Tadalafil

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Tadalafil quick reference

Image:Tadalafil.png
Tadalafil general drug information
 Pronunciation tuh DA luh fill (.wav file)
 Trade Name(s) Cialis
 How Supplied Tablets: 5 mg, 10 mg, 20 mg
 Generic Availability No generics available
 Patent Expiry Date July 12, 2016
 Classification Phosphodiesterase-5 Enzyme Inhibitor
 Schedule Rx
 Pregnancy Category B
 Breast-feeding Tadalafil is not indicated for use in women.
Tadalafil chemical information
 IUPAC Name 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)
 Empirical Formula (C33H34FN2O5)2Ca•3H2O
 Molecular Weight 389.14 g/mol
pharmacokinetic information  |  pharmacogenomic information

Description

Tadalafil is a selective phosphodiesterase-5 enzyme inhibitor (PDE5) similar to sildenafil and vardenafil. It is administered orally for the treatment of erectile dysfunction (ED). Similar to vardenafil, tadalafil is also more selective compared to sildenafil for PDE5 than PDE6 receptors, which are present in the retina. This may explain the higher case reports of visual adverse events associated with sildenafil. Tadalafil has the longest duration of action (~36 hours) among the current PDE5 inhibitors, which allows a greater window for sexual activity. It is the only PDE5 inhibitor whose activity is unaffected by meals. Tadalafil was FDA-approved for treatment of ED in 2003.[1][2]

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.[3]

Time Required for Therapeutic Response

  • Initial: Within 1 hour[3]
  • Maximum: 2 hours[3]

Pharmacokinetics

Absorption
Following oral administration, the Cmax of tadalafil was observed between 30 minutes and 6 hours (median time of 2 hours). Currently the absolute bioavailability of oral tadalafil is not available because it has not been determined. The rate and extent of absorption are not affected by food.

Distribution
Tadalafil shows tissue distribution with a mean steady-state volume of distribution (Vss) of 63 L. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins.

Metabolism
Tadalafil is predominantly metabolized by CYP3A4 to a catechol metabolite. The catechol metabolite undergoes extensive methylation and glucuronidation to form the methylcatechol and methylcatechol glucuronide conjugate, respectively. The major circulating metabolite is the methylcatechol glucuronide, which is not pharmacologically active. Methylcatechol concentrations are less than 10% of glucuronide concentrations.

Excretion
The total body clearance for oral tadalafil is 2.5 L/hr with the mean terminal half-life of 17.5 hours in healthy male subjects. Tadalafil is excreted predominantly as metabolites, mainly in the feces (~61%) and to a lesser extent in the urine (36%).

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Special Population Pharmacokinetics

  • Renal insufficiency: Following a single oral dose of tadalafil (5 or 10 mg) in patients with mild (CrCl = 51 to 80 mL/min) or moderate (ClCr = 31 to 50 mL/min) renal insufficiency, the AUC doubled. For patients with end-stage renal disease on hemodialysis, a single dose of 10 or 20 mg of tadalafil resulted in a 2-fold increase in Cmax and a 2.7 to 4.1-fold increase in AUC.
  • Hepatic insufficiency: For patients with mild or moderate hepatic impairment (Child-Pugh Class A or B), the AUCs were comparable to healthy male subjects when doses of 10 mg were administered. Currently there is not information for doses higher than 10 mg in patients with hepatic impairment. There is insufficient data for subjects with severe hepatic impairment (Child-Pugh Class C).
  • Hemodialysis: Hemodialysis (performed between 24 and 30 hours post-dose) contributed negligibly to tadalafil or metabolite elimination.
  • Geriatric: The clearance of tadalafil in healthy male elderly subjects (≥65 years of age) was reduced compared to healthy male patients (19 to 45 years of age), resulting in a higher AUC (25%). There was no change in the Cmax. No dose adjustment is needed based on patient's age as a single factor.
  • Pediatric: Tadalafil has not been evaluated in patients under 18 years of age.
  • Gender: Tadalafil is only indicated for use in males.

Indications and Dosages

FDA Approved Indications

Erectile dysfunction[4][5][6][7][8][9][10][11]

  • Maintenance dose:
    • 5 to 20 mg to be given as a single dose once per day

Non-FDA Approved Indications

  • Psychotropic-induced sexual dysfunction[12]

Dosage Adjustment

Renal insufficiency:

  • Creatinine clearance of 31 - 50 mL/min: initial dose of 5 mg once daily. Maximum recommended dose of 10 mg not more than once every 48 hours.
  • Creatinine clearance at or below 30 mL/min: dose should be limited to 5 mg, no more than once daily.

