Tadalafil (Page 3 of 12)

5.7 Renal Impairment

Tadalafil for Use as Needed

Tadalafil 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 tadalafil 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)].

Tadalafil for Once Daily Use

ED

Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil 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, tadalafil for once daily use is not recommended in patients with creatinine clearance less than 30 mL/min. In patients with creatinine clearance 30 to 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)].

5.8 Hepatic Impairment

Tadalafil for Use as Needed

In patients with mild or moderate hepatic impairment, the dose of tadalafil should not exceed 10 mg. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil in this group is not recommended [see Use in Specific Populations (8.6)].

Tadalafil for Once Daily Use

Tadalafil for once daily use has not been extensively evaluated in patients with mild or moderate hepatic impairment. Therefore, caution is advised if tadalafil for once daily use is prescribed to these patients. Because of insufficient information in patients with severe hepatic impairment, use of tadalafil in this group is not recommended [see Use in Specific Populations (8.6)].

5.9 Alcohol

Patients should be made aware that 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. Therefore, physicians should inform patients that substantial consumption of alcohol (e.g., 5 units or greater) in combination with tadalafil 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)].

5.10 Concomitant Use of Potent Inhibitors of Cytochrome P450 3A4 (CYP3A4)

Tadalafil is metabolized predominantly by CYP3A4 in the liver. The dose of tadalafil 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 tadalafil for once daily use, the maximum recommended dose is 2.5 mg [see Dosage and Administration (2.7)].

5.11 Combination With Other PDE5 Inhibitors or Erectile Dysfunction Therapies

The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Inform patients not to take tadalafil with other PDE5 inhibitors, including ADCIRCA*.

5.12 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. Tadalafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Although tadalafil 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.

5.13 Counseling Patients About Sexually Transmitted Diseases

The use of tadalafil 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.

5.14 Consideration of Other Urological Conditions Prior to Initiating Treatment for BPH

Prior to initiating treatment with tadalafil for BPH, consideration should be given to other urological conditions that may cause similar symptoms. In addition, prostate cancer and BPH may coexist.

6 ADVERSE REACTIONS

6.1 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 tadalafil 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 tadalafil for use as needed, over 1300 and 1000 subjects were treated for at least 6 months and 1 year, respectively.

Tadalafil 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 tadalafil for use as needed:

Table 1: Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with Tadalafil (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 Tadalafil for Use as Needed for ED

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%

Tadalafil 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 Tadalafil 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 Tadalafil for Once Daily Use for ED
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:

Table 3 Treatment-Emergent Adverse Reactions Reported by ≥2% of Patients Treated with Tadalafil 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 Tadalafil for Once Daily Use for ED
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%

Tadalafil 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 Tadalafil 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 Tadalafil for Once Daily Use for BPH and One Study for ED and BPH
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 tadalafil 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 tadalafil 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 tadalafil for once daily use for ED, BPH and BPH/ED are described in Tables 2, 3 and 4. In studies of tadalafil 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 tadalafil for use as needed for ED, diarrhea was reported more frequently in patients 65 years of age and older who were treated with tadalafil (2.5% of patients) [see Use in Specific Populations (8.5) ].

Across all studies with any tadalafil 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 tadalafil for once daily use or use as needed. A causal relationship of these events to tadalafil 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

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