Erectile Dysfunction
Cialis® is indicated for the treatment of erectile dysfunction (ED).
Benign Prostatic Hyperplasia
Cialis is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
Erectile Dysfunction and Benign Prostatic Hyperplasia
Cialis is indicated for the treatment of ED and the signs and symptoms of BPH (ED/BPH).
Cialis Dosage and Administration
Do not split Cialis tablets; entire dose should be taken.
Cialis for Use as Needed for Erectile Dysfunction
- The recommended starting dose of Cialis for use as needed in most patients is 10 mg, taken prior to anticipated sexual activity.
- The dose may be increased to 20 mg or decreased to 5 mg, based on individual efficacy and tolerability. The maximum recommended dosing frequency is once per day in most patients.
- Cialis for use as needed was shown to improve erectile function compared to placebo up to 36 hours following dosing. Therefore, when advising patients on optimal use of Cialis, this should be taken into consideration.
Cialis for Once Daily Use for Erectile Dysfunction
- The recommended starting dose of Cialis for once daily use is 2.5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.
- The Cialis dose for once daily use may be increased to 5 mg, based on individual efficacy and tolerability.
Cialis for Once Daily Use for Benign Prostatic Hyperplasia
The recommended dose of Cialis for once daily use is 5 mg, taken at approximately the same time every day.
Cialis for Once Daily Use for Erectile Dysfunction and Benign Prostatic Hyperplasia
The recommended dose of Cialis for once daily use is 5 mg, taken at approximately the same time every day, without regard to timing of sexual activity.
Use with Food
Cialis may be taken without regard to food.
Use in Specific Populations
Renal Impairment
Cialis for Use as Needed
- Creatinine clearance 30 to 50 mL/min: A starting dose of 5 mg not more than once per day is recommended, and the maximum dose is 10 mg not more than once in every 48 hours.
- Creatinine clearance less than 30 mL/min or on hemodialysis: The maximum dose is 5 mg not more than once in every 72 hours [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].
Cialis for Once Daily Use
Erectile Dysfunction
- Creatinine clearance less than 30 mL/min or on hemodialysis: Cialis for once daily use is not recommended [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].
Benign Prostatic Hyperplasia and Erectile Dysfunction/Benign Prostatic Hyperplasia
- Creatinine clearance 30 to 50 mL/min: A starting dose of 2.5 mg is recommended. An increase to 5 mg may be considered based on individual response.
- Creatinine clearance less than 30 mL/min or on hemodialysis: Cialis for once daily use is not recommended [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].
Hepatic Impairment
Cialis for Use as Needed
- Mild or moderate (Child Pugh Class A or B): The dose should not exceed 10 mg once per day. The use of Cialis once per day has not been extensively evaluated in patients with hepatic impairment and therefore, caution is advised.
- Severe (Child Pugh Class C): The use of Cialis is not recommended [see Warnings and Precautions (5.8) and Use in Specific Populations (8.6)].
Cialis for Once Daily Use
- Mild or moderate (Child Pugh Class A or B): Cialis for once daily use has not been extensively evaluated in patients with hepatic impairment. Therefore, caution is advised if Cialis for once daily use is prescribed to these patients.
- Severe (Child Pugh Class C): The use of Cialis is not recommended [see Warnings and Precautions (5.8) and Use in Specific Populations (8.6)].
Concomitant Medications
Nitrates
- Concomitant use of nitrates in any form is contraindicated [see Contraindications (4.1)].
Alpha Blockers
ED — When Cialis is coadministered with an alpha blocker in patients being treated for ED, patients should be stable on alpha-blocker therapy prior to initiating treatment, and Cialis should be initiated at the lowest recommended dose [see Warnings and Precautions (5.6), Drug Interactions (7.1), and Clinical Pharmacology (12.2)].
BPH — Cialis is not recommended for use in combination with alpha blockers for the treatment of BPH [see Warnings and Precautions (5.6), Drug Interactions (7.1), and Clinical Pharmacology (12.2)].
CYP3A4 Inhibitors
Cialis for Use as Needed — 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 Warnings and Precautions (5.10) and Drug Interactions (7.2)].
Cialis for Once Daily Use — For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the maximum recommended dose is 2.5 mg [see Warnings and Precautions (5.10) and Drug Interactions (7.2)].
