Pharmacology of Levitra (vardenafil hydrochloride)

LEVITRA (vardenafil hydrochloride)

Vardenafil HCL (20mg/tablet) is a generic long-acting prescription drug used for ED (erectile dysfunction) treatment. ED is a condition involving lack of hardening and expansion of the penis during sexual excitation, or when a man cannot keep an erection for a prolonged time. LEVITRA could help a man with ED to get and maintain erection during sexual stimulation.

Pharmacology

LEVITRA is a monohydrochloride salt of verdanafil which acts in the body to selectively inhibit enzyme PDE5 – the type V cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase. Chemical name for Vardenafil HCl is piperazine, 1-[[3-(1, 4-dihydro-5-methyl-4-oxo-7-propylimidazo[5, 1-f][1, 2, 4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-,monohydrohloride. Levitra tablets contain active ingredient Vardenafil HCl as well as additional inactive ingredients: micro crystalline cellulose, magnesium stearate, silicone dioxide and lactose.

Erection is a haemodynamic process which involves relaxation of the smooth muscle in the corpus cavernosum, part of the penis, and its associated blood vessels (arterioles). At the time of a sexual stimulation an active compound nitric oxide (NO) is locally released from endothelial, and nerve cells innervating them, at the corpus cavernosum; increasing NO activates the guanylate cyclase which here in turn stimulates cGMP production by the smooth muscle cells. The cGMP triggers muscle relaxation resulting in blood flow into the penis, and leading to an erection. Cyclic guanosine monophosphate concentration in the tissues is controlled by both the rate of production and its degradation. In human corpus cavernosum cGMP is degraded by the most prominent phosphodiesterase - PDE5 which is cGMP dependent; inhibiting this type V phospodiesterase increases cGMP levels and enhances erectile function. Since the sexual stimulation is required for triggering NO release, PDE5 inhibition is only effective when the patient is sexually stimulated. Vardenafil has been confirmed by in vitro studies to be a potent and selective inhibitor of PDE5 (acts to constrict blood vessels in genital areas) rather than any other known phosphodiesterases.

Although Verdanafil can help ease up the ED, it cannot cure it; neither is able to boost sexual desire, protect from sexually transmitted diseases or act as a male form of birth control. It should be used by adult males only, following doctor’s recommendations and only when prescribed.

Common Use

Levitra is prescribed to men over 18 years of age with erectile dysfunction. It can be also used by men suffering from diabetes or those after prostatectomy.

It is a long-acting medicament; its effects can last for up to 8 hours.

Warnings and Precautions

The underlying cause for ED should be determined prior the treatment with Levitra – medical assessment is required so any of the following can be taken into consideration:

Cardiovascular effects – as there are potential cardiac risks associated with sexual activity, physician should consider these before prescribing Vardenafil; it should not be used by men who are not supposed to be engaging in sexual activity due to their cardiovascular status, e.g. individuals with unstable blood pressure (hypotension or severe hypertension), angina, or with recent history of a stroke, myocardial infarction, life-threatening arrhythmia, or cardiac failure. Also those who are sensitive to vasodilators, such as patients with left ventricular outflow obstruction.

Interaction with some drugs – potent or moderate CYP3A4 inhibitors tend to increase plasma concentration of vardenafil, thus caution must be taken when Levitra is used in combination with any of such (ritonavir, indinavir, ketoconazole, etc.); in addition treatment with Levitra is not recommended for patients undergoing other treatments for erectile dysfunction.

Priapism (painful prolonged erections) – presentation (rare cases) of erections lasting for longer than 4 hours have been previously reported for this class of compounds; If erection lasts for over 4 hours one should seek medical assistance immediately. Moreover, men predisposed to priapism or with anatomically deformed genitals should be particularly careful, i.e., those with sickle cell anaemia, leukaemia, multiple myeloma and angulation, cavernosal fibrosis, or Peyronie’s disease, respectively.

