Consumer medicine information

Sildatio PHT

Sildenafil

BRAND INFORMATION

Brand name

Sildatio PHT

Active ingredient

Sildenafil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Sildatio PHT.

SUMMARY CMI

SILDATIO PHT

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using SILDATIO PHT?

SILDATIO PHT contains the active ingredient sildenafil (present as sildenafil citrate). SILDATIO PHT is used to treat pulmonary arterial hypertension (high blood pressure in the blood vessels in the lungs). SILDATIO PHT lowers the blood pressure by relaxing these blood vessels.

For more information, see Section 1. Why am I using SILDATIO PHT? in the full CMI.

2. What should I know before I use SILDATIO PHT?

Do not use if you have ever had an allergic reaction to sildenafil or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use SILDATIO PHT? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Sildenafil and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use SILDATIO PHT?

  • The usual dose is one 20 mg tablet taken three times a day (taken 6-8 hours apart)

More instructions can be found in Section 4. How do I use SILDATIO PHT? in the full CMI.

5. What should I know while using SILDATIO PHT?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using SILDATIO PHT.
  • You must stop treatment with SILDATIO PHT if you have sudden vision problems including blurred, decreased or distorted vision, objects appear smaller or further away than they are, changes to colour vision, loss of eyesight in one or both eyes, or have an erection that lasts more than 4 hours. Seek medical attention urgently.
Things you should not do
  • Do not use drugs containing amyl nitrate (sometimes called “poppers”) while you are on SILDATIO PHT.
  • If you get an angina attack do not take nitrate medicines to relieve the pain but tell your doctor immediately.
Driving or using machines
  • If you experience changes in vision, or dizziness when on SILDATIO PHT, you should not drive or operate machinery.
Drinking alcohol
  • You may feel lightheaded if you drink alcohol while you are using SILDATIO PHT
Looking after your medicine
  • Keep SILDATIO PHT tablets where children cannot reach it.
  • Keep SILDATIO PHT in a cool, dry place where the temperature stays below 30°C.

For more information, see Section 5. What should I know while using SILDATIO PHT? in the full CMI.

6. Are there any side effects?

Tell your doctor or pharmacist if you notice headache, dizziness, flushing, indigestion, stuffy nose, muscle aches, back or limb pain, rash, diarrhoea or upset stomach, a numbness or tingling sensation, breathlessness or coughing, fever or flu like symptoms, nose bleeds, difficulty sleeping, hayfever, prolonged erection.

If you lose sight in one or both eyes or experience changes in vision such as blurring, a blue colour to your vision or great awareness of light while on SILDATIO PHT, seek medical attention urgently.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

SILDATIO PHT

Active ingredient(s): Sildenafil (as citrate)

Consumer Medicine Information (CMI)

This leaflet provides important information about using SILDATIO PHT. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using SILDATIO PHT.

Where to find information in this leaflet:

1. Why am I using SILDATIO PHT?
2. What should I know before I use SILDATIO PHT?
3. What if I am taking other medicines?
4. How do I use SILDATIO PHT?
5. What should I know while using SILDATIO PHT?
6. Are there any side effects?
7. Product details

1. Why am I using SILDATIO PHT?

SILDATIO PHT contains the active ingredient sildenafil (present as sildenafil citrate). Sildenafil belongs to a group of medicines called phosphodiesterase type 5 inhibitors.

SILDATIO PHT is used to treat pulmonary arterial hypertension (high blood pressure in the blood vessels in the lungs). Sildenafil lowers the blood pressure by relaxing these vessels.

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.

2. What should I know before I use SILDATIO PHT?

Warnings

Do not use SILDATIO PHT if:

  • You are taking nitrite or nitrate medications.
  • You are being treated for angina (chest pain), or other heart conditions with medicines called nitrates.
    These are available in multiple dosage forms, such as tablets, patches, sprays and injections. Active ingredients in nitrate medicines include, but not limited to:
    - glyceryl trinitrate (also called nitroglycerin)
    - isosorbide mononitrate, isosorbide dinitrate
    - nicorandil
    - sodium nitroprusside.
  • You are taking guanylate cyclase stimulators (GCS) such as Adempas (riociguat)
    GCS is a type of medicine used to treat high blood pressure in the blood vessels in the lungs caused by blood clots in the lungs (chronic thromboembolic pulmonary hypertension, CTEPH) or narrowing of the vessels that carry blood from the heart to the lungs (pulmonary arterial hypertension or PAH)
  • you have suffered a heart attack or stroke in the last 6 months.
  • you have severe liver problems.
  • you have blood pressure that is unusually low and is not effectively treated.
  • an eye disease called retinitis pigmentosa.
  • you have sudden vision problems including loss of vision in one or both eyes from an eye disease called non-arteritic anterior ischaemic optic neuropathy (NAION).
  • you are taking certain medicines used to treat fungal infections including ketoconazole and itraconazole.
  • you are taking ritonavir, a treatment for HIV infection.
  • you are allergic to sildenafil or similar medicines, or any of the ingredients listed at the end of this leaflet.
    An allergic reaction can include:
    - Hives, itching or skin rash
    - Swelling of the face, lips or tongue which may lead to difficulty swallowing or breathing
    Always check the ingredients to make sure you can use this medicine.
  • the packaging is torn or shows signs of tampering.
  • the expiry date on the pack has passed.

