pharmacokinetics of cialis
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Cialis
Erectile Dysfunction
May be used as needed (on demand) or on a daily basis (without regard to timing of sexual activity). 1 59 60 61
Some experts recommend a selective PDE type 5 inhibitor as first-line therapy for ED unless contraindicated. 47 Evidence currently insufficient to support superiority of one selective PDE type 5 inhibitor over another. 47
Benign Prostatic Hyperplasia
Symptomatic management (e.g. to improve lower urinary tract symptoms) of benign prostatic hyperplasia (BPH, benign prostatic hypertrophy). 1 80 81 82 83 84 89
Not recommended for use in combination with an α-adrenergic blocking agent (e.g. doxazosin, terazosin); inadequate data and potential for additive hypotensive effects. 1 (See Concomitant Administration with α-Adrenergic Blocking Agents under Cautions.)
Concomitant ED and BPH
Treatment of both ED and symptomatic BPH in men with such coexisting conditions. 1 82 89
Pulmonary Arterial Hypertension (PAH)
Symptomatic management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity. 70 71 73
Efficacy established principally in patients with NYHA/WHO functional class II–III PAH (idiopathic, heritable, or associated with connective tissue diseases). 70 71 76
Recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed. 242 Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference. 242 245
In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid or endothelin-receptor antagonist (added sequentially). 242 By targeting different pathophysiologic pathways of the disease, such combination therapy may provide additive and/or synergistic benefits. 75 76 77 78 243 244
Cialis Dosage and Administration
Administration
Oral Administration
Administer orally without regard to meals. 1 2 70
May be administered as-needed (just prior to [e.g. ≥0.5 hours before] anticipated sexual activity) or on a daily basis (at approximately the same time every day) for treatment of ED; take entire dose and do not split tablets. 1 Because of prolonged duration of action (up to 36 hours), 1 2 4 7 9 13 timing of administration relative to anticipated sexual activity is less important than with relatively short-acting drugs for ED. 3 9
Administer as a once-daily dose at approximately the same time every day in patients with BPH with or without coexisting ED. 1
When used for the treatment of PAH, administer as a once-daily dosage. 70 Take entire dose at one time and not as divided doses throughout the day. 70
Dosage
Adults
ED
Oral
As-needed therapy: Usual initial dosage is 10 mg just prior to anticipated sexual activity. 1 (See Oral Administration under Dosage and Administration.) Depending on effectiveness and tolerance, may increase dose to 20 mg or decrease to 5 mg. 1 Concomitant use with HIV protease inhibitors or with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) requires dosage adjustment. 1 49 50 52 53 62 63 64 65 66 200 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)
Maximum recommended dosing frequency is once daily for most patients. 1 2
Once-daily therapy: Initially, 2.5 mg once daily. 1 2 Depending on effectiveness and tolerance, may increase dosage to 5 mg once daily. 1
Concomitant use with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) requires dosage adjustment. 1 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)
BPH
Oral
5 mg once daily. 1
Concomitant use with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) requires dosage adjustment. 1 200 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)
Concomitant ED and BPH
Oral
5 mg once daily. 1
Concomitant use with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir) requires dosage adjustment. 1 200 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)
PAH
Oral
40 mg once daily. 70
Concomitant use with ritonavir or other HIV protease inhibitors that are potent inhibitors of CYP3A requires dosage adjustment. 49 50 52 53 62 63 64 65 66 200 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)
Special Populations
Hepatic Impairment
As-needed use for ED: In patients with mild or moderate hepatic impairment (Child-Pugh class A or B), maximum dosage is 10 mg once daily. 1 2
Once-daily use for BPH and/or ED: Use with caution in patients with mild or moderate hepatic impairment. 1
Treatment of PAH: Consider a reduced initial dosage of 20 mg once daily in patients with mild or moderate hepatic cirrhosis (Child-Pugh class A or B). 70
Use not recommended in any patient with severe hepatic impairment (Child-Pugh class C). 1 70 (See Hepatic Impairment under Cautions.)