Dosage Forms and Strengths
Four strengths of almond-shaped tablets are available in different sizes and different shades of yellow:
- 2.5 mg tablets debossed with “C 2 1/2”
- 5 mg tablets debossed with “C 5”
- 10 mg tablets debossed with “C 10”
- 20 mg tablets debossed with “C 20”
Contraindications
Nitrates
Administration of Cialis to patients who are using any form of organic nitrate, either regularly and/or intermittently, is contraindicated. In clinical pharmacology studies, Cialis was shown to potentiate the hypotensive effect of nitrates [see Clinical Pharmacology (12.2)].
Hypersensitivity Reactions
Cialis is contraindicated in patients with a known serious hypersensitivity to tadalafil (Cialis or ADCIRCA®). Hypersensitivity reactions have been reported, including Stevens-Johnson syndrome and exfoliative dermatitis [see Adverse Reactions (6.2)].
Warnings and Precautions
Evaluation of erectile dysfunction and BPH should include an appropriate medical assessment to identify potential underlying causes, as well as treatment options.
Before prescribing Cialis, it is important to note the following:
Cardiovascular
Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Therefore, treatments for erectile dysfunction, including Cialis, should not be used in men for whom sexual activity is inadvisable as a result of their underlying cardiovascular status. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and seek immediate medical attention.
Physicians should discuss with patients the appropriate action in the event that they experience anginal chest pain requiring nitroglycerin following intake of Cialis. In such a patient, who has taken Cialis, where nitrate administration is deemed medically necessary for a life-threatening situation, at least 48 hours should have elapsed 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. Therefore, patients who experience anginal chest pain after taking Cialis should seek immediate medical attention. [See Contraindications (4.1) and Patient Counseling Information (17.1)].
Patients with left ventricular outflow obstruction, (e.g., aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators, including PDE5 inhibitors.
The following groups of patients with cardiovascular disease were not included in clinical safety and efficacy trials for Cialis, and therefore until further information is available, Cialis is not recommended for the following groups of patients:
- myocardial infarction within the last 90 days
- unstable angina or angina occurring during sexual intercourse
- New York Heart Association Class 2 or greater heart failure in the last 6 months
- uncontrolled arrhythmias, hypotension (<90/50 mm Hg), or uncontrolled hypertension
- stroke within the last 6 months.
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 Clinical Pharmacology (12.2)]. 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 severely impaired autonomic control of blood pressure may be particularly sensitive to the actions of vasodilators, including PDE5 inhibitors.
Potential for Drug Interactions When Taking Cialis for Once Daily Use
Physicians should be aware that Cialis for once daily use provides continuous plasma tadalafil levels and should consider this when evaluating the potential for interactions with medications (e.g., nitrates, alpha-blockers, anti-hypertensives and potent inhibitors of CYP3A4) and with substantial consumption of alcohol [see Drug Interactions (7.1, 7.2, 7.3)].
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.
Cialis should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie's disease).
Eye
Physicians should advise patients to stop use of all PDE5 inhibitors, including Cialis, 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 postmarketing 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 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 Adverse Reactions (6.2)].
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.
Sudden Hearing Loss
Physicians should advise patients to stop taking PDE5 inhibitors, including Cialis, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including Cialis. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions (6.1, 6.2)].
Alpha-blockers and Antihypertensives
Physicians should discuss with patients the potential for Cialis to augment the blood-pressure-lowering effect of alpha blockers and antihypertensive medications [see Drug Interactions (7.1) and Clinical Pharmacology (12.2)].
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 (7.1) and Clinical Pharmacology (12.2)], which may lead to symptomatic hypotension (e.g., fainting). Consideration should be given to the following:
ED
- 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 antihypertensive drugs.
[See Dosage and Administration (2.7) and Drug Interactions (7.1)].
BPH
- The efficacy of the co-administration of an alpha-blocker and Cialis for the treatment of BPH has not been adequately studied, and due to the potential vasodilatory effects of combined use resulting in blood pressure lowering, the combination of Cialis and alpha-blockers is not recommended for the treatment of BPH. [See Dosage and Administration (2.7), Drug Interactions (7.1), and Clinical Pharmacology (12.2.)].