Before treatment with SILDATIO PHT, check with your doctor if you:

  • have any allergies to any other medicines or any other substances such as foods, preservatives or dyes
  • have previously had sudden vision problems including blurred, decreased or distorted vision, objects appear smaller or further away than they are, changes to colour vision, loss of eyesight in one or both eyes.
  • have any of the following medical conditions:
    - heart or blood vessel problems
    - high blood pressure o diabetes, especially if you also have eye problems
    - leukaemia (cancer of the blood cells)
    - multiple myeloma (a cancer of the bone marrow)
    - any bleeding disorder such as haemophilia or problems with nose bleeds o stomach ulcer
    - a disease of the blood called sickle cell anaemia
    - pulmonary veno-occlusive disease (blockage or narrow vein in the lung)
    - any disease or deformity of your penis
    - you are receiving any treatment for male erectile dysfunction (impotence), including Viagra, which contains the same medicine, sildenafil as SILDATIO PHT. There are other tradenames for sildenafil containing medicines that are not listed here. Other medicines used to treat impotence include Cialis and Levitra
    - you are receiving other treatments for your condition
    - you previously experienced sudden decrease or loss of hearing.
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

SILDATIO PHT should not be used during pregnancy. Your doctor will discuss the risks with you.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

You should not breastfeed while being treated with SILDATIO PHT.

Use in children

SILDATIO PHT is not for use in children under 18 years of age.

3. What if I am taking other medicines?

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

Do not use SILDATIO PHT if you are using nitrate medicines for angina.

Do not use SILDATIO PHT if you are taking guanylate cyclase stimulators (GCS), such as Adepmas (riociguat).

Tell your doctor if you are taking any other medicines for pulmonary arterial hypertension.

These medicines include Tracleer (bosentan), Flolan (epoprostenol) or Ventavis (Iloprost).

Some medicines may interfere with SILDATIO PHT and affect how it works.

  • medicines called alpha-blockers. These are used to treat high blood pressure or prostate problems.
  • some medicines used to treat epilepsy such as phenytoin, carbamazepine and phenobarbital
  • St John's wort that may be used to treat mild anxiety
  • Rifampicin used to treat leprosy or tuberculosis
  • An antibiotic called erythromycin
  • Saquinavir, a medicine used to treat HIV infection
  • Cimetidine for stomach ulcers

You may need to take different medicines or different amounts of your medicine. Your doctor or pharmacist can tell you what to do if you are taking any of these medicines. They also have a more complete list of medicines to be careful with or avoid while you are being treated with SILDATIO PHT.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SILDATIO PHT.

Avoid drinking grapefruit juice. It may increase the level of sildenafil in your blood.

4. How do I use SILDATIO PHT?

Take SILDATIO PHT tablets exactly as your doctor has prescribed.

Follow all directions given to you by your doctor and pharmacist carefully.

They may differ from the information contained in this leaflet.

How much to take SILDATIO PHT

  • The usual dose is one 20 mg tablet taken three times a day (taken 6-8 hours apart)

When to take SILDATIO PHT

  • Take SILDATIO PHT tablets at the same time each day. This will have the best effect and also help you to remember when to take it. SILDATIO PHT tablets can be taken with or without food.

How to take SILDATIO PHT

  • Swallow the SILDATIO PHT tablet whole with a full glass of water.

How long to take SILDATIO PHT

  • You must take SILDATIO PHT tablets every day. Continue taking your medicine for as long as your doctor tells you.

If you forget to take SILDATIO PHT

If you miss your dose at the usual time and it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much SILDATIO PHT

If you think that you have used too much SILDATIO PHT, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using SILDATIO PHT?

Things you must do

  • You must stop treatment with SILDATIO PHT if you have sudden vision problems including blurred, decreased or distorted vision, objects appear smaller or further away than they are, changes to colour vision, loss of eyesight in one or both eyes, experience loss of hearing or have an erection that lasts more than 4 hours. Seek medical attention urgently.
  • If you are about to start taking any new medicines, especially nitrates or Adepmas (riociguat), tell your doctor and pharmacist that you are being treated with SILDATIO PHT.
    See "Do not use SILDATIO PHT" for a list of common nitrate medications.

