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CIALIS®
(tadalafil)
tablets
DESCRIPTION
CIALIS® (tadalafil), an oral treatment for erectile dysfunction, is a selective inhibitor of cyclic guanosine monophosphate (cGMP)–specific phosphodiesterase type 5 (PDE5). Tadalafil has the empirical formula C22H19N3O4 representing a molecular weight of 389.41. The structural formula is:
The chemical designation is pyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione, 6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)–. It is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.
CIALIS is available as film–coated, almond–shaped tablets for oral administration. Each tablet contains 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
CLINICAL PHARMACOLOGY
Mechanism of Action
Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) enhances erectile function by increasing the amount of cGMP. Tadalafil inhibits PDE5. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 by tadalafil has no effect in the absence of sexual stimulation.
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung, cerebellum, and pancreas.
In vitro studies have shown that the effect of tadalafil is more potent on PDE5 than on other phosphodiesterases. These studies have shown that tadalafil is>10,000–fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes, which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle, and other organs. Tadalafil is>10,000–fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. Additionally, tadalafil is 700–fold more potent for PDE5 than for PDE6, which is found in the retina and is responsible for phototransduction. Tadalafil is>9,000–fold more potent for PDE5 than for PDE8, PDE9, and PDE10. Tadalafil is 14–fold more potent for PDE5 than for PDE11A1 and 40–fold more potent for PDE5 than for PDE11A4, two of the four known forms of PDE11. PDE11 is an enzyme found in human prostate, testes, skeletal muscle and in other tissues. In vitro, tadalafil inhibits human recombinant PDE11A1 and, to a lesser degree, PDE11A4 activities at concentrations within the therapeutic range. The physiological role and clinical consequence of PDE11 inhibition in humans have not been defined.
Pharmacokinetics
Pharmacokinetics in Special Populations
Pharmacodynamics
CLINICAL STUDIES
The efficacy and safety of tadalafil in the treatment of erectile dysfunction has been evaluated in 22 clinical trials of up to 24–weeks duration, involving over 4000 patients. CIALIS, when taken as needed up to once daily, was shown to be effective in improving erectile function in men with erectile dysfunction (ED).
Study Design — CIALIS was studied in the general ED population in 7 randomized, multicenter, double–blinded, placebo–controlled, parallel–arm design, primary efficacy and safety studies of 12–weeks duration. Two of these studies were conducted in the United States and 5 were conducted in centers outside the US. Additional efficacy and safety studies were performed in ED patients with diabetes mellitus and in patients who developed ED status post bilateral nerve–sparing radical prostatectomy.
In these 7 trials, CIALIS was taken as needed, at doses ranging from 2.5 to 20 mg, up to once daily. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted.
Several assessment tools were used to evaluate the effect of CIALIS on erectile function. The 3 primary outcome measures were the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF) and Questions 2 and 3 from Sexual Encounter Profile (SEP). The IIEF is a 4–week recall questionnaire that was administered at the end of a treatment–free baseline period and subsequently at follow–up visits after randomization. The IIEF EF domain has a 30–point total score, where higher scores reflect better erectile function. SEP is a diary in which patients recorded each sexual attempt made throughout the study. SEP Question 2 asks, “Were you able to insert your penis into your partner’s vagina?” SEP Question 3 asks, “Did your erection last long enough for you to have successful intercourse?” The overall percentage of successful attempts to insert the penis into the vagina (SEP2) and to maintain the erection for successful intercourse (SEP3) is derived for each patient.
Study Results —
ED Population in US Trials — The 2 primary US efficacy and safety trials included a total of 402 men with erectile dysfunction, with a mean age of 59 years (range 27 to 87 years). The population was 78% White, 14% Black, 7% Hispanic, and 1% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co–morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (>90%) patients reported ED of at least 1–year duration. Study A was conducted primarily in academic centers. Study B was conducted primarily in community–based urology practices. In each of these 2 trials, CIALIS 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Table 1). The treatment effect of CIALIS did not diminish over time.