- Patients on alpha-blocker therapy for BPH should discontinue their alpha-blocker at least one day prior to starting Cialis for once daily use for the treatment of BPH.
Renal Impairment
Cialis for Use as Needed
Cialis should be limited to 5 mg not more than once in every 72 hours in patients with creatinine clearance less than 30 mL/min or end-stage renal disease on hemodialysis. The starting dose of Cialis in patients with creatinine clearance 30 – 50 mL/min should be 5 mg not more than once per day, and the maximum dose should be limited to 10 mg not more than once in every 48 hours. [See Use in Specific Populations (8.7)].
Cialis for Once Daily Use
ED
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, Cialis for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min [see Use in Specific Populations (8.7)].
BPH and ED/BPH
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, Cialis for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 – 50 mL/min, start dosing at 2.5 mg once daily, and increase the dose to 5 mg once daily based upon individual response [see Dosage and Administration (2.6), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
Hepatic Impairment
Cialis for Use as Needed
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 Use in Specific Populations (8.6)].
Cialis for Once Daily Use
Cialis for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if Cialis for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of Cialis in this group is not recommended [see Use in Specific Populations (8.6)].
Alcohol
Patients should be made aware that both alcohol and Cialis, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with Cialis can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache [see Clinical Pharmacology (12.2)].
Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4)
Cialis is metabolized predominantly by CYP3A4 in the liver. The dose of Cialis for use as needed 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 Drug Interactions (7.2)]. In patients taking potent inhibitors of CYP3A4 and Cialis for once daily use, the maximum recommended dose is 2.5 mg [see Dosage and Administration (2.7)].
Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies
The safety and efficacy of combinations of Cialis and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take Cialis with other PDE5 inhibitors, including ADCIRCA.
Effects on Bleeding
Studies in vitro have demonstrated that tadalafil is a selective inhibitor of PDE5. PDE5 is found in platelets. When administered in combination with aspirin, tadalafil 20 mg did not prolong bleeding time, relative to aspirin alone. Cialis has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although Cialis has not been shown to increase bleeding times in healthy subjects, use in patients with bleeding disorders or significant active peptic ulceration should be based upon a careful risk-benefit assessment and caution.
Counseling Patients About Sexually Transmitted Diseases
The use of Cialis offers no protection against sexually transmitted diseases. Counseling patients about the protective measures necessary to guard against sexually transmitted diseases, including Human Immunodeficiency Virus (HIV) should be considered.
Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH
Prior to initiating treatment with Cialis for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Tadalafil was administered to over 9000 men during clinical trials worldwide. In trials of Cialis for once daily use, a total of 1434, 905, and 115 were treated for at least 6 months, 1 year, and 2 years, respectively. For Cialis for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively.
Cialis for Use as Needed for ED
In eight primary placebo-controlled clinical studies of 12 weeks duration, mean age was 59 years (range 22 to 88) and the discontinuation rate due to adverse events in patients treated with tadalafil 10 or 20 mg was 3.1%, compared to 1.4% in placebo treated patients.
When taken as recommended in the placebo-controlled clinical trials, the following adverse reactions were reported (see Table 1) for Cialis for use as needed:
a The term flushing includes: facial flushing and flushing | ||||
| Adverse Reaction | Placebo (N=476) | Tadalafil 5 mg (N=151) | Tadalafil 10 mg (N=394) | Tadalafil 20 mg (N=635) |
| Headache | 5% | 11% | 11% | 15% |
| Dyspepsia | 1% | 4% | 8% | 10% |
| Back pain | 3% | 3% | 5% | 6% |
| Myalgia | 1% | 1% | 4% | 3% |
| Nasal congestion | 1% | 2% | 3% | 3% |
| Flushinga | 1% | 2% | 3% | 3% |
| Pain in limb | 1% | 1% | 3% | 3% |
Cialis for Once Daily Use for ED
In three placebo-controlled clinical trials of 12 or 24 weeks duration, mean age was 58 years (range 21 to 82) and the discontinuation rate due to adverse events in patients treated with tadalafil was 4.1%, compared to 2.8% in placebo-treated patients.
