Levitra - Treatment for Erectile Dysfunction (ED)

LEVITRA (vardenafil HCl) TABLETS

DESCRIPTION

LEVITRA is an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective®inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Vardenafil HCl is designated chemically as 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-, monohydrochloride and has the following structural formula:

Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL inwater. LEVITRA is formulated as orange, round, film-coated tablets with NBAYER” cross debossed on one side and "2.5", "5","10", and "20" on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. In addition to theactive ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magne-sium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.

CLINICAL PHARMACOLOGY

Mechanism of Action
Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and itsassociated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpuscavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosinemonophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth musclerelaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated byboth the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpuscavernosum is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile functionby increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibitionof PDE5 has no effect in the absence of sexual stimulation.
In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective onPDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative toPDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).
Pharmacokinetics
The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose range. Vardenafil iseliminated predominantly by hepatic metabolism, mainly by CYP3A4 and to a minor extent, CYP2C isoforms. Concomitant usewith strong CYP3A4 inhibitors such as ritonavir, indinavir, ketoconazole, itraconazole as well as moderate CYP3A inhibitorssuch as erythromycin results in significant increases of plasma levels of vardenafil (see PRECAUTIONS, WARNINGS and DOSAGE AND ADMINISTRATION). Mean vardenafil plasma concentrations measured after the administration of a single oraldose of 20 mg to healthy male volunteers are depicted in Figure 1

Figure 1: Plasma Vardenafil Concentration (Mean ±SD) Curve for a
Single 20 mg LEVITRA Dose

Absorption: Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%. Maximum observed plasmaconcentrations after a single 20 mg dose in healthy volunteers are usually reached between 30 minutes and 2 hours (median 60minutes) after oral dosing in the fasted state. Two food-effect studies were conducted which showed that high-fat meals caused a reduction in C_max by 18%-50%.
Distribution: The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations.
Following a single oral dose of 20 mg vardenafil in healthy volunteers, a mean of 0.00018% of the administered dose wasobtained in semen 1.5 hours after dosing.
Metabolism: Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 andCYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 issubject to further metabolism. The plasma concentration of M1 is approximately 26% that of the parent compound. Thismetabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE528% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.
Excretion: The total body clearance of vardenafil is 56 L/h, and the terminal half-life of vardenafil and its primary metabolite(M1) is approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the feces(approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administeredoral dose). Pharmacokinetics in Special Populations
Pediatrics: Vardenafil trials were not conducted in the pediatric population.
Geriatrics: In a healthy volunteer study of elderly males (> 65 years) and younger males (18–45 years), mean C_max and AUC were 34% and 52% higher, respectively, in the elderly males (see PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION). Consequently, a lower starting dose of LEVITRA (5 mg) in patients =65 years of age should be considered.
Renal Insufficiency: In volunteers with mild renal impairment (CL_cr = 50-80 ml/min), the pharmacokinetics of vardenafil werecrsimilar to those observed in a control group with normal renal function. In the moderate (CL_cr = 30-50 ml/min) or severecr(CL_cr <30 ml/min) renal impairment groups, the AUC of vardenafil was 20–30% higher compared to that observed in acrcontrol group with normal renal function (CL_cr >80 ml/min). Vardenafil pharmacokinetics have not been evaluated in patientscrrequiring renal dialysis (see PRECAUTIONS, Renal Insufficiency, and DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency: In volunteers with mild hepatic impairment (Child-Pugh A), the C_max and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. In volunteers with moderate hepaticimpairment (Child-Pugh B), the C_max and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively,compared to healthy control subjects. Consequently, a starting dose of 5 mg is recommended for patients with moderate hepaticimpairment, and the maximum dose should not exceed 10 mg (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment.

LEVITRA TABLETS

(Vardenafil hydrochloride trihydrate)

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about LEVITRA.
This leaflet 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.
As LEVITRA is a prescription medicine, it should only be used under medical supervision.
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

LEVITRA is used to treat erectile dysfunction sometimes known as impotence in men. Erectile dysfunction is the inability to obtain and or maintain a hard erect penis for sexual activity.
LEVITRA tablets contain the active ingredient vardenafil (present as vardenafil hydrochloride trihydrate) which belongs to a group of medicines called phosphodiesterase type 5 inhibitors. These work 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 in the natural way.
LEVITRA will only work if you are sexually excited. It will not increase your sex drive.
LEVITRA is not approved for use in women.
LEVITRA tablets are not addictive.

BEFORE YOU TAKE LEVITRA

When you must not take it
Because sexual activity may place a strain on your heart, your doctor will need to check whether you are fit enough to use LEVITRA.
Do not take LEVITRA if you are being treated for angina (chest pain) or other heart conditions with certain medicines called nitrates.
Nitrate medicines include glyceryl trinitrate (also called nitroglycerine). These medicines can be sold under tradenames:
•  Anginine tablets
•  Glytrin Spray
•  Minitran patches
•  Nitrocor patches
•  Nitro-Dur patches
•  Nitroderm TTS patches
•  Nitrolingual pump spray
•  Rectogesic ointment
•  Transiderm-Nitro patches
Other nitrate medicines include sodium nitroprusside, isosorbide mononitrate and isosorbide dinitrate. Isosorbide mononitrate tablets can be sold under tradenames:
•  Corangin
•  Duride
•  Imdur Durules
•  Imtrate SR
•  ISMO 20
•  Isomonit
•  Monodur
Isosorbide dinitrate tablets can be sold under tradenames:
•  Coronex
•  Isordil
•  Sorbidin
There may be other tradenames not listed here.
Do not take LEVITRA if you are using the unapproved drug amyl nitrite. Amyl nitrite is also known as 'poppers', 'amyl' or 'rush' .
Do not take LEVITRA if you are taking an alpha-blocker (a particular type of medicine used to treat an enlarged prostate or high blood pressure). Examples of alpha-blockers are terazosin, tamsulosin, and prazosin.
Do not take LEVITRA if you are taking HIV protease inhibitors, medicines used to treat HIV infection. Examples of HIV protease inhibitors are indinavir or ritonavir .
You should not use LEVITRA together with other treatments for erectile dysfunction.
Do not take LEVITRA if you have an allergy to vardenafil or other phosphodiesterase type 5 inhibitors, or any of the ingredients in LEVITRA tablets listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include skin rash, itching, or difficulty breathing.
Do not give LEVITRA to children, growing adolescents or women.
Do not take your LEVITRA tablets after the expiry date printed on the pack. The EXPIRY date is marked on the strip of tablets as well as on the label of the carton. For example, 11 05 refers to the eleventh month of 2005.
Do not take your tablets if the packaging is torn or shows sign of tampering.

Before you start to take LEVITRA

Tell your doctor if you:
•  have any allergies to vardenafil or any other ingredients in LEVITRA tablets, or to any other medicines that you have used in the past, or to any other substances such as food, preservatives or dyes
•  have any heart or blood vessel problems
•  have ever suffered a heart attack or stroke
•  have any kidney or liver problems
•  have leukaemia (cancer of the blood cells)
•  have multiple myeloma (a cancer of the bone marrow)
•  have any disease or deformity of your penis
•  have low blood pressure
•  have sickle cell anaemia
•  have stomach ulcers
•  have a serious eye condition called retinitis pigmentosa
•  are receiving any other treatment for impotence
If you have not told your doctor or pharmacist about any of the above, tell them before you start taking LEVITRA.

Taking other medicines
Do not take LEVITRA if you are using nitrate or nitric oxide donor medicines for angina.
Do not take LEVITRA if you are taking HIV protease inhibitors, medicines used to treat HIV infection.
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:
•  ketoconazole and itraconazole, used to treat fungal infections
•  erythromycin, an antibiotic
•  alpha-blockers, medicines used to treat an enlarged prostate (BPH) or high blood pressure. Examples of alpha-blockers are terazosin, tamsulosin and prazosin.
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. 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

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 age, condition and response.
Do not take more than one dose of LEVITRA a day.

When to take it
Take your dose of LEVITRA 25 to 60 minutes before you wish to have sex. Swallow the tablet whole with a glass of water.
Sexual stimulation is required for a natural response to treatment with LEVITRA.
LEVITRA can be taken with or without food.
The medicine may be taken anywhere between 15 minutes to up to 5 hours before sexual activity. The amount of time LEVITRA takes to start working varies from person to person, but it normally takes between 25 to 60 minutes.
If you are not sure what to do, ask your doctor or pharmacist.
If you have trouble remembering when to take your medicine, ask your pharmacist for some hints.

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, tell your doctor or pharmacist that you are taking LEVITRA. See "BEFORE YOU TAKE LEVITRA" for a list of common nitrate medications.
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 . In these cases, your doctor may need to adjust your dose.

Things you must not do
Do not use the unregistered 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.
If you get an angina attack whilst taking LEVITRA, do not take nitrate medicines to relieve the pain. Tell your doctor immediately. Make sure that your doctor knows you are taking LEVITRA.
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 patients. The ability to drive and/or operate machinery may be impaired. If you drink alcohol, dizziness or faintness may be worse.

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 if you notice any of the following and they worry you:
•  headache
•  flushing
•  dyspepsia (heartburn)
•  nausea
•  dizziness or light-headedness
•  a stuffy or runny nose
•  sensitivity of the eye to sunlight
•  high or low blood pressure
•  stiffness in muscles
•  pain in the joints
•  rash
•  stomach or abdominal pain
These are the more common side effects of LEVITRA. They are usually mild and short-lived.
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.
Tell your doctor immediately, or go to the accident and emergency department at your nearest hospital if you notice any of the following:
•  severe chest pain
•  angina
•  irregular heart beats
•  loss of consciousness
These are serious side effects. You may need urgent medical attention or hospitalisation.
Serious life-threatening allergic reactions have been reported. The signs of an allergic reaction are listed below. If the following happens, stop taking Levitra, and tell your doctor immediately, or go to accident and emergency at your nearest hospital:
•  rash
•  swelling of the face, lips, tongue or other parts of the body
•  shortness of breath, wheezing or trouble breathing.
Other side effects not listed above may also occur in some patients. 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 30°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 damp 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 mg tablets are orange film-coated round tablets with an embossed BAYER-cross on one side and "5" on the other side (sold in blister packs of 2 and 4).
LEVITRA 10 mg tablets are orange film-coated round tablets with an embossed BAYER-cross on one side and "10" on the other side (sold in blister packs of 2 and 4).
LEVITRA 20 mg tablets are orange film-coated round tablets with an embossed BAYER-cross on one side and "20" on the other side (sold in blister packs of 2 and 4).

Ingredients
Active Ingredients per tablet:
LEVITRA 5 - vardenafil (as hydrochloride trihydrate) 5 mg
LEVITRA 10 - vardenafil (as hydrochloride trihydrate) 10 mg
LEVITRA 20 - vardenafil (as hydrochloride trihydrate) 20 mg
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)

Manufacturer
BAYER AG, Germany