Study A | Study B | |||||
Placebo | CIALIS | Placebo | CIALIS | |||
(N=49) | (N=146) | p–value | (N=48) | (N=159) | p–value | |
EF Domain Score | ||||||
Endpoint | 13.5 | 19.5 | 13.6 | 22.5 | ||
Change from baseline | –0.2 | 6.9 | <.001 | 0.3 | 9.3 | <.001 |
Insertion of Penis (SEP2) | ||||||
Endpoint | 39% | 62% | 43% | 77% | ||
Change from baseline | 2% | 26% | <.001 | 2% | 32% | <.001 |
Maintenance
of Erection | ||||||
Endpoint | 25% | 50% | 23% | 64% | ||
Change from baseline | 5% | 34% | <.001 | 4% | 44% | <.001 |
General ED Population in Trials Outside the US — The 5 primary efficacy and safety studies conducted in the general ED population outside the US included 1112 patients, with a mean age of 59 years (range 21 to 82 years). The population was 76% White, 1% Black, 3% Hispanic, and 20% of other ethnicities, and included patients with ED of various severities, etiologies (organic, psychogenic, mixed), and with multiple co–morbid conditions, including diabetes mellitus, hypertension, and other cardiovascular disease. Most (90%) patients reported ED of at least 1–year duration. In these 5 trials, CIALIS 5, 10, and 20 mg showed clinically meaningful and statistically significant improvements in all 3 primary efficacy variables (see Tables 2, 3, and 4). The treatment effect of CIALIS did not diminish over time.
Placebo | CIALIS | CIALIS | CIALIS | |
Study C | ||||
Endpoint [Change from baseline] | 15.0 [0.7] | 17.9 [4.0] | 20.0 [5.6] | |
p=.006 | p<.001 | |||
Study D | ||||
Endpoint [Change from baseline] | 14.4 [1.1] | 17.5 [5.1] | 20.6 [6.0] | |
p=.002 | p<.001 | |||
Study E | ||||
Endpoint [Change from baseline] | 18.1 [2.6] | 22.6 [8.1] | 25.0 [8.0] | |
p<.001 | p<.001 | |||
Study F | ||||
Endpoint [Change from baseline] | 12.7 [-1.6] | 22.8 [6.8] | ||
p<.001 | ||||
Study G | ||||
Endpoint [Change from baseline] | 14.5 [-0.9] | 21.2 [6.6] | 23.3 [8.0] | |
p<.001 | p<.001 |
Placebo | CIALIS | CIALIS | CIALIS | |
Study C | ||||
Endpoint [Change from baseline] | 49% [6%] | 57% [15%] | 73% [29%] | |
p=.063 | p<.001 | |||
Study D | ||||
Endpoint [Change from baseline] | 46% [2%] | 56% [18%] | 68% [15%] | |
p=.008 | p<.001 | |||
Study E | ||||
Endpoint [Change from baseline] | 55% [10%] | 77% [35%] | 85% [35%] | |
p<.001 | p<.001 | |||
Study F | ||||
Endpoint [Change from baseline] | 42% [–8%] | 81% [27%] | ||
p<.001 | ||||
Study G | ||||
Endpoint [Change from baseline] | 45% [–6%] | 73% [21%] | 76% [21%] | |
p<.001 | p<.001 |
Placebo | CIALIS | CIALIS | CIALIS | |
Study C | ||||
Endpoint [Change from baseline] | 26% [4%] | 38% [19%] | 58% [32%] | |
p=.040 | p<.001 | |||
Study D | ||||
Endpoint [Change from baseline] | 28% [4%] | 42% [24%] | 51% [26%] | |
p<.001 | p<.001 | |||
Study E | ||||
Endpoint [Change from baseline] | 43% [15%] | 70% [48%] | 78% [50%] | |
p<.001 | p<.001 | |||
Study F | ||||
Endpoint [Change from baseline] | 27% [1%] | 74% [40%] | ||
p<.001 | ||||
Study G | ||||
Endpoint [Change from baseline] | 32% [5%] | 57% [33%] | 62% [29%] | |
p<.001 | p<.001 |
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 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 1 study that specifically assessed CIALIS in ED patients with type 1 or type 2 diabetes (N=216). In this randomized, placebo–controlled, double–blinded, 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 5).