The following adverse reactions were reported (see Table 2) in clinical trials of 12 weeks duration:
| Adverse Reaction | Placebo (N=248) | Tadalafil 2.5 mg (N=196) | Tadalafil 5 mg (N=304) |
| Headache | 5% | 3% | 6% |
| Dyspepsia | 2% | 4% | 5% |
| Nasopharyngitis | 4% | 4% | 3% |
| Back pain | 1% | 3% | 3% |
| Upper respiratory tract infection | 1% | 3% | 3% |
| Flushing | 1% | 1% | 3% |
| Myalgia | 1% | 2% | 2% |
| Cough | 0% | 4% | 2% |
| Diarrhea | 0% | 1% | 2% |
| Nasal congestion | 0% | 2% | 2% |
| Pain in extremity | 0% | 1% | 2% |
| Urinary tract infection | 0% | 2% | 0% |
| Gastroesophageal reflux disease | 0% | 2% | 1% |
| Abdominal pain | 0% | 2% | 1% |
The following adverse reactions were reported (see Table 3) over 24 weeks treatment duration in one placebo-controlled clinical study:
| Adverse Reaction | Placebo (N=94) | Tadalafil 2.5 mg (N=96) | Tadalafil 5 mg (N=97) |
| Nasopharyngitis | 5% | 6% | 6% |
| Gastroenteritis | 2% | 3% | 5% |
| Back pain | 3% | 5% | 2% |
| Upper respiratory tract infection | 0% | 3% | 4% |
| Dyspepsia | 1% | 4% | 1% |
| Gastroesophageal reflux disease | 0% | 3% | 2% |
| Myalgia | 2% | 4% | 1% |
| Hypertension | 0% | 1% | 3% |
| Nasal congestion | 0% | 0% | 4% |
Cialis for Once Daily Use for BPH and for ED and BPH
In three placebo-controlled clinical trials of 12 weeks duration, two in patients with BPH and one in patients with ED and BPH, the mean age was 63 years (range 44 to 93) and the discontinuation rate due to adverse events in patients treated with tadalafil was 3.6% compared to 1.6% in placebo-treated patients. Adverse reactions leading to discontinuation reported by at least 2 patients treated with tadalafil included headache, upper abdominal pain, and myalgia. The following adverse reactions were reported (see Table 4).
| Adverse Reaction | Placebo (N=576) | Tadalafil 5 mg (N=581) |
| Headache | 2.3% | 4.1% |
| Dyspepsia | 0.2% | 2.4% |
| Back pain | 1.4% | 2.4% |
| Nasopharyngitis | 1.6% | 2.1% |
| Diarrhea | 1.0% | 1.4% |
| Pain in extremity | 0.0% | 1.4% |
| Myalgia | 0.3% | 1.2% |
| Dizziness | 0.5% | 1.0% |
Additional, less frequent adverse reactions (<1%) reported in the controlled clinical trials of Cialis for BPH or ED and BPH included: gastroesophageal reflux disease, upper abdominal pain, nausea, vomiting, arthralgia, and muscle spasm.
Back pain or myalgia was reported at incidence rates described in Tables 1 through 4. In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12 to 24 hours after dosing and typically resolved within 48 hours. The back pain/myalgia associated with tadalafil treatment was characterized by diffuse bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency. In general, pain was reported as mild or moderate in severity and resolved without medical treatment, but severe back pain was reported with a low frequency (<5% of all reports). When medical treatment was necessary, acetaminophen or non-steroidal anti-inflammatory drugs were generally effective; however, in a small percentage of subjects who required treatment, a mild narcotic (e.g., codeine) was used. Overall, approximately 0.5% of all subjects treated with Cialis for on demand use discontinued treatment as a consequence of back pain/myalgia. In the 1-year open label extension study, back pain and myalgia were reported in 5.5% and 1.3% of patients, respectively. Diagnostic testing, including measures for inflammation, muscle injury, or renal damage revealed no evidence of medically significant underlying pathology. Incidence rates for Cialis for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of Cialis for once daily use, adverse reactions of back pain and myalgia were generally mild or moderate with a discontinuation rate of <1% across all indications.
Across all studies with any Cialis dose, reports of changes in color vision were rare (<0.1% of patients).
