Consumer medicine information

Terry White Chemists Sildenafil Tablets

Sildenafil

BRAND INFORMATION

Brand name

Terry White Chemists Sildenafil Tablets

Active ingredient

Sildenafil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Terry White Chemists Sildenafil Tablets.

What is in this leaflet

Read this leaflet carefully before taking your medicine.

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

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up-to-date leaflet from www.apotex.com.au.

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

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

Keep this leaflet with your medicine. You may want to read it again.

What this medicine is used for

The name of your medicine is Terry White Chemists Sildenafil. It contains the active ingredient sildenafil.

It is used to treat erectile dysfunction, more commonly known as impotence, in men. This is when a man cannot get, or keep, a hard erect penis suitable for sexual activity.

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

This medicine is available only with a doctor's prescription.

How it works

Sildenafil belongs to a group of medicines called phosphodiesterase type 5 inhibitors.

It works by relaxing the blood vessels in your penis when you are sexually excited. This allows blood to flow into your penis, allowing you to get an erection in the natural way.

Sildenafil will work only if you are sexually excited.

Sildenafil will not increase your sex drive.

There is no evidence that this medicine is addictive.

Use in children

This medicine should not be used in children.

Before you take this medicine

YOU MUST NOT TAKE SILDENAFIL IF YOU ARE TAKING ANY NITRATE MEDICATION. IT MAY LEAD TO A SEVERE DROP IN YOUR BLOOD PRESSURE, WHICH MAY BE DIFFICULT TO TREAT.

BECAUSE SEXUAL ACTIVITY MAY PLACE A STRAIN ON YOUR HEART, YOUR DOCTOR WILL NEED TO CHECK WHETHER YOU ARE FIT ENOUGH TO TAKE SILDENAFIL.

When you must not take it

Do not take this medicine if:

  • You are being treated for angina (chest pain) or other heart conditions with certain medicines called nitrates. It includes glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil or organic nitrates in any form.
  • You have or have had any of the following:
    - heart or blood vessel problems that make sexual intercourse inadvisable
    - suffered a heart attack or stroke in the last 6 months
    - severe liver problems
    - blood pressure is unusually high or low or is not effectively treated
    - loss of vision in one or both eyes from an eye disease called non-arteritic anterior ischaemic optic neuropathy (NAION)
    - eye disease called retinitis pigmentosa.
  • You are hypersensitive to, or have had an allergic reaction to, sildenafil or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you start to take it

Before you start taking this medicine, tell your doctor if:

  1. You have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes.
  2. You have or have had any medical conditions, especially the following:
    - diabetes, especially if you also have eye problems
    - kidney or liver problems
    - leukaemia (cancer of the blood cells)
    - multiple myeloma (a cancer of the bone marrow)
    - any disease or deformity of your penis
    - any bleeding disorder such as haemophilia
    - stomach ulcer
    - a disease of the blood called sickle cell anaemia
    - colour vision problems
    - previously experienced sudden decrease or loss of hearing.
  3. You are taking or using any of the following medications:
    - other medicines containing sildenafil or any other treatment for male erectile dysfunction (impotence). Other medicines used to treat impotence include tadalafil and vardenafil
    - any treatments for pulmonary arterial hypertension (PAH)
    PAH is a type of high blood pressure that affects the arteries of the lungs and right side of your heart.
  4. You are planning to have surgery or an anaesthetic.
  5. You are currently receiving or are planning to receive dental treatment.
  6. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with sildenafil. These include:

  • cimetidine, a medicine used to treat ulcers
  • some medicines used to treat fungal infections including ketoconazole and itraconazole
  • some antibiotics including erythromycin and rifampicin
  • some protease inhibitors such as ritonavir and saquinavir for the treatment of HIV infection.

If you are taking any of these you may need a different dose or you may need to take different medicines.

Do not take sildenafil if you are using nitrate medicines.

Other medicines not listed above may also interact with sildenafil.

How to take this medicine

Follow carefully all directions given to you by your doctor. Their instructions may be different to the information in this leaflet.

How much to take

Your doctor will decide the correct dose for you depending on your condition and response.

This can be one 25 mg tablet a day or one 50 mg tablet a day or one 100 mg tablet a day.