Placebo | CIALIS | CIALIS | ||
(N=71) | (N=73) | (N=72) | p–value | |
EF Domain Score | ||||
Endpoint [Change from baseline] | 12.2 [0.1] | 19.3 [6.4] | 18.7 [7.3] | <.001 |
Insertion of Penis (SEP2) | ||||
Endpoint [Change from baseline] | 30% [–4%] | 57% [22%] | 54% [23%] | <.001 |
Maintenance of Erection (SEP3) | ||||
Endpoint [Change from baseline] | 20% [2%] | 48% [28%] | 42% [29%] | <.001 |
Efficacy 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 6).
Placebo | CIALIS | ||
(N=102) | (N=201) | p–value | |
EF Domain Score | |||
Endpoint [Change from baseline] | 13.3 [1.1] | 17.7 [5.3] | <.001 |
Insertion of Penis (SEP2) | |||
Endpoint [Change from baseline] | 32% [2%] | 54% [22%] | <.001 |
Maintenance of Erection (SEP3) | |||
Endpoint [Change from baseline] | 19% [4%] | 41% [23%] | <.001 |
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 pre–specified 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.
INDICATIONS AND USAGE
CIALIS is indicated for the treatment of erectile dysfunction.
CONTRAINDICATIONS
WARNINGS
Cardiovascular
Patients Not Studied in Clinical Trials
The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for CIALIS, and, therefore, the use of CIALIS is not recommended in these groups until further information is available:
patients with a myocardial infarction within the last 90 days
patients with unstable angina or angina occurring during sexual intercourse
patients with New York Heart Association Class 2 or greater heart failure in the last 6 months
patients with uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension (>170/100 mm Hg)
patients with a stroke within the last 6 months
In addition, patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical trials, and use in these patients is not recommended.
Prolonged Erection
There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention.
PRECAUTIONS
Alpha-blockers
Caution is advised when PDE5 inhibitors are coadministered with alpha–blockers. PDE5 inhibitors, including CIALIS, 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 under PRECAUTIONS), which may lead to symptomatic hypotension (e.g., 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 recommended dose.
In those patients already taking an optimized dose of 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.
Renal Insufficiency
CIALIS should be limited to 5 mg not more than once daily in patients with severe renal insufficiency or end–stage renal disease. The starting dose of CIALIS in patients with a moderate degree of renal insufficiency should be 5 mg not more than once daily, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. No dose adjustment is required in patients with mild renal insufficiency (see Pharmacokinetics in Special Populations under CLINICAL PHARMACOLOGY).
Hepatic Impairment
In patients with mild or moderate hepatic impairment, the dose of CIALIS should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of CIALIS in this group is not recommended (see Pharmacokinetics in Special Populations under CLINICAL PHARMACOLOGY).
Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4)
CIALIS is metabolized predominantly by CYP3A4 in the liver. The dose of CIALIS should be limited to 10 mg no more than once every 72 hours in patients taking potent inhibitors of CYP3A4 such as ritonavir, ketoconazole, and itraconazole (see Effects of Other Drugs on CIALIS under Drug Interactions).
General
As with other PDE5 inhibitors, tadalafil has mild systemic vasodilatory properties that may result in transient decreases in blood pressure. In a clinical pharmacology study, tadalafil 20 mg resulted in a mean maximal decrease in supine blood pressure, relative to placebo, of 1.6/0.8 mm Hg in healthy subjects (see Pharmacodynamics under CLINICAL PHARMACOLOGY). While this effect should not be of consequence in most patients, prior to prescribing CIALIS, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects. Patients with significant left ventricular outflow obstruction or severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators.