The following section identifies additional, less frequent events (<2%) reported in controlled clinical trials of Cialis for once daily use or use as needed. A causal relationship of these events to Cialis is uncertain. Excluded from this list are those events that were minor, those with no plausible relation to drug use, and reports too imprecise to be meaningful:
Body as a Whole — asthenia, face edema, fatigue, pain
Cardiovascular — angina pectoris, chest pain, hypotension, myocardial infarction, postural hypotension, palpitations, syncope, tachycardia
Digestive — abnormal liver function tests, dry mouth, dysphagia, esophagitis, gastritis, GGTP increased, loose stools, nausea, upper abdominal pain, vomiting, gastroesophageal reflux disease, hemorrhoidal hemorrhage, rectal hemorrhage
Musculoskeletal — arthralgia, neck pain
Nervous — dizziness, hypesthesia, insomnia, paresthesia, somnolence, vertigo
Renal and Urinary — renal impairment
Respiratory — dyspnea, epistaxis, pharyngitis
Skin and Appendages — pruritus, rash, sweating
Ophthalmologic — blurred vision, changes in color vision, conjunctivitis (including conjunctival hyperemia), eye pain, lacrimation increase, swelling of eyelids
Otologic — sudden decrease or loss of hearing, tinnitus
Urogenital — erection increased, spontaneous penile erection
Postmarketing Experience
The following adverse reactions have been identified during post approval use of Cialis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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.
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 and Precautions (5.1)].
Body as a Whole — hypersensitivity reactions including urticaria, Stevens-Johnson syndrome, and exfoliative dermatitis
Nervous — migraine, seizure and seizure recurrence, transient global amnesia
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 Warnings and Precautions (5.4)].
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 [see Warnings and Precautions (5.5)].
Urogenital — priapism [see Warnings and Precautions (5.3)].
Drug Interactions
Potential for Pharmacodynamic Interactions with Cialis
Nitrates — Administration of Cialis to patients who are using any form of organic nitrate, is contraindicated. In clinical pharmacology studies, Cialis was shown to potentiate the hypotensive effect of nitrates. 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 Dosage and Administration (2.7), Contraindications (4.1), and Clinical Pharmacology (12.2)].
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. Clinical pharmacology studies have been conducted with coadministration of tadalafil with doxazosin, tamsulosin or alfuzosin. [See Dosage and Administration (2.7), Warnings and Precautions (5.6), and Clinical Pharmacology (12.2)].
Antihypertensives — PDE5 inhibitors, including tadalafil, are mild systemic vasodilators. Clinical pharmacology studies were conducted to assess the effect of tadalafil on the potentiation of the blood-pressure-lowering effects of selected antihypertensive medications (amlodipine, angiotensin II receptor blockers, bendrofluazide, enalapril, and metoprolol). Small reductions in blood pressure occurred following coadministration of tadalafil with these agents compared with placebo. [See Warnings and Precautions (5.6) and Clinical Pharmacology (12.2)].
Alcohol — Both alcohol and tadalafil, a PDE5 inhibitor, act as mild vasodilators. When mild vasodilators are taken in combination, blood-pressure-lowering effects of each individual compound may be increased. Substantial consumption of alcohol (e.g., 5 units or greater) in combination with Cialis can increase the potential for orthostatic signs and symptoms, including increase in heart rate, decrease in standing blood pressure, dizziness, and headache. Tadalafil did not affect alcohol plasma concentrations and alcohol did not affect tadalafil plasma concentrations. [See Warnings and Precautions (5.9) and Clinical Pharmacology (12.2)].
Potential for Other Drugs to Affect Cialis
[See Dosage and Administration (2.7) and Warnings and Precautions (5.10)].
Antacids — Simultaneous administration of an antacid (magnesium hydroxide/aluminum hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.
H2 Antagonists (e.g. Nizatidine) — An increase in gastric pH resulting from administration of nizatidine had no significant effect on pharmacokinetics.
Cytochrome P450 Inhibitors — Cialis is a substrate of and predominantly metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase tadalafil exposure.
CYP3A4 (e.g., Ketoconazole) — Ketoconazole (400 mg daily), a selective and potent inhibitor of CYP3A4, increased tadalafil 20 mg single-dose exposure (AUC) by 312% and Cmax by 22%, relative to the values for tadalafil 20 mg alone. Ketoconazole (200 mg daily) increased tadalafil 10-mg single-dose exposure (AUC) by 107% and Cmax by 15%, relative to th
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