Remind any doctor, dentist or pharmacist you visit that you are using SILDATIO PHT.

Things you must not do

  • Do not use drugs containing amyl nitrite (sometimes called "poppers") while you are on SILDATIO PHT.
  • 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 being treated with SILDATIO PHT.
  • Do not take or use SILDATIO PHT to treat any other conditions unless your doctor says so.
  • Do not give SILDATIO PHT to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how SILDATIO PHT affects you.

SILDATIO PHT can cause dizziness and effects on vision.

If you experience changes in vision, or dizziness when on SILDATIO PHT, you should not drive or operate machinery.

Drinking alcohol

Tell your doctor if you drink alcohol.

You may feel lightheaded if you drink alcohol while you are using SILDATIO PHT.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep the tablets in their pack until it is time to take them. If you take your tablets out of the pack they will not keep as well.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Headache
  • Dizziness
  • Flushing
  • Indigestion
  • Stuffy nose
  • Muscle aches, back or limb pain
  • Rash
  • Diarrhoea or upset stomach
  • A numbness or tingling skin sensation
  • Breathlessness or coughing
  • Fever or flu like symptoms
  • Nose bleeds
  • Difficulty sleeping
  • Hayfever
  • Prolonged erection
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Rarely men have lost vision in one or both eyes sometime after taking drugs such as sildenafil, tadalafil or vardenafil to treat impotence (known as erectile dysfunction).
  • A small number of people have reported a loss of hearing, which may include a ringing or other persistent noise in the ears and dizziness, while being treated with SILDATIO PHT. It is not known whether hearing loss is related to SILDATIO PHT.
If you have sudden vision problems, lose sight in one or both eyes or experience changes in vision such as blurring, decreased or distored vision, objects appear smaller or further away than they are, changes to your colour vision, a blue colour to your vision or a greater awareness of light while on SILDATIO PHT, seek medical attention urgently. If you experience any loss of hearing, tell your doctor as soon as possible.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What SILDATIO PHT contains

Active ingredient
(main ingredient)		Sildenafil (as citrate) equivalent to 20 mg sildenafil per tablet
Other ingredients
(inactive ingredients)
  • Cellulose microcrystalline
  • Calcium hydrogen phosphate
  • Croscarmellose
  • Magnesium stearate
  • Opadry II - 31K58643 White (hypromellose, titanium dioxide, lactose monohydrate, triacetin) ARTG No. 107652
Potential allergensN/A

Do not take this medicine if you are allergic to any of these ingredients.

What SILDATIO PHT looks like

SILDATIO PHT are white to off white, round shaped, biconvex, film-coated tablets, debossed with '20' on one side and plain on other side.

The tablets are available in blister packs containing 90 tablets in each box.

ARTG No. 188711

Who distributes SILDATIO PHT

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel St,
Cremorne, Victoria, 3121
Australia
www.arrotex.com.au

This leaflet was prepared in January 2025.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Sildatio PHT

Active ingredient

Sildenafil

Schedule

S4

 

1 Name of Medicine

Sildenafil (as citrate).

2 Qualitative and Quantitative Composition

Each tablet contains 20 mg sildenafil (as citrate).
Sildenafil 20 mg, an oral therapy for pulmonary arterial hypertension, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE5).
Sildenafil citrate is an off-white, crystalline powder. Its aqueous solubility is equivalent to 2.6 mg sildenafil per mL at 25°C.

Excipients with known effect.

This product contains lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sildatio PHT are white to off white, round shaped, biconvex, film-coated tablets, debossed with '20' on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Sildatio PHT tablets are for the treatment of patients with pulmonary arterial hypertension classified as WHO functional classes II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension and pulmonary hypertension associated with connective tissue disease.
The efficacy of sildenafil has not been evaluated in patients currently on bosentan therapy.

4.2 Dose and Method of Administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of pulmonary arterial hypertension. In case of clinical deterioration in spite of sildenafil treatment, alternative therapies should be considered.

Use in adults (≥ 18 years).

The recommended dose for sildenafil is 20 mg three times a day (TID). Sildenafil tablets should be taken approximately 6-8 hours apart, with or without food.
No greater efficacy was achieved with doses higher than 20 mg TID therefore treatment with doses higher than 20 mg TID is not recommended (see Section 5.1 Pharmacodynamic Properties). Dosages lower than 20 mg TID have not been examined and the efficacy of these doses is not known.

Use in the elderly (over 65 years of age).

