 Prescribing Information CIALIS
DESCRIPTION
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 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. 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.
Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual
stimulation.
Studies in vitro have demonstrated that tadalafil 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 tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil 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. Tadalafil is >10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels.
Additionally, tadalafil is 700-fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is >9,000-fold more potent for PDE5 than for PDE8, PDE9, and PDE10 and 14-fold more potent for PDE5 than for PDE11A1, an enzyme found in human skeletal muscle. Tadalafil inhibits human recombinant PDE11A1 activity at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.
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-daily dosing, and exposure is approximately 1.6-fold greater than after a single dose.
Tadalafil is eliminated predominantly by hepatic metabolism, mainly by cytochrome P450 3A4 (CYP3A4). The concomitant use of potent CYP3A4 inhibitors such as ritonavir or ketoconazole resulted in significant increases in tadalafil AUC values (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Mean tadalafil
concentrations measured after the administration of a single oral dose of 20 mg to healthy
male subjects are depicted in Figure 1.
Figure 1: Plasma tadalafil concentrations (mean ± SD) following a single 20-mg tadalafil dose
Absorption - After single oral-dose administration, the maximum observed plasma
concentration (Cmax) of tadalafil is achieved between 30 minutes and 6 hours (median time of 2 hours). Absolute bioavailability of tadalafil following oral dosing has not been determined.
The rate and extent of absorption of tadalafil are not influenced by food; thus CIALIS may be taken with or without food.
Distribution - The mean apparent volume of distribution following oral administration is
approximately 63 L, indicating that tadalafil is distributed into tissues. At therapeutic
concentrations, 94% of tadalafil in plasma is bound to proteins.
Less than 0.0005% of the administered dose appeared in the semen of healthy subjects.
Metabolism - Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite.
The catechol metabolite undergoes extensive methylation and glucuronidation to form the
methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide. Methylcatechol concentrations are less than 10% of glucuronide concentrations. In vitro data suggests that metabolites are not expected to be pharmacologically active at observed metabolite concentrations.
Elimination - The mean oral clearance for tadalafil is 2.5 L/hr and the mean terminal half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Pharmacokinetics in Special Populations
Geriatric - Healthy male elderly subjects (65 years or over) had a lower oral clearance of
tadalafil, resulting in 25% higher exposure (AUC) with no effect on Cmax relative to that
observed in healthy subjects 19 to 45 years of age. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered (see Geriatric Use under PRECAUTIONS).
Pediatric - Tadalafil has not been evaluated in individuals less than 18 years old.
Hepatic Impairment - In clinical pharmacology studies, tadalafil exposure (AUC) in subjects with mild or moderate hepatic impairment (Child-Pugh Class A or B) was comparable to exposure in healthy subjects when a dose of 10 mg was administered. There are no available data for doses higher than 10 mg of tadalafil in patients with hepatic impairment. Insufficient data are available for subjects with severe hepatic impairment (Child-Pugh Class C). Therefore, for patients with mild or moderate hepatic impairment, the maximum dose should not exceed 10 mg, and use in patients with severe hepatic impairment is not recommended (see DOSAGE AND ADMINISTRATION).
Renal Insufficiency - In clinical pharmacology studies using single-dose tadalafil (5 to 10 mg), tadalafil exposure (AUC) doubled in subjects with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal insufficiency. In subjects with end-stage renal disease on hemodialysis, there was a two-fold increase in Cmax and 2.7- to 4.1-fold increase in AUC following single-dose administration of 10 or 20 mg tadalafil. Exposure to total methylcatechol (unconjugated plus glucuronide) was 2- to 4-fold higher in subjects with renal impairment, compared to those with normal renal function. Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination. In a clinical pharmacology study (N=28) at a dose of 10 mg, back pain was reported as a limiting adverse event in male patients with moderate renal impairment. At a dose of 5 mg, the incidence and severity of back pain was not significantly different than in the general population. In patients on hemodialysis taking 10- or 20-mg tadalafil, there were no reported cases of back pain. The dose of tadalafil should be limited to 5 mg not more than once daily in patients with severe renal insufficiency or end-stage renal disease. A starting dose of 5 mg not more than once daily is recommended for patients with moderate renal insufficiency; the maximum recommended dose is 10 mg not more than once in every 48 hours. No dose adjustment is required in patients with mild renal insufficiency (see DOSAGE AND ADMINISTRATION).
Patients with Diabetes Mellitus - In male patients with diabetes mellitus after a 10 mg
tadalafil dose, exposure (AUC) was reduced approximately 19% and Cmax was 5% lower than that observed in healthy subjects. No dose adjustment is warranted.
Pharmacodynamics
Effects on Blood Pressure - Tadalafil 20 mg administered to healthy male subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (difference in the mean maximal decrease of 1.6/0.8 mm Hg, respectively) and in standing systolic and diastolic blood pressure (difference in the mean maximal decrease of 0.2/4.6 mm Hg, respectively). In addition, there was no significant effect on heart rate. Effects on Blood Pressure when CIALIS is Administered with Nitrates - In clinical pharmacology studies, tadalafil (5 to 20 mg) was shown to potentiate the hypotensive effect of nitrates. Therefore, the use of CIALIS in patients taking any form of nitrates is contraindicated (see CONTRAINDICATIONS).
A study was conducted to assess the degree of interaction between nitroglycerin and tadalafil, should nitroglycerin be required in an emergency situation after tadalafil was taken. This was a double-blind, placebo-controlled, crossover study in 150 male subjects at least 40 years of age (including subjects with diabetes mellitus and/or controlled hypertension) and receiving daily doses of tadalafil 20 mg or matching placebo for 7 days. Subjects were administered a single dose of 0.4 mg sublingual nitroglycerin (NTG) at pre-specified timepoints, following their last dose of tadalafil (2, 4, 8, 24, 48, 72, and 96 hours after tadalafil). The objective of the study was to determine when, after tadalafil dosing, no apparent blood pressure interaction was observed.
In this study, a significant interaction between tadalafil and NTG was observed at each timepoint up to and including 24 hours. At 48 hours, by most hemodynamic measures, the interaction between tadalafil and NTG was not observed, although a few more tadalafil subjects compared to placebo experienced greater blood-pressure lowering at this timepoint. After 48 hours, the
interaction was not detectable.
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