CIALIS for Once Daily Use
The efficacy and safety of CIALIS for once daily use in the
treatment of erectile dysfunction has been evaluated in 2 clinical
trials of 12-weeks duration and 1 clinical trial of 24-weeks duration,
involving a total of 853 patients. CIALIS, when taken once daily, was
shown to be effective in improving erectile function in men with
erectile dysfunction (ED). CIALIS was studied in the general ED
population in 2 randomized, multicenter, double-blinded,
placebo-controlled, parallel-arm design, primary efficacy and safety
studies of 12- and 24-weeks duration, respectively.
One of these studies was conducted in the United States and one was
conducted in centers outside the US. An additional efficacy and safety
study was performed in ED patients with diabetes mellitus. CIALIS was
taken once daily at doses ranging from 2.5 to 10 mg. Food and alcohol
intake were not restricted. Timing of sexual activity was not
restricted relative to when patients took Cialis.
CIALIS: CLINICAL STUDIES
CIALIS for Use as Needed
The efficacy and safety of CIALIS in the treatment of erectile
dysfunction has been evaluated in 22 clinical trials of up to 24-weeks
duration, involving over 4000 patients. CIALIS, when taken as needed up
to once per day, was shown to be effective in improving erectile
function in men with erectile dysfunction (ED).
CIALIS was studied in the general ED population in 7 randomized,
multicenter, double-blinded, placebo-controlled, parallel-arm design,
primary efficacy and safety studies of 12-weeks duration. Two of these
studies were conducted in the United States and 5 were conducted in
centers outside the US. Additional efficacy and safety studies were
performed in ED patients with diabetes mellitus and in patients who
developed ED status post bilateral nerve-sparing radical prostatectomy.
In these 7 trials, CIALIS was taken as needed, at doses ranging from
2.5 to 20 mg, up to once per day. Patients were free to choose the time
interval between dose administration and the time of sexual attempts.
Food and alcohol intake were not restricted.
CIALIS: Pharmacokinetics
Over a dose range of 2.5 to 20 mg, tadalafil exposure (AUC)
increases proportionally with dose in healthy subjects. Steady-state
plasma concentrations are attained within 5 days of once per day dosing
and exposure is approximately 1.6-fold greater than after a single
dose. Mean tadalafil concentrations measured after the administration
of a single oral dose of 20 mg and single and once daily multiple doses
of 5 mg, from a separate study, to healthy male subjects are depicted.
CIALIS: CLINICAL PHARMACOLOGY
Mechanism of Action
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum.
The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. CIALIS inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by CIALIS has no effect in the absence of sexual stimulation.
Studies in vitro have demonstrated that CIALIS is a selective inhibitor of PDE5. PDE5 is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.
In vitro studies have shown that the effect of CIALIS is more potent on PDE5 than on other phosphodiesterases. These studies have shown that CIALIS is >10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. CIALIS is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, CIALIS is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. CIALIS is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10. CIALIS is 14-fold more potent for PDE5 than for PDE11A1 and 40-fold more potent for PDE5 than for
PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, CIALIS inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy
Category B — CIALIS (tadalafil) is not indicated for use in women. There are no
adequate and well controlled studies of CIALIS use in pregnant women. Animal
reproduction studies in rats and mice revealed no evidence of fetal harm.
Non-teratogenic
effects — Animal reproduction studies showed no evidence of teratogenicity,
embryotoxicity, or fetotoxicity when tadalafil was given to pregnant rats or
mice at exposures up to 11 times the maximum recommended human dose (MRHD) of
20 mg/day during organogenesis. In one of two perinatal/postnatal developmental
studies in rats, postnatal pup survival decreased following maternal exposure
to tadalafil doses greater than 10 times the MRHD based on AUC. Signs of
maternal toxicity occurred at doses greater than 16 times the MRHD based on
AUC. Surviving offspring had normal development and reproductive performance.
DRUG INTERACTIONS
7.1 Potential for Pharmacodynamic Interactions with
CIALIS
Nitrates — Administration of CIALIS to patients who are using any form of
organic nitrate, is contraindicated. In clinical pharmacology studies, CIALIS
was shown to potentiate the hypotensive effect of nitrates. In a patient who
has taken CIALIS, where nitrate administration is deemed medically necessary in
a life-threatening situation, at least 48 hours should elapse after the last
dose of CIALIS before nitrate administration is considered. In such
circumstances, nitrates should still only be administered under close medical
supervision with appropriate hemodynamic monitoring.
Alpha Blockers — Caution is advised when PDE5 inhibitors are
coadministered with alpha blockers. PDE5 inhibitors, including CIALIS, and
alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering
effects. When asodilators are used in combination, an additive effect on blood
pressure may be anticipated. Clinical pharmacology studies have been conducted
with coadministration of tadalafil with doxazosin or tamsulosin.
ADVERSE REACTIONS
6.1 Clinical Studies Experience
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates
observed in practice.
Tadalafil was
administered to over 6550 men during clinical trials worldwide. In trials of
CIALIS for once daily use, a total of 716, 389, and 115 were treated for at
least 6 months, 1 year, and 2 years, respectively. For CIALIS for use as
needed, over 1300 and 1000 subjects were treated for at least 6 months and 1
year, respectively.
CIALIS for Use
as Needed
In eight primary placebo-controlled Phase 3
studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and 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.
5 WARNINGS AND PRECAUTIONS
Evaluation of
erectile dysfunction should include an appropriate medical assessment to
identify potential underlying causes, as well as treatment options.
Before
prescribing CIALIS, it is important to note the following:
5.1 Cardiovascular
Physicians
should consider the cardiovascular status of their patients, since there is a
degree of cardiac risk associated with sexual activity. Therefore, treatments
for erectile dysfunction, including CIALIS, should not be used in men for whom
sexual activity is inadvisable as a result of their underlying cardiovascular
status. Patients who experience symptoms upon initiation of sexual activity should
be advised to refrain from further sexual activity and seek immediate medical
attention.
Physicians
should discuss with patients the appropriate action in the event that they
experience anginal chest pain requiring nitroglycerin following intake of
CIALIS. In such a patient, who has taken CIALIS, where nitrate administration
is deemed medically necessary for a life-threatening situation, at least 48
hours should have elapsed after the last dose of CIALIS before nitrate administration
is considered. In such circumstances, nitrates should still only be
administered under close medical supervision with appropriate hemodynamic monitoring.
Therefore, patients who experience anginal chest pain after taking CIALIS
should seek immediate medical attention.
1 INDICATIONS AND USAGE
1.1 Erectile Dysfunction
CIALIS is
indicated for the treatment of erectile dysfunction.
CIALIS (tadalafil), an oral treatment for erectile dysfunction, is a selective
inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase
type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4
representing a molecular weight of 389.41. The structural formula is:
The chemical designation is
pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione,
6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a- hexahydro-2-methyl-,
(6R,12aR)-. It is a crystalline solid that is practically insoluble in
water and very slightly soluble in ethanol.
CIALIS is available as film-coated, almond-shaped tablets for oral
administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil
and the following inactive ingredients: croscarmellose sodium,
hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate,
magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate,
talc, titanium dioxide, and triacetin.
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