Renal Impairment
As-needed use for ED: For patients with Clcr 30–50 mL/minute, reduce initial dosage to 5 mg administered no more frequently than once daily; maximum dosage 10 mg no more frequently than once every 48 hours. 1 For patients with Clcr 0 mL/minute or those undergoing hemodialysis, maximum dosage 5 mg no more frequently than once every 72 hours. 1
Once-daily use for ED: Dosage adjustments not necessary in patients with Clcr ≥30 mL/minute. 1 Use not recommended in patients with Clcr 0 mL/minute or those on hemodialysis. 1
Once-daily use for BPH with or without ED: For Clcr 30–50 mL/minute, initial dosage of 2.5 mg once daily recommended; may increase to 5 mg once daily based on patient response and tolerance. 1 Use not recommended in patients with Clcr 0 mL/minute or those on hemodialysis. 1
Treatment of PAH: Reduce initial dosage to 20 mg once daily in patients with mild (Clcr 51–80 mL/minute) or moderate (Clcr 31–50 mL/minute) renal impairment; may increase to 40 mg once daily based on patient response and tolerance. 70 Avoid use in severe renal impairment (Clcr 0 mL/minute and those on hemodialysis). 70
Geriatric Patients
No dosage adjustments necessary based solely on age. 1
Cautions for Cialis
Contraindications
Known hypersensitivity to tadalafil or any ingredient in the formulation. 1 70
Concomitant use of any form of organic nitrates (e.g. nitrates, nitrites, or nitric oxide donors). 1 2 10 70 Concomitant use of riociguat. 247 (See Specific Drugs and Foods under Interactions.)
Warnings/Precautions
Patient Assessment
Thorough medical history and physical examination is recommended to determine potential underlying causes and identify appropriate treatment options for ED and/or BPH. 1 14 15 16 17 18 19 20 21 22 Prior to initiating therapy in patients with BPH, consider possibility of other urologic conditions, including prostate cancer, that may cause similar symptoms. 1
Cardiovascular Effects
Serious, potentially fatal cardiovascular events reported. 1 70 Most, but not all, of these events occurred in individuals with preexisting cardiovascular risk factors. 1 70
Safety and efficacy for treatment of ED not established and use not recommended in patients with a recent MI (within 90 days) or stroke (within 6 months); uncontrolled arrhythmias, hypotension (NYHA class II) in the previous 6 months; or those with unstable angina or angina occurring during sexual intercourse. 1 Also not evaluated in patients with PAH who have clinically important mitral and/or aortic valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, substantial left ventricular dysfunction, life-threatening arrhythmias, symptomatic coronary artery disease, hypotension (BP <90/50 mm Hg), or uncontrolled hypertension. 70
Possible hypotension, particularly in patients with left-ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and in patients with severely impaired autonomic control of blood pressure. 1 70 Additive BP-lowering effects may occur when used concomitantly with other vasodilating agents (e.g. α-adrenergic blocking agents or other antihypertensive drugs, alcohol, riociguat). 1 70 247 (See Specific Drugs and Foods under Interactions.)
Potentiation of hypotensive effect with organic nitrates, which may result in life-threatening hypotension and/or hemodynamic compromise; concomitant use contraindicated. 1 70 (See Specific Drugs and Foods under Interactions.)
Consider whether patients with underlying cardiovascular disease could be adversely affected by tadalafil’s vasodilatory activity, especially in combination with sexual activity. 1
Use not recommended in patients with pulmonary veno-occlusive disease (PVOD). 70 Current lack of data on use of tadalafil in such patients. 70 If pulmonary edema occurs, consider possibility of PVOD. 70
Ocular Effects
Nonarteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, reported rarely during postmarketing experience in temporal association with use of all PDE type 5 inhibitors. 1 35 36 37 38 39 41 42 43 44 70 Potential increased risk of NAION in the second eye in patients who have already experienced NAION in one eye. 1 70
Possible visual disturbances (e.g. blurred vision, changes in color vision, conjunctivitis, eye pain, increased lacrimation, periorbital edema). 1 2 13 70
Use not recommended in patients with hereditary degenerative retinal disorders, including retinitis pigmentosa. 1
Otic Effects
Sudden decrease or loss of hearing reported rarely during postmarketing experience with all PDE type 5 inhibitors. 1 2 54 57 70 Adverse otic effects (e.g. vertigo, tinnitus) also observed in a few patients in controlled clinical trials of tadalafil. 1 57 In at least 1 case, permanent, bilateral sensorineural deafness occurred. 57 58
Although not clear whether such effects are directly related to PDE type 5 inhibitors or to other factors (e.g. patient’s underlying medical condition, concomitant use of other ototoxic drugs), a strong temporal relationship has been observed. 1 2 54 57 70