In general, dose selection of sildenafil for elderly PAH patients should be undertaken cautiously due to higher incidence of compromised renal, hepatic or cardiac function, and of concomitant disease or drug therapy (see Section 5.2 Pharmacokinetic Properties, Elderly (over 65 years of age).

Use in patients with impaired renal function.

Initial dose adjustments are not required in patients with renal impairment. A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.

Use in patients with impaired hepatic function.

Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and B). A downward dose adjustment to 20 mg twice daily should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.
Sildenafil is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see Section 5.2 Pharmacokinetic Properties, Hepatic impairment).

Use in children (< 18 years).

Safety and effectiveness in paediatric pulmonary hypertension patients has not been established. Therefore, the use of sildenafil is not recommended in these patients.

Discontinuation of treatment.

Limited data suggests that the abrupt discontinuation of sildenafil is not associated with rebound worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified monitoring is recommended during the discontinuation period.

Co-administration with other PAH treatments.

The safety and efficacy of sildenafil when co-administered with medicines for PAH other than epoprostenol has not been studied in controlled clinical trials. Caution is recommended in the case of co-administration. The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients.

Use with CYP3A4 inhibitors and CYP3A4 inducers.

See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions for dosing instructions.
Also see Section 5.2 Pharmacokinetic Properties for information regarding the pharmacokinetics of the intravenous formulation.

4.3 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 co-administration 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.
Combination with potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir).
Co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension.
Sildenafil is not recommended in patients with pulmonary arterial hypertension with a previous episode of non-arteritic anterior ischaemic optic neuropathy (NAION) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing data, Other events).
The safety of sildenafil has not been studied in the following sub groups of patients and its use is therefore contraindicated: severe hepatic impairment, severe hypotension (blood pressure < 90/50 mmHg) at initiation, recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of patients have genetic disorders of retinal phosphodiesterases).

4.4 Special Warnings and Precautions for Use

The efficacy of sildenafil has not been established in patients with severe pulmonary arterial hypertension (functional class IV). If the clinical situation deteriorates, therapies that are recommended for the severe stage of the disease should be considered.

Vasodilatory effects.

Sildenafil has vasodilator properties, resulting in mild and transient decreases in blood pressure and, as such, potentiates the hypotensive effect of nitrates (see Section 4.3 Contraindications). Prior to prescribing sildenafil, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, for example patients with resting hypotension (blood pressure < 90/50 mmHg), patients with fluid depletion, severe left ventricular outflow obstruction or autonomic dysfunction.

Coronary artery disease.

There are no controlled clinical data on the safety and efficacy of sildenafil in patients with coronary artery disease causing unstable angina, life-threatening arrhythmia within the last 6 months, patients with hypertension (BP > 170/110 mmHg), or who are currently on bosentan or prostacyclin therapy.

Cardiovascular events.

In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported post-marketing in temporal association with the use of sildenafil. Most, but not all, of these patients had pre-existing cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse 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.

Vision.

Visual defects including central serous chorioretinopathy (CSCR) have been reported in connection with the intake of sildenafil and other PDE5 inhibitors. Most cases of CSCR resolved spontaneously after stopping sildenafil. Physicians should advise patients to stop use of all PDE5 inhibitors, including sildenafil, and seek immediate medical attention in the event of sudden visual defect, visual acuity impairment, visual distortion and/or loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischaemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors when used in the treatment of male-erectile dysfunction. 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 inhibitors use. In case of sudden visual loss patient should be advised to stop taking sildenafil and consult a physician immediately.
Individuals who already experienced NAION are at increased risk of NAION recurrence. PDE5 inhibitors, including sildenafil, are not recommended in patients with pulmonary arterial hypertension with a previous episode of NAION (see Section 4.3 Contraindications; Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing data, Other events).

Anatomical deformation of the penis or predisposition to priapism.

Sildenafil 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). Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. 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.

Co-administration with alpha-blockers.

Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the co-administration may lead to symptomatic hypotension in a few susceptible individuals (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). In order to minimise the potential for developing postural hypotension, patients should be haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians should advise patients what to do in the event of postural hypotensive symptoms.

Co-administration with bosentan.

In a study of PAH patients (primary PAH and secondary PAH associated with CTD on bosentan therapy, no incremental benefit (6-MWD) of sildenafil co-administered with bosentan was demonstrated with bosentan alone. The mean result of the combination of sildenafil and bosentan was numerically worse than bosentan alone in patients with PAH associated with CTD but numerically better than bosentan alone in patients with primary PAH. Physicians should assess the clinical response when sildenafil is used in combination with bosentan in primary PAH. Co-administration of sildenafil and bosentan in patients with PAH associated with CTD is not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Concomitant use with other PDE5 inhibitors.