Effects on the eye – the event of a sudden loss of vision in one, or both eyes, should be treated as a medical emergency; this may be a sign of NAION – non-arteritic anterior ischemic optic neuropathy – which is an underlying cause of decrease or permanent loss of vision; it is unclear if this is directly associated with the use of PDE5 inhibitors however the risk should be considered before starting to use Vardenafil. Levitra has not yet been evaluated in patients suffering from degenerative retinal conditions, thus use by such is not recommended.

Hearing – decrease or loss of hearing accompanied by tinnitus or dizziness have been previously reported while taking PDE5 inhibitors; it is not yet determined if these problems can be caused directly by verdanafil, nevertheless any early signs should be reported immediately to a doctor.

Co-administration with alpha-blockers – particular caution must be taken if a patient is using alpha-adrenergic blocking agents since Levitra may have an additive lowering effect on blood pressure and in the worst case scenario this can lead to a symptomatic hypotension. PDE5 inhibitor should be only used if a patient is stable on alpha-blocker therapy, and only at reduced doses. Any hypertensive drugs or intravascular volume depletion may also affect safety of a combined PDE5 and alpha-blocker therapy.

QT intervals (heart’s electrical cycle) – patients with a history of QT prolongation or those taking QT-prolonging drugs should be careful when using Levitra. Those taking class 1A or class CIII antiarrhythmic medication or who have a congenital QT prolongation should avoid taking Vardenafil.

STDs – Levitra does not protect against sexually transmitted diseases.

Liver or Kidney dysfunction – dosage of Levitra should be adjusted in patients with moderate hepatic impairment. Individuals on renal dialysis or with severe hepatic impairment should not use Levitra.

Before Levitra is prescribed patient must tell his doctor if any of the following apply:

• Uncontrolled elevated or reduced blood pressure;
• History of a stroke or a seizure;
• Family history of Long QT syndrome;
• Liver disease
• Kidney disease where dialysis is required;
• Retinitis pigmentosa;
• History of a severe vision loss;
• Non-arteritic anterior ischemic optic neuropathy (NAION);
• Stomach ulcers;
• Any bleeding problems;
• Prolonged erections for over 4 hours;
• Hearing problems;
• Blood cell diseases;

Drug interaction

Doctor must be informed if patient is taking:

• Other drugs to treat ED;
• Medicine to treat abnormal heartbeat, e.g. sotalol, quinidine, procainamide and amiodarone;
• Certain antibiotics – clarithromycin or erythromycin;
• Itraconazole (Nizoral, Sporanox);
• Ketoconazole;
• Ritonavir (Norvir);
• Indinavir sulfate (Crixivan);
• Saquinavir (Fortavase or Invirase);
• Atazanavir (Reyataz).

Also any other prescribed or non-prescribed drugs, food or herbal supplements or vitamins.

If a patient is undergoing treatment with potent CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin, itraconazole, saquinavir, indinavir, atazanavir) or moderate CYP3A4 inhibitors (erythromycin) the dosage of Levitra should be adjusted:

• When taking ritonavir, the maximum dose of Levitra is 2.5mg/72hours;
• When taking 400mg of atazanavir, ketoconazole, indinavir, saquinavir or, itraconazole daily, the maximum dose of Levitra is 2.5mg/24 hours;
• When taking clarithromycin, no more than 2.5 mg Levitra can be consumed in 24 hours;
• When taking ketoconazole or itraconazole at 200mg/day, the maximum dose of Levitra is 5mg/24hrs;
• When taking erythromycin the dose of Levitra should not exceed 5mg in a 24-hour period.

Some patients with ED may be undergoing treatment with alpha-adrenergic blocking agents, e.g. terazosin HCl (Hytrin), doxazosin mesylate (Cardur), tamsulosin HCl (Flomax), prazosin HCl (Minipress), alfuzosin HCl (Uroxatral), silodosin (Rapaflo). These may be prescribed for high blood pressure or prostate problems, and when co-administered with PDE5 inhibitors may produce an additive lowering effect on blood pressure. In some patients such effect can lead to fainting therefore, PDE5 inhibitor should be initiated at the lowest recommended starting dose. Concomitant treatment should be administered only if the patient is stable on his alpha-blocker therapy; the starting dose of Levitra should be 5 mg.