Priapism
Possible prolonged erections (>4 hours) and priapism (painful erection >6 hours). 1 2 70
May result in penile tissue damage and permanent loss of potency if priapism is not treated immediately. 1 70 Use with caution in patients with conditions that may predispose to priapism (e.g. sickle cell anemia, multiple myeloma, leukemia) and in those with anatomic deformation of the penis (e.g. angulation, cavernosal fibrosis, Peyronie’s disease). 1
Hematologic Effects
Tadalafil inhibits PDE type 5, which is found in platelets. 1 70 Although increase in bleeding time not observed in healthy individuals, manufacturer recommends caution in patients with bleeding disorders or substantial, active peptic ulcers; carefully weigh risks versus benefits of therapy. 1 70
Concomitant Use with Other PDE Type 5 Inhibitors or ED Therapies
Safety and efficacy not established for use in combination with other PDE type 5 inhibitors or other treatments for ED; do not use concomitantly with other PDE type 5 inhibitors. 1 70
Concomitant Administration with α-Adrenergic Blocking Agents
Use with caution in patients receiving α-adrenergic blocking agents; possible potentiation of hypotensive effects due to additive vasodilatory action. 1 70 In some cases, dosage adjustments are necessary, while in other cases, concomitant administration not recommended. 1 (See Specific Drugs and Foods under Interactions.) Safety of concomitant therapy also may be affected by intravascular volume depletion and use of additional antihypertensive agents. 1 70
Concomitant Administration with Potent CYP3A4 Inhibitors or Inducers
Consider potential for increased or decreased tadalafil concentrations when used concomitantly with potent inhibitors or inducers of CYP3A4; in some cases, dosage adjustments may be necessary, while in other cases, concomitant administration not recommended. 1 49 50 52 53 62 63 64 65 66 70 200 (See Specific Drugs and Foods under Interactions.)
Specific Populations
Pregnancy
Category B. 1 70 Tadalafil (Cialis ) not indicated for use in women. 1
Lactation
Excreted into milk in rats. 1 70 Not known if tadalafil is excreted into milk in humans. 1 70 Tadalafil (Cialis ) not indicated for use in women. 1 Use caution if tadalafil (Adcirca ) is used in nursing women. 70
Pediatric Use
Safety and efficacy for the treatment of BPH or ED not established in patients <18 years of age and not indicated for such use in children or neonates. 1
Manufacturer states that safety and efficacy for treatment of PAH not established in pediatric patients; 70 however, PDE type 5 inhibitors have been used in a limited number of children with PAH. 79
Geriatric Use
Safety and efficacy in those >65 years of age is similar to that in younger patients. 1 8 Possibility exists of greater sensitivity to the drug in some geriatric individuals. 1 (See Geriatric Patients under Dosage and Administration.)
Hepatic Impairment
Insufficient experience in patients with severe hepatic impairment (Child-Pugh C); use not recommended. 1 70 88
Data limited in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) receiving once-daily tadalafil for ED, BPH, or for both conditions; caution advised in such patients. 1 Dosage adjustments recommended in patients with mild or moderate hepatic impairment receiving as-needed therapy for ED or once-daily therapy for PAH. 1 70 (See Hepatic Impairment under Dosage and Administration.)
Renal Impairment
Use of once-daily tadalafil not recommended in any patient with severe renal impairment. 1 70
Dosage adjustments recommended in patients with mild or moderate renal impairment receiving once-daily tadalafil for PAH. 70 Dosage adjustments also recommended in patients with moderate to severe renal impairment receiving as-needed tadalafil for ED. 1 (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
PAH: Headache, 70 myalgia, 70 nasopharyngitis, 70 flushing, 70 upper/lower respiratory tract infection, 70 pain in extremity, 70 nausea, 70 back pain, 70 dyspepsia, 70 nasal/sinus congestion. 70
Interactions for Cialis
Metabolized principally by CYP3A4. 1 70 Does not appear to induce or inhibit the clearance of other drugs metabolized by CYP isoforms 1A2, 3A4, 2C9, 2C19, 2D6, or 2E1. 1 70
Drugs Affecting Hepatic or Metabolized by Hepatic Microsomal Enzymes
Potent inhibitors of CYP3A4: Potential pharmacokinetic interaction (increased tadalafil exposure) and increased risk of PDE type 5 inhibitor-associated adverse effects (e.g. hypotension, syncope, visual changes, priapism). 1 29 31 48 49 50 52 53 62 63 64 65 66 70 85 200 When used concomitantly in patients with BPH and/or ED, do not exceed tadalafil dosage of 2.5 mg once daily; avoid concomitant use of tadalafil (Adcirca ) with potent CYP3A inhibitors (with exception of ritonavir). (See Specific Drugs and Foods under Interactions.)
