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Special Alerts
Phosphodiesterase Type-5 (PDE-5) Inhibitors: Sudden Hearing Loss - October 2007
The Food and Drug Administration (FDA) is notifying healthcare professionals of changes to the product labeling for sildenafil (Viagra®, Revatio™), tadalafil (Cialis®), and vardenafil (Levitra®) to include the potential for sudden decrease or loss of hearing. Labeling changes were prompted by 29 postmarketing reports of sudden hearing loss (some occurring with tinnitus, vertigo or dizziness) associated with PDE-5 inhibitors. In a majority of the reports, hearing loss was onesided involving partial or complete loss of usual hearing. In one-third of the cases, the loss was temporary although details in the remainder of the cases concerning a temporary nature of the change are either unavailable or the loss was on-going at the time of reporting. A causal relationship between sudden hearing changes and PDE-5 inhibitors use cannot be determined; however, the FDA believes a strong temporal relationship exists. There is not enough data to determine if a dose-relationship contributes to the potential risk.
Patients experiencing sudden hearing changes and using either sildenafil (Viagra®), tadalafil, or vardenafil for erectile dysfunction should discontinue the medication immediately and contact their healthcare provider. Patients receiving sildenafil (Revatio™) for the treatment of pulmonary arterial hypertension who experience sudden hearing changes should not stop taking the medication, but should contact their healthcare provider immediately.
Additional information can be found at http://www.fda.gov/medwatch/safety/2007/safety07.htm#PDE5.
Pronunciation
(tah DA la fil)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use
Treatment of erectile dysfunction (ED)
Pregnancy Risk Factor
B
Pregnancy Implications
Teratogenic events were not reported in animal reproduction studies. Postnatal development and pup survival was decreased at some doses. Tadalafil is not indicated for use in women. Less than 0.0005% is found in the semen of healthy males.
Lactation
Excretion in breast milk unknown
Breast-Feeding Considerations
Tadalafil is not indicated for use in women.
Contraindications
Concurrent use of organic nitrates in any form (eg, nitroglycerin, isosorbide dinitrate)
Warnings/Precautions
Concerns related to adverse effects:
• Color discrimination: May cause dose-related impairment of color discrimination. Use caution in patients with retinitis pigmentosa; a minority have genetic disorders of retinal phosphodiesterases (no safety information available).
• Hearing loss: Sudden decrease or loss of hearing has been reported rarely; hearing changes may be accompanied by tinnitus and dizziness. A direct relationship between therapy and hearing loss has not been determined.
• Hypotension: Decreases in blood pressure may occur due to vasodilator effects; use with caution in patients with left ventricular outflow obstruction (aortic stenosis or IHSS); may be more sensitive to hypotensive actions. Concurrent use with alpha-adrenergic antagonist therapy or substantial alcohol consumption may cause symptomatic hypotension; patients should be hemodynamically stable prior to initiating therapy at the lowest possible dose.
• Vision loss: Vision loss may occur rarely and be a sign of nonarteritic anterior ischemic optic neuropathy (NAION). Risk may be increased with history of vision loss. Other risk factors for NAION include low cup-to-disc ratio ("crowded disc"), coronary artery disease, diabetes, hypertension, hyperlipidemia, smoking, and >50 years of age. Safety and efficacy were not studied in patients with known degenerative retinal disorders (eg, retinitis pigmentosa); use is not recommended.
Disease-related concerns:
• Anatomical penis deformation: Use with caution in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie's disease).
• Bleeding disorders: Use with caution in patients with bleeding disorders; safety and efficacy have not been established.
• Cardiovascular disease: Use is not recommended in patients with hypotension (<90/50 mm Hg), uncontrolled hypertension (>170/100 mm Hg), NYHA class II-IV heart failure within the last 6 months, uncontrolled arrhythmias, stroke within the last 6 months, unstable angina or angina occurring with sexual intercourse, MI within the last 3 months; safety and efficacy have not been studied in these patients. Use caution in patients with left ventricular outflow obstruction (eg, aortic stenosis). There is a degree of cardiac risk associated with sexual activity; therefore, physicians may wish to consider the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction.
• Conditions predisposing to priapism: Use with caution in patients who have conditions which may predispose them to priapism (sickle cell anemia, multiple myeloma, leukemia). All patients should be instructed to seek immediate medical attention if erection persists >4 hours.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment/limitation is needed.
• Peptic ulcer disease: Use with caution in patients with active peptic ulcer disease; safety and efficacy have not been established.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment/limitation is needed.
Concurrent drug therapy issues:
• Alpha-blockers: Use with caution in patients taking alpha-blockers; may cause hypotension. Safety of this combination may be affected by other antihypertensives and intravascular volume depletion. Patients should be hemodynamically stable prior to initiating therapy. Initiate tadalafil at the lowest recommended dose.
