CIALIS®
(tadalafil tablets)

DESCRIPTION

CIALIS®, an oral therapy for erectile therapy is tadalafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Tadalafil is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl] -4-methylpiperazine citrate and has the following structural formula:

Tadalafil is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. CIALIS (tadalafil) is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 10 mg and 20 mg of tadalafil for oral administration. In addition to the active ingredient, tadalafil, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake.

Cialis

Clinical Pharmacology

 

CLINICAL PHARMACOLOGY

Mechanism of Action

The physiologic mechanism of erection of the 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 relaxation in the corpus cavernosum and allowing inflow of blood. Tadalafil has no direct effect on isolated human corpus cavernosum, but enhances the effect of (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by tadalafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Tadalafil at recommended doses has no effect in the absence of sexual stimulation.

Studies in vitro have shown that tadalafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, >80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Tadalafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels (see Pharmacodynamics).

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, smooth muscle, and The inhibition of PDE5 in these tissues by tadalafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and arterial-venous in vivo.

Pharmacokinetics and Metabolism

CIALIS (including generic cialis tadalafil) is rapidly absorbed after oral administration, with absolute bioavailability of about 40%. Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, tadalafil. The concomitant use of potent cytochrome P450 3A4 inhibitors (e.g., ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of tadalafil). Both tadalafil and the metabolite have terminal half lives of about 4 hours.

Mean tadalafil plasma concentrations measured after the administration of a single oral dose of 20 mg to healthy male volunteers is depicted below:

Figure 1: Mean Tadalafil Plasma Concentrations
in Healthy Male Volunteers.

Absorption and Distribution

CIALIS (including generic cialis tadalafil) is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When CIALIS (including generic cialis tadalafil) is taken with a high

Based upon measurements of tadalafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.

Metabolism and Excretion

Tadalafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of tadalafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to tadalafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for tadalafil, so that the metabolite accounts for about 20% of tadalafil’s pharmacologic effects.

After either oral or intravenous administration, tadalafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach.

Pharmacokinetics in Special Populations

Geriatrics

Healthy elderly volunteers (65 years or over) had a reduced clearance of tadalafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18-45 years).

Renal Insufficiency

In volunteers with mild (CL_cr=50-80 mL/min) and moderate (CL_cr=30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of CIALIS (10 mg) were not altered. In volunteers with severe (CL_cr=<30 mL/min) renal impairment, tadalafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.

Hepatic Insufficiency

In volunteers with hepatic cirrhosis (Child-Pugh A and B), tadalafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.

Therefore, age >65, hepatic impairment and severe renal impairment are associated with increased plasma levels of tadalafil. A starting oral dose of 10 mg should be considered in those patients

Pharmacodynamics

Effects of CIALIS (including generic cialis tadalafil) on Erectile Response

In eight double-blind, placebo-controlled crossover studies of patients with either or, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan®), after CIALIS administration compared with placebo. Most studies assessed the efficacy of CIALIS approximately 60 minutes post dose. The erectile response, as assessed by RigiScan®, generally increased with increasing tadalafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.

Effects of CIALIS (including generic cialis tadalafil) on Blood Pressure

Single oral doses of tadalafil (20 mg) administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.4/5.5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 10 mg and 20 mg of CIALIS, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates (see

 

Figure 2: Mean Change from Baseline in Sitting
Systolic Blood Pressure, Healthy Volunteers.

Effects of CIALIS (including generic cialis tadalafil) on Cardiac Parameters

Single oral doses of tadalafil up to 20 mg produced no clinically relevant changes in the ECGs of normal male volunteers.

Studies have produced relevant data on the effects of CIALIS (including generic cialis tadalafil) on. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic Swan-Ganz catheterization. A total dose of 40 mg tadalafil was administered by four intravenous infusions.

The results from this pilot study are shown in Table 1; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, occluded pressure and cardiac output decreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma tadalafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 20 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.

TABLE 1. HEMODYNAMIC DATA IN PATIENTS WITH STABLE ISCHEMIC HEART
DISEASE AFTER IV ADMINISTRATION OF 40 MG SILDENAFIL

 

In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or CIALIS (including generic cialis tadalafil) 20 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for tadalafil (N=70) and placebo, respectively. These results demonstrated that the effect of CIALIS (including generic cialis tadalafil) on the primary endpoint was statistically non-inferior to placebo.