Potent inducers of CYP3A: Potential pharmacokinetic interaction (decreased tadalafil exposure) and possible decreased efficacy of tadalafil. 70 85 No dosage adjustment warranted in patients with BPH and/or ED; avoid concomitant use of tadalafil (Adcirca ) with potent CYP3A inducers. 70
Specific Drugs and Foods
Eur J Clin Pharmacol. 2007 Jun;63(6):583-90. Epub 2007 Apr 13.
Abstract
OBJECTIVE: The purpose of this study was to characterize pharmacokinetics of tadalafil (Cialis) and potential sources of variability in patients with erectile dysfunction (ED).
METHODS: Population models were developed to describe tadalafil pharmacokinetics in 227 patients with mild to severe ED in a phase III trial. Parallel groups of patients received 2, 5, or 10 mg tadalafil or placebo orally, as needed, for 12 weeks.
RESULTS: Tadalafil pharmacokinetics in patients with ED were linear with respect to dose and duration of treatment, and a one-compartment model adequately described the data. The absorption rate was rapid (1.86 h(-1)), and the typical population estimates of the apparent oral clearance (CL/F) and apparent volume of distribution were 1.6 l/h and 63.8 l, respectively. Disposition parameters showed a moderate degree of interindividual variability (39-45%). The value of CL/F decreased slightly with increasing serum gamma-glutamyl transferase (GGT) concentration, the only statistically significant covariate detected. Systemic exposure to tadalafil was not influenced by age, weight, smoking status, alcohol consumption, liver enzyme status, ED severity, cardiovascular condition, or diabetes mellitus.
CONCLUSION: Pharmacokinetics in the efficacy/safety trial population are essentially similar to pharmacokinetics in healthy subjects, and no patient-specific factor warranting clinical consideration of dose regimen adjustment was identified in these analyses.
PMID
17431603 [PubMed - indexed for MEDLINE]
Full text
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.
The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum and pulmonary arteries is also observed in the smooth muscle of the prostate. the bladder and their vascular supply. The mechanism for reducing BPH symptoms has not been established.
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in the smooth muscle of the corpus cavernosum, prostate, and bladder as well as in vascular and visceral smooth muscle, skeletal muscle. urethra. platelets, kidney, lung, cerebellum. heart, liver, testis, seminal vesicle. 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 (e.g. adrenal cortex ). 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.
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 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 1).
Figure 1: 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. 4 8, 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 ].
Effect On Blood Pressure When Administered With Alpha-Blockers
Six randomized, double-blinded, crossover clinical pharmacology studies were conducted to investigate the potential interaction of tadalafil with alpha-blocker agents in healthy male subjects [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS ]. In four studies, a single oral dose of tadalafil was administered to healthy male subjects taking daily (at least 7 days duration) an oral alphablocker. In two studies, a daily oral alpha-blocker (at least 7 days duration) was administered to healthy male subjects taking repeated daily doses of tadalafil.
Doxazosin — Three clinical pharmacology studies were conducted with tadalafil and doxazosin, an alpha[1]-adrenergic blocker.
In the first doxazosin study, a single oral dose of tadalafil 20 mg or placebo was administered in a 2- period, crossover design to healthy subjects taking oral doxazosin 8 mg daily (N=18 subjects). Doxazosin was administered at the same time as tadalafil or placebo after a minimum of seven days of doxazosin dosing (see Table 5 and Figure 2).
Table 5: Doxazosin (8 mg/day) Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure
Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg)
Tadalafil 20 mg
Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours post dose on the first day of each doxazosin dose, (1 mg, 2 mg, 4 mg), as well as on the seventh day of 4 mg doxazosin administration.
Following the first dose of doxazosin 1 mg, there were no outliers on tadalafil 5 mg and one outlier on placebo due to a decrease from baseline in standing systolic BP of > 30 mm Hg.
There were 2 outliers on tadalafil 5 mg and none on placebo following the first dose of doxazosin 2 mg due to a decrease from baseline in standing systolic BP of > 30 mm Hg.
There were no outliers on tadalafil 5 mg and two on placebo following the first dose of doxazosin 4 mg due to a decrease from baseline in standing systolic BP of > 30 mm Hg. There was one outlier on tadalafil 5 mg and three on placebo following the first dose of doxazosin 4 mg due to standing systolic BP 30 mm Hg in standing systolic blood pressure, and one subject on placebo had standing systolic blood pressure 85 mm Hg. All adverse events potentially related to blood pressure effects were rated as mild or moderate. Thre were two episodes of syncope in this study, one subject following a dose of tadalafil 5 mg alone, and another subject following coadministration of tadalafil 5 mg and doxazosin 4 mg.
Tamsulosin — In the first tamsulosin study, a single oral dose of tadalafil 10, 20 mg, or placebo was administered in a 3 period, crossover design to healthy subjects taking 0.4 mg once per day tamsulosin, a selective alpha[1A]-adrenergic blocker (N=18 subjects). Tadalafil or placebo was administered 2 hours after tamsulosin following a minimum of seven days of tamsulosin dosing.
Table 8: Tamsulosin (0.4 mg/day) Study 1: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure
Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg)
Tadalafil 10 mg
Tadalafil 20 mg
Blood pressure was measured manually at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours after tadalafil or placebo dosing. There were 2, 2, and 1 outliers (subjects with a decrease from baseline in standing systolic blood pressure of > 30 mm Hg at one or more time points) following administration of tadalafil 10 mg, 20 mg, and placebo, respectively. There were no subjects with a standing systolic blood pressure < 85 mm Hg. No severe adverse events potentially related to blood-pressure effects were reported. No syncope was reported.
In the second tamsulosin study, healthy subjects (N=39 treated; and 35 completed) received 14 days of once per day dosing of tadalafil 5 mg or placebo in a two-period crossover design. Daily dosing of tamsulosin 0.4 mg was added for the last seven days of each period.
Table 9: Tamsulosin Study 2: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure
Placebo-subtracted mean maximal decrease in systolic blood pressure
Day 1 of 0.4 mg Tamsulosin
Day 7 of 0.4 mg Tamsulosin
Blood pressure was measured manually pre-dose at two time points (-30 and -15 minutes) and then at 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 hours post dose on the first, sixth and seventh days of tamsulosin administration. There were no outliers (subjects with a decrease from baseline in standing systolic blood pressure of > 30 mm Hg at one or more time points). One subject on placebo plus tamsulosin (Day 7) and one subject on tadalafil plus tamsulosin (Day 6) had standing systolic blood pressure < 85 mm Hg. No severe adverse events potentially related to blood pressure were reported. No syncope was reported.
Alfuzosin — A single oral dose of tadalafil 20 mg or placebo was administered in a 2-period, crossover design to healthy subjects taking once-daily alfuzosin HCl 10 mg extended-release tablets, an alpha[1]- adrenergic blocker (N=17 completed subjects). Tadalafil or placebo was administered 4 hours after alfuzosin following a minimum of seven days of alfuzosin dosing.
Table 10: Alfuzosin (10 mg/day) Study: Mean Maximal Decrease (95% CI) in Systolic Blood Pressure
Placebo-subtracted mean maximal decrease in systolic blood pressure (mm Hg)
Tadalafil 20 mg
Blood pressure was measured manually at 1, 2, 3, 4, 6, 8, 10, 20, and 24 hours after tadalafil or placebo dosing. There was 1 outlier (subject with a standing systolic blood pressure 30 mm Hg at one or more time points. No severe adverse events potentially related to blood pressure effects were reported. No syncope was reported.
Effects On Blood Pressure When Administered With Antihypertensives
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.
Angiotensin II receptor blockers (with and without other antihypertensives) — 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 antihypertensive regimen. Following dosing, ambulatory measurements of blood pressure revealed differences between tadalafil and placebo of 8/4 mm Hg in systolic/diastolic blood pressure.
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.
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.
Effects On Blood Pressure When Administered With 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 one 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.
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 postexercise 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 pupilometry. 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.
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, (see Figure 4) to healthy male subjects are depicted in Figure 4.
Figure 4. Plasma tadalafil concentrations (mean ± SD) following a single 20-mg tadalafil dose and single and once daily multiple doses of 5 mg
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.
Excretion
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).
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 Use in Specific Populations ].
Pediatric
Tadalafil has not been evaluated in individuals less than 18 years old [see Use in Specific Populations ].
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.
Patients With BPH
In patients with BPH following single and multiple-doses of 20 mg tadalafil, no statistically significant differences in exposure (AUC and Cmax) were observed between elderly (70 to 85 years) and younger ( ≤ 60 years of age) subjects. No dose adjustment is warranted.
Animal Toxicology And/Or Pharmacology
Animal studies showed vascular inflammation in tadalafil-treated mice, rats, and dogs. In mice and rats, lymphoid necrosis and hemorrhage were seen in the spleen. thymus. and mesenteric lymph nodes at unbound tadalafil exposure of 2- to 33-fold above the human exposure (AUCs) at the MRHD of 20 mg. In dogs, an increased incidence of disseminated arteritis was observed in 1- and 6-month studies at unbound tadalafil exposure of 1- to 54-fold above the human exposure (AUC) at the MRHD of 20 mg. In a 12-month dog study, no disseminated arteritis was observed, but 2 dogs exhibited marked decreases in white blood cells (neutrophils) and moderate decreases in platelets with inflammatory signs at unbound tadalafil exposures of approximately 14- to 18-fold the human exposure at the MRHD of 20 mg. The abnormal blood-cell findings were reversible within 2 weeks after stopping treatment.
Clinical Studies
CIALIS For Use As Needed For ED
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 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.
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 the 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.
Results In 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 11). The treatment effect of CIALIS did not diminish over time.
Table 11: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two Primary US Trials
a Treatment duration in Study F was 6 months
In addition, there were improvements in EF domain scores, success rates based upon SEP Questions 2 and 3, and patient-reported improvement in erections across patients with ED of all degrees of disease severity while taking CIALIS, compared to patients on placebo.
Therefore, in all 7 primary efficacy and safety studies, CIALIS showed statistically significant improvement in patients' ability to achieve an erection sufficient for vaginal penetration and to maintain the erection long enough for successful intercourse, as measured by the IIEF questionnaire and by SEP diaries.
Efficacy Results In ED Patients With Diabetes Mellitus
CIALIS was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in all 7 primary efficacy studies in the general ED population (N=235) and in one study that specifically assessed CIALIS in ED patients with type 1 or type 2 diabetes (N=216). In this randomized, placebo-controlled, doubleblinded, parallel-arm design prospective trial, CIALIS demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 15).
Table 15: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study in ED Patients with Diabetes
CIALIS 10 mg
(N=73)
CIALIS 20 mg
(N=72)
Efficacy Results In ED Patients following Radical Prostatectomy
CIALIS was shown to be effective in treating patients who developed ED following bilateral nerve-sparing radical prostatectomy. In 1 randomized, placebo-controlled, double-blinded, parallel-arm design prospective trial in this population (N=303), CIALIS demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 16).
Table 16: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a Study in Patients who Developed ED Following Bilateral Nerve-Sparing Radical Prostatectomy
CIALIS 20 mg
(N=201)
EF Domain Score
Endpoint [Change from baseline]
Insertion of Penis (SEP2)
Endpoint [Change from baseline]
Maintenance of Erection (SEP3)
Endpoint [Change from baseline]
Results In Studies To Determine The Optimal Use Of CIALIS
Several studies were conducted with the objective of determining the optimal use of CIALIS in the treatment of ED. In one of these studies, the percentage of patients reporting successful erections within 30 minutes of dosing was determined. In this randomized, placebo-controlled, double-blinded trial, 223 patients were randomized to placebo, CIALIS 10, or 20 mg. Using a stopwatch, patients recorded the time following dosing at which a successful erection was obtained. A successful erection was defined as at least 1 erection in 4 attempts that led to successful intercourse. At or prior to 30 minutes, 35% (26/74), 38% (28/74), and 52% (39/75) of patients in the placebo, 10-, and 20-mg groups, respectively, reported successful erections as defined above.
Two studies were conducted to assess the efficacy of CIALIS at a given timepoint after dosing, specifically at 24 hours and at 36 hours after dosing.
In the first of these studies, 348 patients with ED were randomized to placebo or CIALIS 20 mg. Patients were encouraged to make 4 total attempts at intercourse; 2 attempts were to occur at 24 hours after dosing and 2 completely separate attempts were to occur at 36 hours after dosing. The results demonstrated a difference between the placebo group and the CIALIS group at each of the prespecified timepoints. At the 24-hour timepoint, (more specifically, 22 to 26 hours), 53/144 (37%) patients reported at least 1 successful intercourse in the placebo group versus 84/138 (61%) in the CIALIS 20-mg group. At the 36-hour timepoint (more specifically, 33 to 39 hours), 49/133 (37%) of patients reported at least 1 successful intercourse in the placebo group versus 88/137 (64%) in the CIALIS 20-mg group.
