Drug Monograph

By: Kristen Walls

Brand name:  Cialis

Generic name:  tadalafil

Manufacturer:  Eli Lilly and Company

Drug Class:  Phosphodiesterase – 5 (PDE-5) enzyme inhibitor

Uses: 

Labeled:  Cialis is approved for the treatment of erectile dysfunction (ED); including ED patients with diabetes mellitus or following radical prostatectomy.^{1, 2, 3, 4} 

Unlabeled:  Some studies show that Cialis may be helpful for pulmonary hypertension, although the changes will be small.^{1, 2, 3, 4} Cialis may also help to decrease the LES tone, making it useful for certain motor disorders involving the esophagus such as diffuse spasm, peristaltic esophageal contractions, and hypertensive LES.^{2, 5} Cialis may help treat female arousal disorder.²

Mechanism of Action:  Cialis does not directly cause penile erections, but affects the response to sexual stimulation.  The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation.  NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation and inflow of blood to the corpus cavernosum.  Cialis enhances the effect of NO by inhibiting PDE-5, which is responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE5 by Cialis causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.  At recommended doses, it has no effect in the absence of sexual stimulation.^{1, 2,  7}

Pharmacokinetics:^{1, 2, 6, 7}    

Metabolism:  Hepatic, mainly via CYP3A4 to metabolites (inactive)

Elimination:  Feces (61%, as metabolites), urine (36%, as metabolites)

Efficacy:

Efficacy of Tadalafil for the Treatment of Erectile Dysfunction at 24 and 36 Hours After Dosing: A Randomized Controlled Trial⁸

Study Design:  The study was a multicentre, randomized, double-blind, placebo-controlled, parallel-group study that took place in Europe and the United States.

Description of Study:  The study’s purpose was to determine the number of successful sexual intercourse attempts (completed to ejaculation) after treatment with tadalafil at 24 and 36 hours after dosing.  The safety outcome measure was the incidence of adverse events in the tadalafil and placebo groups.

Results:  Tadalafil was effective for 36 hours, with 132 (59%) of 223 intercourse attempts successfully completed compared with 60 (28%) of 212 in those assigned to placebo.  At 24 hours 120 (53%) of 227 intercourse attempts were successful in those assigned to tadalafil vs. 72 (29%) of 247 in the placebo group.  Most of the adverse events were mild or moderate in severity.  A total of four patients discontinued the study early because of adverse events:  1 in the placebo group and 3 in the tadalafil group. 

Limitations:  The study’s results were dependent on the patients’ self-reporting, which is subject to error.  Patients might have felt the need to exaggerate their successful intercourse attempts in order to ease embarrassment, to evade their problem before resolution, or to offer the results they believe the study’s examiners want.  Also, the study was funded by Lilly so it is subject to bias.

Conclusion:  Tadalafil allows a period of responsiveness (to sexual stimulation) of up to 36 hours, which removes some of the time restrictions couples often encounter.

Efficacy and Safety of Tadalafil for the Treatment of Erectile Dysfunction:                                   Results of Integrated Analyses⁹

Study Design:  This was an integrated analysis done on 5 randomized, double blind placebo controlled trials that were conducted at 74 centers from April 1999 to April 2001.

Description of Study:  The purpose was to evaluate the safety and effectiveness of tadalafil for the treatment of erectile dysfunction.  The effects of tadalafil on erectile function were evaluated using the International Index of Erectile Function (IIEF), Sexual Encounter Profile (SEP) and Global Assessment Question (GAQ).  The analyses were conducted on an intent-to-treat basis.

Results:  Tadalafil considerably improved all efficacy outcomes.  For the patients that took the 20 mg dose of tadalafil a mean improvement of 7.9 in the International Index of Erectile Function occurred, 75% of intercourse attempts were successfully completed and 81% reported improved erections at end point.  Tadalafil was well tolerated and adverse events were mostly mild or moderate and decreased in frequency with continued treatment in most patients.  Headache and dyspepsia were the most frequent adverse events.

Limitations:  There were domains in IIEF, which consisted of patient ratings on point scales.  The problem with this is that people will rate their problems differently based on their perception, which could alter the dose of treatment used and possibly the results.

Conclusion:  Tadalafil is effective in the treatment of erectile dysfunction in patients of various ages and disease states.  Increasing efficacy is seen with increasing dose.

Effects of Tadalafil on Erectile Dysfunction in Men with Diabetes¹⁰

Study Design:  This was a multicenter, randomized, double-blind, placebo controlled, parallel-group trial that was conducted at 18 sites in Spain from December 1999 through August 2000.

Description of Study:  The purpose of this study was to evaluate the efficacy and safety of tadalafil in patients with type 1 or type 2 diabetes.  Treatment improved efficacy variables regardless of baseline HbA_1c levels and it did not alter mean HgA_1c levels.  Safety was assessed by evaluating all reported adverse events and changes in clinical laboratory values, vital signs, physical examination results, and ECG results.

Results:  Therapy with tadalafil significantly enhanced erectile function across all three coprimary efficacy outcome variables:  IIEF erectile function domain, erection vaginal penetration rates (SEP-Q2), and successful intercourse rates (SEP-Q3).  Tadalafil did not change HbA_1c levels form baseline to endpoint and baseline HbA_1c level did not influence response to treatment.  There were also improved scores on intercourse satisfaction, orgasmic function, and overall satisfaction from baseline to endpoint.  Tadalafil was well tolerated, with dyspepsia and headache being the most frequent adverse events.