Effects of CIALIS (including generic cialis tadalafil) on Vision

At single oral doses of 20 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected 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. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of CIALIS (including generic cialis tadalafil) on intraocular pressure, or pupillometry.

Clinical Studies

In clinical studies, CIALIS (including generic cialis tadalafil) was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. CIALIS (including generic cialis tadalafil) was evaluated primarily at doses of 10 mg and 20 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). CIALIS was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. CIALIS demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.

The effectiveness of CIALIS (including generic cialis tadalafil) was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function - IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.

The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 3, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 20 mg doses. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 20 mg, showed similar results. Figure 3 shows that regardless of the baseline levels of function, subsequent function in patients treated with CIALIS (including generic cialis tadalafil) was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline.

Effect of CIALIS (including generic cialis tadalafil) on Maintenance of Erection by
Baseline Score

Effect of Placebo on Maintenance of Erection by
Baseline Score

Figure 3. Effect of CIALIS and Placebo
on Maintenance of Erection by Baseline Score.

The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 4. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including and excluding), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 10 mg and 20 mg of CIALIS, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 20 mg), results were similar.

Overall treatment p<0.0001

Figure 4. Percentage of Patients Reporting
an Improvement in Erections.

The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.

In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of CIALIS on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50-20 mg of CIALIS vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on CIALIS vs about 20% on placebo.

During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that CIALIS (including generic cialis tadalafil) improved their erections.

Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. CIALIS improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction.

One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 10 mg and allowed to adjust the dose up to 20 mg of CIALIS; all patients, however, were receiving 10 mg or 20 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on CIALIS compared to placebo. On a global improvement question, 57% of CIALIS patients reported improved erections versus 10% on placebo. Diary data indicated that on CIALIS, 48% of intercourse attempts were successful versus 12% on placebo.

One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 20 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of CIALIS. On a global improvement question, 83% of patients reported improved erections on CIALIS versus 12% on placebo. Diary data indicated that on CIALIS, 59% of attempts at sexual intercourse were successful compared to 13% on placebo.

Across all trials, CIALIS (including generic cialis tadalafil) improved the erections of 43% of patients compared to 15% on placebo.

Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of CIALIS patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of CIALIS (including generic cialis tadalafil). Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for CIALIS and 29% for placebo.

A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. CIALIS (including generic cialis tadalafil) was effective in a broad range of ED patients, including those with a history of of the (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and antihypertensives/diuretics.

Analysis of the safety database showed no apparent difference in the side effect profile in patients taking CIALIS (including generic cialis tadalafil) with and without. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.

 

 

Cialis

Indications & Dosage

 

 

INDICATIONS

CIALIS (including generic cialis tadalafil) is indicated for the treatment of erectile dysfunction.

DOSAGE AND ADMINISTRATION

For most patients, the recommended dose is 10 mg taken, as needed, approximately 1 hour before sexual activity. However, CIALIS (including generic cialis tadalafil) may be taken anywhere from 4 hours to 0.5 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 20 mg . The maximum recommended dosing frequency is once per day.

The following factors are associated with increased plasma levels of tadalafil: age >65 (40% increase in AUC), hepatic impairment (e.g., cirrhosis, 80%), severe renal impairment (creatinine clearance <30 mL/min, 100%), and concomitant use of potent cytochrome P450 3A4 inhibitors [ketoconazole, itraconazole, erythromycin (182%), saquinavir (210%)]. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 10 mg should be considered in these patients.

Ritonavir greatly increased the systemic level of tadalafil in a study of healthy, non-HIV infected volunteers (11-fold increase in AUC, see DRUG INTERACTIONS.) Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 10 mg of CIALIS in a 48 hour period.

CIALIS (including generic cialis tadalafil) was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use donors or nitrates in any form is therefore contraindicated.

When CIALIS (including generic cialis tadalafil) is co-administered with an alpha-blocker, patients should be stable on alpha-blocker therapy prior to initiating CIALIS (including generic cialis tadalafil) treatment and CIALIS should be initiated at the lowest dose (see

HOW SUPPLIED

CIALIS (including generic cialis tadalafil)® (tadalafil) is supplied as blue, film-coated, rounded-diamond-shaped tablets containing tadalafil equivalent to the nominally indicated amount of tadalafil as follows:

Recommended Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Cialis

Side Effects & Drug Interactions

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SIDE EFFECTS

Pre-marketing Experience

CIALIS (including generic cialis tadalafil) was administered to over 3700 patients (aged 19-87 years) during clinical trials worldwide. Over 550 patients were treated for longer than one year.

In placebo-controlled clinical studies, the discontinuation rate due to adverse events for CIALIS (2.5%) was not significantly different from placebo (2.3%). The adverse events were generally transient and mild to moderate in nature.

In trials of all designs, adverse events reported by patients receiving CIALIS (including generic cialis tadalafil) were generally similar. In fixed-dose studies, the incidence of some adverse events increased with dose. The nature of the adverse events in flexible-dose studies, which more closely reflect the recommended dosage regimen, was similar to that for fixed-dose studies.

When CIALIS (including generic cialis tadalafil) was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials, the following adverse events were reported:

TABLE 2. ADVERSE EVENTS REPORTED BY ≥2% OF PATIENTS TREATED WITH CIALIS AND
MORE FREQUENT ON DRUG THAN PLACEBO IN PRN FLEXIBLE-DOSE PHASE II/III
STUDIES

^{† Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision.}

^{Other adverse reactions occurred at a rate of >2%, but equally common on placebo: respiratory tract infection, back pain, flu syndrome, and arthralgia.}

^{In fixed-dose studies, dyspepsia (17%) and abnormal vision (11%) were more common at 20 mg than at lower doses. At doses above the recommended dose range, adverse events were similar to those detailed above but generally were reported more frequently.}

^{The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to CIALIS is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful:}

^{Body as a whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury.}

^{Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy.}

^{Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis.}

^{Hemic and Lymphatic: anemia and leukopenia.}

^{Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.}

^{Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.} Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia.

Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased.

Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis.

Special Senses: mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, deafness, ear pain, eye hemorrhage, cataract, dry eyes.

Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia.

Post-Marketing Experience

Cardiovascular and cerebrovascular

Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of CIALIS (including generic cialis tadalafil). Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of CIALIS (including generic cialis tadalafil) without sexual activity. Others were reported to have occurred hours to days after the use of CIALIS (including generic cialis tadalafil) and sexual activity. It is not possible to determine whether these events are related directly to CIALIS (including generic cialis tadalafil), to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors (see WARNINGS for further important cardiovascular information).

Other events

Other events reported post-marketing to have been observed in temporal association with CIALIS (including generic cialis tadalafil) and not listed in the pre-marketing adverse reactions section above include:

Nervous: seizure and anxiety.

Urogenital: prolonged erection, priapism (see WARNINGS), and hematuria.

Special Senses: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal vascular disease or bleeding, vitreous detachment/traction, paramacular edema and epistaxis.

Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including CIALIS (including generic cialis tadalafil). Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ("crowded disc"), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors (see PRECAUTIONS/INFORMATION FOR PATIENTS).

DRUG INTERACTIONS

Effects of Other Drugs on CIALIS (including generic cialis tadalafil)

In vitro studies: Tadalafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce tadalafil clearance.

In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma tadalafil concentrations when coadministered with CIALIS (10 mg) to healthy volunteers.

When a single 20 mg dose of CIALIS (including generic cialis tadalafil) was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in tadalafil systemic exposure (AUC). In addition, in a study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with CIALIS (20 mg single dose) resulted in a 140% increase in tadalafil Cmax and a 210% increase in tadalafil AUC. CIALIS had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in tadalafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) (see DOSAGE AND ADMINISTRATION).

In another study in healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with CIALIS (including generic cialis tadalafil) (20 mg single dose) resulted in a 300% (4-fold) increase in tadalafil Cmax and a 1000% (11-fold) increase in tadalafil plasma AUC. At 24 hours the plasma levels of tadalafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when tadalafil was dosed alone. This is consistent with ritonavir’s marked effects on a broad range of P450 substrates. CIALIS (including generic cialis tadalafil) had no effect on ritonavir pharmacokinetics (see DOSAGE AND ADMINISTRATION).

Although the interaction between other protease inhibitors and tadalafil has not been studied, their concomitant use is expected to increase tadalafil levels.

In a study of healthy male volunteers, co-administration of tadalafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of tadalafil AUC and a 55% decrease in tadalafil Cmax . Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of tadalafil.

Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of CIALIS (including generic cialis tadalafil).

Pharmacokinetic data from patients in clinical trials showed no effect on tadalafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl tadalafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

Effects of CIALIS (including generic cialis tadalafil) on Other Drugs

In vitro studies: Tadalafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µM). Given tadalafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that CIALIS (including generic cialis tadalafil) will alter the clearance of substrates of these isoenzymes.

In vivo studies: Three double-blind, placebo-controlled, randomized, two-way crossover studies were conducted to assess the interaction of CIALIS (including generic cialis tadalafil) with doxazosin, an alpha-adrenergic blocking agent.

In the first study, a single oral dose of CIALIS 20 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, CIALIS 20 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the CIALIS dose was reduced to 10 mg. Thereafter, 17 subjects were treated with CIALIS 10 mg or matching placebo in combination with doxazosin 4 mg (15 subjects) or doxazosin 8mg (2 subjects). The mean subject age was 66.5 years.

For the 17 subjects who received CIALIS 10 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

 

Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after CIALIS or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of <85 mmHg or a decrease from baseline in standing systolic blood pressure of >30 mmHg at one or more timepoints. There were no subjects treated with CIALIS 10 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP >30mmHg following CIALIS 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both CIALIS and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.

Of the four subjects who received CIALIS 20 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with CIALIS with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients. For these four subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg, respectively. Two of these subjects had a standing SBP < 85mmHg. Both of these subjects were protocol violators, one due to a low baseline standing SBP, and the other due to baseline orthostatic hypotension.

In the second study, a single oral dose of CIALIS 10 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, CIALIS 50mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years.

Twenty subjects received CIALIS 10 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with CIALIS 10 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.

For the 19 subjects who received both CIALIS and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

 

Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

Blood pressure was measured after administration of CIALIS (including generic cialis tadalafil) at the same times as those specified for the first doxazosin study. There were two subjects who had a standing SBP of < 85 mmHg. In these two subjects, hypotension was reported as a moderately severe adverse event, beginning at approximately 1 hour after administration of CIALIS 10 mg and resolving after approximately 7.5 hours. There was one subject with a decrease from baseline in standing systolic BP >30mmHg following CIALIS 10 mg and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both CIALIS 10 mg and placebo. There were no severe adverse events potentially related to blood pressure and no episodes of syncope reported in this study.

In the third study, a single oral dose of CIALIS 20 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of CIALIS 10 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using CIALIS 10 mg), including no significant hemodynamic adverse events, were allowed to skip dose period 1. Treatment with doxazosin continued for at least 7 days after dose period 1. Thereafter, CIALIS 20mg or matching placebo was administered simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years.

Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label CIALIS 10 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using CIALIS 10 mg).

For the 20 subjects who received CIALIS 20 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

 

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

Blood pressure was measured after administration of CIALIS (including generic cialis tadalafil) at the same times as those specified for the previous doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were taking CIALIS 20 mg, and all three reported mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP >30mmHg following CIALIS 20 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both CIALIS and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both CIALIS 10 mg and 20 mg. There were no episodes of syncope reported in this study.

When CIALIS 20 mg oral was coadministered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

No significant interactions were shown with tolbutamide (210 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

CIALIS (10 mg) did not potentiate the increase in bleeding time caused by aspirin (110 mg).

CIALIS (10 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

In a study of healthy male volunteers, tadalafil (20 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.

Tadalafil at steady state (80 mg t.i.d.) resulted in a 50 % increase in AUC and a 42 % increase in Cmax of bosentan (125 mg b.i.d.).

Cialis

Warnings & Precautions

 

WARNINGS

There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including CIALIS (including generic cialis tadalafil), should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

CIALIS (including generic cialis tadalafil) has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg), (see CLINICAL PHARMACOLOGY: Pharmacodynamics). While this normally would be expected to be of little consequence in most patients, prior to prescribing CIALIS (including generic cialis tadalafil), physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

Patients with the following underlying conditions can be particularly sensitive to the actions of vasodilators including CIALIS (including generic cialis tadalafil) – those with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure.

There is no controlled clinical data on the safety or efficacy of CIALIS (including generic cialis tadalafil) in the following groups; if prescribed, this should be done with caution.

• Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;
• Patients with resting hypotension (BP <90/50) or hypertension (BP >170/110);
• Patients with cardiac failure or coronary artery disease causing unstable angina;
• Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of CIALIS (including generic cialis tadalafil). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of tadalafil (11-fold increase in AUC). If CIALIS (including generic cialis tadalafil) is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of tadalafil are limited. Visual disturbances occurred more commonly at higher levels of tadalafil exposure. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of tadalafil (200-800 mg). To decrease the chance of adverse events in patients taking ritonavir, a decrease in tadalafil dosage is recommended (see DRUG INTERACTIONS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).

PRECAUTIONS

General

The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.

Before prescribing CIALIS (including generic cialis tadalafil), it is important to note the following:

Caution is advised when Phosphodiesterase Type 5 (PDE5) inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including CIALIS (including generic cialis tadalafil), and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly (see DRUG INTERACTIONS) leading to symptomatic hypotension (e.g. dizziness, lightheadedness, fainting).

Consideration should be given to the following:

• Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose.
• In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.
• Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

Cialis has systemic vasodilatory properties and may augment the blood pressure lowering effect of other anti-hypertensive medications.

Patients on multiple antihypertensive medications were included in the pivotal clinical trials for CIALIS (including generic cialis tadalafil). In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and CIALIS, 20 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted (see DRUG INTERACTIONS).

The safety of Cialis is unknown in patients with bleeding disorders and patients with active peptic ulceration.

CIALIS (including generic cialis tadalafil) should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

The safety and efficacy of combinations of CIALIS (including generic cialis tadalafil) with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

In humans, CIALIS (including generic cialis tadalafil) has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that tadalafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). The combination of heparin and CIALIS (including generic cialis tadalafil) had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Tadalafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound tadalafil and its major metabolite of 29- and 42-times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 20 mg. Tadalafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m² basis.

Tadalafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.

There was no impairment of fertility in rats given tadalafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.

There was no effect on sperm motility or morphology after single 20 mg oral doses of CIALIS (including generic cialis tadalafil) in healthy volunteers.

Pregnancy, Nursing Mothers and Pediatric Use

CIALIS (including generic cialis tadalafil) is not indicated for use in newborns, children, or women.

Pregnancy Category B

No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the MRHD on a mg/m² basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant rat the AUC at this dose was about 20 times human AUC. There are no adequate and well-controlled studies of tadalafil in pregnant women.

Geriatric Use

Healthy elderly volunteers (65 years or over) had a reduced clearance of tadalafil (see CLINICAL PHARMACOLOGY: Pharmacokinetics in Special Populations). Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 10 mg should be considered (see DOSAGE AND ADMINISTRATION).

Cialis

Overdosage & Contraindications

 

OVERDOSE

In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates were increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as tadalafil is highly bound to plasma proteins and it is not eliminated in the urine.

CONTRAINDICATIONS

Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL PHARMACOLOGY), CIALIS (including generic cialis tadalafil) was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated.

After patients have taken CIALIS (including generic cialis tadalafil), it is unknown when nitrates, if necessary, can be safely administered. Based on the pharmacokinetic profile of a single 20 mg oral dose given to healthy normal volunteers, the plasma levels of tadalafil at 24 hours post dose are approximately 2 ng/mL (compared to peak plasma levels of approximately 440 ng/mL) (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism). In the following patients: age >65, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin), plasma levels of tadalafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of tadalafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely coadministered at this time point.

CIALIS (including generic cialis tadalafil) is contraindicated in patients with a known hypersensitivity to any component of the tablet.

Cialis

 

PATIENT INFORMATION

Physicians should discuss with patients the contraindication of CIALIS (including generic cialis tadalafil) with regular and/or intermittent use of organic nitrates.

Physicians should advise patients of the potential for CIALIS (including generic cialis tadalafil) to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of CIALIS (including generic cialis tadalafil) and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when CIALIS (including generic cialis tadalafil) is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating CIALIS (including generic cialis tadalafil) treatment and CIALIS should be initiated at the lowest dose.

Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician.

Physicians should advise patients to stop use of all PDE5 inhibitors, including CIALIS (including generic cialis tadalafil), and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors (see POST-MARKETING EXPERIENCE/Special Senses).

Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of CIALIS. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

The use of CIALIS (including generic cialis tadalafil) offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.

Tadalafil is also marketed as REVATIO®for pulmonary arterial hypertension.