Consumer medicine information

Levitra 5; Levitra 10; Levitra 20

Vardenafil

BRAND INFORMATION

Brand name

Levitra

Active ingredient

Vardenafil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Levitra 5; Levitra 10; Levitra 20.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Levitra. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Levitra against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT LEVITRA IS USED FOR

This medicine is used to treat erectile dysfunction.

Erectile dysfunction, also known as impotence in adult males, is the inability to obtain and/or maintain a hard erect penis sufficient for sexual activity.

Levitra tablet contains the active ingredient vardenafil which works by relaxing the blood vessels in the penis when you are sexually aroused. This allows blood to flow into the penis, allowing you to get an erection.

Levitra will only work if you are sexually aroused. It will not increase your sex drive.

Levitra is not addictive.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

BEFORE YOU TAKE LEVITRA

When you must not take it

Do not take Levitra if you have an allergy to:

  • any medicine containing vardenafil hydrochloride trihydrate
  • any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take Levitra if you are taking nitrate medicines which include:

  • glyceryl trinitrate (also called nitroglycerine)
  • nicorandil
  • sodium nitroprusside
  • isosorbide mononitrate
  • isosorbide dinitrate
  • amyl nitrite (also known as ‘poppers’, ‘amyl’ or ‘rush’)

Do not take Levitra if you are taking:

  • HIV protease inhibitors, medicines used to treat HIV infection. Examples of HIV protease inhibitors are cobicistat, indinavir or ritonavir.
  • Riociguat, used to treat a disease called pulmonary arterial hypertension.

Because sexual activity may place a strain on your heart, your doctor will need to check whether you are fit enough to have sexual intercourse.

Do not take Levitra if you have:

  • unstable angina (chest pain)
  • hypotension (low blood pressure)
  • uncontrolled hypertension (high blood pressure)
  • uncontrolled arrhythmia (irregular heart beat)
  • ever had a condition involving loss of vision due to damage to the optic nerve from insufficient blood supply known as non-arteritic anterior optic neuropathy (NAION)
  • hereditary degenerative retinal disorders (such as retinitis pigmentosa)
  • severe liver problems
  • severe kidney problems requiring dialysis
  • been diagnosed with a disease called pulmonary arterial hypertension

Do not take Levitra if you have, or have had, any of the following conditions within the previous 6 months:

  • myocardial infarction (heart attack)
  • stroke
  • cardiac ischaemia
  • serious arrhythmia (irregular heart beat)

Do not give Levitra to children, adolescents or women.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal. The EXPIRY date is marked on the strip of tablets as well as on the label of the carton. For example, 11 18 refers to the eleventh month of 2018.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • any heart or blood vessel problems
  • leukaemia (cancer of the blood cells)
  • multiple myeloma (a cancer of the bone marrow)
  • any disease or deformity of your penis
  • low or high blood pressure
  • sickle cell anaemia
  • bleeding disorders
  • active stomach ulcer
  • liver problems

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking Levitra.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including those that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by Levitra or vice versa. These medicines include:

  • nitrates, medicines for angina, or nitric oxide donors, such as amyl nitrite. Taking these medicines with Levitra could seriously affect your blood pressure
  • cobicistat, ritonavir or indinavir, medicines for HIV
  • ketoconazole and itraconazole, used to treat fungal infections
  • erythromycin, clarithromycin and gatifloxacin, which are antibiotics
  • alpha-blockers, medicines used to treat an enlarged prostate or high blood pressure. Examples of alpha-blockers are terazosin, alfuzosin, tamsulosin and prazosin
  • Riociguat, a type of medicine used to treat high blood pressure in the arteries carrying blood from your heart to your lungs
  • other treatments for erectile dysfunction

Levitra might increase the amount of some medicines in your blood (sensitive P-gp substrates).

Dabigatran is an example for these medicines.

You may need to use different amounts of your medicine, or you may need to take different medicines. Your doctor will be able to advise you.

Talk to your doctor if you are taking certain medicines for arrhythmia, including quinidine, procainamide, amiodarone and sotalol. Levitra should not be used with these medicines.

Levitra tablets may be used together with an alpha-blocker if you are on stable alpha-blocker therapy. If your doctor recommends this, they will start your Levitra treatment with a lower dose.

Concomitant use of Levitra with alpha-blockers may contribute to dizziness or fainting.

Your doctor or pharmacist will also have a more complete list of medicines to be careful with or avoid while taking Levitra.

Ask your doctor or pharmacist, if you are not sure if you are taking any of these medicines.

HOW TO TAKE LEVITRA

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

Swallow the tablet whole with water. Levitra can be taken with or without food.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Your doctor or pharmacist will tell you how much and how often you should take Levitra. Follow the directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

The dose ranges from 5 mg to 20 mg. Your doctor will determine the correct dose for you depending on your condition, other medicines and response.

Do not take more than one dose of Levitra a day.

When to take it

Sexual stimulation is required for a natural response to treatment with Levitra.

Take your dose of Levitra 25 to 60 minutes before you wish to have sex.

Levitra may work as soon as 15 minutes and as long as 4-5 hours after taking it. The amount of time it takes to start working varies from person to person.

If you are also taking an alpha-blocker other than tamsulosin or alfuzosin, allow at least 6 hours between the time you take it and the time you take your Levitra tablet (see Taking other medicines). Tamsulosin can be taken at the same time as Levitra or separately as you prefer.

If you are not sure what to do, ask your doctor or pharmacist.

If you take too much (overdose)

Immediately telephone your doctor, or the Poisons Information Centre (telephone in Australia 13 11 26, in New Zealand 0800 POISON or 0800 764 766), or go to the accident and emergency department at your nearest hospital, if you think you or anyone else may have taken too much Levitra. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

WHILE YOU ARE USING LEVITRA

Things you must do

Tell all the doctors, dentists and pharmacists who are treating you that you are taking Levitra. If you are about to start taking any new medicines, especially nitrates or some medicines to treat HIV, e.g. cobicistat, indinavir or ritonavir, tell your doctor or pharmacist that you are taking Levitra.