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products has not been studied in PAH patients and such concomitant use is not recommended.

Bleeding disorders or active peptic ulceration.

Sildenafil had no effect on bleeding time, including during co-administration 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.

Epistaxis in patients with PAH secondary to connective tissue disease.

The incidence of epistaxis was higher in patients with PAH secondary to connective tissue disease (sildenafil 12.9%, placebo 0%) than in PPH patients (sildenafil 3.0%, placebo 2.4%). Incidence was also higher in sildenafil-treated patients with concomitant oral vitamin K antagonist (8.8% versus 1.7% not treated with concomitant vitamin K antagonist).

Pulmonary veno occlusive disease.

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno occlusive disease. Since there are no clinical data on administration of sildenafil to patients with pulmonary veno occlusive disease, administration of sildenafil to such patients is not recommended.

Diabetic retinopathy.

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.

Sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness has been reported in a small number of post-marketing 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 consult a physician promptly.

Effects on fertility.

There was no impairment of fertility in rats given sildenafil for 36 days to females and 102 days to males at plasma exposure levels more than 25 times the human male AUC at an oral dose of 100 mg.

Use in the elderly.

No data available.

Paediatric use.

Safety and effectiveness in paediatric pulmonary hypertension patients has not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicines on sildenafil.

In vitro studies.

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.

In vivo studies.

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. Reduction in sildenafil clearance was also observed when sildenafil was co-administered with mild/moderate CYP3A4 inhibitors and with betablockers. These were the only factors with a statistically significant impact on oral sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. The exposure to oral sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43% and 66% higher, respectively, compared to patients not receiving these classes of medicines. Sildenafil exposure, without concomitant medication, was 5-fold higher at a dose of 80 mg three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration range covers the increase in sildenafil exposure observed in specifically designed drug interaction studies with CYP3A4 inhibitors (except more potent CYP3A4 inhibitors e.g. ketoconazole, itraconazole, ritonavir).
CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of oral sildenafil in pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with CYP3A4 inducer bosentan. Concomitant administration of potent CYP3A4 inducers is expected to cause substantial decrease in plasma levels of sildenafil (see Section 4.4 Special Warnings and Precautions for Use).
In a study of healthy male volunteers co-administration of the endothelin antagonist bosentan, which is a moderate inducer of CYP3A4, 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 a 62.6% decrease of sildenafil AUC and a 55.4% decrease in sildenafil Cmax. The same effect was also observed with lower doses of sildenafil (20 mg three times a day) and bosentan therapy (62.5 mg - 125 mg twice daily). The combination of both drugs did not lead to clinically significant changes of blood pressure (supine and standing).
Efficacy of oral sildenafil should be closely monitored in patients using concomitant potent CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John's wort and rifampicin.
Co-administration of 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 1,000% (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 administered alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see Section 4.3 Contraindications).
Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times a day) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics.
When a single 100 mg dose of oral 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). In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC, Cmax, Tmax, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite. Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.
Potent CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected to have effects similar to ritonavir (see Section 4.3 Contraindications). CYP3A4 inhibitors of intermediate potency (e.g. clarithromycin, telithromycin and nefazodone) are expected to have an effect in between that of ritonavir and CYP3A4 inhibitors of medium potency (e.g. saquinavir/erythromycin), a seven-fold increase in exposure is assumed. Therefore downward dose adjustments are recommended when using CYP3A4 inhibitors of intermediate potency and consideration should be given to a downward dose adjustment when using CYP3A4 inhibitors of medium potency.
The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that co-administration of beta-blockers in combination with CYP3A4 substrates might result in an additional increase in oral sildenafil exposure compared with administration of CYP3A4 substrates alone.
The mean reduction of sildenafil (80 mg TID) bioavailability due to co-administration of epoprostenol was 28%, resulting in about 22% lower mean average steady state concentrations. Therefore, the slight decrease of sildenafil exposure in the presence of epoprostenol is not considered clinically relevant. The effect of sildenafil on epoprostenol pharmacokinetics is not known.
Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma levels of oral sildenafil.

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 sildenafil. There was no evidence of favourable clinical effect of the combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated as it may potentially lead to symptomatic hypotension (see Section 4.3 Contraindications).
Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of oral sildenafil.
Co-administration of oral contraceptives (ethinyloestradiol 30 microgram and levonorgestrel 150 microgram) did not affect the pharmacokinetics of oral sildenafil.

Effects of sildenafil on other medicines.

In vitro studies.

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 > 150 microM).
There are no data on the interaction of sildenafil with non-specific phosphodiesterase inhibitors such as theophylline or dipyridamole.

