23 . October , 2018 - Tuesday
Check todays hot topics or new products

Find a Drug: Advanced

Please Sign in or Register

All about: Cialis

Big Image
Generic Name: tadalafil
Dosage Form: Tablets

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.

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. 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. Tadalafil 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, tadalafil 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.

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 (see Figure 2).

Figure 2: Mean Maximal Change in Blood Pressure (Tadalafil Minus Placebo, Point Estimate with 90% CI) in Response to Sublingual Nitroglycerin at 2 (Supine Only), 4, 8, 24, 48, 72, and 96 Hours after the Last Dose of Tadalafil 20 mg or Placebo

Therefore, Cialis administration with nitrates is contraindicated. 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 (see CONTRAINDICATIONS).

Effects on Exercise Stress Testing— The effects of tadalafil on cardiac function, hemodynamics, and exercise tolerance were investigated in a single clinical pharmacology study. In this blinded crossover trial, 23 subjects with stable coronary artery disease and evidence of exercise–induced cardiac ischemia were enrolled. The primary endpoint was time to cardiac ischemia. The mean difference in total exercise time was 3 seconds (tadalafil 10 mg minus placebo), which represented no clinically meaningful difference. Further statistical analysis demonstrated that tadalafil was non–inferior to placebo with respect to time to ischemia. Of note, in this study, in some subjects who received tadalafil followed by sublingual nitroglycerin in the post–exercise period, clinically significant reductions in blood pressure were observed, consistent with the augmentation by tadalafil of the blood–pressure–lowering effects of nitrates.

Effects on Vision— Single oral doses of phosphodiesterase inhibitors have demonstrated transient dose–related impairment of color discrimination (blue/green), using the Farnsworth–Munsell 100–hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. In a study to assess the effects of a single dose of tadalafil 40 mg on vision (N=59), no effects were observed on visual acuity, intraocular pressure, or pupillometry. Across all clinical studies with Cialis, reports of changes in color vision were rare (<0.1% of patients).

Effects on Sperm Characteristics— Three studies were conducted in men to assess the potential effect on sperm characteristics of tadalafil 10 mg (one 6 month study) and 20 mg (one 6 month and one 9 month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo, although these differences were not clinically meaningful. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In addition there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinizing hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.

Effects on Cardiac Electrophysiology— The effect of a single 100–mg dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomized, double–blinded, placebo, and active (intravenous ibutilide)–controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two–sided 90% CI=1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two–sided 90% CI=1.2, 4.4). A 100–mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100–mg dose of tadalafil compared to placebo was 3.1 beats per minute.

Clinical Studies

The efficacy and safety of tadalafil 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 daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).

Study Design— 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 daily. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted.

Several assessment tools were used to evaluate the effect of Cialis on erectile function. The 3 primary outcome measures were the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4–week recall questionnaire that was administered at the end of a treatment–free baseline period and subsequently at follow–up visits after randomization. The IIEF EF domain has a 30–point total score, where higher scores reflect better erectile function. SEP is a diary in which patients recorded each sexual attempt made throughout the study. SEP Question 2 asks, “Were you able to insert your penis into your partner’s vagina?” SEP Question 3 asks, “Did your erection last long enough for you to have successful intercourse?” The overall percentage of successful attempts to insert the penis into the vagina (SEP2) and to maintain the erection for successful intercourse (SEP3) is derived for each patient.

Study Results—

ED Population in US Trials— The 2 primary US efficacy and safety trials included a total of 402 men with erectile dysfunction, with a mean age of 59 years (range 27 to 87 years). The population was 78% White, 14% Black, 7% Hispanic, and 1% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co–morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (>90%) patients reported ED of at least 1–year duration. Study A was conducted primarily in academic centers. Study B was conducted primarily in community–based urology practices. In each of these 2 trials, Cialis 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Table 1). The treatment effect of Cialis did not diminish over time.

Table 1: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Primary US Trials

Study A

Study B

Placebo

Cialis
20 mg

Placebo

Cialis
20 mg

(N=49)

(N=146)

p–value

(N=48)

(N=159)

p–value

  EF Domain Score

     Endpoint

13.5

19.5

13.6

22.5

     Change from baseline

–0.2

6.9

<.001

0.3

9.3

<.001

  Insertion of Penis (SEP2)

     Endpoint

39%

62%

43%

77%

     Change from baseline

2%

26%

<.001

2%

32%

<.001

  Maintenance of Erection
  (SEP3)

     Endpoint

25%

50%

23%

64%

     Change from baseline

5%

34%

<.001

4%

44%

<.001

General ED Population in Trials Outside the US — The 5 primary efficacy and safety studies conducted in the general ED population outside the US included 1112 patients, with a mean age of 59 years (range 21 to 82 years). The population was 76% White, 1% Black, 3% Hispanic, and 20% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co–morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (90%) patients reported ED of at least 1–year duration. In these 5 trials, Cialis 5, 10, and 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Tables 2, 3, and 4). The treatment effect of Cialis did not diminish over time.