Stop taking Levitra and tell your doctor if you notice a sudden decrease or loss of hearing. Ringing of the ears and dizziness may also occur.

Stop taking Levitra and tell your doctor if you notice a sudden loss in vision.

Please also be aware that you may have to take treatments like Levitra a few times before you get the best response. If you’re still not getting a response, speak to your doctor.

Things you must not do

Do not use the recreational drug amyl nitrite (sometimes called ‘poppers’, ‘amyl’ or ‘rush’) while you are taking Levitra.

Do not take Levitra if you are taking HIV protease inhibitors, medicines used to treat HIV infection.

Do not take Levitra if you are taking Riociguat, used to treat pulmonary arterial hypertension.

If you get an angina attack whilst taking Levitra, do not take nitrate medicines to relieve the pain. Tell your doctor immediately or contact your nearest emergency department. Make sure that your doctor knows you are taking Levitra tablets.

Do not take more than one dose of Levitra a day. If Levitra does not help you get an erection, or if your erection does not last long enough to complete sexual intercourse, tell your doctor.

Do not give your Levitra tablets to anyone else, even if they have the same condition as you.

What to be careful of

Drinking alcohol can temporarily impair the ability to get an erection. To reduce impairment, do not drink large amounts of alcohol before sexual activity.

Be careful driving or operating machinery until you know how Levitra affects you. Levitra tablets may cause dizziness or faintness in some people. The ability to drive and/or operate machinery may be impaired. Dizziness or faintness may be worse if you are also taking alpha-blocker medicines.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Levitra. Levitra helps most men with erectile dysfunction, but it may have unwanted side effects. Sometimes they are serious, most of the time they are not. You may need to stop taking the tablets or have medical treatment if you get some of the serious side effects.

Tell your doctor or pharmacist if you notice any of the following and they worry you.

These are the common side effects of Levitra. They are usually mild and short-lived.

  • headache
  • dizziness or light-headedness
  • flushing
  • a stuffy or runny nose
  • dyspepsia (heartburn)
  • nausea

Very rarely, your erection may persist for longer than usual. If your erection continues for longer than four hours, or if you have a painful erection, you should seek medical attention.

In rare instances, men have lost eyesight some time after taking drugs to treat erectile dysfunction. It is not known at this time if Levitra causes this. If you experience sudden decrease or loss of vision – stop taking Levitra and seek immediate medical attention.

Sudden decrease in hearing or loss of hearing has been reported in men taking medicines to treat erectile dysfunction. It is not known at this time if Levitra causes this. If you experience sudden decrease or loss of hearing – stop taking Levitra and seek immediate medical attention.

You should tell your doctor immediately, or be reviewed in the accident and emergency department at your nearest hospital if you have any of the following:

  • angina (chest pain)
  • myocardial infarction
  • irregular heart beats or palpitations
  • loss of consciousness
  • allergic reactions such as rash, wheezing, swelling of the face, lips, tongue which may cause difficulty in swallowing or breathing

These are serious side effects. You may need urgent medical attention or hospitalisation.

Other side effects not listed above may also occur in some people. Tell your doctor if you notice anything else that is making you feel unwell. Do not be alarmed by this list of possible side effects. You may not experience any of them.

AFTER USING LEVITRA

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the box or the blister pack they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 25°C.

Do not leave the tablets in the car on hot days. Do not store it or any other medicine in the bathroom or near a sink. Heat and dampness can destroy some medicines.

Keep your tablets where children cannot reach them. A locked cupboard at least one and a half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking Levitra tablets or the tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

PRODUCT DESCRIPTION

What it looks like

Levitra 5 tablets are orange film-coated round tablets marked with BAYER-cross on one side and “5” on the other side.

Levitra 10 tablets are orange film-coated round tablets marked with BAYER-cross on one side and “10” on the other side.

Levitra 20 tablets are orange film-coated round tablets marked with BAYER-cross on one side and “20” on the other side.

Not all pack sizes are marketed.

Ingredients

Active ingredients:

  • Levitra 5 - 5 mg vardenafil per tablet
  • Levitra 10 - 10 mg vardenafil per tablet
  • Levitra 20 - 20 mg vardenafil per tablet

Inactive ingredients:

  • Colloidal anhydrous silica
  • Crospovidone
  • Hypromellose
  • Iron oxide red (CI 77491-E172)
  • Iron oxide yellow (CI 77492-E172)
  • Macrogol 400
  • Magnesium stearate
  • Microcrystalline cellulose
  • Titanium dioxide (CI 77891-E171)

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Made in Germany for:

Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Bayer New Zealand Limited
3 Argus Place, Hillcrest,
North Shore
Auckland 0627

Australian Registration Numbers

Levitra 5 - AUST R 90498

Levitra 10 - AUST R 90499

Levitra 20 - AUST R 90500

Date of preparation

December 2019

See TGA website
(www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website
(www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered trademark

© Bayer Australia Ltd

All rights reserved

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Levitra

Active ingredient

Vardenafil

Schedule

S4

 

1 Name of Medicine

Vardenafil (as hydrochloride trihydrate).

6.7 Physicochemical Properties

Vardenafil, as vardenafil hydrochloride trihydrate is 2-[2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) -phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4] triazin-4-one hydrochloride trihydrate. It is a nearly colourless solid. Vardenafil hydrochloride trihydrate is soluble in 0.1 M HCl, very slightly soluble in water, freely soluble in methanol, soluble in ethanol and slightly soluble in acetone.
The empirical formula of vardenafil hydrochloride trihydrate is C23H32N6O4S.HCl.3H2O and its molecular weight is 579.1 g/mol.

Chemical structure.

Its chemical structure is:

CAS number.

224785-90-4.