In vivo studies.

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 stabilised on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light headedness, but not syncope. Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension in a few susceptible individuals. (See Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration.)
No significant interactions were shown when oral sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolised by CYP2C9.
Sildenafil had no significant effect on atorvastatin exposure (AUC increased 11%), suggesting that sildenafil does not have a clinically relevant effect on CYP3A4.
Oral sildenafil (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Oral 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.
In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 49.8% increase in bosentan AUC and a 42% increase in bosentan Cmax (125 mg twice daily). The same effect was also observed with lower doses of sildenafil (20 mg three times a day) and bosentan therapy (62.5 mg - 125 mg twice a day).
In a specific interaction study, where sildenafil (100 mg) was co-administered with amlodipine in hypertensive patients, there was an additional reduction on supine systolic blood pressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was administered alone to healthy volunteers.
Oral sildenafil (100 mg single dose) did not affect the steady state pharmacokinetics of the HIV protease inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.
Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form is therefore contraindicated (see Section 4.3 Contraindications).
Oral sildenafil had no clinically significant impact on the plasma levels of oral contraceptives (ethinyloestradiol 30 microgram and levonorgestrel 150 microgram).

Co-administration with other PAH treatments.

The safety and efficacy of sildenafil when co-administered with medicines for PAH other than epoprostenol has not been studied in controlled clinical trials. Caution is recommended in the case of co-administration. The safety and efficacy of Revatio when co-administered with other PDE5 inhibitors has not been studied in pulmonary arterial hypertension patients.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There was no impairment of fertility in rats given sildenafil for 36 days to females and 102 days to males at plasma exposure levels more than 25 times the human male AUC at an oral dose of 100 mg.
There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil in healthy volunteers.
(Category B1)
No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits, which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 30 and 70 times the recommended human dose (RHD) on a mg/m2 basis in a 50 kg subject. In the rat, pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day given for 36 days. In the non-pregnant rat the AUC for unbound sildenafil and its major metabolite at this dose was about 20 times the unbound human AUC at the MHRD of 20 mg three times a day. There are no adequate and well-controlled studies of sildenafil in pregnant women.
 There are no adequate and well controlled studies in lactating women. Limited data indicate that sildenafil and its active metabolite are excreted into breast milk at very low levels. There is a lack of information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Prescribers should carefully assess the mother's clinical need for sildenafil and any potential adverse effects on the breastfed child. Sildenafil should not be administered to breast-feeding mothers.

4.7 Effects on Ability to Drive and Use Machines

No studies on the ability to drive or use machines have been performed. However, as transient visual disturbances and dizziness have been reported in some patients taking sildenafil, patients should be aware of how they react to sildenafil before driving or operating machinery, and the doctor should advise accordingly.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial in pulmonary arterial hypertension.

Safety data were obtained from the pivotal study and an open-label extension study in 277 (207 on sildenafil and 70 on placebo) treated patients with pulmonary arterial hypertension. 259 subjects who completed the pivotal study entered a long-term extension study. Doses up to 80 mg TID (4 times the recommended dose of 20 mg TID) were studied (N = 149 patients treated for at least 1 year).
The overall frequency of discontinuation in sildenafil-treated patients at the recommended dose of 20 mg TID was low (2.9%) and the same as placebo (2.9%). In the pivotal placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions that occurred in at least 3% of sildenafil-treated patients at any of the 20, 40 or 80 mg TID. doses, and more commonly on sildenafil than on placebo, are shown in Table 1.
The adverse reactions that occurred in ≥ 1% and < 3% and more frequently with sildenafil than with placebo were the following.

Blood and lymphatic disorders.

Anaemia NOS.

Ear.

Vertigo.

Eye disorders.

Abnormal sensation in eye, chromatopsia, cyanopsia, diplopia, eye irritation, photophobia, retinal haemorrhage, visual acuity reduced.

Gastrointestinal disorders.

Abdominal distension, gastritis (not otherwise specified, NOS), gastroenteritis NOS, gastroesophageal reflux disease, haemorrhoids.

Infections and infestations.

Sinusitis NOS, cellulitis.

Investigations.

Weight increased.

Metabolism disorders.

Fluid retention.

Nervous system disorders.

Paraesthesia, tremor, burning sensation NOS, migraine NOS, hypoaesthesia.

Psychiatric disorders.

Anxiety.

Respiratory, thoracic and mediastinal disorders.

Bronchitis NOS, rhinitis NOS.

Reproductive system disorders.

Gynaecomastia.

Skin and subcutaneous tissue disorders.

Alopecia, erythema.

Post-marketing data.

Cardiovascular.