• High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
• Nitrates: Concomitant use with all forms of nitrates is contraindicated. If nitrate administration is medically necessary following the use of tadalafil, at least 48 hours should elapse after the tadalafil dose and nitrate administration and should be given under close medical supervision with hemodynamic monitoring.
• Other treatments for erectile dysfunction: Safety and efficacy with other treatments for erectile dysfunction have not been established; use is not recommended.
Special populations:
• Elderly: Use with caution in the elderly.
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Appropriate use: Potential underlying causes of erectile dysfunction should be evaluated prior to treatment.
Adverse Reactions
Similar adverse events are reported with once-daily dosing, but are generally lower than with doses used as needed.
>10%: Central nervous system: Headache (3% to 15%)
2% to 10%:
Cardiovascular: Flushing (1% to 3%), hypertension (1% to 3%)
Gastrointestinal: Dyspepsia (3% to 10%)
Neuromuscular & skeletal: Back pain (3% to 6%), CPK increased (2%), myalgia (1% to 4%), limb pain (1% to 3%)
Respiratory: Upper respiratory tract infection (3% to 4%), nasal congestion (2% to 3%)
<2%, postmarketing, and/or case reports: Abdominal pain (upper), abnormal liver function tests, angina pectoris, arthralgia, blurred vision, chest pain, color perception change, color vision decreased, conjunctival hyperemia, conjunctivitis, diaphoresis, diarrhea, dizziness, dysphagia, dyspnea, epistaxis, esophagitis, exfoliative dermatitis, eye pain, eyelid swelling, facial edema, fatigue, gastritis, gastroesophageal reflux, hearing decreased, hearing loss, hepatic enzymes increased, hyper-/hypotension, hypoesthesia, GGTP increased, insomnia, lacrimation, migraine, MI, nausea, neck pain, nonarteritic ischemic optic neuropathy, pain, palpitation, paresthesia, pharyngitis, photophobia, postural hypotension, priapism (reported with drugs in this class), pruritus, rash, retinal artery occlusion, retinal vein occlusion, seizure, somnolence, Stevens-Johnson syndrome, stroke, sudden cardiac death, syncope, tachycardia, tinnitus, urinary tract infection, urticaria, vertigo, visual changes (color vision), visual field loss, vomiting, weakness, xerostomia
Drug Interactions
Substrate of CYP3A4 (major)
Alpha1-blockers: Phosphodiesterase-5 inhibitors may enhance the hypotensive effect of alpha1-blockers. Initiate tadalafil or alpha1-blocker at lowest recommended dose.
Antifungal agents (imidazole): May decrease the metabolism, via CYP isoenzymes, of phosphodiesterase-5 inhibitors. Ketoconazole significantly increased tadalafil levels.
CYP3A4 inhibitors: May increase the levels/effects of tadalafil. Dose reduction of tadalafil is recommended with strong CYP3A4 inhibitors. When used on an as-needed basis, the dose of tadalafil should not exceed 10 mg, and tadalafil should not be taken more frequently than once every 72 hours. When used on a once-daily basis, the dose of tadalafil should not exceed 2.5 mg. Example inhibitors include azole antifungals, clarithromycin, diclofenac, doxycycline, erythromycin, grapefruit juice, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, telithromycin, and verapamil.
Macrolide antibiotics (clarithromycin, erythromycin, telithromycin, troleandomycin): May decrease the metabolism, via cyp isoenzymes, of phosphodiesterase-5 inhibitors.
Nitrates: Concomitant use with all forms of nitrates is contraindicated. If nitrate administration is medically necessary following the use of tadalafil, at least 48 hours should elapse after the tadalafil dose and nitrate administration.
Protease inhibitors (amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir): May decrease the metabolism, via CYP isoenzymes, of phosphodiesterase-5 inhibitors. Ritonavir increased tadalafil levels.
Vasodilators (organic nitrates): Concomitant use is contraindicated due to the potential for severe, life-threatening hypotension; separate doses by 48 hours.
Ethanol/Nutrition/Herb Interactions
Ethanol: Substantial consumption of ethanol may increase the risk of hypotension and orthostasis. Lower ethanol consumption has not been associated with significant changes in blood pressure or increase in orthostatic symptoms.
Food: Rate and extent of absorption are not affected by food. Grapefruit juice may increase serum levels/toxicity of tadalafil. When used on an as-needed basis, do not give more than a single 10 mg dose of tadalafil more frequently than every 72 hours in patients who regularly consume grapefruit juice. When used on a once-daily basis, the dose of tadalafil should not exceed 2.5 mg/day in patients who regularly consume grapefruit juice.
Storage
Store at controlled room temperature of 25°C (77°F).