2 Qualitative and Quantitative Composition

Levitra 5 film-coated tablets contain 5 mg vardenafil (as 5.926 mg of vardenafil hydrochloride trihydrate).
Levitra 10 film-coated tablets contain 10 mg vardenafil (as 11.852 mg of vardenafil hydrochloride trihydrate).
Levitra 20 film-coated tablets contain 20 mg vardenafil (as 23.705 mg of vardenafil hydrochloride trihydrate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Levitra 5, 10 and 20 tablets are orange film-coated round tablets marked with the BAYER cross on one side and the dose strength ("5", "10" or "20") on the other side.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Penile erection is a haemodynamic process based on the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, from nerve ends in the corpus cavernosum, nitric oxide (NO) is released, which activates the enzyme guanylate cyclase, resulting in an increased level of cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This in turn triggers smooth muscle relaxation, allowing increased inflow of blood into the penis resulting in erection. The actual cGMP level is regulated by the rate of synthesis via the guanylate cyclase on the one hand, and by the rate of degradation via cGMP hydrolyzing phosphodiesterases (PDEs) on the other hand.
The most prominent PDE in the human corpus cavernosum is the cGMP specific phosphodiesterase type 5 (PDE5).
By inhibiting PDE5, the enzyme responsible for cGMP degradation in the corpus cavernosum, vardenafil potently enhances the effect of endogenous NO, locally released in corpus cavernosum upon sexual stimulation. The inhibition of PDE5 by vardenafil leads to increased cGMP levels in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Vardenafil thus potentiates the natural response to sexual stimulation.
In vitro assays have shown that vardenafil is a selective inhibitor of PDE5, with an IC50 of 0.7 nanoM for human platelet PDE5.
The inhibitory effect of vardenafil is more potent on PDE5 than on other known phosphodiesterases (> 15-fold relative to PDE6, > 130-fold relative to PDE1, > 300-fold relative to PDE11, and > 1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10). In vitro, vardenafil causes an elevation of cGMP in the isolated human corpus cavernosum resulting in muscle relaxation.
In the conscious rabbit, vardenafil causes a penile erection which is dependent upon endogenous NO synthesis and is potentiated by NO donors.

Effects on visual perception.

In a specific clinical trial, evaluation of visual function at a vardenafil dose of 40 mg (twice the maximum recommended daily dose) revealed no effects of vardenafil on visual acuity, visual fields, intraocular pressure, ERG latency, fundoscopic and slit lamp findings. A subset of patients was found to have mild and transient impairment of colour discrimination in the blue/green range and in the purple range 1 hour after dosing. These changes had improved by 6 hours and no changes were present at 24 hours. The majority of these patients had no subjective visual symptoms.
In other trials, daily use of vardenafil at doses of 10 mg to 40 mg for 31 days was not associated with changes in visual acuity, intraocular pressure, or findings on fundoscopic or slit lamp examination.

Effects on blood pressure.

Vardenafil causes mild and transient decreases in blood pressure which, in the majority of the cases, do not translate into clinical effects. The mean maximum decreases in supine systolic blood pressure following 20 mg and 40 mg vardenafil were -6.9 mmHg with 20 mg and -4.3 mmHg with 40 mg of vardenafil, when compared to placebo.

Effects on cardiac parameters.

A single dose, double blind, crossover, randomised trial in 59 healthy males compared the effects on the QT interval of vardenafil (10 mg and 80 mg), sildenafil (50 mg and 400 mg) and placebo. Moxifloxacin (400 mg) was included as an active internal control. Effects on the QT interval were measured one hour post-dose (average tmax for vardenafil). The primary objective of this study was to rule out a greater than 10 msec effect (i.e. to demonstrate lack of effect) of a single 80 mg oral dose of vardenafil on QTc interval compared to placebo, as measured by the change in Fridericia's correction formula (QTcF=QT/RR1/3) from baseline at the 1 hour post-dose time point. The vardenafil results showed an increase in QTc (Fridericia) of 8 msec (90% CI: 6-9) and 10 msec (90% CI: 8-11) at 10 and 80 mg doses compared to placebo and an increase in QTci of 4 msec (90% CI: 3-6) and 6 msec (90% CI: 4-7) at 10 and 80 mg doses compared to placebo, at one hour post-dose. At tmax, only the mean change in QTcF for vardenafil 80 mg was out of the study established limit (mean 10 msec, 90% CI: 8-11). When using the individual correction formulae, none of the values were out of the limit.
In a separate postmarketing study of 44 healthy volunteers, single doses of 10 mg Levitra resulted in a placebo-subtracted mean change from baseline of QTcF (Fridericia correction) of 5 msec (90% CI: 2,8). Single doses of gatifloxacin 400 mg resulted in a placebo-subtracted mean change from baseline QTcF of 4 msec (90% CI: 1,7). When Levitra 10 mg and gatifloxacin 400 mg were co-administered, the mean QTcF change from baseline was additive when compared to either drug alone and produced a mean QTcF change of 9 msec from baseline (90% CI: 6,11) at one hour post-dose. The clinical impact of these QT changes is unknown.

Effects on exercise performance in patients with coronary artery disease.

In a two-period, placebo-controlled, cross-over trial, 10 mg vardenafil did not alter the total treadmill exercise time compared to placebo in 39 male patients aged 48-77 years with coronary artery disease and exercise induced ischaemia. The total time to angina was not altered compared to placebo; however, the total time to 1 mm or greater ST-segment depression was prolonged 15% in the vardenafil group compared to the placebo group (p < 0.001). All patients who entered the trial completed the exercise treadmill tests without significant drug-related side effects.

Clinical trials.