In post-marketing experience at doses indicated for male erectile dysfunction, serious cardiovascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack and hypertension, have been reported post-marketing 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 post-marketing.

Other events.

When used to treat male-erectile dysfunction, non-arteritic anterior ischaemic 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 phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil citrate. 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 Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Cases of sudden decrease or loss of hearing have been reported post-marketing 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 Section 4.4 Special Warnings and Precautions for Use).
Other events, reported post-marketing at doses indicated for male erectile dysfunction, to have been observed in temporal association with sildenafil and not listed in the clinical trials adverse reactions section include the following.

Immune system disorders.

Hypersensitivity (including skin rash).

Gastrointestinal disorders.

Vomiting, nausea.

Eye disorders.

Eye pain, red eyes/bloodshot eyes, central serous chorioretinopathy (CSCR).

Reproductive system and breast disorders.

Prolonged erection and/or priapism.

Musculoskeletal and connective tissue disorders.

Pain in extremity/pain in jaw/arthralgia.

Respiratory, thoracic and mediastinal disorders.

Nasal congestion.

Vascular disorders.

Hypotension.

Cardiac disorders.

Cardiac arrest.

General disorders and administration site conditions.

Oedema/peripheral oedema.

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.

4.9 Overdose

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 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type-5 (PDE5) in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary hypertension, this can lead to selective vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.
Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases. There is a 10-fold selectivity over PDE6 which is involved in the phototransduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over 700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 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.
In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.
Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. The mean maximum decrease in supine systolic blood pressure following 100 mg oral dosing of sildenafil was 8.3 mmHg. The corresponding change in supine diastolic blood pressure was 5.3 mmHg. After chronic dosing of 80 mg three times a day to healthy male volunteers, the largest average change from baseline of supine systolic blood pressure was a decrease of 9.0 mmHg. The corresponding change in supine diastolic blood pressure was a decrease of 8.4 mmHg.
After chronic dosing of 80 mg three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9.4 mmHg and 9.1 mm Hg respectively.
After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). This may be due to improvements in cardiac output secondary to the beneficial effects of sildenafil on pulmonary vascular resistance.
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported.
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 post-dose.
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.

Clinical trials.

A randomized, double-blind, placebo-controlled study [A1481140] was conducted in 277 patients with pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure of ≥ 25 mmHg at rest with a pulmonary capillary wedge pressure < 15 mmHg. Allowed background therapy included a combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction < 45% or left ventricular shortening fraction < 0.2 also were not studied.
Patients were randomized to receive placebo (n = 70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) t.d.s. for a period of 12 weeks. They had either primary pulmonary hypertension (63%), PAH associated with connective tissue disease (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18-81 years) and baseline 6-minute walk test distance between 100 and 450 metres. Most patients were functional class II (107/277, 39%) or class III (160/277, 58%) with a mean baseline 6 minute walking distance of 378 meters and 326 meters respectively; fewer patients were class I (1/277, 0.4%) or IV (9/277, 3%).
The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance. A statistically significant increase in 6-minute walk distance was observed in all 3 sildenafil dose groups compared to those on placebo. Placebo corrected increases in walk distance were 45 metres (p < 0.0001), 46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg respectively. There was no significant difference in effect between sildenafil doses (see Figure 1).
The improvement in walk distance was apparent after 4 weeks of treatment and this effect was maintained at weeks 8 and 12. Results were generally consistent in subgroups according to baseline walking distance, aetiology (primary and CTD-associated PAH), WHO functional class, gender, race, location, mean PAP and PVRI (see Figure 2).
Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo. Doses of 20 mg, 40 mg, and 80 mg t.d.s. produced a placebo-corrected decrease in mPAP of -2.7 mmHg, -3.0 mmHg, and -5.1 mmHg, respectively. These comparisons to placebo were planned, but no pre-defined comparisons were specified between sildenafil dose groups. Summaries of changes from baseline for haemodynamic parameters can be found in Table 2.

Extension study.

Following the pivotal study, 259 of the 277 sildenafil-treated patients entered an extension study, for which an interim data analysis was performed after 24 weeks of therapy. In the extension study, patients were allocated to either one of two dosage regimens (A or B). In regimen A patients received 40 mg sildenafil TID for 6 weeks and were then titrated to 80 mg TID for the remainder of the study. In regimen B, patients received 80 mg sildenafil TID for 6 weeks and were then dummy titrated to 80 mg TID. Patients who had initially been on 20 mg TID or 40 mg TID were allocated to regimen A while those initially on 80 mg TID were allocated to continue 80 mg TID in Regimen B. Patients could be down-titrated if they did not tolerate the 40 mg TID or 80 mg TID dose. There was no placebo arm in the extension study. Results of the extension study are represented in Figure 3.
The long term effects of sildenafil on mortality or functional class have not been established.

Efficacy in adult patients with PAH when used in combination with epoprostenol.

A randomised, double-blind, placebo controlled study (A1481141) was conducted in 265 patients with PAH who were stabilised on intravenous epoprostenol (131 to placebo and 134 to sildenafil). The PAH patients included those with primary pulmonary arterial hypertension, PAH associated with CTD and PAH following surgical repair of congenital heart lesions. Patients were randomised to placebo or subject-optimized dose of sildenafil (20, 40, or 80 mg sildenafil TID). Patients started with 20 mg for the first 4 weeks and were then titrated to 40 mg for 4 weeks, and then to 80 mg for 8 weeks. Subjects were allowed to down titrate after each increase if unable to tolerate the higher dose.
The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance. For the ITT population there was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk distance. The mean change from baseline at week 16 was 30.1 m for the sildenafil group compared with 4.1 m for the placebo group, giving an adjusted treatment difference of 26.0 m (95% CI: 10.8, 41.2) (p = 0.0009) (ANOVA). Patients on sildenafil achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favour of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003) (ANOVA). A summary of change from baseline to week 16 (LOCF) in pulmonary hypertension criteria for functional capacity and therapeutic class (ITT Population) is presented in Table 3.

Delay to clinical worsening.

Treatment with sildenafil significantly delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074) with Kaplan-Meier (K-M) estimates demonstrating that placebo patients were 3 times more likely to experience an event (see Table 4).
Time to clinical worsening was defined as the time from randomisation to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, hospitalisation due to PAH, or clinical deterioration requiring a change in epoprostenol therapy).
The Kaplan-Meier curves in Figure 4 show separation between treatment groups occurred as early as the week 4 visit, when all of sildenafil/epoprostenol subjects were on the 20 mg TID dose.

5.2 Pharmacokinetic Properties

Absorption.

Sildenafil is rapidly absorbed 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%). After oral doses of 80 mg three times a day a more than dose proportional increase in sildenafil plasma levels has been observed. In pulmonary arterial hypertension patients, the oral bioavailability of sildenafil after 80 mg three times a day was on average 43% (90% CI: 27% - 60%) higher compared to the lower doses.
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%.

Distribution.

The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration of sildenafil at steady state is approximately 113 nanogram/mL. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

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 50% of the parent drug. In healthy volunteers, 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 h. In patients with pulmonary arterial hypertension, however, the ratio of the N-desmethyl metabolite to sildenafil is higher. Plasma concentrations of the N-desmethyl metabolite are approximately 72% those of sildenafil after 20 mg three times a day dosing (translating into a 36% contribution to sildenafil's pharmacological effects). The subsequent effect on efficacy is unknown.

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).

Renal impairment.

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 impairment.

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 has not been studied.

Elderly (over 65 years of age).

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%.

Population pharmacokinetics.

Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in pulmonary arterial hypertension patients. None of these factors had a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary hypertension. The data set available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function.
Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on the pharmacokinetics in patients with pulmonary arterial hypertension (PAH). The exposure to sildenafil in patients on CYP3A4 substrates and CYP3A4 substrates plus beta-blockers was 43% and 66% higher respectively, compared to patients not receiving these drug classes.
In patients with pulmonary hypertension, the average steady-state concentrations were 20-50% higher over the investigated dose range of 20-80 mg three times daily (t.d.s.), when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary hypertension compared to healthy volunteers.

5.3 Preclinical Safety Data

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 33- and 48-times, for male and female rats, respectively, the exposures observed in human males given the RHD of 20 mg three times a day. 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 RHD.

6 Pharmaceutical Particulars

6.1 List of Excipients

In addition to sildenafil citrate, each sildenafil tablet contains the following inactive ingredients: microcrystalline cellulose, calcium hydrogen phosphate, croscarmellose sodium, hypromellose, magnesium stearate. The film-coating contains opadry II complete film coating system 31K58643 white which consists of hypromellose, titanium dioxide, lactose monohydrate, triacetin.

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. Store in a dry place.

6.5 Nature and Contents of Container

Sildatio PHT tablets are presented in a PVC/aluminium blister pack of 90 tablets.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Sildenafil citrate is 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin5-yl)phenylsulphonyl]-4-methylpiperazine citrate.

Chemical structure.


Molecular formula: C22H30N6O4S.C6H807.
Molecular weight: 666.7.

CAS number.

171599-83-0.

7 Medicine Schedule (Poisons Standard)

Schedule 4, Prescription Only Medicine.

Summary Table of Changes