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

How to take it

Swallow the tablet whole with a full glass of water.

When to take it

Take your dose of sildenafil about one hour before you intend to have sex.

Sildenafil Tablets 25 mg, 50 mg or 100 mg.

The amount of time sildenafil takes to start working varies from person to person, but it normally takes between half an hour and one hour.

You may find sildenafil takes longer to work if you take it with a heavy meal.

Sildenafil will work only if you are sexually excited.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

If you take too much (overdose)

If you think that you or anyone else may have taken too much of this medicine, immediately telephone your doctor or the Poisons Information Centre (Tel: 13 11 26 in Australia) for advice. Alternatively, go to the Accident and Emergency department at your nearest hospital.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

Stop using sildenafil if you have a loss of eyesight in one or both eyes, experienced loss of hearing or have an erection that persists more than 4 hours. Seek medical attention urgently.

If sildenafil 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 decide that you need a higher dose.

If you are about to start taking any new medicines, especially nitrates, tell your doctor and pharmacist that you are taking sildenafil.

See "Before you take Sildenafil" for a list of common nitrate medications.

Tell your doctor that you are taking this medicine if:

  • you are about to be started on any new medicine
  • you are about to have any blood tests
  • you are going to have surgery or an anaesthetic or are going into hospital.

Your doctor may occasionally do tests to make sure the medicine is working and to prevent side effects. Go to your doctor regularly for a check-up.

Tell any other doctors, dentists and pharmacists who are treating you that you take this medicine.

Things you must not do

Do not use the drug amyl nitrite (sometimes called "poppers") while you are taking sildenafil.

If you get an angina attack do not take nitrate medicines to relieve the pain but tell your doctor immediately. Make sure your doctor knows you are taking sildenafil.

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

Things to be careful of

Be careful drinking alcohol while taking sildenafil.

Drinking alcohol can temporarily impair the ability to get an erection.

Do not drink large amounts of alcohol before sexual activity.

If you experience changes in vision, or dizziness, when taking sildenafil, you should not drive or operate machinery.

Possible side effects

Tell your doctor as soon as possible if you do not feel well while you are taking sildenafil or if you have any questions or concerns.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • headache, dizziness
  • flushing
  • indigestion or heartburn
  • nasal and/or sinus congestion
  • swelling of your nose
  • diarrhoea
  • rash
  • tightness in your throat
  • feeling hot or irritable
  • dry or irritated eye(s)

Tell your doctor as soon as possible if you notice any of the following.

These may be serious side effects and you may need medical attention:

  • unusual heart beat
  • urinary tract infection (stinging or burning urine, more frequent need to pass urine)
  • persistent headache or fainting
  • blood in the urine
  • nose bleeds
  • pain or tingling in your hands, toes or feet
  • decreased sensitivity or numbness in your mouth
  • "red eye" due to excess of blood in the white part of the eye and/or in the eyelids
  • swollen or puffy eye(s)
  • fatigue, pain in or around the eye(s)
  • muscle pain.

If you experience any of the following, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

These are very serious side effects and you may need urgent medical attention or hospitalisation:

  • chest pain
  • increased heart rate
  • sudden decrease or loss of hearing
  • seizures, fits or convulsions
  • visual disturbances such as:
    - red or yellow colour tinges to your vision or colourless objects appear coloured
    - you see a halo around lights, sparks or lights when your eyes are closed.

Very rarely your erection may persist for longer than usual. If your erection continues for four hours, or sooner if there is pain, you should seek medical attention urgently.

Rarely men have lost eyesight some time after taking drugs to treat erectile dysfunction (known as impotence). It is not known at this time if sildenafil causes this. If you lose eyesight in one or more eyes, seek medical attention urgently.

Other side effects not listed above may occur in some patients.

Allergic reactions

If you think you are having an allergic reaction to sildenafil, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it.

If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 30°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine where children cannot reach it.

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 this medicine or it has passed its expiry date, your pharmacist can dispose of the remaining medicine safely.