Vardenafil may also contribute to the blood pressure lowering effect of antihypertensive agents: clinical studies have shown a single dose of Levitra 20mg to reduce blood pressure between 1 and 4 hours after dosing, and to increase heart rate. If using antihypertensives one should speak to their doctor before taking Levitra.

Contraindications

Levitra is contraindicated if a patient is using nitrates (either regularly or intermittently) and/or nitric oxide donors. Nitrates include nitroglycerin which is commonly found in tablets, pastes, sprays, patches, or ointments; also in other medicaments like isosorbide dinitrate, isosorbide mononitrate, and in recreational drugs (‘poppers’) such as amyl nitrate and butyl nitrate. Moreover, nitrates are used to treat angina. Nitrates and nitric oxide donors have hypotensive effects; therefore concomitant intake of Vardenafil and nitrates is contraindicated. One should ask their doctor if unsure if any medicines they take could be, or contain, nitrates.

A sufficient time following administration of Levitra for the safe use of nitrates or nitric oxide donors has not been determined yet; also the potentiation of the hypotensive effects of nitrates for people suffering from ischemic heart disease is not yet evaluated, therefore Levitra and nitrates should be never used at the same time.

It is advisory to not engage in sexual activities, hence use of Levitra, if one’s heart is already weakened from heart attack or heart disease since sexual activity can put extra strain on the heart.

Dosage and direction

The usual dose of vardenafil is 10 mg taken roughly 60 minutes prior sexual activity. Depending on the efficacy and side effects, the initial dose may be tailored in the range of 5 - 20 mg. Levitra should be taken with or without food, orally, with the maximum dosing frequency of one a day. The minimum of 24 hours should be allowed between the doses.

If a patient is over 65 years of age, has prostate or liver problems, or an elevated blood pressure for which is taking alpha-blockers, he may start with a lower dose of Levitra. When taking certain medication patient may be prescribed a lower dose limited to one in 72-hour period.

Doctor’s prescription MUST be strictly followed at all times: do not change the dose of Levitra without talking to your doctor first, and contact him immediately if taken more than prescribed.

Sexual stimulation is needed for a successful response to treatment.

Side effects:

Vardenafil is considerably well tolerated however some reversible (usually subside after a few hours) side effects exist:

• dizziness;
• headache;
• nausea;
• back pain;
• diarrhoea;
• nasal congestion;
• long lasting painful erections;
• skin flushing;
• reduced blood pressure;
• visual impairment;
• indigestion;
• upset stomach;

In order to minimise any side effects, drinking plenty of fluid is required.

There are some side effects that present in rare cases. These are uncommon and include:

• Priapism (an erection that does not go away). In case of an erection that lasts longer than 4 hours one should seek medical help immediately. Priapism must be treated as soon as possible since it may lead to a long-lasting damage (inability to have erections);
• Colour vision changes, including inability to differentiate between the green and blue colours, or seeing a blue tinge to objects;
• A sudden decrease or loss of vision in one or both eyes. However, it is unclear if that is caused by the PDE5 inhibitors, or other factors like diabetes or high blood pressure, or combination of these. In case of vision problems Levitra treatment should be terminated and one should speak to their doctor immediately.
• Although impossible to determine if caused by vardenafil or other factors or combination of factors and medication, in rare cases patients have reported hearing problems with ringing in the ears and dizziness. If such symptoms arise, one should seek medical assistance.

Overdose

The maximum dose of Levitra for which data from clinical trials is available is 120 mg. It is known to cause reversible side effects: back pain, myalgia and abnormal vision.

Lower doses (single doses of up to 80 mg or multiple of up to 40 mg) are considerably well tolerated without serious adverse side effects. If 40 mg of Levitra are taken twice daily this may lead to severe back pain but without any muscle or neurological toxicity.

In the case of an overdose one should seek medical assistance. It should be noted that vardenafil is bound to plasma proteins therefore renal dialysis will not accelerate clearance as it does not get passed out in the urine significantly.

Storage

Store at 59–86° F (15–30° C), out of the reach of children.