In the second of these studies, a total of 483 patients were evenly randomized to 1 of 6 groups: 3 different dosing groups (placebo, CIALIS 10, or 20 mg) that were instructed to attempt intercourse at 2 different times (24 and 36 hours post-dosing). Patients were encouraged to make 4 separate attempts at their assigned dose and assigned timepoint. In this study, the results demonstrated a statistically significant difference between the placebo group and the CIALIS groups at each of the pre-specified timepoints. At the 24-hour timepoint, the mean, per patient percentage of attempts resulting in successful intercourse were 42, 56, and 67% for the placebo, CIALIS 10-, and 20-mg groups, respectively. At the 36-hour timepoint, the mean, per-patient percentage of attempts resulting in successful intercourse were 33, 56, and 62% for placebo, CIALIS 10-, and 20-mg groups, respectively.
CIALIS For Once Daily Use For ED
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.
Results In General ED Population
The primary US efficacy and safety trial included a total of 287 patients, with a mean age of 59 years (range 25 to 82 years). The population was 86% White, 6% Black, 6% Hispanic, and 2% 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 ( > 96%) patients reported ED of at least 1-year duration.
The primary efficacy and safety study conducted outside the US included 268 patients, with a mean age of 56 years (range 21 to 78 years). The population was 86% White, 3% Black, 0.4% Hispanic, and 10% 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. Ninety-three percent of patients reported ED of at least 1-year duration.
In each of these trials, conducted without regard to the timing of dose and sexual intercourse, CIALIS demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 17). When taken as directed, CIALIS was effective at improving erectile function. In the 6 month double-blind study, the treatment effect of CIALIS did not diminish over time.
Table 17: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in the Two CIALIS for Once Daily Us e Studies
a Twenty-four-week study conducted in the US.
b Twelve-week study conducted outside the US.
c Statistically significantly different from placebo.
Efficacy Results In ED Patients With Diabetes Mellitus
CIALIS for once daily use was shown to be effective in treating ED in patients with diabetes mellitus. Patients with diabetes were included in both studies in the general ED population (N=79). A third randomized, multicenter, double-blinded, placebocontrolled, parallel-arm design trial included only ED patients with type 1 or type 2 diabetes (N=298). In this third trial, CIALIS demonstrated clinically meaningful and statistically significant improvement in erectile function, as measured by the EF domain of the IIEF questionnaire and Questions 2 and 3 of the SEP diary (see Table 18).
Table 18: Mean Endpoint and Change from Baseline for the Primary Efficacy Variables in a CIALIS for Once Daily Use Study in ED Patients with Diabetes
CIALIS 2.5 mg
(N=100)
CIALIS 5 mg
(N=98)
a Statistically significantly different from placebo.
CIALIS 5 mg For Once Daily Use For Benign Prostatic Hyperplasia (BPH)
The efficacy and safety of CIALIS for once daily use for the treatment of the signs and symptoms of BPH was evaluated in 3 randomized, multinational, double-blinded, placebo-controlled, parallel-design, efficacy and safety studies of 12 weeks duration. Two of these studies were in men with BPH and one study was specific to men with both ED and BPH [see Clinical Studies ]. The first study (Study J) randomized 1058 patients to receive either CIALIS 2.5 mg, 5 mg, 10 mg or 20 mg for once daily use or placebo. The second study (Study K) randomized 325 patients to receive either CIALIS 5 mg for once daily use or placebo. The full study population was 87% White, 2% Black, 11% other races; 15% was of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.
The primary efficacy endpoint in the two studies that evaluated the effect of CIALIS for the signs and symptoms of BPH was the International Prostate Symptom Score (IPSS), a four week recall questionnaire that was administered at the beginning and end of a placebo run-in period and subsequently at follow-up visits after randomization. The IPSS assesses the severity of irritative (frequency, urgency, nocturia ) and obstructive symptoms (incomplete emptying, stopping and starting, weak stream, and pushing or straining), with scores ranging from 0 to 35; higher numeric scores representing greater severity. Maximum urinary flow rate (Q ), an objective measure of urine flow, was assessed as a secondary efficacy endpoint in Study J and as a safety endpoint in Study K.
The results for BPH patients with moderate to severe symptoms and a mean age of 63.2 years (range 44 to 87) who received either CIALIS 5 mg for once daily use or placebo (N=748) in Studies J and K are shown in Table 19 and Figures 5 and 6, respectively.
In each of these 2 trials, CIALIS 5 mg for once daily use resulted in statistically significant improvement in the total IPSS compared to placebo. Mean total IPSS showed a decrease starting at the first scheduled observation (4 weeks) in Study K and remained decreased through 12 weeks.
Table 19: Mean IPSS Changes in BPH Patients in Two CIALIS for Once Daily Use Studies
Figure 6: Mean IPSS Changes in BPH Patients by Visit in Study K
In Study J, the effect of CIALIS 5 mg once daily on maximum urinary flow rate (Qmax) was evaluated as a secondary efficacy endpoint. Mean Q increased from baseline in both the treatment and placebo groups (CIALIS 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.
In Study K, the effect of CIALIS 5 mg once daily on Qmax was evaluated as a safety endpoint. Mean Q increased from baseline in both the treatment and placebo groups (CIALIS 5 mg: 1.6 mL/sec, placebo: 1.1 mL/sec); however, these changes were not significantly different between groups.
Efficacy Results In Patients With BPH initiating CIALIS And Finasteride
CIALIS for once daily use initiated together with finasteride was shown to be effective in treating the signs and symptoms of BPH in men with an enlarged prostate ( > 30 cc) for up to 26 weeks. This additional double-blinded, paralleldesign study of 26 weeks duration randomized 696 men to initiate either CIALIS 5 mg with finasteride 5 mg or placebo with finasteride 5 mg. The study population had a mean age of 64 years (range 46-86). Patients with multiple co-morbid conditions such as erectile dysfunction, diabetes mellitus, hypertension, and other cardiovascular disease were included.
CIALIS with finasteride demonstrated statistically significant improvement in the signs and symptoms of BPH compared to placebo with finasteride, as measured by the total IPSS at 12 weeks, the primary study endpoint (see Table 20). Key secondary endpoints demonstrated improvement in total IPSS starting at the first scheduled observation at week 4 (CIALIS -4.0, placebo -2.3: p < .001) and the score remained decreased through 26 weeks (CIALIS -5.5, placebo -4.5; p=.022). However, the magnitude of the treatment difference between placebo/finasteride and CIALIS/finasteride decreased from 1.7 points at Week 4 to 1.0 point at Week 26, as shown in Table 20 and in Figure 7. The incremental benefit of CIALIS beyond 26 weeks is unknown.
Table 20: Mean Total IPSS Changes in BPH Patients in a CIALIS for Once Daily Use Study Together with Finasteride
Placebo and finasteride 5 mg
CIALIS 5mg and finasteride 5 mg
Figure 7: Mean Total IPSS Changes By Visit in BPH Patients Taking CIALIS for Once Daily Use Together With Finasteride
In the 404 patients who had both ED and BPH at baseline, changes in erectile function were assessed as key secondary endpoints using the EF domain of the IIEF questionnaire. CIALIS with finasteride (N=203) was compared to placebo with finasteride (N=201). A statistically significant improvement from baseline (CIALIS/finasteride 13.7, placebo/finasteride 15.1) was observed at week 4 (CIALIS/finasteride 3.7, placebo/finasteride -1.1; p < .001), week 12 (CIALIS/finasteride 4.7, placebo/finasteride 0.6; p .001), and week 26 (CIALIS/finasteride 4.7, placebo/finasteride 0.0; p .001).
CIALIS 5 mg For Once Daily Use For ED And BPH
The efficacy and safety of CIALIS for once daily use for the treatment of ED, and the signs and symptoms of BPH, in patients with both conditions was evaluated in one placebo-controlled, multinational, double-blind, parallel-arm study which randomized 606 patients to receive either CIALIS 2.5 mg, 5 mg, for once daily use or placebo. ED severity ranged from mild to severe and BPH severity ranged from moderate to severe. The full study population had a mean age of 63 years (range 45 to 83) and was 93% White, 4% Black, 3% other races; 16% were of Hispanic ethnicity. Patients with multiple co-morbid conditions such as diabetes mellitus, hypertension, and other cardiovascular disease were included.
In this study, the co-primary endpoints were total IPSS and the Erectile Function (EF) domain score of the International Index of Erectile Function (IIEF). One of the key secondary endpoints in this study was Question 3 of the Sexual Encounter Profile diary (SEP3). Timing of sexual activity was not restricted relative to when patients took CIALIS.
The efficacy results for patients with both ED and BPH, who received either CIALIS 5 mg for once daily use or placebo (N=408) are shown in Tables 21 and 22 and Figure 8.
CIALIS 5 mg for once daily use resulted in statistically significant improvements in the total IPSS and in the EF domain of the IIEF questionnaire. CIALIS 5 mg for once daily use also resulted in statistically significant improvement in SEP3. CIALIS 2.5 mg did not result in statistically significant improvement in the total IPSS.
Table 21: Mean IPSS and IIEF EF Domain Changes in the CIALIS 5 mg for Once Daily Use Study in Patients with ED and BPH