Product description

What Terry White Chemists Sildenafil looks like

  • 25 mg tablets
    The 25 mg tablets are white diamond shaped, biconvex film-coated tablets, engraved "APO" on one side and "SIL25" on the other side.
  • 50 mg tablets
    The 50 mg tablets are white diamond shaped, biconvex film-coated tablets, engraved "APO" on one side and "SIL50" on the other side.
  • 100 mg tablets
    The 100 mg tablets are white diamond shaped, biconvex film-coated tablets, engraved "APO" on one side and "SIL100" on the other side.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Terry White Chemists Sildenafil 25 mg tablets:
Each tablet contains 25 mg of sildenafil as the active ingredient.

It also contains the following inactive ingredients:

  • Microcrystalline cellulose
  • Colloidal anhydrous silica
  • Magnesium stearate
  • Croscarmellose sodium
  • Hydroxypropylcellulose
  • Hypromellose
  • Macrogol 8000
  • Titanium dioxide

Terry White Chemists Sildenafil 50 mg tablets:
Each tablet contains 50 mg of sildenafil as the active ingredient.

It also contains the following inactive ingredients:

  • Microcrystalline cellulose
  • Colloidal anhydrous silica
  • Magnesium stearate
  • Croscarmellose sodium
  • Hydroxypropylcellulose
  • Hypromellose
  • Macrogol 8000
  • Titanium dioxide

Terry White Chemists Sildenafil 100 mg tablets:
Each tablet contains 100 mg of sildenafil as the active ingredient.

It also contains the following inactive ingredients:

  • Microcrystalline cellulose
  • Colloidal anhydrous silica
  • Magnesium stearate
  • Croscarmellose sodium
  • Hydroxypropylcellulose
  • Hypromellose
  • Macrogol 8000
  • Titanium dioxide

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

  • Terry White Chemists Sildenafil 25 mg tablets
    Blister pack of 1, 4, 8, 12 tablets: AUST R 164815
  • Terry White Chemists Sildenafil 50 mg tablets
    Blister pack of 1, 4, 8, 12 tablets: AUST R 164820
  • Terry White Chemists Sildenafil 100 mg tablets
    Blister pack of 1, 4, 8, 12 tablets: AUST R 164818

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

This leaflet was last updated in September 2014.

BRAND INFORMATION

Brand name

Terry White Chemists Sildenafil Tablets

Active ingredient

Sildenafil

Schedule

S4

 

Name of the medicine

Sildenafil citrate.

Excipients.

Microcrystalline cellulose, croscarmellose sodium, anhydrous colloidal silica, magnesium stearate, hydroxypropyl cellulose, hypromellose, macrogol 8000 and titanium dioxide.

Description

Chemical name: 1-[4-ethoxy-3 -(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl)phenylsulphonyl] -4-methylpiperazine citrate. Molecular formula: C22H30N6O4S.C6H8O7. MW: 666.7. CAS: 171599-83-0. Sildenafil citrate is an orally active selective inhibitor of cGMP specific PDE5 (phosphodiesterase type 5) which is the predominant PDE isoenzyme in human corpora cavernosa. Sildenafil citrate is an off white, crystalline powder. Its aqueous solubility is equivalent to 2.6 mg sildenafil per mL at 25°C.

Pharmacology

Pharmacological actions.

Sildenafil tablets are an oral therapy for erectile dysfunction which restores impaired erectile function by increasing blood flow to the penis, resulting in a natural response to sexual stimulation.
The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide then activates the enzyme, guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood.
Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on this tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its beneficial pharmacological effects.
Single oral doses of sildenafil tablets up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. The mean maximum decreases in supine systolic blood pressure following 100 mg oral dosing was 8.4 mmHg. The corresponding change in supine diastolic blood pressure was 5.5 mmHg. These decreases in blood pressure are consistent with the vasodilatory effects of sildenafil, probably due to increased cGMP levels in vascular smooth muscle.
Sildenafil has no effect on visual acuity or contrast sensitivity. Mild and transient differences in colour discrimination (blue/ green) were detected in some subjects using Farnsworth Munsell 100 hue test at 1 hour following a 100 mg dose, with no effects evident after 2 hours postdose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the phototransduction cascade of the retina. In vitro studies show that sildenafil is 10-fold less potent against PDE6 than PDE5.
Human platelets contain PDE5 enzyme system. Sildenafil, in limited studies, did not affect platelet function in vivo. In in vitro studies sildenafil was shown to potentiate the antiaggregatory effect of the nitric oxide donor, sodium nitroprusside.
Studies in vitro have shown that sildenafil has between 10 and 10,000-fold greater selectivity for PDE5 than for other phosphodiesterase isoforms (PDEs 1, 2, 3, 4, 6, 7 to 11). In particular, sildenafil has greater than 4,000-fold selectivity for PDE5 over PDE3, the cAMP specific phosphodiesterase isoform involved in the control of cardiac contractility.