Mechanism of Action
Does not directly cause penile erections, but affects the response to sexual stimulation. The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation and inflow of blood to the corpus cavernosum. Tadalafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE-5 by tadalafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. At recommended doses, it has no effect in the absence of sexual stimulation.
Pharmacodynamics/Kinetics
Onset: Within 1 hour
Duration: Up to 36 hours
Distribution: Vd: 63 L
Protein binding: 94%
Metabolism: Hepatic, via CYP3A4 to metabolites (inactive)
Half-life elimination: 17.5 hours
Time to peak, plasma: ~2 hours (range: 30 minutes to 6 hours)
Excretion: Feces (61%, as metabolites); urine (36%, as metabolites)
Dosage
Oral: Erectile dysfunction:
Adults:
As-needed dosing: 10 mg at least 30 minutes prior to anticipated sexual activity (dosing range: 5-20 mg); to be given as one single dose and not given more than once daily. Note: Erectile function may be improved for up to 36 hours following a single dose; adjust dose.
Once-daily dosing: 2.5 mg once daily. Dosing range: 2.5-5 mg/day
Elderly: Dosage is based on renal function; refer to “Dosage adjustment in renal impairment”
Dosing adjustment with concomitant medications:
Alpha1-blockers: If stabilized on either alpha-blockers or tadalafil therapy, initiate new therapy with the other agent at the lowest possible dose.
CYP3A4 inhibitors: Dose reduction of tadalafil is recommended with strong CYP3A4 inhibitors. When used on an as-needed basis, the dose of tadalafil should not exceed 10 mg, and tadalafil should not be taken more frequently than once every 72 hours. When used on a once-daily basis, the dose of tadalafil should not exceed 2.5 mg. Examples of such inhibitors include amprenavir, atazanavir, clarithromycin, conivaptan, delavirdine, diclofenac, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, miconazole, nefazodone, nelfinavir, nicardipine, propofol, quinidine, ritonavir, and telithromycin.
Dosage adjustment in renal impairment:
As-needed use:
Clcr 31-50 mL/minute: Initial dose 5 mg once daily; maximum dose 10 mg not to be given more frequently than every 48 hours
Clcr <30 mL/minute and on hemodialysis: Maximum dose 5 mg not to be given more frequently than every 72 hours
Once-daily use:
Clcr 31-50 mL/minute: Dose adjustment not needed
Clcr <30 mL/minute and on hemodialysis: Use not recommended
Dosage adjustment in hepatic impairment:
As-needed use:
Mild-to-moderate hepatic impairment (Child-Pugh class A or B): Dose should not exceed 10 mg once daily
Severe hepatic impairment (Child-Pugh class C): Use is not recommended
Once-daily use:
Mild-to-moderate hepatic impairment (Child-Pugh class A or B): Use with caution
Severe hepatic impairment: Use is not recommended
Administration: Oral
May be administered with or without food, prior to anticipated sexual activity. When used on an as-needed basis, should be taken at least 30 minutes prior to sexual activity. When used on a once-daily basis, should be taken at the same time each day, without regard to timing of sexual activity.
Monitoring Parameters
Monitor for response and adverse effects.
Dietary Considerations
May be taken with or without food.
Patient Education
Inform prescriber of all other prescriptions, OTC medications, or herbal products you are taking and any allergies you have; serious side effects can result when tadalafil is used with some other medications. Avoid substantial consumption of alcohol. Do not combine tadalafil with other approaches to treating erectile dysfunction without consulting prescriber. Note: This drug provides no protection against sexually-transmitted diseases, including HIV. Take exactly as directed; do not take more often than prescribed. You may experience headache, fatigue, dizziness, or blurred vision (use caution when driving or engaging in hazardous tasks until response to drug is known); back or limb pain (consult prescriber for appropriate analgesic). Report immediately chest pain, palpitations; respiratory difficulty; unusual dizziness; change in vision; change in hearing or ringing in the ears; sign of urinary tract infection; skin rash; genital swelling or priapism, erection lasting >4 hours, or other persistent adverse reactions.
Geriatric Considerations
No significant differences in pharmacokinetics were seen in elderly men versus younger men. Dosing should be adjusted for renal function. Since older adults often have concomitant diseases, many of which may be contraindicated with the use of tadalafil, prescriber should complete a thorough review of diseases and medications prior to prescribing tadalafil.
Cardiovascular Considerations
Tadalafil, when used in conjunction with nitrates, may be associated with severe hypotension, myocardial infarction, and possibly death. While there are no clear significant increased cardiovascular events with PDE-5 inhibitors alone, these drugs should be absolutely avoided in conjunction with nitrates and may also induce significant and possibly fatal hypotension in patients with heart failure. Hemodynamic effects of PDE-5 inhibitors alone include a very slight drop in blood pressure without significant changes in heart rate. The most recent guidelines on the use of sildenafil (prototype PDE-5 inhibitor) in patients with cardiovascular disease are outlined in detail (Cheitlin, 1999). The general clinical recommendations are as follows.
Use of PDE-5 inhibitors is contraindicated in patients currently taking nitrate preparations.
Cardiovascular effects of PDE-5 inhibitors may be potentially hazardous in patients with:
• active coronary ischemia (not on nitrates)
• heart failure and with borderline low blood pressure and borderline low volume status
• complicated, multidrug antihypertensive regimens
• potential for drug-drug interactions that may prolong PDE-5 inhibitor half-life (eg, drugs that inhibit cytochrome P450 3A4)
Additional guidelines for the treatment of ED in patients with cardiovascular disease have also been published (Jackson, 2006). These guidelines, referred to as the Princeton II Guidelines, support the use of PDE-5 inhibition only in patients with asymptomatic coronary disease and <3 of the following risk factors: Controlled hypertension, mild stable angina, successful coronary revascularization, previous uncomplicated MI (>6-8 weeks), mild valvular disease, and left ventricular dysfunction (with or without NYHA Class I limitations).
When nitrate administration becomes medically necessary, the ACC/AHA 2004 guidelines on treatment of ST-segment elevation MI and the ACC/AHA 2007 guidelines on treatment of unstable angina/non ST-segment elevation MI supports administration of nitrates only if 24 hours have elapsed after use of sildenafil and 48 hours after use of tadalafil. The appropriate delay for the use of nitrates after vardenafil has not been determined.
Tadalafil is selective for PDE-5 and has limited effect on PDE-3, which controls cardiac contractility.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness, insomnia, or fatigue
Mental Health: Effects on Psychiatric Treatment
Concurrent use with antidepressants (eg, TCAs) and antipsychotics may produce significant hypotension secondary to alpha-receptor blockade; alpha-blockers contraindicated with tadalafil (except tamsulosin). Nefazodone may increase levels of tadalafil; dosage adjustment needed.
Nursing: Physical Assessment/Monitoring
Assess potential for interactions with other prescription, OTC medications, or herbal products patient may be using. Assess for therapeutic effectiveness and adverse reactions. Instruct patient on appropriate use and cautions, possible side effects, and symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet:
Cialis®: 2.5 mg, 5 mg, 10 mg, 20 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Cialis)
2.5 mg (10): $49.99
5 mg (10): $135.99
10 mg (10): $145.99
20 mg (10): $142.99
References
Anderson JL, Adams CD, Antman EM, et al, “ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration With the American College of Emergency Physicians, The Society of Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons,” J Am Coll Cardiol, 2007, 50(7):1-157. Available at http://content.onlinejacc.org/cgi/reprint/50/7/e1
Antman EM, Anbe DT, Armstrong PW, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction)," Circulation, 2004, 110(9):e82-292.
Cheitlin MD, Hutter AM Jr, Brindis RG, et al, “Use of Sildenafil (Viagra®) in Patients With Cardiovascular Disease,” J Am Coll Cardiol, 1999, 33(1):273-82.
Curran M and Keating G, “Tadalafil,” Drugs, 2003, 63(20):2203-12; discussion 2213-4.
Daugan A, Grondin P, Ruault C, et al, “The Discovery of Tadalafil: A Novel and Highly Selective PDE-5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1?,2?:1,6]pyrido[3,4-b]indole-1,4-dione Analogues,” J Med Chem, 2003, 46(21):4533-42.
Fraunfelder FW, “Visual Side Effects Associated With Erectile Dysfunction Agents,” Am J Ophthal, 2005, 140 (4):723-24.
Jackson G, Rosen RC, Kloner RA, et al, “The Second Princeton Consensus on Sexual Dysfunction and Cardiac Risk: New Guidelines for Sexual Medicine,” J Sex Med, 2006, 3(1):28-36.
Kloner RA, Mitchell M, and Emmick JT, “Cardiovascular Effects of Tadalafil,” Am J Cardiol, 2003, 92(9A):37M-46M.
Kloner RA, Mitchell M, and Emmick JT, “Cardiovascular Effects of Tadalafil in Patients on Common Antihypertensive Therapies,” Am J Cardiol, 2003, 92(9A):47M-57M.
McVary KT, “Clinical Practice. Erectile Dysfunction,” N Engl J Med, 2007, 357(24):2472-81.
Padma-Nathan H, “Efficacy and Tolerability of Tadalafil, A Novel Phosphodiesterase 5 Inhibitor, in Treatment of Erectile Dysfunction,” Am J Cardiol, 2003, 92(9A):19M-25M.
International Brand Names
Lexi-Comp.com
Last full review/revision April 2008
Content last modified April 2008
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