events were
reported (see Table 7):
|
Table 7: Treatment-Emergent Adverse Events Reported
by ³2% of Patients Treated with Tadalafil
(10 or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary
Placebo-Controlled Phase 3 Studies (Including a Study in Patients with
Diabetes)
|
| |
Placebo
|
Tadalafil 5 mg
|
Tadalafil 10 mg
|
Tadalafil 20 mg
|
|
Adverse Event
|
(N=476)
|
(N=151)
|
(N=394)
|
(N=635)
|
|
Headache
|
5%
|
11%
|
11%
|
15%
|
|
Dyspepsia
|
1%
|
4%
|
8%
|
10%
|
|
Back pain
|
3%
|
3%
|
5%
|
6%
|
|
Myalgia
|
1%
|
1%
|
4%
|
3%
|
|
Nasal congestion
|
1%
|
2%
|
3%
|
3%
|
|
Flushing*
|
1%
|
2%
|
3%
|
3%
|
|
Pain in limb
|
1%
|
1%
|
3%
|
3%
|
|
* The term flushing includes: facial flushing and flushing
|
Back pain or myalgia was reported at incidence rates
described in Table 7. In tadalafil clinical pharmacology trials, back pain or
myalgia generally occurred 12 to 24 hours after dosing and typically resolved
within 48 hours. The back pain/myalgia associated with tadalafil treatment was
characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar
muscular discomfort and was exacerbated by recumbancy. In general, pain was
reported as mild or moderate in severity and resolved without medical treatment,
but severe back pain was reported infrequently (<5% of all reports). When
medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory
drugs were generally effective; however, in a small percentage of subjects who
required treatment, a mild narcotic (e.g. codeine) was used. Overall, approximately
0.5% of all tadalafil-treated subjects discontinued treatment as a consequence
of back pain/myalgia. Diagnostic testing, including measures for inflammation,
muscle injury, or renal damage revealed no evidence of medically significant
underlying pathology.
Across all studies with any tadalafil dose, reports of changes
in color vision were rare (<0.1% of patients).
The following section identifies additional, less frequent
events (<2%) reported in controlled clinical trials; a causal relationship
of these events to CIALIS is uncertain. Excluded from this list are those events
that were minor, those with no plausible relation to drug use, and reports too
imprecise to be meaningful:
Body as a whole: asthenia, face edema, fatigue, pain
Cardiovascular: angina pectoris, chest pain, hypotension,
hypertension, myocardial infarction, postural hypotension, palpitations, syncope,
tachycardia
Digestive: abnormal liver function tests, diarrhea,
dry mouth, dysphagia, esophagitis, gastroesophageal reflux, gastritis, GGTP
increased, loose stools, nausea, upper abdominal pain, vomiting
Musculoskeletal: arthralgia, neck pain Nervous:
dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo
Respiratory: dyspnea, epistaxis, pharyngitis
Skin and Appendages: pruritus, rash, sweating
Ophthalmologic: blurred vision, changes in color vision,
conjunctivitis (including conjunctival hyperemia), eye pain, lacrimation increase,
swelling of eyelids
Urogenital: erection increased, spontaneous penile erection
DRUG INTERACTIONS
Effects of Other Drugs on CIALIS
Cytochrome P450 Inhibitors
CIALIS is a substrate of and predominantly metabolized by CYP3A4.
Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure
(see PRECAUTIONS and DOSAGE
AND ADMINISTRATION).
Ketoconazole — Ketoconazole (400 mg daily), a selective
and potent inhibitor of CYP3A4, increased tadalafil 20-mg single-dose exposure
(AUC) by 312% and Cmax by 22%, relative to the values for tadalafil
20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose
exposure (AUC) by 107% and Cmax by 15%, relative to the values for
tadalafil 10 mg alone.
HIV Protease inhibitor — Ritonavir (200 mg twice daily),
an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg
single-dose exposure (AUC) by 124% with no change in Cmax, relative
to the values for tadalafil 20 mg alone. Although specific interactions have
not been studied, other HIV protease inhibitors would likely increase tadalafil
exposure (see DOSAGE AND ADMINISTRATION).
Based upon these results, in patients taking concomitant potent
CYP3A4 inhibitors, the dose of CIALIS should not exceed 10 mg, and CIALIS should
not be taken more frequently than once in every 72 hours (see DOSAGE
AND ADMINISTRATION).
Other cytochrome P450 inhibitors — Although specific
interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin,
itraconazole, and grapefruit juice, would likely increase tadalafil exposure.
Cytochrome P450 Inducers
Studies have shown that drugs that induce CYP3A4 can decrease
tadalafil exposure.
Rifampin — Rifampin (600 mg daily), a CYP3A4 inducer,
reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and Cmax by
46%, relative to the values for tadalafil 10 mg alone. Although specific interactions
have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin,
and phenobarbitol, would likely decrease tadalafil exposure. No dose adjustment
is warranted.
Gastrointestinal Drugs
H2 antagonists — An increase in gastric pH
resulting from administration of nizatidine had no significant effect on tadalafil
pharmacokinetics.
Antacids — Simultaneous administration of an antacid
(magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent
rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.
Effects of CIALIS on Other Drugs
Drugs Metabolized by Cytochrome P450
CIALIS is not expected to cause clinically significant inhibition
or induction of the clearance of drugs metabolized by cytochrome P450 (CYP)
isoforms. Studies have shown that tadalafil does not inhibit or induce P450
isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
CYP1A2 substrate — Tadalafil had no clinically significant
effect on the pharmacokinetics of theophylline. When tadalafil was administered
to subjects taking theophylline, a small augmentation (3 beats per minute) of
the increase in heart rate associated with theophylline was observed.
CYP3A4 substrates — Tadalafil had no clinically significant
effect on exposure (AUC) to midazolam or lovastatin.
CYP2C9 substrate — Tadalafil had no clinically significant
effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect
changes in prothrombin time induced by warfarin.
Alcohol
Alcohol and PDE5 inhibitors, including tadalafil, are mild
systemic vasodilators. The interaction of tadalafil with alcohol was evaluated
in 3 clinical pharmacology studies. In 2 of these, alcohol was administered
at a dose of 0.7 g/kg, which is equivalent to approximately 6 ounces of 80-proof
vodka in an 80-kg male, and tadalafil was administered at a dose of 10 mg in
1 study and 20 mg in another. In both these studies, all patients imbibed the
entire alcohol dose within 10 minutes of starting. In one of these two studies,
blood alcohol levels of 0.08% were confirmed. In these two studies, more patients
had clinically significant decreases in blood pressure on the combination of
tadalafil and alcohol as compared to alcohol alone. Some subjects reported postural
dizziness, and orthostatic hypotension was observed in some subjects. When tadalafil
20 mg was administered with a lower dose of alcohol (0.6 g/kg, which is equivalent
to approximately 4 ounces of 80-proof vodka, administered in less than 10 minutes),
orthostatic hypotension was not observed, dizziness occurred with similar frequency
to alcohol alone, and the hypotensive effects of alcohol were not potentiated.
Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect
tadalafil plasma concentrations. Both alcohol and CIALIS, a PDE5 inhibitor,
act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering
effects of each individual compound may be increased. Substantial consumption
of alcohol (e.g., 5 units or greater) in combination with CIALIS can increase
the potential for orthostatic signs and symptoms, including increase in heart
rate, decrease in standing blood pressure, dizziness, and headache.
Anti-Hypertensives
PDE5 inhibitors, including tadalafil, are mild systemic vasodilators.
Clinical pharmacology studies were conducted to assess the effect of tadalafil
on the potentiation of the blood-pressure-lowering effects of selected anti-hypertensive
medications.
Alpha Blockers
Doxazosin — When tadalafil 20 mg was administered to
healthy subjects taking doxazosin (8 mg daily), an alpha[1]-adrenergic blocker,
there was significant augmentation of the blood-pressure-lowering effect of
doxazosin.
Tamsulosin — In a clinical pharmacology study, when
a single dose of tadalafil 20 mg was administered to healthy subjects taking
0.4 mg once-daily tamsulosin, a selective alpha[1A]-adrenergic blocker, no significant
decreases in blood pressure were observed. Therefore, based upon significant
augmentation of the blood-pressure-lowering effect of doxazosin, an alpha[1]-adrenergic
blocker, and no significant effect seen with 0.4 mg once-daily tamsulosin, a
selective alpha[1A]-adrenergic blocker, administration of CIALIS to patients
taking any alpha-adrenergic blocker other than 0.4 mg once-daily tamsulosin
is contraindicated.
Other Anti-Hypertensive Agents
Amlodipine — A study was conducted to assess the interaction
of amlodipine (5 mg daily) and tadalafil 10 mg. There was no effect of tadalafil
on amlodipine blood levels and no effect of amlodipine on tadalafil blood levels.
The mean reduction in supine systolic/diastolic blood pressure due to tadalafil
10 mg in subjects taking amlodipine was 3/2 mm Hg, compared to placebo. In a
similar study using tadalafil 20 mg, there were no clinically significant differences
between tadalafil and placebo in subjects taking amlodipine.
Metoprolol — A study was conducted to assess the interaction
of sustained-release metoprolol (25 to 200 mg daily) and tadalafil 10 mg. Following
dosing, the mean reduction in supine systolic/diastolic blood pressure due to
tadalafil 10 mg in subjects taking metoprolol was 5/3 mm Hg, compared to placebo.
Bendrofluazide — A study was conducted to assess the
interaction of bendrofluazide (2.5 mg daily) and tadalafil 10 mg. Following
dosing, the mean reduction in supine systolic/diastolic blood pressure due to
tadalafil 10 mg in subjects taking bendrofluazide was 6/4 mm Hg, compared to
placebo.
Enalapril — A study was conducted to assess the interaction
of enalapril (10 to 20 mg daily) and tadalafil 10 mg. Following dosing, the
mean reduction in supine systolic/diastolic blood pressure due to tadalafil
10 mg in subjects taking enalapril was 4/1 mm Hg, compared to placebo.
Angiotensin II receptor blocker (and other anti-hypertensives)
— A study was conducted to assess the interaction of angiotensin II receptor
blockers and tadalafil 20 mg. Subjects in the study were taking any marketed
angiotensin II receptor blocker, either alone, as a component of a combination
product, or as part of a multiple anti-hypertensive regimen. Following dosing,
ambulatory measurements of blood pressure revealed differences between tadalafil
and placebo of 8/4 mm Hg in systolic/diastolic blood pressure.
Aspirin
Tadalafil did not potentiate the increase in bleeding time
caused by aspirin.
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