Pharmacokinetics.

Absorption.

Sildenafil is rapidly absorbed after oral administration. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). The oral pharmacokinetics of sildenafil are proportional over the recommended dose range (25 mg-100 mg).
When sildenafil is taken with a high fat meal, the rate of absorption is reduced with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. Patients may need to individualise their dosing relative to their food intake based on their own experienced clinical response.

Distribution.

The mean steady-state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
In sixteen healthy volunteers receiving sildenafil (100 mg single dose), the mean semen concentrations of sildenafil 1.5 and 4 hours postdose were 18% and 17% respectively of the plasma concentration at the same time point. The amount in the ejaculate at 90 minutes after dosing was less than 0.0002% of the administered dose.

Metabolism.

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 40% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised with a terminal half-life of approximately 4 hours.

Excretion.

The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 hours. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) to a lesser extent in the urine (approximately 13% of administered oral dose).

Special patient populations.

Elderly.

Healthy elderly volunteers (65 years or older) had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in younger volunteers (18-45 years). However, analysis of the safety database showed that age had no effect on the incidence of adverse events.

Renal insufficiency.

In volunteers with mild (Clcr = 50-80 mL/min) and moderate (Clcr = 30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were not altered. In volunteers with severe (Clcr ≤ 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in increases in AUC (100%) and Cmax (88%) compared to age matched volunteers with no renal impairment.

Hepatic insufficiency.

In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severe hepatic impairment have not been studied.

Clinical Trials

The efficacy and safety of sildenafil was evaluated in 21 randomised, double blind placebo controlled trials up to 6 months duration. Sildenafil was administered to more than 3,000 patients aged 19-87, with erectile dysfunction of various aetiologies (organic, psychogenic, mixed). The efficacy was evaluated by global assessment questions, diary of erections, the International Index of Erectile Function (IIEF, a validated sexual function questionnaire) and a partner questionnaire.
Sildenafil efficacy, determined as the ability to achieve and maintain an erection sufficient for sexual intercourse, was demonstrated in all 21 studies and was maintained in long-term extension studies (one year). In fixed dose studies the proportions of patients reporting that treatment improved their erections were 62% (25 mg), 74% (50 mg), 82% (100 mg) compared to 25% on placebo. In addition to improvements in erectile function, analysis of IIEF showed that sildenafil treatment also improved the domains of orgasm, satisfaction with intercourse and overall satisfaction.
Across all trials, the proportion of patients reporting improvement on sildenafil were 59% of diabetic patients, 43% of radical prostatectomy patients and 83% of patients with spinal cord injury (versus 16%, 15% and 12% on placebo respectively).

Indications

Sildenafil is indicated for the treatment of erectile dysfunction in adult males.
Sildenafil is not indicated for use by women.

Contraindications

Use of sildenafil is contraindicated in patients with known hypersensitivity to any component of the tablet.
Nitrates and sildenafil must not be used concomitantly. Sildenafil was shown to potentiate the hypotensive effects of both acute and chronic nitrate administration and therefore, its coadministration with nitric oxide donors, organic nitrates or organic nitrites in any form, either regularly or intermittently is contraindicated. Drugs which must not be used concomitantly include glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil or organic nitrates in any form.
Sildenafil is contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors (e.g. patients with severe cardiovascular disease such as established cardiac failure and unstable angina pectoris) (see Precautions). The possibility of undiagnosed cardiovascular disorders in men with erectile dysfunction should be considered before prescribing sildenafil.
Sildenafil is not recommended in patients with male erectile dysfunction with a previous episode of nonarteritic anterior ischaemic optic neuropathy (NAION) (see Precautions and Adverse Effects, Postmarketing experience).
The safety of sildenafil has not been studied in the following subgroups of patients and its use is therefore contraindicated until further information is available: severe hepatic impairment, hypotension (blood pressure < 90/50 mmHg), hypertension (blood pressure > 170/110), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).

