Side Effects of Cialis (tadalafil)

Cialis (tadalafil) is a phosphodiesterase-5 (PDE5) inhibitor used to treat impotence (the inability to attain or maintain a penile erection) and benign prostatic hyperplasia (BPH). 

Erection of the penis is caused by the filling of the penis with blood which occurs because the blood vessels that bring blood to the penis increase in size and deliver more blood to the penis, and the blood vessels that take blood away from the penis decrease in size and remove less blood from the penis. 

Sexual stimulation that leads to an erection causes the production and release of nitric oxide in the penis that causes an enzyme, guanylate cyclase, to produce cyclic guanosine monophosphate (cGMP) that is primarily responsible for increasing and decreasing the size of blood vessels carrying blood to and from the penis and causing an erection. 

When cGMP is destroyed the enzyme phosphodiesterase-5, the blood vessels return to normal size, blood leaves the penis, and the erection ends. Cialis prevents phosphodiesterase-5 from destroying cGMP so cGMP stays around longer. The persistence of cGMP leads to a more prolonged erection. 

The mechanism whereby Cialis improves the symptoms of BPH is not clear, but phosphodiesterase-5 also is present in the muscles of the bladder and the prostate, and it has been suggested that the relaxation of these muscles may make the passage of urine less difficult by reducing the pressure in the muscle surrounding the opening to the urethra that controls the flow of urine from the bladder.

Common side effects of Cialis include:

• facial flushing,
• headaches,
• stomach upset,
• diarrhea,
• flu-like symptoms, and
• nausea.

Serious side effects of Cialis include:

• low blood pressure,
• blurred vision,
• changes in color vision,
• abnormal ejaculation, and
• an erection that is painful or lasts longer than 4 hours (priapism).

Drug interactions of Cialis include the following drugs, which may increase levels of Cialis in the blood:

• erythromycin,
• ketoconazole,
• itraconazole,
• indinavir, and
• ritonavir. 

The following drugs may decrease blood levels of Cialis, possibly reducing the effect of Cialis:

• rifampin,
• carbamazepine,
• phenytoin, and
• phenobarbital. 

In patients taking nitrates for angina, Cialis could cause heart pain or possibly even a heart attack by exaggerating the increase in heart rate and the lowering of blood pressure. 

Cialis also exaggerates the blood pressure lowering effects of some alpha-blocking drugs that primarily are used for treating high blood pressure or enlargement of the prostate (BPH). 

Combining Cialis with alcohol may cause excessive drops in blood pressure and cause dizziness, headaches, and increased heart rate. PDE5 inhibitors such as Cialis may affect platelet function and therefore prolong bleeding. 

Cialis should be used cautiously in patients with bleeding disorders or active ulcers. 

Cialis should not be combined with Adcirca (another form of tadalafil) or other PDE5 inhibitors. 

Cialis is not approved for women and is not intended for use in women who are pregnant or breastfeeding.

The most common side effects of tadalafil are

• facial flushing (reddening),
• headaches,
• stomach upset,
• diarrhea,
• flu-like symptoms, and
• nausea.
• Tadalafil also may cause low blood pressure,
• blurred vision,
• changes in color vision, and
• abnormal ejaculation.

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:

Table 1: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with Cialis (10 or 20 mg) and More Frequent on Drug than Placebo in the Eight Primary Placebo-Controlled Clinical Studies (Including a Study in Patients with Diabetes) for Cialis for Use as Needed for ED

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:

Table 2: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with Cialis for Once Daily Use (2.5 or 5 mg) and More Frequent on Drug than Placebo in the Three Primary Placebo-Controlled Phase 3 Studies of 12 weeks Treatment Duration (Including a Study in Patients with Diabetes) for Cialis for Once Daily Use for ED

The following adverse reactions were reported (see Table 3) over 24 weeks treatment duration in one placebo-controlled clinical study:

Table 3: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with Cialis for Once Daily Use (2.5 or 5 mg) and More Frequent on Drug than Placebo in One Placebo-Controlled Clinical Study of 24 Weeks Treatment Duration for Cialis for Once Daily Use for ED

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).

Table 4: Treatment-Emergent Adverse Reactions Reported by ≥1% of Patients Treated with Cialis for Once Daily Use (5 mg) and More Frequent on Drug than Placebo in Three Placebo-Controlled Clinical Studies of 12 Weeks Treatment Duration, including Two Studies for Cialis for Once Daily Use for BPH and One Study for ED and BPH

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 placebo-controlled studies with Cialis for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with Cialis (2.5% of patients).

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, peripheral edema

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.

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 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.

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.

Urogenital - priapism.

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.

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.

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.

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.

Potential For Other Drugs To Affect Cialis

See prescribing information for more on dosage, warnings, and precautions.

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 the values for tadalafil 10 mg alone.

Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.

HIV Protease Inhibitor

Ritonavir (500 mg or 600 mg twice daily at steady state), an inhibitor of CYP3A4, CYP2C9, CYP2C19, and CYP2D6, increased tadalafil 20-mg single-dose exposure (AUC) by 32% with a 30% reduction in Cmax, relative to the values for tadalafil 20 mg alone. Ritonavir (200 mg twice daily), increased tadalafil 20-mg single-dose exposure (AUC) by 124% with no change in Cmax, relative to the values for tadalafil 20 mg alone. Although specific interactions have not been studied, other HIV protease inhibitors would likely increase tadalafil exposure.

Cytochrome P450 Inducers

Studies have shown that drugs that induce CYP3A4 can decrease tadalafil exposure.

CYP3A4 (e.g., Rifampin)

Rifampin (600 mg daily), a CYP3A4 inducer, reduced tadalafil 10-mg single-dose exposure (AUC) by 88% and Cmax by 46%, relative to the values for tadalafil 10 mg alone. Although specific interactions have not been studied, other CYP3A4 inducers, such as carbamazepine, phenytoin, and phenobarbital, would likely decrease tadalafil exposure. No dose adjustment is warranted. The reduced exposure of tadalafil with the coadministration of rifampin or other CYP3A4 inducers can be anticipated to decrease the efficacy of Cialis for once daily use; the magnitude of decreased efficacy is unknown.

Potential For Cialis To Affect Other Drugs

Aspirin

Tadalafil did not potentiate the increase in bleeding time caused by aspirin.

Cytochrome P450 Substrates

Cialis is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolized by cytochrome P450 (CYP) isoforms. Studies have shown that tadalafil does not inhibit or induce P450 isoforms CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.

CYP1A2 (e.g. Theophylline)

Tadalafil had no significant effect on the pharmacokinetics of theophylline. When tadalafil was administered to subjects taking theophylline, a small augmentation (3 beats per minute) of the increase in heart rate associated with theophylline was observed.

CYP2C9 (e.g. Warfarin)

Tadalafil had no significant effect on exposure (AUC) to S-warfarin or R-warfarin, nor did tadalafil affect changes in prothrombin time induced by warfarin.

CYP3A4 (e.g. Midazolam or Lovastatin)

Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin.

P-glycoprotein (e.g. Digoxin)

Coadministration of tadalafil (40 mg once per day) for 10 days did not have a significant effect on the steady-state pharmacokinetics of digoxin (0.25 mg/day) in healthy subjects.