Information for Patients
Drug Interactions
Effects of Other Drugs on CIALIS
Effects of CIALIS on Other Drugs
Carcinogenesis, Mutagenesis, Impairment of Fertility
Animal Toxicology
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 upon removal of the drug.
Pregnancy, Nursing Mothers, and Pediatric Use
Geriatric Use
Approximately 25% of patients in the primary efficacy and safety studies of tadalafil were greater than 65 years of age. No overall differences in efficacy and safety were observed between older and younger patients. No dose adjustment is warranted based on age alone. However, greater sensitivity to medications in some older individuals should be considered (see Special Populations under CLINICAL PHARMACOLOGY).
ADVERSE REACTIONS
Postmarketing surveillance
Cardiovascular and cerebrovascular: Serious cardiovascular events, including myocardial infarction, sudden cardiac death, stroke, chest pain, palpitations, and tachycardia, have been reported postmarketing in temporal association with the use of 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 without sexual activity. Others were reported to have occurred hours to days after the use of CIALIS and sexual activity. It is not possible to determine whether these events are related directly to CIALIS, to sexual activity, to the patient’s underlying cardiovascular disease, to a combination of these factors, or to other factors (see WARNINGS for additional information).
Other adverse events: The following ul includes other adverse events that have been identified during postmarketing use of CIALIS. The ul does not include adverse events that are reported from clinical trials and that are uled elsewhere in this section. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a whole: hypersensitivity reactions including urticaria, Stevens–Johnson syndrome, and exfoliative dermatitis
Nervous: migraine
Ophthalmologic: visual field defect, retinal vein occlusion, retinal artery occlusion
Non–arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including CIALIS. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of 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 Information for Patients under PRECAUTIONS).
Otologic: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including CIALIS. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of CIALIS, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors (seeInformation for Patients under PRECAUTIONS).
Urogenital: priapism (see WARNINGS)
OVERDOSAGE
Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Hemodialysis contributes negligibly to tadalafil elimination.
DOSAGE AND ADMINISTRATION
Renal Insufficiency
No dose adjustment is required in patients with mild renal insufficiency. For patients with moderate (creatinine clearance 31 to 50 mL/min) renal insufficiency, a starting dose of 5 mg not more than once daily is recommended, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. For patients with severe (creatinine clearance <30 mL/min) renal insufficiency on hemodialysis, the maximum recommended dose is 5 mg (see General and Patients with Renal Insufficiency under PRECAUTIONS and Pharmacokinetics in Special Populations under CLINICAL PHARMACOLOGY).
Hepatic Impairment
For patients with mild or moderate degrees of hepatic impairment (Child–Pugh Class A or B), the dose of CIALIS should not exceed 10 mg once daily. In patients with severe hepatic impairment (Child–Pugh Class C), the use of CIALIS is not recommended (see Patients with Hepatic Impairment under PRECAUTIONS and Pharmacokinetics in Special Populations under CLINICAL PHARMACOLOGY).
Concomitant Medications
When CIALIS is coadministered with an alpha–blocker, patients should be stable on alpha–blocker therapy prior to initiating treatment with CIALIS, and CIALIS should be initiated at the lowest recommended dose (see PRECAUTIONS).
For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose of CIALIS is 10 mg, not to exceed once every 72 hours (see PRECAUTIONS).
Concomitant use of nitrates in any form is contraindicated (see CONTRAINDICATIONS).
Geriatrics
No dose adjustment is required in patients >65 years of age.
HOW SUPPLIED
Literature revised October 18, 2007
Eli Lilly and Company
Indianapolis, IN 46285, USA
Copyright © 2003, 2007, Eli Lilly and Company. All rights reserved.
PV 5216 AMP