Hepatic insufficiency: for patients with mild or moderate hepatic impairment, the maximum dose should not exceed 10 mg. Tadalafil has not been studied in patients with severe hepatic impairment and its use is therefore not recommended.
Hemodialysis: dose should be limited to 5 mg no more than once daily.

Dosage Limits

  • Adults: 20 mg once a day
  • Elderly: 20 mg once a day
  • Adolescents and children: Not indicated


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Administration

  • Route: Oral
  • Method:
    • Swallow tablet followed by a drink of water.
    • Should be taken ~1 hour prior to anticipated sexual activity.

Monitoring Parameters

  • No laboratory monitoring parameters necessary.
  • Monitor for response and adverse reactions.

Contraindications/Precautions

Contraindications

  • Patients using nitrates: tadalafil has shown to potentiate the hypotensive effects of nitrates, and its administration in patients who are using nitrates of any form, either regularly and/or intermittently, is contraindicated. In a patient who has taken tadalafil, where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours should elapse after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should still only be administered under close medical supervision with appropriate hemodynamic monitoring.[3][13]
  • Known hypersensitivity to tadalafil or any component of the tablet

Precautions

  • Patients taking alpha-blockers: both agents are vasodilators with blood-pressure lowering effects. When used in combination, there is potential for additive effects on significantly lowering blood pressure leading to symptomatic hypotension (e.g. fainting, lightheadedness, dizziness).
  • Anatomical deformation of the penis
  • Patients with conditions which may predispose them to priapism
  • Sickle cell anemia
  • Multiple myeloma
  • Leukemia
  • Left ventricular outflow obstruction: patients with left ventricular outflow obstruction (e.g. aortic stenosis) can be sensitive to the vasodilatory affects of PDE5 inhibitors.
  • Unstable angina
  • Hypotension (resting systolic blood pressure of <90mmHg)
  • Uncontrolled hypertension (>170/110 mmHg)
  • Recent history (within 6 months) of stroke, life-threatening arrhythmia, or MI
  • Severe cardiac failure
  • Retinitis pigmentosa
  • Post-marketing reports of sudden vision loss: attributed to NAION (non arteritic ischemic optic neuropathy), a condition where blood flow is blocked to the optic nerve. FDA advises patients to stop taking these medicines, and call a doctor or healthcare provider right away if they experience sudden or decreased vision loss in one or both eyes. Patients taking or considering taking these products should inform their health care professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Such patients are at an increased risk of developing NAION again. At this time, it is not possible to determine whether these oral medicines for erectile dysfunction were the cause of the loss of eyesight or whether the problem is related to other factors such as high blood pressure or diabetes, or to a combination of these problems. Link to MedWatch form available at end of page.

Pregnancy indications

Category B

There are no adequate and well-controlled studies of tadalafil in pregnant women.

Breast-feeding indications

It is not known if tadalafil and/or its metabolites are excreted in human breast milk. Use of tadalafil in nursing mothers is not recommended.

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Drug-Drug, -Food, -Herb Interactions

Click the link above to go to the drug interactions page.

Adverse Reactions/Side Effects

Tadalafil was administered to over 5,700 men (mean age 59, range 19 to 87 years) during clinical trials worldwide. Over 1,000 patients were treated for 1 year or longer and over 1,300 patients were treated for 6 months or more. In placebo-controlled phase III clinical trials, 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.[3]

Tadalafil Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Headache (11-15%), dyspepsia (4-10%)
1-10% Cardiovascular Flushing (2-3%)
Neuromuscular/skeletal Myalgia (1-4%), back pain (3-6%), limb pain (1-3%)
Respiratory Nasal congestion (2-3%)
<1% All abnormal liver function tests, angina pectoris, arthralgia, asthenia, blurred vision, changes in color vision, chest pain, conjunctivitis, conjunctival hyperemia, diarrhea, dizziness, dry mouth, dyspnea, dysphagia, epistaxis, erection increased, esophagitis, exfoliative dermatitis, eye pain, face edema, fatigue, gastritis, gastroesophageal reflux, GGTP increased, hypersensitivity reactions, hypertension, hypesthesia, hypotension, insomnia, lacrimation increase, loose stools, migraine, myocardial infarction, nausea, neck pain, non-arteritic anterior ischemic optic neuropathy pain, palpitations, paresthesia, pharyngitis, postural hypotension, pruritus, rash, retinal vein occlusion, retinal artery occlusion, somnolence, spontaneous penile erection, priapism, Stevens-Johnson syndrome, stroke, sudden cardiac death, sweating, swelling of eyelids, syncope, tachycardia, upper abdominal pain, urticaria, vertigo, visual field defect, vomiting.

Overdosage Measures

Single doses up to 500 mg have been given to healthy subjects, and multiple daily doses up to 1000 mg have been given to patients. Adverse events were similar to those seen at lower doses.
Treatment:

  • In cases of overdose, standard supportive measures should be adopted as required.
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Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
5 mg tablet yellow egg C 5
10 mg tablet dark yellow egg C 10
20 mg tablet dark yellow egg C 20
  • Inactive ingredients for tablets: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, triacetin

Patient Information

  • May be taken with or without food.
  • Sexual stimulation is required for an erection to occur.
  • Patients who experience chest pain after taking tadalafil should seek immediate medical attention.
  • Stop use of tadalafil and seek medical attention in the event of a sudden loss of vision in one or both eyes
  • Avoid consumption of alcohol in combination with tadalafil.
  • Patients who have an erection lasting greater than 4 hours, whether painful or not, should seek emergency medical attention. If not treated promptly, it may result in irreversible damage to the erectile tissue.
  • Tadalafil offers no protection against sexually transmitted diseases.
  • Avoid use with nitrates. A minimum of 48 hours must pass before administration of nitrates in situations deemed medically necessary.
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References

  1. ↑ Shabsigh R. Seftel AD. Rosen RC. Porst H. Ahuja S. Deeley MC. Garcia CS. Giuliano F. Review of time of onset and duration of clinical efficacy of phosphodiesterase type 5 inhibitors in treatment of erectile dysfunction. Urology. 68(4):689-96, 2006 Oct.
  2. ↑ Setter SM. Iltz JL. Fincham JE. Campbell RK. Baker DE. Phosphodiesterase 5 inhibitors for erectile dysfunction. Annals of Pharmacotherapy. 39(7-8):1286-95, 2005 Jul-Aug.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Cialis® (Tadalafil) Package Insert. Indianapolis, IN; Eli Lilly and Company; 2007 Jan.
  4. ↑ Goldstein I, Kim E, Steers WD, Pryor JL, Wilde DW, Natanegara F, et al. Efficacy and safety of tadalafil in men with erectile dysfunction with a high prevalence of comorbid conditions: results from MOMENTUS: multiple observations in men with erectile dysfunction in National Tadalafil Study in the US. J Sex Med. 2007 Jan;4(1):166-75.
  5. ↑ Morgentaler A, Barada J, Niederberger C, Donatucci C, Garcia CS, Natanegara F, et al. Efficacy and safety of tadalafil across ethnic groups and various risk factors in men with erectile dysfunction: Use of a novel noninferiority study design. J Sex Med. 2006 May;3(3):492-503.
  6. ↑ Seftel AD, Wilson SK, Knapp PM, Shin J, Wang WC, Ahuja S, et al. The efficacy and safety of tadalafil in United States and Puerto Rican men with erectile dysfunction. J Urol. 2004 Aug;172(2):652-7.
  7. ↑ Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R, et al. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003 Jul;62(1):121-5; discussion 5-6.
  8. ↑ Skoumal R, Chen J, Kula K, Breza J, Calomfirescu N, Basson BR, et al. Efficacy and treatment satisfaction with on-demand tadalafil (Cialis) in men with erectile dysfunction. Eur Urol. 2004 Sep;46(3):362-9; discussion 9.
  9. ↑ Montorsi F, Verheyden B, Meuleman E, Junemann KP, Moncada I, Valiquette L, et al. Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction. Eur Urol. 2004 Mar;45(3):339-44; discussion 44-5.
  10. ↑ Mirone V. Costa P. Damber JE. Holmes S. Moncada I. Van Ahlen H. Wespes E. Cordell WH. Chan M. Lembo D. Varanese L. An evaluation of an alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14 European countries. European Urology. 47(6):846-54; discussion 854, 2005 Jun.
  11. ↑ Rajfer J. Aliotta PJ. Steidle CP. Fitch WP 3rd. Zhao Y. Yu A. Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. International Journal of Impotence Research. 19(1):95-103, 2007 Jan-Feb.
  12. ↑ Segraves RT, Lee J, Stevenson R, Walker DJ, Wang WC, Dickson RA, et al. Tadalafil for treatment of erectile dysfunction in men on antidepressants. J Clin Psychopharmacol. 2007 Feb;27(1):62-6.
  13. ↑ Kloner RA. Hutter AM. Emmick JT. Mitchell MI. Denne J. Jackson G. Time course of the interaction between tadalafil and nitrates. Journal of the American College of Cardiology. 42(10):1855-60, 2003 Nov 19.

PUBMED References

Efficacy Trial Articles

  1. Morgentaler A, Barada J, Niederberger C, Donatucci C, Garcia CS, Natanegara F, et al. Efficacy and safety of tadalafil across ethnic groups and various risk factors in men with erectile dysfunction: Use of a novel noninferiority study design. J Sex Med. 2006 May;3(3):492-503.
  2. Goldstein I, Kim E, Steers WD, Pryor JL, Wilde DW, Natanegara F, et al. Efficacy and safety of tadalafil in men with erectile dysfunction with a high prevalence of comorbid conditions: results from MOMENTUS: multiple observations in men with erectile dysfunction in National Tadalafil Study in the US. J Sex Med. 2007 Jan;4(1):166-75.
  3. Mirone V. Costa P. Damber JE. Holmes S. Moncada I. Van Ahlen H. Wespes E. Cordell WH. Chan M. Lembo D. Varanese L. An evaluation of an alternative dosing regimen with tadalafil, 3 times/week, for men with erectile dysfunction: SURE study in 14 European countries. European Urology. 47(6):846-54; discussion 854, 2005 Jun.
  4. Seftel AD, Wilson SK, Knapp PM, Shin J, Wang WC, Ahuja S, et al. The efficacy and safety of tadalafil in United States and Puerto Rican men with erectile dysfunction. J Urol. 2004 Aug;172(2):652-7.
  5. Rajfer J. Aliotta PJ. Steidle CP. Fitch WP 3rd. Zhao Y. Yu A. Tadalafil dosed once a day in men with erectile dysfunction: a randomized, double-blind, placebo-controlled study in the US. International Journal of Impotence Research. 19(1):95-103, 2007 Jan-Feb.
  6. Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R, et al. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003 Jul;62(1):121-5; discussion 5-6.
  7. Montorsi F, Verheyden B, Meuleman E, Junemann KP, Moncada I, Valiquette L, et al. Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction. Eur Urol. 2004 Mar;45(3):339-44; discussion 44-5.
  8. Segraves RT, Lee J, Stevenson R, Walker DJ, Wang WC, Dickson RA, et al. Tadalafil for treatment of erectile dysfunction in men on antidepressants. J Clin Psychopharmacol. 2007 Feb;27(1):62-6.
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Therapeutic Class Comparison Articles

  1. Tolra JR. Campana JM. Ciutat LF. Miranda EF. Prospective, randomized, open-label, fixed-dose, crossover study to establish preference of patients with erectile dysfunction after taking the three PDE-5 inhibitors. Journal of Sexual Medicine. 3(5):901-9, 2006 Sep.
  2. Govier F. Potempa AJ. Kaufman J. Denne J. Kovalenko P. Ahuja S. A multicenter, randomized, double-blind, crossover study of patient preference for tadalafil 20 mg or sildenafil citrate 50 mg during initiation of treatment for erectile dysfunction. Clinical Therapeutics. 25(11):2709-23, 2003 Nov.

Pharmacokinetics Articles

  1. Daugan A. Grondin P. Ruault C. Le Monnier de Gouville AC. Coste H. Linget JM. Kirilovsky J. Hyafil F. Labaudiniere R. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. Journal of Medicinal Chemistry. 46(21):4533-42, 2003 Oct 9.
  2. Ring BJ. Patterson BE. Mitchell MI. Vandenbranden M. Gillespie J. Bedding AW. Jewell H. Payne CD. Forgue ST. Eckstein J. Wrighton SA. Phillips DL. Effect of tadalafil on cytochrome P450 3A4-mediated clearance: studies in vitro and in vivo. Clinical Pharmacology & Therapeutics. 77(1):63-75, 2005 Jan.
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Drug Interaction Articles

  1. Kloner RA. Jackson G. Emmick JT. Mitchell MI. Bedding A. Warner MR. Pereira A. Interaction between the phosphodiesterase 5 inhibitor, tadalafil and 2 alpha-blockers, doxazosin and tamsulosin in healthy normotensive men. Journal of Urology. 172(5 Pt 1):1935-40, 2004 Nov.
  2. Kloner RA. Hutter AM. Emmick JT. Mitchell MI. Denne J. Jackson G. Time course of the interaction between tadalafil and nitrates. Journal of the American College of Cardiology. 42(10):1855-60, 2003 Nov 19.

Adverse Effects Articles

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Compliance Articles

Pharmacoeconomic Articles

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External Links

Clinical treatment guidelines

Patient information pages

Other resources

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