In a placebo controlled Rigiscan study, Levitra (vardenafil) 20 mg produced erections sufficient for penetration (≥ 60% rigidity by Rigiscan) in some men as early as 15 minutes. The overall response of these subjects to vardenafil became statistically significant compared to placebo at 25 minutes post dosing.
Vardenafil demonstrated clinically meaningful and statistically significant improvement of erectile function compared to placebo in all major efficacy trials including special populations.
Across all trials, vardenafil was administered to over 3750 men with erectile dysfunction (ED) aged 18 to 89 years, many of whom had multiple other medical conditions. Over 1630 patients were treated with vardenafil for 6 months or longer.
In all major efficacy trials, including studies in post-prostatectomy patients and patients with diabetes, vardenafil 10 mg and 20 mg produced statistically significant and clinically meaningful improvements, compared to placebo, in the International Index of Erectile Function (IIEF) erectile function domain score, the percentage of patients achieving successful penetration and maintenance of erections, and the percentage of patients who rated their erections as improved (see Table 4 and Table 5).
In a randomised, double blind, placebo controlled, fixed dose trial in 749 patients, based on a global assessment question (GAQ), vardenafil improved erections in 56%, 77%, and 81% of the patients on 5 mg, 10 mg, and 20 mg, respectively, at 6 months compared to 23% on placebo.
In pooled data from the major efficacy trials, including special population studies, those patients who had successful penetration on first dose of treatment were 37% on placebo, 68% for 10 mg, and 70% for 20 mg. For those patients who had successful penetration on first dose, on average, patients on vardenafil 10 mg and 20 mg responded successfully in 86% and 90% of all subsequent attempts, respectively, over a 3 month study period. Vardenafil was efficacious in patients regardless of baseline severity, aetiology (organic, psychogenic and mixed), duration of ED, ethnicity and age as determined in subgroup analyses.
In post-prostatectomy patients, vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a 3 month prospective, fixed dose, placebo controlled, double blind trial. Erectile function domain score, the rate of obtaining an erection sufficient for penetration, the rate of maintaining an erection sufficient for successful intercourse, and hardness were significantly improved compared to placebo for the tested doses of 10 mg and 20 mg at all time points. Improved erectile function response rates as based on GAQ were 57% on 10 mg, and 60% on 20 mg compared to 9% on placebo at 3 months. In the subgroup of patients with bilateral nerve-sparing prostatectomy the response rates as based on GAQ in patients at 3 months were 61% for 10 mg, and 66% for 20 mg, compared to 8% for placebo.
In patients with diabetes mellitus, vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a 3 month prospective, fixed dose, placebo controlled, double blind trial. Significant improvements were shown in the erectile function domain score, the rate of obtaining an erection sufficient for penetration, the rate of maintaining an erection sufficient for successful intercourse, and hardness, when 10 mg and 20 mg vardenafil doses were compared to placebo. These improvements were seen at all time points during three months of treatment. In this population, which is typically more resistant to therapy, response rates at 3 months for improvement of erection as based on GAQ were 54% on 10 mg, and 70% on 20 mg vardenafil compared to 13% on placebo. Patients in the active treatment group were continued on blinded active therapy of vardenafil for a total of 6 months. These patients demonstrated response rates of 66% and 74% for 10 mg and 20 mg, respectively.

5.2 Pharmacokinetic Properties

Absorption.

Vardenafil is rapidly absorbed after oral administration. Cmax is reached as early as 15 minutes, in 90% of the time Cmax is reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state.
There is extensive first-pass metabolism of vardenafil, resulting in considerable inter-subject and intra-subject variability in the observed pharmacokinetic parameters. The mean absolute bioavailability is approximately 15% after a 10 mg dose. After oral dosing of vardenafil, AUC and Cmax increase almost dose proportionally over the recommended dose range (5 mg - 20 mg).
When vardenafil was taken with a high fat meal (~57% fat), the mean Cmax was reduced by approximately 20%, median tmax was delayed by approximately 1 hour, and mean AUC was not affected. After a ‘normal meal’ (~30% fat) pharmacokinetic parameters were not significantly affected. Based on these results vardenafil can be taken with or without food.

Distribution.

The mean steady state volume of distribution (Vss) for vardenafil is about 2.5 L/kg, indicating distribution into the tissues.
Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins (about 95% for parent drug or M1). This protein binding is reversible and independent of total drug concentrations.
Based upon measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more than 0.0002% of the administered dose may appear in the semen of patients.

Metabolism.

Vardenafil is metabolised predominantly by hepatic enzymes via CYP3A4, with some contribution from CYP3A5 and CYP2C9 isoforms. Mean terminal elimination half-life from plasma is approximately 4 - 5 hours.
In humans, the major circulating metabolite (M1) results from desethylation at the piperazine moiety of vardenafil, and is subject to further metabolism. The terminal plasma elimination half-life of the metabolite M1 is approximately 4 hours, comparable to the parent drug. M1 is also present in its glucuronide-conjugated (glucuronic acid) form in the systemic circulation. The plasma concentration of non-glucuronidated M1 is about 26% that of the parent compound. The metabolite M1 shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 of approximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.

Excretion.

The total body clearance of vardenafil is 56 L/hour with a resultant terminal half-life of about 4 - 5 hours.
After oral administration, vardenafil is excreted as metabolites predominantly in the faeces (approximately 91 - 95% of administered oral dose) and to a lesser extent in the urine (approximately 2 - 6% of administered oral dose).

Pharmacokinetics in special populations.

Renal insufficiency.

In patients with mild (CLcr > 50 - 80 mL/min) to moderate (CLcr > 30 - 50 mL/min) renal impairment vardenafil pharmacokinetics were similar to that of a normal renal function control group. In volunteers with severe renal impairment (CLcr < 30 mL/min) the mean AUC was increased by 21% and the mean Cmax decreased by 23%, compared to volunteers with no renal impairment. No statistically significant correlation between creatinine clearance and vardenafil plasma exposure (AUC and Cmax) was observed. Based on these data, no dose adjustment is needed in patients with impaired renal function.
The pharmacokinetics of vardenafil have not been studied in patients requiring dialysis and Levitra should not be used in this situation.

Hepatic impairment.

In patients with mild to moderate hepatic impairment (Child-Pugh A and B), vardenafil clearance was reduced in proportion to the degree of hepatic impairment.
In patients with mild hepatic impairment (Child-Pugh A), vardenafil AUC and Cmax were increased 1.2-fold (AUC by 17% and Cmax by 22%) following a 10 mg vardenafil dose, compared to healthy control subjects. In patients with moderate hepatic impairment (Child-Pugh B), vardenafil AUC was increased by 160% and Cmax was increased by 130%, compared to healthy control subjects.
Therefore, in patients with mild hepatic impairment, Levitra 5 mg should be used as a starting dose, which may subsequently be increased to 10 mg and 20 mg based on tolerability and efficacy. The maximum dose recommended in patients with moderate hepatic impairment (Child-Pugh B) is Levitra 10 mg.
The pharmacokinetics of vardenafil have not been studied in patients with severe hepatic impairment (Child-Pugh C). Levitra should not be used in this population.