Limitations:  The domains of the IIEF were evaluated based on the patients’ perception of where they fall on the scales, which could affect the results of the study.  The patients that discontinued treatment may not have been excluded from the study’s results, which could alter the results slightly.  The study was funded by Lilly, so bias is possible.

Conclusion:  The use of tadalafil is a safe and effective treatment for diabetic patients with ED.  However, improvement in erectile dysfunction was not as pronounced in patients with diabetes as in patients without diabetes in other studies. 

Adverse effects:  Adverse effects of Cialis include:  headache (> 10%), flushing (2 - 3%), dyspepsia (4 - 10%), myalgia (1 - 3%), back pain (3 - 6%), increased CPK (2%), nasal congestion (2 – 3%), and limb pain (1 – 3%).  Adverse effects that occur in less than 2% (limited to important or life-threatening):  abdominal pain (upper), abnormal liver function tests, arthralgia, asthenia, angina pectoris, blurred vision, chest pain, conjunctivitis, diaphoresis, diarrhea, dizziness, dysphagia, dyspnea, epistaxis, esophagitis, eye pain, eyelid swelling, facial edema, fatigue, gastroesophageal reflux, gastritis, hypesthesia, hypotension, hypertension, GGTP increased, insomnia, MI, nausea, pain, paresthesia, pharyngitis, postural hypotension, priapism (reported with drugs in this class), pruritus, rash, somnolence, syncope, tachycardia, vertigo, visual changes (color vision), vomiting, xerostomia.^{1, 2,  6}

Drug Interactions:  Taking Cialis with nitrate therapy should be avoided because of the potential for significant hypotensive effects.^{1, 2, 4, 7}  The combination of Cialis with alpha-blockers would increase the risk of symptomatic hypotensive effects.  Taking Cialis with yohimbine may increase the risk of adverse effects.  The combination of Cialis with the following drugs/drug classes will cause an increase in the Cialis levels:  amiodarone, azole antifungals, protease inhibitors, fluvoxamine, cyclosporine, metronidazole, grapefruit, verapamil, erythromycins, clarithromycins, nefazodone, diltiazem, imatinab, sildenafil, quinupristin/dalfopristin, delavirdine, and zafirlukast.  The combination of Cialis with the following drugs/drug classes will cause a decrease in the Cialis levels:  barbiturates, rifabutin, phenytoins, bosentan, modafinil, rifampins, nevirapine, carbamazepine, oxcarbazepine, griseofulvins, rifapentine, and St. John’s Wort.  The combination of Cialis with aprepitant or efvirenz can cause an increase or decrease in Cialis levels.^{1, 2, 7}

Dosing/Administration: 

Usual dose:  Most patients start with 10 mg, taken prior to sexual activity.  Based on individual efficacy and tolerability, the dose may be increased to 20 mg or decreased to 5 mg.  The maximum dosing frequency is once per day.  Cialis may be taken with or without food.^{1, 6, 7}

            Geriatric dose:  No dose adjustment is needed based on age alone.^{1, 2,  6, 7}

          Pediatric dose:  N/A

Renal impairment:  For patients with mild renal insufficiency no dose adjustment is required.  For patients with moderate (creatinine clearance 31 to 50 mL/min) renal insufficiency, a starting dose of 5 mg not more than once daily is recommended, and the maximum dose should be limited to 10 mg not more than once in every 48 hours.  The maximum recommended dose is 5 mg, for patients with severe (creatinine clearance < 30 mL/min) renal insufficiency on hemodialysis.^{1, 2, 6, 7}

Hepatic impairment:  The dose of Cialis should not exceed 10 mg once daily in patients with mild or moderate hepatic impairment.  In patients with severe hepatic impairment, the use of Cialis is not recommended.^{1, 2, 6, 7}

Conclusion:  Cialis is a safe and effective drug for the treatment of erectile dysfunction (ED) in men of various ages and disease states (such as diabetes and hypertension).  The advantage Cialis has over other drugs in its class or other drugs used for the treatment of ED is that is an oral medication that has a duration of 36 hours, which gives partners more freedom in the timing of their sexual activity.  Cialis can be taken without regard to food or alcohol.

Recommended References:

1.  Cialis (tadalafil) Product Labeling, Eli Lilly and Company, November 2003.

2.  Clinical Pharmacology online

3.  Sussman DO. Pharmacokinetics, pharmacodynamics, and efficacy of phosphodiesterase type 5 inhibitors. J Am Osteopath Assoc. 2004 Mar; 104(3 Suppl 4): S11-5.

4.  Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of tadalafil. Am J Cardiol. 2003 Nov 6; 92(9A): 37M-46M.

5.  Park H, Clark E, Conklin JL. Effects of phosphodiesterase inhibitors on oesophageal neuromuscular functions. Neurogastroenterol Motil. 2003 Dec; 15(6): 625-33.

6.  Lexi-Comp; Lexi-Drugs (Essential) File Date: May 14, 2004

7.  ePocrates RxPro Version 6.51; last update Jun 24, 2004

8.  Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003 Jul;62(1):121-5; discussion 125-6.

9.  Brock GB, McManhon CG, Chen KK, Costigan T, Shen W, Watkins V, Anglin G, Whitaker S. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses. J Urol. 2002 Oct; 168(4 Pt. 1): 1332-6.

10.  Saenz de Tejada I, Anglin G, Knight JR, Emmick JT.  Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care. 2002 Dec;25(12):2159-64