Precautions

A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine potential underlying causes, and identify appropriate treatment.
Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their patients, including those with recent onset angina, since there is a degree of cardiovascular risk associated with sexual intercourse. Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure and, as such, potentiates the hypotensive effect of nitrates (see Contraindications).
Physicians should advise patients to stop use of all PDE5 inhibitors, including sildenafil, and seek immediate medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of nonarteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors. An observational study evaluating whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION suggests an increase in the risk of NAION with PDE5 inhibitor use. In case of sudden visual loss, patients should be advised to stop taking sildenafil and consult a physician immediately.
Individuals who have already experienced NAION are at increased risk of NAION recurrence. PDE5 inhibitors, including sildenafil, are not recommended in patients with male erectile dysfunction with a previous episode of NAION (see Contraindications and Adverse Effects, Postmarketing experience).
In clinical trials, sildenafil has been shown to have systemic vasodilatory properties that result in transient decreases in blood pressure (see Clinical Trials). This is of little or no consequence in most patients. However, prior to prescribing sildenafil, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to vasodilators include those with left ventricular outflow obstruction (e.g. aortic stenosis, hypertrophic obstructive cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired autonomic control of blood pressure.
Agents for the treatment of erectile dysfunction should 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 sildenafil with other PDE5 inhibitors, or other pulmonary arterial hypertension (PAH) treatments containing sildenafil or with other treatments for erectile dysfunction have not been studied. Therefore the use of such combinations is not recommended.
Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the coadministration may lead to symptomatic hypotension in a few susceptible individuals (see Interactions with Other Medicines). In order to minimise the potential for developing postural hypotension, patients should be haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at lower doses should be considered (see Dosage and Administration). In addition, physicians should advise patients what to do in the event of postural hypotensive symptoms.
Sildenafil had no effect on bleeding time, including during coadministration with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). There is no safety information on the administration of sildenafil to patients with bleeding disorders or active peptic ulceration. Therefore sildenafil should be administered with caution to these patients.
There are limited safety data in patients with diabetic retinopathy. The safety of sildenafil in patients with untreated diabetic retinopathy has not been studied and therefore sildenafil should be administered to these patients only after careful benefit-risk assessment.
Sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, has been reported in a small number of postmarketing and clinical trials cases with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden decrease or loss of hearing. No causal relationship has been made between the use of PDE5 inhibitors and sudden decrease or loss of hearing. In case of sudden decrease or loss of hearing patients should be advised to stop taking sildenafil and consult a physician promptly.
The incidence of adverse events may be greater in those patients who require the maximum recommended dose of 100 mg (e.g. some diabetic and spinal cord injury patients).
Patients with cardiovascular disease who have not engaged in sexual intercourse for a number of years should have their cardiovascular status carefully assessed prior to initiating treatment with sildenafil.
Prolonged erections greater than four hours in duration and priapism (painful erections greater than 6 hours) have been reported infrequently since market approval of sildenafil commenced. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

Effects on fertility.

There was no impairment of fertility in rats given sildenafil for 36 days to females and 102 days to males at a dose producing an AUC value of more than 25 times the human male AUC.
There is no information on the effects of sildenafil on semen production, sperm motility/ morphology in patients suffering from erectile dysfunction. There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.

Use in pregnancy.

(Category B1)
Sildenafil is not indicated for use by women.
No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. The dose results in total systemic drug exposure (AUC) for unbound sildenafil and its major metabolite of greater than 60 times the exposure observed in human males given the maximum recommended human dose (MRHD) of 100 mg. In the rat prenatal and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In nonpregnant rat the AUC at this dose was about 20 times human AUC. There are no adequate and well controlled studies of sildenafil in pregnant women.

Use in lactation.

Sildenafil is not indicated for use in women. No information is available on its secretion into breast milk.

Genotoxicity.

Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.

Carcinogenicity.