Elderly.

No dosage adjustment is required in elderly patients. Vardenafil half-life in healthy elderly volunteers (65 years or over) was reduced as compared to volunteers of younger age (45 years and below). On average, elderly males had a 52% higher AUC than younger males which is within the variability observed in clinical trials.

5.3 Preclinical Safety Data

Genotoxicity.

Vardenafil was not genotoxic in assays for gene mutation (reverse mutations in bacterial cells and forward mutations in Chinese hamster V79 cells in vitro) or chromosomal damage (Chinese hamster V79 cells in vitro and mouse micronucleus assay in vivo).

Carcinogenicity.

Vardenafil showed no carcinogenic activity when administered orally to rats at doses up to 75 (males) or 25 (females) mg/kg/day or via the drinking water to mice at doses up to 150 (males) or 193 (females) mg/kg/day. The highest doses in these studies were associated with systemic exposure (AUC) to vardenafil > 300 (rats) or about 25 (mice) times that expected in men taking 20 mg/day vardenafil.

4 Clinical Particulars

4.1 Therapeutic Indications

Levitra is indicated for the treatment of erectile dysfunction in adult males (inability to achieve or maintain penile erection sufficient for satisfactory sexual performance).
Levitra is not indicated for use by women.

4.3 Contraindications

Patients with known hypersensitivity to the active substance or to any of the excipients.
Co-administration with nitrates, nitric oxide donors, or organic nitrites in any form either regularly or intermittently. Drugs which must not be used concomitantly include, but are not limited to, glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil or organic nitrates in any form. Consistent with the effects of PDE inhibition on the nitric oxide/cGMP - pathway, PDE5 inhibitors may potentiate the hypotensive effects of nitrates.
Concomitant use with potent inhibitors of CYP3A4 (e.g. medicinal products containing cobicistat, HIV protease inhibitors such as indinavir or ritonavir, and combinations of these).
Concomitant use of Levitra with riociguat, a stimulator of soluble guanylate cyclase (sGC) as it may lead to potentially life-threatening symptomatic hypotension and syncope.
Patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection with previous exposure to PDE5 inhibitor.
Known hereditary degenerative retinal disorders such as retinitis pigmentosa.
Patients in whom sexual intercourse is inadvisable due to cardiovascular risk factors (see Section 4.4 Special Warnings and Precautions for Use). The possibility of undiagnosed cardiovascular disorders in men with erectile dysfunction should be considered before prescribing the medicine.
Patients with the following cardiac conditions: unstable angina; resting or orthostatic hypotension (systolic blood pressure < 90 mmHg); uncontrolled hypertension; myocardial infarction, stroke, cardiac ischaemia (except stable angina) or life-threatening arrhythmia within the previous 6 months; and uncontrolled arrhythmia.
Severe hepatic impairment.
End-stage renal disease requiring dialysis.

4.4 Special Warnings and Precautions for Use

Cardiovascular disease.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity. Vardenafil has vasodilator properties which may result in mild and transient decreases in blood pressure. Patients with left ventricular outflow obstruction, e.g. aortic stenosis and idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators including PDE5 inhibitors.
In men for whom sexual activity is not recommendable because of their underlying cardiovascular status, agents for the treatment of erectile dysfunction should generally not be used.
In a study of the effect of vardenafil on QT interval in 59 healthy males, therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced increases in QTc interval (see Section 5.1 Pharmacodynamic Properties). A postmarketing study evaluating the effect of combining vardenafil with gatifloxacin, another drug of comparable QT effect showed an additive QT effect when compared with either drug alone (see Section 5.1 Pharmacodynamic Properties). These observations should be considered in clinical decisions when prescribing vardenafil to patients, including those with a known history of QT prolongation or patients who are taking medications known to prolong QT interval. Patients with congenital QT prolongation (long QT syndrome) and those taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications should avoid using vardenafil.

Other pre-existing medical conditions.

Agents for the treatment of erectile dysfunction should generally be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).
The safety and efficacy of combinations of vardenafil with other treatments for erectile dysfunction (including other PDE5 inhibitors) have not been studied. Therefore the use of such combinations is not recommended.
Vardenafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore vardenafil should be given to these patients only after careful benefit-risk assessment. In humans, vardenafil has no effect on bleeding time alone or with aspirin. In vitro studies with human platelets indicate that vardenafil alone did not inhibit platelet aggregation induced by a variety of platelet agonists. With supertherapeutic concentrations of vardenafil a small concentration-dependent enhancement of the antiaggregatory effect of sodium nitroprusside, a NO donor, was observed. The combination of heparin and vardenafil had no effect on bleeding time in rats, but this interaction has not been studied in humans.

Use with alpha-blockers.

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including Levitra tablets and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions) leading to symptomatic hypotension (e.g. fainting). Consideration should be given to the following:
Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate haemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5 mg. Patients treated with alpha-blockers who have previously used 5 mg film-coated tablets may be switched to a higher dose.
In those patients already taking an optimised dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increases in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor.
Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

Use with CYP3A4 inhibitors.

Concomitant use of moderate or potent CYP3A4 inhibitors cobicistat, ketoconazole, itraconazole, erythromycin, clarithromycin, indinavir or ritonavir can be expected to produce markedly increased vardenafil plasma levels. A maximum vardenafil dose of 5 mg should not be exceeded if used in combination with ketoconazole, itraconazole, erythromycin or clarithromycin. Levitra must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg (see Section 4.2 Dose and Method of Administration). Concomitant use with medicinal products containing cobicistat, HIV protease inhibitors such as indinavir or ritonavir, and combinations of these is contraindicated, as these drugs are potent inhibitors of CYP3A4 (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Non-arteritic anterior ischemic optic neuropathy.

