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Tadalafil

Pronunciation

Pronunciation: ta-DA-la-fil
Class: Phosphodiesterase type 5 inhibitor

Trade Names

Adcirca
- Tablets, oral 20 mg

Cialis
- Tablets, oral 2.5 mg
- Tablets, oral 5 mg
- Tablets, oral 10 mg
- Tablets, oral 20 mg

Pharmacology

Adcirca

Inhibition of phosphodiesterase type 5 (PDE5) by tadalafil increases the concentrations of cyclic guanosine monophosphate (cGMP), resulting in relaxation of pulmonary vascular smooth muscle cells and vasodilation of the pulmonary vascular bed.

Slideshow: Flashback: FDA Drug Approvals 2013

Cialis

Enhances the effect of nitric oxide at the nerve ending and endothelial cells in the corpus cavernosum by inhibiting PDE5 in the corpus cavernosum of the penis. This results in vasodilation, increased inflow of blood into the corporus cavernosum, and ensuing penile erection upon sexual stimulation.

Pharmacokinetics

Absorption

Bioavailability undetermined. T max is 2 to 8 h (median, 4 h) ( Adcirca ) and 30 min to 6 h (median, 2 h) ( Cialis ). Steady state is attained within 5 days of once-daily dosing.

Distribution

Vd of tadalafil is approximately 77 L ( Adcirca ) and 63 L ( Cialis ). Tadalafil is 94% protein bound.

Metabolism

Predominantly metabolized by CYP3A4 to a catechol metabolite, which undergoes further metabolism to the major circulating metabolite, methylcatechol glucuronide.

Elimination

Mean oral Cl is 3.4 L/h ( Adcirca ) and 2.5 L/h ( Cialis ). The terminal half-life is 15 h ( Adcirca ) and 17.5 h ( Cialis ). Tadalafil is excreted predominantly as metabolites, mainly in the feces (approximately 61%) and to a lesser degree in the urine (approximately 36%).

Special Populations

Renal Function Impairment

Tadalafil exposure (AUC) doubled in subjects with CrCl 31 to 80 mL/min. In patients with ESRD on hemodialysis, there was a 2-fold increase in C max and 2.7- to 4.8-fold increase in AUC.

Hepatic Function Impairment

Tadalafil exposure (AUC) after a 10 mg dose in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) was comparable with exposure in healthy subjects. There are insufficient data for subjects with severe hepatic impairment.

Elderly

Subjects older than 65 y have a 25% higher exposure compared with subjects 19 to 45 y of age.

Children

Tadalafil has not been evaluated in patients younger than 18 y.

Gender

No clinically relevant differences in AUC and C max have been observed.

Race

No differences in the typical exposure to tadalafil have been identified among different ethnic groups.

Diabetes mellitus

AUC was reduced approximately 19% and C max was 5% lower in patients with diabetes mellitus than in healthy subjects.

Indications and Usage

Treatment of pulmonary arterial hypertension (WHO group I) ( Adcirca only); treatment of erectile dysfunction, treatment of benign prostatic hyperplasia (BPH), and the treatment of combined erectile dysfunction and BPH ( Cialis only).

Unlabeled Uses

Raynaud phenomenon.

Contraindications

Administration with organic nitrates (regularly and/or intermittently); serious hypersensitivity to tadalafil.

Dosage and Administration

Benign Prostatic Hyperplasia (With or Without Concomitant Erectile Dysfunction) ( Cialis )
Adults

PO 5 mg once daily, taken at approximately the same time every day without regard to sexual activity.

Pulmonary Arterial Hypertension ( Adcirca )
Adults

PO 40 mg once daily.

Erectile Dysfunction ( Cialis )
Adults For use as needed

PO 10 mg prior to anticipated sexual activity. The dose may be adjusted to 5 or 20 mg based on efficacy and tolerability. The max recommended frequency is once per day for most patients.

Once-daily use

PO Start with 2.5 mg once daily, taken at approximately the same time each day, without regard to timing of sexual activity. The dosage may be increased to 5 mg daily based on individual efficacy and tolerability.

Hepatic Function Impairment
Adults Adcirca Mild or moderate hepatic impairment (Child-Pugh class A or B)

PO Consider a starting dosage of 20 mg/day.

Severe hepatic impairment (Child-Pugh class C)

PO Avoid use.

Cialis Erectile dysfunction For use as needed Mild or moderate hepatic impairment (Child-Pugh class A or B)

PO Use with caution. Dosage should not exceed 10 mg/day.

Severe hepatic impairment (Child-Pugh class C)

PO Use is not recommended.

For once-daily use Mild or moderate hepatic impairment (Child-Pugh class A or B)

PO Use with caution.