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUC) for unbound sildenafil and its major metabolite of 35 and 39 times, for male and female rats, respectively, the exposures observed in human males given the maximum recommended human dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the maximum tolerated dose of 10 mg/kg/day, but resulting in total systemic drug exposure for unbound sildenafil and its major metabolite of less than the exposures observed in human males given the MRHD.

Effects on ability to drive and use machines.

As transient visual disturbances and dizziness have been reported in some patients taking sildenafil, particularly at the 100 mg dose, patients should be aware of how they react to sildenafil before driving or operating machinery, and the doctor should advise accordingly.

Interactions

Effects of other medicines on sildenafil.

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance *and inducers of these isoenzymes may increase sildenafil clearance.
Population pharmacokinetics analysis of clinical trial data indicated a reduction in sildenafil clearance when coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine). However, there was no increased incidence of adverse events in these patients.
Cimetidine (800 mg), a nonspecific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil (50 mg) to healthy volunteers.
When a single 100 mg dose of sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC).
Coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg three times daily) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. (See Dosage and Administration). Stronger CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have still greater effects.
Coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg twice daily) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 nanogram/mL, compared to approximately 5 nanogram/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates (see Dosage and Administration).
Since systemic exposure to sildenafil increases on coadministration with inhibitors of CYP3A4 the sildenafil dose may have to be reduced depending on tolerability.
Single doses of antacid (magnesium hydroxide/ aluminium hydroxide) did not affect the bioavailability of sildenafil.
There is no information on the interaction between sildenafil and cyclosporin.
It can be expected that concomitant administration of CYP3A4 inducers, such as rifampicin, will decrease plasma levels of sildenafil.
Population pharmacokinetics analysis showed no effect of concomitant medication on sildenafil pharmacokinetics when grouped as CYP2C9 inhibitors, CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, loop and potassium sparing diuretics, ACE inhibitors, calcium channel blockers, beta-adrenoreceptor antagonists or inducers of CYP450 metabolism (such as barbiturates).
In a study of healthy male volunteers. coadministration of the endothelin antagonist, bosentan, (an inducer of CYP3A4 [moderate], CYP2C9 and possibly of CYP2C19) at steady state (125 mg twice a day) with sildenafil at steady state (80 mg three times a day) resulted in 62.6% and 55.4% decrease in sildenafil AUC and Cmax, respectively. Sildenafil (80 mg three times a day) increased bosentan AUC and Cmax by 49.8% and 42%, respectively.

Effects of sildenafil on other medicines.

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 > 150 micromolar). Given sildenafil peak plasma concentrations of approximately 1 micromolar after recommended doses, it is unlikely that sildenafil will alter the clearance of substrates of these isoenzymes.
There are no data on the interaction of sildenafil and nonspecific phosphodiesterase inhibitors such as theophylline or dipyridamole.
In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25 mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilised on doxazosin therapy. In these study populations, mean additional reductions of supine blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were observed. When sildenafil and doxazosin were administered simultaneously to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and lightheadedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals. (See Precautions and Dosage and Administration.)
No significant interactions were shown when sildenafil 50 mg was coadministered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.
Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil causes a small reduction in supine and tilted diastolic blood pressure (3.5 and 6.1 mmHg respectively) in healthy subjects who had a blood alcohol level of 80 mg/dL.
No interaction was seen when sildenafil (100 mg) was coadministered with amlodipine in hypertensive patients. The mean additive reduction on supine blood pressure (systolic, 8 mmHg; diastolic, 7 mmHg) was of a similar magnitude to that seen when sildenafil was administered alone to healthy volunteers (see Pharmacology, Pharmacological actions).
Analysis of the safety data base showed no difference in the side effect profile in patients taking sildenafil with and without antihypertensive medication.
Sildenafil was shown to potentiate the hypotensive effect of acute and chronic nitrate administration. Therefore, use of nitric oxide donors, organic nitrates, or organic nitrites in any form either regularly or intermittently with sildenafil is contraindicated (see Contraindications).

Adverse Effects

Clinical trial data.

Sildenafil was administered to over 3700 patients (aged 19-87) during clinical trials worldwide. Over 550 patients were treated for longer than one year.
Treatment with sildenafil was well tolerated. In placebo controlled clinical studies, the discontinuation rate due to adverse events was low and similar to placebo. The adverse events were generally transient and mild to moderate in nature.
Across trials of all designs, the profile of adverse events reported by patients receiving sildenafil was similar. In fixed dose studies, the incidence of adverse events increased with dose. The nature of the adverse events in flexible dose studies, which more closely reflect the recommended dosage regimen, was similar to that for fixed dose studies.
When sildenafil was taken as recommended (on an as needed basis in flexible dose placebo controlled clinical trials) the following adverse events were reported (see Table 1).
Other adverse reactions occurred at a rate of > 2%, but equally commonly on placebo: respiratory tract infection, back pain, flu syndrome and arthralgia.
In fixed dose studies, dyspepsia (17%) and abnormal vision (11%) were more common at 100 mg than at lower doses.
At doses above the recommended dose range, adverse events were similar to those detailed above but generally were reported more frequently.
No cases of priapism were reported during controlled clinical trials.
The following events occurred in < 2% of patients in controlled clinical trials; a causal relationship to sildenafil is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful.

General disorders and administrative site conditions.

Face oedema, oedema, peripheral oedema, asthenia, pain, chills, chest pain, thirst.

Immune systems disorders.

Hypersensitivity.

Cardiac disorders.

Angina pectoris, AV block, tachycardia, palpitation, myocardial ischaemia, cardiac arrest, heart failure, cardiomyopathy.

Vascular disorders.

Hypotension, postural hypotension, vasodilation, shock.

Gastrointestinal disorders.

Nausea, vomiting, glossitis, colitis, dysphagia, gastritis, oesophagitis, stomatitis, dry mouth, rectal haemorrhage, abdominal pain.

Blood and lymphatic system disorders.

Anaemia and leukopenia.

Metabolic and nutritional disorders.

Gout, unstable diabetes, hyperglycaemia, hyperuricemia, hypoglycaemic reaction, hypernatremia.

Musculoskeletal and connective tissue disorders.

Arthritis, arthrosis, myalgia, tenosynovitis, bone pain, myasthenia, synovitis.

Injury, poisoning and procedural complications.

Accidental fall, accidental injury, tendon rupture.

Nervous system disorders.

Ataxia, hypertonia, neuralgia, neuropathy, paraesthesia, tremor, vertigo, somnolence, hyporeflexia, hypaesthesia, migraine, syncope, cerebral thrombosis.

Psychiatric disorders.

Depression, insomnia, abnormal dreams.

Respiratory, thoracic and mediastinal disorders.

Respiratory disorder, asthma, dyspnoea, sputum increased, cough increased.

Infections and infestations.

Infection, rhinitis, sinusitis, bronchitis, laryngitis, pharyngitis, herpes simplex, gastroenteritis, gingivitis, cystitis.

Skin and subcutaneous tissue disorders.

Urticaria, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis, photosensitivity reaction.

Eye disorders.

Mydriasis, conjunctivitis, photophobia, eye pain, eye haemorrhage, cataract, dry eyes.

Ear and labyrinth disorders.

Sudden decrease or loss of hearing, ear pain, tinnitus.

Reproductive and breast disorders.

Prostatic disorder, breast enlargement, abnormal ejaculation, genital oedema and anorgasmia.

Renal and urinary disorders.

Nocturia, urinary frequency, urinary incontinence.

Investigations.

Abnormal electrocardiogram, liver tests abnormal.
In two pharmacokinetic studies involving 48 subjects, four (8.3%) subjects experienced oropharyngeal treatment related adverse events following a single administration of the orally disintegrating tablets without water. These events included oral mucosal erythema and dry throat. (The orally disintegrating tablet is not available in this brand.)
Adverse reactions reported in clinical trials that are not included in the above section include the following.

Eye disorders.

Visual disturbance, cyanopsia, photopsia, chromatopsia, ocular hyperaemia, visual brightness, eye oedema, eye swelling, dry eye, asthenopia, halo vision, xanthopsia, erythropsia, eye disorder, conjunctival hyperaemia, eye irritation, abnormal sensation in eye, eyelid oedema.

Vascular disorders.

Hot flush.

Respiratory, thoracic and mediastinal disorders.

Sinus congestion, epistaxis, throat tightness, nasal dryness, nasal oedema.

Gastrointestinal disorders.

Gastro-oesophageal reflux disease, hypoaesthesia oral.

Musculoskeletal and connective tissue disorders.

Pain in extremity.

Reproductive system and breast disorders.

Erection increased.

General disorders and administration site conditions.

Feeling hot, irritability.

Investigations.

Heart rate increased.

Postmarketing experience.

Cardiac disorders and vascular disorders.

Serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack and hypertension, have been reported postmarketing in temporal association with the use of sildenafil. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil and sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors.
Tachycardia, hypotension, syncope, and epistaxis have also been reported postmarketing. Rare spontaneous reports have been received of hypotensive events after the use of sildenafil in combination with alpha blockers.
Other events reported postmarketing to have been observed in temporal association with sildenafil and not listed in the clinical trials adverse reactions section include the following.

Nervous system disorders.

Seizure, seizure recurrence and anxiety.

Reproductive systems and breast disorders.

Priapism and prolonged erection.

Renal disorders.

Haematuria.

Eye disorders.

Diplopia, temporary vision loss/ decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/ pressure, increased intraocular pressure, retinal vascular disease or bleeding, vitreous detachment/ traction and paramacular oedema.
Nonarteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio ('crowded disc'), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidaemia and smoking. An observational study evaluating whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION suggests an increase in the risk of NAION with PDE5 inhibitor use (see Contraindications and Precautions).

Immune system disorders.

Hypersensitivity reaction.

Ear and labyrinth disorders.

Sudden decrease or loss of hearing.
Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including sildenafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of sildenafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors (see Precautions).

Dosage and Administration

Sildenafil tablets are for oral administration.

Use in adults.

The recommended dose is 50 mg taken as needed approximately one hour before sexual activity. Based on the efficacy and toleration, the dose may be increased to 100 mg or decreased to 25 mg. The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day.

Use in the elderly.

Since sildenafil clearance is reduced in elderly patients, a first dose of 25 mg should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and 100 mg.

Dosage adjustment in renal impairment.

The dosing recommendations for ‘Use in adults’ should be followed for patients with mild to moderate renal impairment (Clcr = 30-80 mL/min).
Since sildenafil clearance is reduced in patients with severe renal impairment (Clcr < 30 mL/min) a 25 mg starting dose should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and 100 mg.

Dosage adjustment in hepatic impairment.

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg starting dose should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and 100 mg.

Use in patients using other medicines.

Concomitant use of potent CYP3A4 inhibitors has been associated with increased plasma levels of sildenafil (e.g. erythromycin, 182%, saquinavir, 210%). It can also be expected that more potent CYP3A4 inhibitors such as ketoconazole and itraconazole would result in increased plasma levels of sildenafil. (See Interactions with Other Medicines, Effects of other medicines on sildenafil.) Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients.
Given the extent of the interaction with patients receiving concomitant therapy with ritonavir, it is recommended not to exceed a maximum single dose of 25 mg of sildenafil in a 48 hour period. (See Interactions with Other Medicines, Effects of other medicines on sildenafil.)
In order to minimise the potential for developing postural hypotension, patients should be stable on alpha-blocker therapy prior to initiating sildenafil treatment. In addition, initiation of sildenafil at lower doses should be considered (see Precautions and Interactions with Other Medicines).

Use in children.

Sildenafil is not indicated for use in children.

Overdosage

Overdose information is limited. In studies with healthy volunteers, of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates and severities were increased.
In cases of overdose, standard supportive measures should be adopted as required. Sildenafil blood levels are not clinically useful. Monitor ECG and blood pressure in symptomatic patients. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminated in the urine.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Tablets (white to off white, diamond shaped, biconvex, film coated, marked APO), 25 mg* (marked SIL25 on reverse, AUST R 14815), 50 mg* (marked SIL50 on reverse, AUST R 164820), 100 mg (marked SIL100 on reverse, AUST R 164818): 1's*, 4's, 8's*, 12's* (Aluminium/PVC blister).
*Not currently marketed in Australia.
Terry White Chemists Sildenafil tablets are intended for oral administration.

Storage

Store below 30°C.

Poison Schedule

S4.