Transient vision loss and cases of non-arteritic anterior ischemic optic neuropathy (NAION) have been reported in connection with the intake of PDE5 inhibitors, including vardenafil. The patient should be advised that in case of sudden vision loss, he should stop taking Levitra and consult a physician immediately.
Observational studies have evaluated the risk of NAION within 5 half-lives of PDE5 inhibitor use. The results suggest an approximate 2 to 4-fold increase in the risk of NAION following exposure to PDE5 inhibitors (see Section 4.8 Adverse Effects (Undesirable Effects)).

Sudden decrease or loss of hearing.

Physicians should advise patients to stop taking PDE5 inhibitors, including vardenafil, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly.

No dosage adjustment is required in elderly patients (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Levitra is not indicated for use in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Vardenafil is metabolised predominantly by hepatic enzymes via cytochrome P450 (CYP) isoform 3A4, with some contribution from CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these enzymes may reduce vardenafil clearance.

Demonstrated interactions.

Macrolide antibiotics.

Erythromycin (500 mg three times a day), a CYP3A4 inhibitor, caused a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with vardenafil (5 mg) to healthy volunteers. When used in combination with erythromycin or clarithromycin, a maximum vardenafil dose of 5 mg should not be exceeded.

Potent CYP3A4 inhibitors.

Ketoconazole.

Ketoconazole (200 mg), which is a potent CYP3A4 inhibitor, caused a 10-fold increase in vardenafil AUC and a 4-fold increase in Cmax when co-administered with Levitra 5 mg to healthy volunteers. When used in combination with ketoconazole, a maximum vardenafil dose of 5 mg should not be exceeded. Levitra must not be taken with dosages of ketoconazole higher than 200 mg (see Section 4.2 Dose and Method of Administration).

Indinavir.

Indinavir is a potent CYP3A4 inhibitor. Co-administration of Levitra 10 mg with the HIV protease inhibitor indinavir (800 mg three times a day) resulted in a 16-fold increase in vardenafil AUC and a 7-fold increase in vardenafil Cmax. At 24 hours after co-administration, the plasma levels of vardenafil were approximately 4% of the maximum vardenafil plasma level (Cmax). Concomitant use of indinavir and vardenafil is contraindicated.

Ritonavir.

Ritonavir (600 mg twice daily) resulted in a 13-fold increase of vardenafil Cmax and a 49-fold increase in vardenafil AUC0-24 when co-administered with Levitra 5 mg. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a very potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 25.7 hours. Concomitant use with ritonavir is contraindicated.

Potential interactions.

Other CYP3A4 inhibitors.

Concomitant use of other moderate or potent CYP3A4 inhibitors such as cobicistat, ketoconazole, itraconazole, erythromycin, clarithromycin, indinavir or ritonavir can be expected to produce markedly increased vardenafil plasma levels (see Section 4.4 Special Warnings and Precautions for Use). A maximum dose of Levitra 5 mg should not be exceeded if used in combination with ketoconazole, itraconazole, erythromycin or clarithromycin.

Nitrates, nitric oxide donors.

There is limited information on the potential hypotensive effects of vardenafil when given in combination with nitrates. Based on experience with other PDE5 inhibitors, some patients may experience clinically significant hypotension if vardenafil and nitrates are co-administered. Concomitant use is therefore contraindicated (see Section 4.3 Contraindications).
Nitrates should not be administered for at least 24 hours (approximately 5 half-lives) after the last dose of vardenafil. A longer washout period should be observed if the patient has been taking concomitant drugs, such as CYP3A4 inhibitors, which impair vardenafil metabolism.
Nicorandil is a hybrid of potassium channel opener and nitrate. Due to the nitrate component it has the potential to have serious interaction with vardenafil (see Section 4.3 Contraindications).

Antihypertensive agents.

Limited information is available on concomitant use of vardenafil and antihypertensive agents. Population pharmacokinetic investigations of Phase III data revealed no significant effect of ACE-inhibitors, beta-blockers or diuretics on the pharmacokinetics of vardenafil. However, a potential for additive hypotensive effect exists, and until further information is available, caution should be exercised when prescribing vardenafil in combination with antihypertensive agents.

Alpha-blockers.

Since alpha-blocker monotherapy can cause marked lowering of blood pressure, especially postural hypotension and syncope, interaction studies were conducted with vardenafil.
Hypotension, in some cases symptomatic, was reported in a significant number of subjects after co-administration of Levitra film-coated tablets to healthy normotensive volunteers force titrated, over a period of 14 days or less, to high doses of the alpha-blockers tamsulosin or terazosin.
Among subjects treated with terazosin, hypotension, standing systolic blood pressure below 85 mmHg, was observed more frequently when vardenafil and terazosin were given to achieve Cmax simultaneously than when the doses were administered to separate Cmax by 6 hours. Because these studies were conducted using healthy volunteers, after force titration of the alpha-blocker to high doses (subjects were not stable on alpha-blocker therapy), these studies may have limited clinical relevance.
Three interaction studies were conducted with Levitra film-coated tablets in patients with benign prostatic hyperplasia (BPH) on stable alpha-blocker therapy consisting of alfuzosin, tamsulosin or terazosin.
When Levitra film-coated tablets were given at doses of 5 mg, 10 mg or 20 mg on a background of stable therapy with tamsulosin, there was no clinically relevant mean maximal additional reduction in blood pressure. When Levitra 5 mg film-coated tablets were dosed simultaneously with 0.4 mg of tamsulosin, 2 of 21 patients experienced a standing systolic blood pressure below 85 mmHg. When Levitra 5 mg film-coated tablets were dosed 6 hours after tamsulosin administration, 2 of 21 patients experienced a standing systolic blood pressure below 85 mmHg.
Levitra film-coated tablets 5 mg or 10 mg were administered four hours after alfuzosin dosing. The four-hour dosing interval was chosen to elicit the maximum potential interaction. No clinically relevant mean maximal additional reduction in blood pressure was observed over the 10-hour interval following dosing with Levitra film-coated tablets 4 hours after alfuzosin. One patient experienced decreases from baseline in standing systolic blood pressure greater than 30 mm Hg on two occasions i.e. after administration of Levitra 5 mg film-coated tablet and Levitra 10 mg film-coated tablet. No instances of standing systolic blood pressure below 85 mm Hg were observed during this study. Four patients, one dosed with placebo, two dosed with Levitra 5 mg film-coated tablets and one dosed with Levitra 10 mg film-coated tablets, reported dizziness. Based on these results no time interval between dosing with alfuzosin and Levitra is required.
In a subsequent study in patients with BPH, when Levitra 10 mg and 20 mg film-coated tablets were dosed simultaneously with 0.4 or 0.8 mg of tamsulosin no cases of standing systolic blood pressure below 85 mmHg were observed. Based on these results no time interval between dosing with tamsulosin and Levitra is required.
When Levitra 5 mg film-coated tablets were dosed simultaneously with 5 or 10 mg of terazosin, 1 out of 21 patients experienced symptomatic postural hypotension. Hypotension was not observed when Levitra was dosed 6 hours after terazosin administration. This should be considered when deciding about a time separation of dosing between Levitra and terazosin. There was no case of syncope in this study or in the earlier alfuzosin or terazosin studies. See Figures 1 and 2.
Concomitant treatment should be initiated only if the patient is stable on his alpha-blocker therapy. In those patients who are stable on alpha-blocker therapy, Levitra should be initiated at the lowest recommended starting dose of 5 mg.
Levitra may be administered at any time with alfuzosin or tamsulosin. With terazosin and other alpha-blockers, an appropriate time interval (separation of at least 6 hours) between dosing is recommended when Levitra is prescribed concomitantly (see Section 4.2 Dose and Method of Administration). Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive medication.