Severe hepatic impairment (Child-Pugh class C)

PO Use is not recommended.

Renal Function Impairment
Adults Adcirca Mild or moderate renal impairment (CrCl 31 to 80 mL/min)

PO Start with 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Severe renal impairment (CrCl less than 30 mL/min or on hemodialysis)

PO Avoid use.

Cialis Benign Prostatic Hyperplasia (With or Without Concomitant Erectile Dysfunction) CrCl 30 to 50 mL/min

PO Start with 2.5 mg. Increase to 5 mg based on individual response.

CrCl less than 30 mL/min or hemodialysis

PO Use is not recommended.

Erectile dysfunction For use as needed CrCl 30 to 50 mL/min

PO Start with 5 mg not more than once a day (max, 10 mg every 48 h).

CrCl less than 30 mL/min, ESRD, or hemodialysis

PO Max recommended dosage is 5 mg not more than once every 72 h.

For once-daily use CrCl less than 30 mL/min or on hemodialysis

PO Once-daily use is not recommended.

Concomitant therapy
Adults Alpha-blockers Cialis

PO Patients should be stable on alpha-blocker therapy prior to starting tadalafil for erectile dysfunction. Tadalafil should be started at the lowest recommended dose. Not recommended for use in combination with alpha-blockers for the treatment of BPH.

Nitrates

PO Concomitant use with nitrates in any form is contraindicated.

Potent CYP3A4 inhibitors (eg, ketoconazole, ritonavir) Adcirca

PO Avoid use during the initiation of ritonavir; stop Adcirca at least 24 h before staring ritonavir. After at least 1 wk of ritonavir, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Cialis Erectile dysfunction For use as needed

PO Max recommended dose is 10 mg, not to exceed once every 72 h.

For once-daily use

PO Max dose should not exceed 2.5 mg.

General Advice

  • May be taken without regard to food.
  • Cialis tablets should not be split; the entire dose should be taken.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Alcohol

Coadministration increases the risk of orthostatic signs and symptoms, including increased heart rate, decreased standing BP, dizziness, and headache.

Alpha-blockers (eg, doxazosin, tamsulosin)

Anticipate additive effects on BP. Use with caution. See also Administration and Dosage.

Antacids (magnesium/aluminum-containing)

Coadministration of a magnesium/aluminum-containing antacid and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil.

Antihypertensive agents (eg, amlodipine, enalapril, metoprolol)

Decreased BP may occur.

Contraceptives, oral

Tadalafil increased ethinyl estradiol exposure.

CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin)

Plasma tadalafil levels may be decreased. Avoid use with potent CYP3A4 inducers.

CYP3A4 inhibitors (eg, erythromycin, fluvoxamine, itraconazole, ketoconazole, ritonavir)

Tadalafil plasma concentrations may be elevated, increasing the risk of adverse reactions. See Administration and Dosage for dosage recommendations.

Nitrates

Coadministration is contraindicated.

In life-threatening situations where nitrate administration is deemed medically necessary, allow at least 48 h to elapse after the last dose of tadalafil before nitrate administration is considered.

Adverse Reactions

Cardiovascular

Flushing (13%); hypertension (3%); angina pectoris, chest pain, hypotension, MI, palpitations, postural hypotension, syncope, tachycardia (less than 2%); stroke, sudden cardiac death (postmarketing).

CNS

Headache (42%); asthenia, dizziness, fatigue, hypesthesia, insomnia, paresthesia, somnolence, vertigo (less than 2%); migraine, seizure and seizure recurrence, transient global amnesia (postmarketing).

Dermatologic

Pruritus, rash, sweating (less than 2%).

EENT

Nasopharyngitis (13%); nasal congestion (9%); blurred vision, changes in color vision, conjunctivitis including conjunctival hyperemia, epistaxis, eye pain, increased lacrimation, pharyngitis, sudden decrease or loss of hearing, swelling of eyelids, tinnitus (less than 2%); nonarteritic anterior ischemic optic neuropathy, retinal artery occlusion, retinal vein occlusion, visual field defect (postmarketing).

GI

Dyspepsia (13%); nausea (11%); gastroenteritis (5%); gastroesophageal reflux (3%); abdominal pain, diarrhea (2%); dry mouth, dysphagia, esophagitis, gastritis, hemorrhoidal hemorrhage, increased GGT, loose stools, rectal hemorrhage, upper abdominal pain, vomiting (less than 2%).

Genitourinary

UTI (2%); increased erection, renal impairment, spontaneous penile erection (less than 2%); priapism (postmarketing).

Hepatic

Abnormal LFTs (less than 2%).