Table 2: Mean Endpoint and Change from Baseline for the EF Domain of the IIEF in the General ED Population in Five Primary Trials Outside the US
*
Treatment duration in Study F was 6 months

Placebo

Cialis
5 mg

Cialis
10 mg

Cialis
20 mg

  Study C

     Endpoint [Change from baseline]

15.0 [0.7]

17.9 [4.0]

20.0 [5.6]

p=.006

p<.001

  Study D

     Endpoint [Change from baseline]

14.4 [1.1]

17.5 [5.1]

20.6 [6.0]

p=.002

p<.001

  Study E

     Endpoint [Change from baseline]

18.1 [2.6]

22.6 [8.1]

25.0 [8.0]

p<.001

p<.001

  Study F*

     Endpoint [Change from baseline]

12.7 [-1.6]

22.8 [6.8]

p<.001

  Study G

     Endpoint [Change from baseline]

14.5 [-0.9]

21.2 [6.6]

23.3 [8.0]

p<.001

p<.001

Table 3: Mean Post-Baseline Success Rate and Change from Baseline for SEP Question 2 (“Were you able to insert your penis into the partner’s vagina?”) in the General ED Population in Five Pivotal Trials Outside the US
*
Treatment duration in Study F was 6 months

Placebo

Cialis
5 mg

Cialis
10 mg

Cialis
20 mg

  Study C

     Endpoint [Change from baseline]

49% [6%]

57% [15%]

73% [29%]

p=.063

p<.001

  Study D

     Endpoint [Change from baseline]

46% [2%]

56% [18%]

68% [15%]

p=.008

p<.001

  Study E

     Endpoint [Change from baseline]

55% [10%]

77% [35%]

85% [35%]

p<.001

p<.001

  Study F*

     Endpoint [Change from baseline]

42% [–8%]

81% [27%]

p<.001

  Study G

     Endpoint [Change from baseline]

45% [–6%]

73% [21%]

76% [21%]

p<.001

p<.001

Table 4: Mean Post–Baseline Success Rate and Change from Baseline for SEP Question 3 (“Did your erection last long enough for you to have successful intercourse?”) in the General ED Population in Five Pivotal Trials Outside the US
*
Treatment duration in Study F was 6 months

Placebo

Cialis
5 mg

Cialis
10 mg

Cialis
20 mg

  Study C

     Endpoint [Change from baseline]

26% [4%]

38% [19%]

58% [32%]

Recent Drug Updates at DrugIndexOnline:





Actamin Actamin
Some commonly used brand names are: In the U.S.— Aceta Elixir 1 Aceta Tablets 1 Acetaminophen Uniserts 1 Actamin 1 Actamin Extra 1 Actamin Super 2 Aminofen 1 Aminofen Max 1 Apacet Capsules 1 Apacet Elixir 1 Apacet Extra Strength Caplets 1 Apacet Extra Strength Tablets 1 Apacet, Infants' 1 more...

Actisite Actisite
Some commonly used brand names are: In the U.S.— Actisite † Not commercially available in Canada. Category Antibacterial, dental Description Tetracycline periodontal fibers (tet-ra-SYE-kleen pare-ee-o-DON-tal FI-bers) are used to help treat periodontal disease (a disease o more...

Clotrimazole And Betamethasone Topical Clotrimazole And Betamethasone Topical
Some commonly used brand names are: In the U.S.— Lotrisone In Canada— Lotriderm Category Antifungal-corticosteroid, topical Description Clotrimazole and betamethasone (kloe-TRIM-a-zole and bay-ta-METH-a-sone) combination is used to treat fungus infections. Clotrimazole wo more...

dorzolamide and timolol ophthalmic dorzolamide and timolol ophthalmic
Generic Name: dorzolamide and timolol ophthalmic (dor ZOLE a mide and TYE moe lole) Brand Names: Cosopt What is dorzolamide and timolol ophthalmic? Dorzolamide ophthalmic reduces the amount of fluid in the eye, which decreases pressure inside the eye. Timolol ophthalmic is a beta-blocker more...

Estradiol Estradiol
Generic Name: Estradiol Oral Tablets (ES-tra-DYE-ol) Brand Name: Examples include Estrace and Gynodiol Estradiol should not be used to prevent heart disease, heart attacks, strokes, or dementia. Estrogens have been shown to increase the risk of heart disease (including heart attack), stroke, d more...

Hydroxypropyl Methylcellulose Ophthalmic Hydroxypropyl Methylcellulose Ophthalmic
Some commonly used brand names are: In the U.S.— Artificial Tears Bion Tears Gonak Goniosoft Goniosol Isopto Alkaline Isopto Plain Isopto Tears Just Tears Lacril Moisture Drops Nature's Tears Ocucoat Ocucoat PF Tearisol Tears Naturale Tears Naturale II Tears Naturale Free Tears Renewed Ul more...

Octyl Methoxycinnamate, Octyl Salicylate, Oxybenzone, and Titanium Dioxide Topical Octyl Methoxycinnamate, Octyl Salicylate, Oxybenzone, and Titanium Dioxide Topical
Some commonly used brand names are: In the U.S.— A-Fil 33 Aquaderm Sunscreen Moisturizer 49 Aquaray Sunscreen 42 Bain de Soleil All Day For Kids 38 Bain de Soleil All Day Sunfilter 39 Bain de Soleil Mega Tan 34 Bain de Soleil Orange Gelee 41 Bain de Soleil Sand Buster 41 Bain de Soleil SP more...

Oracit Oracit
Generic Name: citric acid and sodium citrate (sit trick acid and sew dee umm sit trayt) Brand Names: Bicitra, Cytra-2, Oracit What is Oracit (citric acid and sodium citrate)? Citric acid and sodium citrate are alkalinizing agents that make the urine less acidic. Citric acid and sodium c more...