Riociguat.

Preclinical studies showed an additive systemic blood pressure lowering effect when PDE5 inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5 inhibitors. There was no evidence of a favourable clinical effect of the combination in the population studied. Concomitant use of PDE5 inhibitors, including Levitra with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to life-threatening episodes of symptomatic hypotension or syncope (see Section 4.3 Contraindications).

Interactions shown not to exist.

Glibenclamide.

Vardenafil (20 mg), when co-administered with glibenclamide (3.5 mg), did not affect the relative bioavailability of glibenclamide (no effect on AUC and Cmax of glibenclamide).

Warfarin.

No pharmacokinetic or pharmacodynamic (prothrombin time and clotting Factor II, VII and X) interactions were shown when warfarin (25 mg) was co-administered with vardenafil (20 mg). Vardenafil pharmacokinetics were not affected by co-administration of warfarin.

Nifedipine.

Co-administration of vardenafil (20 mg) did not alter the bioavailability (AUC and Cmax) of nifedipine (30 mg or 60 mg). The combined treatment of vardenafil and nifedipine did not lead to pharmacodynamic interaction (as compared to placebo, vardenafil produced mean additional blood pressure reductions of 5.9 mmHg and 5.2 mmHg for supine systolic and diastolic blood pressure, respectively).

Digoxin.

Lack of pharmacokinetic interaction was shown when digoxin (0.375 mg daily) in steady-state was co-administered with vardenafil (20 mg) over 14 days every other day.
In vitro data suggest that effects of vardenafil on P-gp substrates more sensitive than digoxin cannot be excluded. Published literature shows that dabigatran is an example for a highly sensitive P-gp substrate.

Antacids.

Single doses of Mylanta (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability (AUC) or the maximum concentration (Cmax) of vardenafil.

Ranitidine, cimetidine.

Bioavailability of vardenafil (20 mg) was not affected by co-administration of the H2-antagonists ranitidine (150 mg twice daily) and cimetidine, a non-specific cytochrome P450 inhibitor (400 mg twice daily).

Aspirin.

Vardenafil (10 mg) did not influence bleeding time when taken alone or in combination with low dose aspirin (2 x 81 mg tablets).

Ethanol.

Vardenafil (20 mg) did not potentiate the hypotensive effects of ethanol (0.5 g/kg bodyweight). The pharmacokinetics of ethanol and vardenafil were not significantly altered by co-administration.

Other drugs.

Population pharmacokinetic investigations of Phase III data revealed no significant effect of aspirin, weak CYP3A4 inhibitors, and medications for the treatment of diabetes (sulfonylureas and metformin) on the pharmacokinetics of vardenafil.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a specific clinical trial, single oral doses of 20 mg of vardenafil did not produce any effects on sperm motility or morphology or a variety of parameters indicative for male reproductive function. Based upon measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more than 0.0002% of the administered dose appeared in the semen of patients.
Studies in rats showed no effects on fertility, reproductive performance or reproductive organ morphology in males or females given oral doses of vardenafil up to 100 mg/kg/day (systemic exposure > 200 times that expected at the maximum recommended dose of 20 mg, based on AUC).
(Category B3)
Vardenafil is not indicated for use by women.
Studies in rats have shown that vardenafil and/or its metabolites cross the placenta and distribute to the fetus. No evidence of embryofetal toxicity or teratogenicity was observed in pregnant rats or rabbits given oral doses of vardenafil up to 18 mg/kg/day. These doses were associated with systemic exposure to vardenafil 125- (rat) or 7- (rabbit) fold greater than that expected at the maximum recommended dose of 20 mg, based on AUC. Higher doses were associated with maternal toxicity, increased embryonic resorptions and delayed fetal development in both species.
Administration of vardenafil 60 mg/kg/day to pregnant rats during late gestation and throughout lactation resulted in increased postnatal pup mortality and delayed physical development. The no-effect-dose of 8 mg/kg/day was associated with systemic exposure approximately 28-fold that expected in humans at the maximum recommended dose of 20 mg vardenafil.
There are no studies of vardenafil in pregnant women.
Vardenafil is not indicated for use by women.
Vardenafil and/or its metabolites are excreted in the milk of lactating rats at concentrations up to 19-fold higher than the corresponding maternal plasma concentrations. Increased pre- and post-natal mortality and delayed physical development were observed in offspring from rats treated with oral vardenafil at 60 mg/kg/day during gestation and lactation.
There are no human data on the excretion of vardenafil into breast milk or on the safety of vardenafil exposure in infants.