Hypersensitivity

Hypersensitivity reactions, including exfoliative dermatitis, Stevens-Johnson syndrome, and urticaria.

Musculoskeletal

Myalgia (14%); back pain (12%); pain in extremities (11%); limb pain (3%); arthralgia, neck pain (less than 2%).

Respiratory

Upper and lower respiratory tract infection (13%); cough (4%); dyspnea (less than 2%).

Miscellaneous

Face edema, pain (less than 2%).

Precautions

Monitor

Monitor patients for response to therapy, any changes in BP or heart rate, and hearing or vision loss.


Pregnancy

Category B .

Lactation

Undetermined.

Children

Not indicated for use in children. Safety and efficacy not established.

Elderly

No dosage adjustments are needed based on age alone; a greater sensitivity to medications in some older individuals should be considered.

Hypersensitivity

Has been reported, including Stevens-Johnson syndrome and exfoliative dermatitis.

Renal Function

Dosage adjustment is needed in patients with mild to moderate renal impairment; avoid use in patients with severe renal impairment. Once-daily tadalafil is not recommended in patients with CrCl less than 30 mL/min.

Hepatic Function

Use with caution in patients with mild to moderate hepatic impairment; adjust dose as needed. Use is not recommended in patients with severe hepatic impairment.

Special Risk Patients

Because there are no clinical data on safety and efficacy, use is not recommended in patients with unstable angina or angina occurring during sexual intercourse, MI within last 90 days, New York Heart Association class II or higher heart failure in last 6 months, uncontrolled or life-threatening arrhythmias, hypotension (less than 90/50 mm Hg), uncontrolled hypertension, stroke within last 6 months, clinically significant aortic or mitral valve disease, pericardial constriction, restrictive or congestive cardiomyopathy, significant left ventricular dysfunction, symptomatic coronary artery disease, pulmonary veno-occlusive disease, or hereditary degenerative retinal disorder (eg, retinitis pigmentosa).

Bleeding disorders

Safety of tadalafil is unknown in patients with bleeding disorders or active peptic ulceration.

CV risk

Evaluate CV status and left ventricular outflow obstruction (eg, aortic stenosis) before treatment.

Hearing loss

Sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, has been reported.

Ophthalmic effects

Sudden loss of vision in one or both eyes has been reported rarely and may be a sign of nonarteritic anterior optic neuropathy.

Other erectile dysfunction therapy

Combined use with tadalafil is not recommended.

Priapism

Prolonged erections, exceeding 4 h, may occur and require immediate medical attention. Use with caution in patients with conditions that may predispose them to priapism (eg, sickle cell anemia, multiple myeloma, leukemia) and in patients with anatomical deformation of the penis (eg, angulation, cavernosal fibrosis, Peyronie disease).

Overdosage

Symptoms

Adverse events following a single oral dose of up to 500 mg in healthy subjects were similar to those seen with lower doses.

Patient Information

  • Advise patients taking Cialis for once-daily use for erectile dysfunction or erectile dysfunction/BPH to take prescribed dose at approximately the same time every day, regardless of time of anticipated sexual activity.
  • Advise patients taking Cialis for use as needed to take prescribed dose at least 30 min before anticipated sexual activity. In most patients, the ability to have sexual intercourse is improved for up to 36 h.
  • Advise patients to take each dose without regard to meals but to take with food if stomach upset occurs.
  • Advise patients that sexual stimulation will be required for medication to work and an erection to occur.
  • Caution patients not to increase the dose or frequency of use unless advised by health care provider.
  • Advise patients to contact their health care provider if unsatisfied with sexual performance after taking medication or if bothersome side effects occur.
  • Instruct patients to stop using and contact their health care provider immediately if any of the following occur: chest pain, dizziness, fainting, ringing in the ears, vision changes, decrease or loss of hearing.
  • Caution patients to limit alcohol intake while taking tadalafil.
  • Counsel patients that concomitant use of tadalafil with nitrates could cause BP to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.
  • Discuss with patients the potential for tadalafil to augment the BP–lowering effect of alpha-blockers and other antihypertensive medications.
  • Advise patients that there have been rare reports of prolonged erections longer than 4 hours in duration and priapism (painful erections longer than 6 hours in duration) for this class of compounds. Priapism, if not treated promptly, can result in irreversible damage to the erectile tissue. Advise patients who have an erection lasting longer than 4 hours, whether painful or not, to seek emergency medical attention.
  • Caution patients that medication is not a male form of birth control nor does it provide protection against STDs, and to use protective measures as indicated.
  • Inform patients that tadalafil is marketed as both Adcirca and Cialis and to not take them together.

Copyright © 2009 Wolters Kluwer Health.

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