4.8 Adverse Effects (Undesirable Effects)

Vardenafil was generally very well tolerated. Adverse events were generally transient and mild to moderate in nature.

Placebo controlled clinical trials.

When vardenafil was taken as recommended, the following adverse drug reactions were reported more commonly with vardenafil than placebo in placebo controlled clinical trials (as of March 2004) (see Table 1):
Dizziness was found to be more frequent in patients also taking alpha-blockers.

All clinical trials.

Levitra has been administered to 17,748 men during controlled and uncontrolled clinical trials worldwide. The number of patients treated for 6 months or longer was 3357, and 1350 patients were treated for at least 1 year. When Levitra film-coated tablet or Levitra orodispersible tablet was taken as recommended, the following adverse drug reactions were reported in all clinical trials. See Table 2.

Post-marketing experience.

From post-marketing experience with another drug of this class, the following serious adverse events have been reported (see Table 3).
Myocardial infarction (MI) has been reported in temporal association with the use of vardenafil and sexual activity, but it was not possible to determine whether MI is related directly to vardenafil or to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these factors.
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of PDE5 inhibitors, including vardenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
Observational studies evaluating whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION suggest an approximate 2 to 4-fold increase in the risk of NAION with PDE5 inhibitor use (see Section 4.4 Special Warnings and Precautions for Use).
Visual disturbances including vision loss (temporary or permanent) have been reported rarely post-marketing in temporal association with the use of PDE5 inhibitors, including vardenafil. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or to other factors.
Sudden decrease or loss of hearing has been reported in a small number of postmarketing and clinical trials cases with the use of all PDE5 inhibitors, including vardenafil. It is not possible to determine whether these reported events are related directly to the use of Levitra, to the underlying risk factors for hearing loss, a combination of these factors or to other factors.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage (dose and interval).

The recommended starting dose of Levitra is 10 mg, taken orally 25 to 60 minutes before sexual activity. Sexual activity can be initiated as soon as 15 minutes and as long as 4 - 5 hours after taking Levitra. Depending on co-morbidities and concomitant medications, it may be necessary to commence on a lower dose of 5 mg film-coated tablet.
The maximum recommended dose frequency is once daily.

Method of administration.

Levitra can be taken with or without food.
Sexual stimulation is required for a natural response to treatment.

Dosage adjustment.

Based on efficacy and tolerability, the Levitra dose may be increased to 20 mg or decreased to 5 mg. The maximum recommended dose is 20 mg once daily.

Renal impairment.

No dose adjustment is needed in patients with mild (CLcr > 50-80 mL/min), moderate (CLcr > 30-50 mL/min), or severe (CLcr < 30 mL/min) renal impairment.
The pharmacokinetics of vardenafil have not been studied in patients requiring dialysis, therefore Levitra should not be used in these patients.

Hepatic impairment.

In patients with mild and moderate hepatic impairment (Child-Pugh A and B), 5 mg should be used as a starting dose, which may subsequently be increased to a higher dose based on tolerability and efficacy. The maximum dose recommended in patients with moderate hepatic impairment (Child-Pugh B) is Levitra 10 mg.
The pharmacokinetics of vardenafil have not been studied in patients with severe hepatic impairment (Child-Pugh C), therefore Levitra should not be used in these patients.

Elderly (above 65 years).

Dose adjustment is not warranted based on age alone. It should be considered that co-morbidities increase with age.

Children (from birth to 18 years).

Levitra is not indicated for use in children.

Concomitant alpha-blockers.

Consistent with vasodilatory effects of alpha-blockers and vardenafil, the concomitant use of Levitra with alpha-blockers may lead to symptomatic hypotension in some patients. Concomitant treatment should only be initiated if the patient is stable on his alpha-blocker therapy (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In those patients who are stable on alpha-blocker therapy, Levitra should be initiated at the lowest recommended starting dose of 5 mg. Patients treated with alpha-blockers who have previously used 5 mg film-coated tablets may be switched to a higher dose.
Levitra may be administered at any time with alfuzosin or tamsulosin. With other alpha-blockers a time separation of dosing should be considered when Levitra is prescribed concomitantly (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
In those patients already taking an optimised dose of vardenafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor, including vardenafil.

Concomitant use of potent CYP3A4 inhibitors.

The dosage of Levitra may require adjustment in patients receiving certain CYP3A4 inhibitors.
A maximum dose of 5 mg should not be exceeded when Levitra is used in combination with the potent cytochrome P450 (CYP) 3A4 inhibitors ketoconazole, itraconazole, erythromycin or clarithromycin. Levitra must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg daily. Concomitant use with medicinal products containing cobicistat, HIV protease inhibitors such as indinavir and ritonavir, and a combination of these is contraindicated, as these medicines are potent inhibitors of CYP3A4 (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.7 Effects on Ability to Drive and Use Machines

Patients should be aware of how they react to vardenafil before driving or operating machinery. Due to the vasodilatory properties of PDE5 inhibitors, concomitant use with alpha-blockers, may contribute to dizziness.

4.9 Overdose

The maximum dose of vardenafil for which human data are available is a single 120 mg dose of the film-coated tablets administered to eight healthy male volunteers. The majority of these subjects experienced reversible back pain/myalgia and/or "abnormal vision".
The adverse side effects observed were similar both in type and severity to those observed throughout clinical development.
In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and not significantly eliminated in the urine.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Levitra 5, Levitra 10 and Levitra 20 contain the following excipients: crospovidone, magnesium stearate, microcrystalline cellulose, colloidal anhydrous silica, macrogol 400, hypromellose, titanium dioxide (CI77891), iron oxide yellow (CI77492), iron oxide red (CI77491).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Levitra 5 is registered in Al/Al blister packs of 1 (sample pack), 2, 4, 6, 8 and 12 tablets.
Levitra 10 is registered in PP/Al blister packs of 1 (sample pack), 2, 4, 6 and 8 tablets.
Levitra 20 is registered in PP/Al blister packs of 1 (sample pack), 2, 4, 6, 8 and 12 tablets.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes