Consumer medicine information

Tadalafil Sandoz

Tadalafil

BRAND INFORMATION

Brand name

Tadalafil Sandoz

Active ingredient

Tadalafil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tadalafil Sandoz.

SUMMARY CMI

Tadalafil Sandoz®

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 Tadalafil Sandoz?

Tadalafil Sandoz contains the active ingredient tadalafil. Tadalafil Sandoz is used to treat erectile dysfunction and urinary symptoms associated with benign prostatic hyperplasia in adult men.

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

2. What should I know before I use Tadalafil Sandoz?

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

Do not take Tadalafil Sandoz if you are currently taking any nitrates or amyl nitrite.

Talk to your doctor if you have any other medical conditions such as heart problems or take any other medicines.

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

3. What if I am taking other medicines?

Some medicines may interfere with Tadalafil Sandoz 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 Tadalafil Sandoz?

  • Always take Tadalafil Sandoz exactly as your doctor has told you.
  • Follow all directions given to you by your doctor or pharmacist.

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

5. What should I know while using Tadalafil Sandoz?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Tadalafil Sandoz.
  • If you have emergency treatment for any suspected heart condition tell the emergency medical or ambulance staff that you are taking Tadalafil Sandoz.
Things you should not do
  • Do not take Tadalafil Sandoz to treat any other complaints.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful driving or operating machinery until you know how Tadalafil Sandoz affects you.
Drinking alcohol
  • Tadalafil Sandoz can be taken with or without food or alcohol. However, drinking alcohol may affect your ability to get an erection, so avoid excessive alcohol.
Looking after your medicine
  • Store below 25°C.
  • Keep it where young children cannot reach it.

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

6. Are there any side effects?

Tadalafil Sandoz may cause chest pain, headache or migraine, flushing, sweating, nausea or vomiting, fatigue, back pain, muscle pain. Serious side effects may include: chest pain, increased heart beat, prolonged and painful erection, erection that lasts longer than 4 hours, partial, temporary or permanent vision changes in one or both eyes, sudden decrease or loss of hearing and seizures.

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

Tadalafil Sandoz®

Active ingredient(s): tadalafil

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tadalafil Sandoz. 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 Tadalafil Sandoz.

Where to find information in this leaflet:

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

1. Why am I using Tadalafil Sandoz?

Tadalafil Sandoz contains the active ingredient tadalafil. Tadalafil Sandoz belongs to a group of medicines called phosphodiesterase type 5 inhibitors.

Tadalafil Sandoz is used to treat:

  • erectile dysfunction, also known as impotence, in men. This is when a man cannot get, or maintain, a hard erect penis suitable for sexual activity. Following sexual stimulation, Tadalafil Sandoz works by helping the blood vessels in your penis to relax, allowing the flow of blood into your penis. The result of this is improved erectile function. Tadalafil Sandoz will only treat erectile dysfunction if you are sexually aroused. You and your partner will need to engage in foreplay, just as you would if you were not taking a medicine for erectile dysfunction.
  • urinary symptoms associated with a common condition called benign prostatic hyperplasia. This is when the prostate gland gets bigger with age. Symptoms include difficulty in starting to pass urine, a feeling of not completely emptying the bladder and a more frequent need to pass urine even at night. Tadalafil Sandoz improves blood flow to, and relaxes the muscles of, the prostate and bladder which may reduce symptoms of benign prostatic hyperplasia.

Your doctor may have prescribed you Tadalafil Sandoz to treat either, or both of these conditions.

2. What should I know before I use Tadalafil Sandoz?

Warnings

Do not use Tadalafil Sandoz if:

  • you are allergic to tadalafil, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you are currently taking any nitrates, medicines used for the treatment of angina ("chest pain") or other heart conditions. Tadalafil has been shown to increase the effects of these medicines.
  • if you use recreational drugs called "poppers" or "amyl" like amyl nitrite and butyl nitrite that are normally taken through inhalation
  • if you use guanylate cyclase stimulators such as riociguat, used to treat pulmonary arterial hypotension
  • if you have heart or blood vessel problems that make sexual intercourse inadvisable. Sexual activity carries a possible risk to patients with a heart condition because it puts extra strain on the heart
  • if you have heart problems such as angina, arrhythmias (change in rhythm or rate of heart beat), heart failure
  • if you have suffered a heart attack in the last 3 months
  • if you have suffered a stroke in the last 6 months
  • if your blood pressure is unusually high or low or is not effectively treated
  • if you have vision loss in one eye because of non-arteritic interior ischaemic optic neuropathy (NAION).

Check with your doctor if you have or have had:

  • liver or kidney problems
  • heart problems or if you have had a heart attack
  • blood vessel problems
  • sickle cell anaemia (an abnormality or red blood cells)
  • multiple myeloma (cancer of the bone marrow)
  • leukaemia (cancer of the blood cells)
  • any deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease)
  • sudden decrease in vision, loss of vision, distorted vision and/or dimmed vision affecting one or both eyes. If you experience any of these while you are taking Tadalafil Sandoz, stop taking Tadalafil Sandoz and contact your doctor immediately.

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?

Tell your doctor if you:

  • are aged 75 years and over.

You have a higher chance of experiencing side effects like dizziness and diarrhea.

Your doctor will assess if Tadalafil Sandoz is suitable for you.

Use in women

Tadalafil Sandoz is not intended for use by women.

Use in children

Tadalafil Sandoz is not intended for use by children under the age of 18 years.

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.

Some medicines may interfere with Tadalafil Sandoz and affect how it works.

These include:

  • nitrates, medicines such as glyceryl trinitrate, isosorbide mononitrate and sodium nitroprusside used to treat angina and other heart conditions (see Section 2. What should I know before I use Tadalafil Sandoz?)
  • guanylate cyclase stimulators such as riociguat, used to treat pulmonary arterial hypotension (see Section 2. What should I know before I use Tadalafil Sandoz?)
  • some antibiotic medicines such as rifampicin, erythromycin and clarithromycin
  • some medicines used to treat seizures such as phenytoin, phenobarbitone and carbamazepine
  • some medicines used to treat fungal infections such as ketoconazole and itraconazole
  • protease inhibitors used to treat HIV such as ritonavir and saquinavir
  • medicines used to treat hypertension (high blood pressure) such as metoprolol, irbesartan and enalapril
  • alpha-blockers (used to treat hypertension and some prostate problems) such as prazosin and doxazosin
  • a 5-alpha reductase inhibitor, such as finasteride (used to treat prostate and hair loss problems)
  • warfarin, a medicine used to prevent or treat blood clots
  • other PDE5 inhibitors such as sildenafil used to treat erectile dysfunction or pulmonary arterial hypertension (high blood pressure in the blood vessels in the lungs)
  • grapefruit juice
  • large amounts of alcohol.

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

4. How do I use Tadalafil Sandoz?

For Erectile Dysfunction:

  • Tadalafil Sandoz can be taken as either on-demand dosing or once-a-day dosing:
    - Tadalafil Sandoz on-demand (10 mg or 20 mg) is intended for use prior to anticipated sexual activity and is not for continuous daily use
    - Tadalafil Sandoz once-a-day (5 mg) is for patients who anticipate frequent use of Tadalafil Sandoz (i.e. at least twice weekly). Your doctor can advise on the appropriateness of once-a-day treatment. When taken once a day, Tadalafil Sandoz allows you to obtain an erection, when sexually stimulated, at any time point during the 24 hours of the day.
  • Do not take once-a-day dosing and on-demand dosing concurrently
  • When taking Tadalafil Sandoz once-a-day (5 mg), it may take up to 1 week for a full effect on erectile dysfunction.

For urinary symptoms associated with benign prostate hyperplasia

  • Tadalafil Sandoz once-a-day (5 mg) is taken daily. It may take up to a week to notice an improvement and 1 month for a full effect on urinary symptoms such as urinating too frequently during the day or at night, the need to urinate being too urgent, or too soon after relieving your bladder.

How much to take

You should not take Tadalafil Sandoz more than once a day.

On-demand dosing for Erectile Dysfunction:

  • the maximum recommended dose of Tadalafil Sandoz is one 20 mg tablet taken before sexual activity
  • if you have kidney disease, the recommended dose of Tadalafil Sandoz is one 10 mg tablet. This dose may be increased up to 20 mg. For patients with severe renal impairment, 10 mg is the maximum recommended dose
  • if you have liver disease, the recommended dose of Tadalafil Sandoz is one 10 mg tablet. Patients with severe hepatic impairment should follow their doctor's advice
  • no special dosing consideration is needed for the elderly or people with diabetes.

Once-a-day dosing for Erectile Dysfunction and/or urinary symptoms associated with Benign Prostate hyperplasia:

  • the recommended dose of Tadalafil Sandoz is one 5 mg tablet taken once per day
  • dose adjustments are not required in patients with kidney disease unless you have severe renal impairment. Once-a-day dosing of Tadalafil Sandoz is not recommended in patients with severe renal impairment.
  • patients with liver disease should follow their doctor's advice. Once-a-day dosing is not recommended in patients with severe hepatic impairment.
  • no special dosing consideration is needed for the elderly or people with diabetes.

When to take Tadalafil Sandoz

Tadalafil Sandoz be taken with or without food or alcohol. However, drinking alcohol may affect your ability to get an erection, so avoid excessive drinking.

On-demand dosing for Erectile Dysfunction:

  • Tadalafil Sandoz(10 mg or 20 mg) should be taken at least 30-60 minutes prior to anticipated sexual activity
  • The amount of time Tadalafil Sandoz takes to work varies from person to person. In some men Tadalafil Sandoz can work as early as 16 minutes after taking the tablet but it is recommended that you allow 1 hour the first time you take it
  • Tadalafil Sandoz has been proven to be effective for up to 36 hours. This means you can take Tadalafil Sandoz and it will allow you to obtain an erection when sexually stimulated, at any time during the 36 hours after taking it.
  • Sometimes if you're feeling anxious or nervous you may not respond to the first tablet. Don't give up, it may take a few doses before you get the full benefit of Tadalafil Sandoz.

Once-a-day dosing for Erectile Dysfunction and/or urinary symptoms associated with Benign Prostate hyperplasia:

  • Tadalafil Sandoz should be taken daily at approximately the same time of day
  • Tadalafil Sandoz must be taken daily to maintain effect.

How to take Tadalafil Sandoz

Swallow one tablet whole with a full glass of water.

If you use too much Tadalafil Sandoz

If you think that you have used too much Tadalafil Sandoz, you may need urgent medical attention.

You should immediately:

  • phone the Australian Poisons Information Centre (by calling 13 11 26), or the New Zealand National Poisons Information Centre (by calling 0800 POISONS or 0800 764 766), 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 Tadalafil Sandoz?

Things you should do

If you have emergency treatment for any suspected heart condition, tell the emergency medical or ambulance staff that you are taking Tadalafil Sandoz.

Remind any doctor, dentist or pharmacist you visit that you are using Tadalafil Sandoz.

Things you should not do

  • Do not take Tadalafil Sandoz for any other complaints unless your doctor tells you to.
  • Do not give you medicine 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 Tadalafil Sandoz affects you.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may affect your ability to get an erection. Avoid excessive drinking.

When taking Tadalafil Sandoz with large amounts of alcohol, some men may experience dizziness.

Looking after your medicine

  • Store below 25°C.
  • Keep your tablets in the original pack until it is time to take them.

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.

Keep it where young children cannot reach it.

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
Allergic reaction:
  • including skin rash, swelling of the face and hives
Gastrointestinal:
  • indigestion
  • nausea or vomiting
  • stomach pain
  • diarrhoea
  • heart burn
Nervous system:
  • headache or migraine
  • dizziness
  • fainting
Musculoskeletal:
  • back pain
  • muscle pain
Skin related:
  • sweating
Vascular:
  • facial flushing
  • tiredness (fatigue)
  • bleeding nose
Infection:
  • sore throat and discomfort when swallowing
  • nasal congestion (blocked nose)
Eye related:
  • red eyes, eye pain, swelling of eyelids
  • temporary blurred vision
  • changes in colour vision
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
Heart related:
  • chest pain
  • increased heart beat
If you experience chest pain during or after sexual activity: stop what you are doing, sit up and sit forward. Call an ambulance if the pain does not resolve. Do not use nitrates (medicines used for the treatment of angina ("chest pain") or other heart conditions).
Urogenital:
  • prolonged and painful erection
  • erection that lasts longer than 4 hours
Ear related:
  • sudden decrease or loss of hearing*
Nervous system:
  • seizures*
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

*Sudden loss or decrease in hearing which may be accompanied by ringing in the ears and dizziness, loss of vision in one or both eyes and seizures have been reported in people taking tadalafil. It is not possible to determine whether these events are related directly to tadalafil, to other diseases or medications, to other factors, or to a combination of factors. If you experience these symptoms, stop taking Tadalafil Sandoz and contact a doctor immediately.

Very serious side effects

Very serious side effectsWhat to do
Eye related:
  • Central serous chorioretinopathy, a condition affecting the vision. Symptoms may include:
    - distorted, dimmed or blurred vision
    - a dark area in your central vision
    - straight lines may appear bent, or irregular in one or both eyes
    - objects may appear smaller or further away than they are
    - a white object may appear brownish or appear duller in colour.
  • Non-arteritic anterior ischaemic optic neuropathy (NAION), a condition that causes sudden vision loss in one eye or both eyes. Vision loss may be partial, temporary or permanent.
Stop taking Tadalafil Sandoz and call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effect.

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 or to Medsafe at pophealth.my.site.com/carmreportnz/s/. 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 Tadalafil Sandoz contains

Active ingredient
(main ingredient)		tadalafil
Other ingredients
(inactive ingredients)		croscarmellose sodium
hypromellose
lactose monohydrate
magnesium stearate
microcrystalline cellulose
sorbitan stearate
Opadry II complete film-coating system 32K520007 Yellow (5 mg tablets only)
Opadry II complete film-coating system 32K520017 Yellow (10 mg tablets only)
Opadry II complete film-coating system 32K520009 Yellow (20 mg tablets only)
Potential allergenslactose

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

What Tadalafil Sandoz looks like

Tadalafil Sandoz 5 mg – light yellow, capsule shaped, biconvex, bevel-edged, film-coated tablets, debossed with "T 5" on one side and plain on the other side. Pack size of 28 tablets (Aust R 282105).

Tadalafil Sandoz 10 mg – light yellow, capsule shaped, biconvex, bevel-edged, film-coated tablets, debossed with "T 10" on one side and plain on the other side. Pack size of 4 tablets (Aust R 282106).

Tadalafil Sandoz 20 mg – yellow, capsule shaped, biconvex, bevel-edged, film-coated tablets, debossed with "T 20" on one side and plain on the other side. Pack sizes of 4 and 8 tablets (Aust R 282107).

Who distributes Tadalafil Sandoz

Tadalafil Sandoz is distributed in Australia by:

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia
Tel 1800 726 369

Tadalafil Sandoz is distributed in New Zealand by:

Sandoz New Zealand Limited
12 Madden Street
Auckland 1010
New Zealand
Tel: 0800 726 369

This leaflet was prepared in January 2025.

® Registered Trade Mark. The trade marks mentioned in this material are the property of their respective owners.

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Tadalafil Sandoz

Active ingredient

Tadalafil

Schedule

S4

 

1 Name of Medicine

Tadalafil.

2 Qualitative and Quantitative Composition

Tadalafil Sandoz 5 mg, 10 mg, and 20 mg.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tadalafil Sandoz 20 mg tablets are yellow, capsule shaped, biconvex, bevel-edged, film-coated tablets, debossed with "T 20" on one side and plain on the other side.
Tadalafil Sandoz 10 mg tablets are light yellow, capsule shaped, biconvex, bevel-edged, film-coated tablets, debossed with "T 10" on one side and plain on the other side.
Tadalafil Sandoz 5 mg tablets are light yellow, capsule shaped, biconvex, bevel-edged, film-coated tablets, debossed with "T 5" on one side and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Tadalafil Sandoz is indicated for the treatment of:
erectile dysfunction (ED) in adult males;
moderate to severe lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) in adult males.

4.2 Dose and Method of Administration

Note that 2.5 mg tablets can be available from other brand/s.
Tadalafil Sandoz can be taken with or without food.
Tadalafil Sandoz is for oral use.

For erectile dysfunction in adult males - on-demand dosing.

The recommended dose of Tadalafil Sandoz is either 10 mg or 20 mg, taken prior to anticipated sexual activity. The maximum recommended dose is 20 mg. The maximum recommended dosing frequency is once per day. Tadalafil Sandoz 10 and 20 mg is intended for use prior to anticipated sexual activity and is not for continuous daily use.
Tadalafil has been proven effective up to 36 hours after dosing and, in some patients, as early as 16 minutes after dosing. Patients may initiate sexual activity at varying time points relative to dosing in order to determine their own optimal window of responsiveness.

For erectile dysfunction in adult males - once-a-day dosing.

In patients who anticipate a frequent use of tadalafil (i.e. at least twice weekly), a once daily regimen with the lowest dose of Tadalafil Sandoz might be considered suitable, based on patient choice and the physician's judgement.
In these patients the recommended dose is 5 mg taken once a day at approximately the same time of day. The dose must not exceed 5 mg daily. The dose may be decreased to 2.5 mg once a day based on individual tolerability.
There is insufficient evidence on the maximum duration of treatment. The appropriateness of continued use of the once-a-day regimen should be reassessed periodically.

For lower urinary tract symptoms associated with benign prostatic hyperplasia in adult males.

The recommended dose is 5 mg, taken at approximately the same time every day.

For adult men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia.

The recommended dose is 5 mg taken at approximately the same time every day.
There is insufficient evidence on the maximum duration of treatment. The appropriateness of continued use of the once-a-day regimen should be reassessed periodically taking into account any safety concerns and efficacy benefits.

Patients with renal impairment.

For on-demand dosing for erectile dysfunction, the recommended dose of Tadalafil Sandoz is 10 mg taken prior to anticipated sexual activity and without regard to food for patients with mild or moderate renal impairment. Based on efficacy and tolerability the dose may be increased up to 20 mg. For patients with severe renal impairment 10 mg is the maximum recommended dose.
For once-a-day dosing for erectile dysfunction and/or lower urinary tract symptoms associated with benign prostatic hyperplasia, dosage adjustments are not required in patients with mild or moderate renal impairment. The dose may be decreased to 2.5 mg once a day in these patients based on individual tolerability. Once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment.

Patients with hepatic impairment.

For on-demand dosing for erectile dysfunction, the recommended dose of Tadalafil Sandoz is 10 mg taken prior to anticipated sexual activity with or without food for patients with mild to moderate hepatic impairment (Child-Pugh Class A or B). There are no available data about the administration of doses higher than 10 mg of tadalafil to patients with hepatic impairment. There is limited clinical data on the safety of tadalafil in patients with severe hepatic impairment (Child-Pugh Class C); if prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician, see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations.
Once-a-day dosing has not been evaluated in patients with hepatic impairment therefore, if prescribed for erectile dysfunction and/or lower urinary tract symptoms associated with benign prostatic hyperplasia, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician, see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations.
Once-a-day dosing is not recommended for patients with severe hepatic impairment, see Section 4.4 Special Warnings and Precautions for Use.

Patients with diabetes.

Dosage adjustments are not required in patients with diabetes.

Elderly patients.

Dosage adjustments are not required in elderly patients. If tadalafil is prescribed in this patient group, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician, including an evaluation of concomitant illnesses, any renal impairment and other medications, at treatment initiation and during treatment, see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly.

Patients taking potent CYP3A4 inhibitors.

For once-a-day dosing for erectile dysfunction and/or lower urinary tract symptoms associated with benign prostatic hyperplasia, dosage adjustments are not required in patients taking protease inhibitors (e.g. ritonavir) or other potent CYP3A4 inhibitors (e.g. ketoconazole). The dose may be decreased to 2.5 mg once a day in these patients based on individual tolerability.

Children.

Tadalafil has not been studied in subjects under 18 years of age.

4.3 Contraindications

Nitrates and tadalafil must not be used concomitantly. Co-administration of tadalafil 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, but are not limited to, glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil or organic nitrates in any form. In clinical studies, tadalafil was shown to potentiate the hypotensive effects of both acute and chronic nitrate administration. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway.
Administration of tadalafil to patients who are using any form of organic nitrate is contraindicated. In a patient prescribed tadalafil where nitrate administration is deemed medically necessary in a life-threatening situation, at least 48 hours in most patients and 4-5 days in the elderly (approximately 4-5 half-lives) should have elapsed after the last dose of tadalafil before nitrate administration is considered. In such circumstances, nitrates should only be administered under close medical supervision with appropriate haemodynamic monitoring, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Tadalafil is contraindicated in men for whom sexual intercourse is inadvisable due to unstable cardiovascular disease (e.g. patients with unstable angina and severe congestive heart failure), see Section 4.4 Special Warnings and Precautions for Use. The possibility of undiagnosed cardiovascular disorders in men with erectile dysfunction should be considered before prescribing tadalafil.
Tadalafil is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure, (see Section 4.4 Special Warnings and Precautions for Use).
The following groups of patients with cardiovascular disease were not included in clinical trials and the use of tadalafil is therefore contraindicated:
patients with a myocardial infarction within the last 90 days;
patients with unstable angina or angina occurring during sexual intercourse;
patients with New York Heart Association Class 2 or greater heart failure in the last 6 months;
patients with uncontrolled arrhythmias, hypotension (< 90/50 mmHg), or uncontrolled hypertension;
patients with a stroke within the last 6 months.
Tadalafil should not be used in patients with a known hypersensitivity to tadalafil or to any ingredient of the tablet.

Guanylate cyclase stimulators.

The combination of tadalafil and guanylate cyclase stimulators, such as riociguat, is contraindicated because it may lead to symptomatic hypotension.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Before treatment with tadalafil.

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine potential underlying causes, before pharmacological treatment is considered.
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following an appropriate medical assessment.
Prior to initiating treatment with tadalafil for lower urinary tract symptoms associated with benign prostatic hyperplasia, a medical history and physical examination should be undertaken to rule out the presence of carcinoma of the prostate as well as other potential underlying causes of urinary symptoms and the patient should be carefully assessed for cardiovascular conditions, see Section 4.3 Contraindications; Section 5.1 Pharmacodynamic Properties, Clinical trials.

Cardiovascular.

Physicians should consider the potential cardiac risk of sexual activity in patients with pre-existing cardiovascular disease. Patients who experience symptoms upon initiation of sexual activity should be advised to refrain from further sexual activity and should report the episode to their physician.
As with other PDE5 inhibitors, tadalafil has systemic vasodilatory properties that may result in mild and transient decreases in blood pressure. Prior to prescribing tadalafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by vasodilatory effects. Tadalafil potentiates the hypotensive effect of nitrates. Therefore, coadministration of tadalafil and nitrates is contraindicated, see Section 4.3 Contraindications. Tadalafil also potentiates the effect of some classes of antihypertensive medications, and this may be clinically important in some individuals. When initiating daily treatment with tadalafil, appropriate clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Caution should be exercised when prescribing tadalafil to patients who are taking alpha [1] blockers, such as doxazosin, as simultaneous administration may lead to symptomatic hypotension in some patients. The efficacy of the co-administration of an alpha-blocker and tadalafil for the treatment of BPH has not been adequately studied and, therefore, not recommended for use, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
Specific studies examining potential withdrawal effects from daily use have not been conducted. Rebound effects on blood pressure have not been observed after follow-up assessments at 2 weeks and 4 weeks following cessation of up to 1 year of chronic daily treatment of tadalafil. Blood pressure was not specifically monitored leading up to or between the 2 and 4 weeks post-treatment assessments. Based upon the limited clinical data examining withdrawal effects, it is recommended that physicians continue monitoring the cardiovascular status, including blood pressure changes, of their patients after discontinuation of tadalafil.

Hearing.

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

Vision.

Visual defects including central serous chorioretinopathy (CSCR) have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. Most cases of CSCR resolved spontaneously after stopping tadalafil. Physicians should advise patients to stop use of all PDE5 inhibitors, including Cialis, and seek medical attention in the event of sudden visual defect, visual acuity impairment, visual distortion and/or loss of vision in one or both eyes, see Section 4.3 Contraindications. 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. An increased risk of acute NAION has been suggested from analyses of observation data in men with erectile dysfunction within 1 to 4 days of episodic PDE5 inhibitor use, see Section 4.8 Adverse Effects (Undesirable Effects), Adverse drug reactions identified from spontaneous post marketing surveillance.

Tadalafil and other treatments of erectile dysfunction.

The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Priapism and anatomical deformation of the penis.

Priapism has been reported with PDE5 inhibitors, including tadalafil. Patients who experience erections lasting 4 hours or more should be instructed to seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.
Tadalafil should be used with caution in patients who have conditions that might predispose them to priapism (such as sickle cell anaemia, multiple myeloma, or leukaemia), or in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease).

Use with CYP3A4 inhibitors.

Caution should be exercised when prescribing tadalafil to patients using potent CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, itraconazole, and erythromycin) as increased tadalafil exposure (AUC) has been observed if the medicinal products are combined.

Lactose.

Tadalafil Sandoz tablets contain lactose.

Use in hepatic impairment.

Caution should be exercised when prescribing tadalafil to patients with severe hepatic insufficiency (Child-Pugh Class C) or to those taking CYP3A4 inhibitors or HIV protease inhibitors.
Once-a-day administration either for the treatment of erectile dysfunction or lower urinary tract symptoms associated with benign prostatic hyperplasia has not been evaluated extensively in patients with hepatic insufficiency. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. Once-a-day dosing is not recommended for patients with severe hepatic impairment.

Use in renal impairment.

In a clinical pharmacology study, administration of tadalafil 10 mg to patients with moderate renal failure (creatinine clearance = 31 to 50 mL/min) was determined to be safe but appeared to be less well tolerated in terms of back pain than in patients with mild renal failure (creatinine clearance = 51 to 80 mL/min) and in healthy subjects.
In a single dose, pharmacodynamic study of 8 patients with End Stage Renal Disease who were stable on haemodialysis, the reported adverse effects included headache, dizziness, and somnolence.
Tadalafil should be prescribed with caution for patients with creatinine clearance ≤ 50 mL/min.
Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, once-a-day dosing of tadalafil is not recommended in patients with severe renal impairment.

Use in the elderly.

The number of patients aged 75 years and older who received tadalafil 5 mg for more than 12 weeks is small and therefore the safety and efficacy of long-term use of tadalafil for the treatment of LUTS/BPH for this age group is limited.
In clinical trials with tadalafil 5 mg taken once a day for the treatment of benign prostatic hyperplasia, dizziness and diarrhoea were reported more frequently in patients over 75 years of age. In the clinical pharmacology study LVHN, the mean maximum decrease in standing and supine systolic and diastolic BP at both Day 1 (following a single dose of tadalafil 20 mg) and Day 10, (following once daily dosing with tadalafil 20 mg) was higher in the elderly subjects (70-85 years) compared with younger subjects aged ≤ 60 years. In addition, a higher number of elderly subjects (70-85 years) experienced clinically significant decreases in blood pressure compared with younger subjects. In study LVHS of men with BPH-LUTS on concomitant alpha blockers, a higher proportion of patients aged ≥ 75 years in the tadalafil group had at least one treatment-emergent positive orthostatic test compared with patients aged < 75 years. Based on these data, hypotensive events are a potential risk in patients aged ≥ 75 years treated with tadalafil 5 mg.
If tadalafil is prescribed in this patient group, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician, including an evaluation of concomitant illnesses, any renal impairment and other medications at treatment initiation and during treatment, see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials.

Paediatric use.

Tadalafil has not been studied in subjects under 18 years of age.

Effects on laboratory tests.

There are no data available that shows that tadalafil has an effect on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Tadalafil is not expected to cause clinically significant inhibition or induction of the clearance of drugs metabolised by CYP450 isoforms. Studies have confirmed that tadalafil does not inhibit or induce CYP450 isoforms, including CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.

Potential for other drugs to affect tadalafil.

Tadalafil is principally metabolised by CYP3A4. A selective inhibitor of CYP3A4, ketoconazole (400 mg daily), increased tadalafil single-dose exposure (AUC) by 312% and Cmax by 22%, and ketoconazole (200 mg daily), increased tadalafil single-dose exposure (AUC) by 107%, and Cmax by 15% relative to the AUC and Cmax values for tadalafil (10 mg) alone.
Ritonavir (200 mg twice daily), an inhibitor of CYP3A4, 2C9, 2C19, and 2D6, increased tadalafil single-dose exposure (AUC) by 124% with no change in Cmax. Ritonavir (500 mg or 600 mg twice daily) increased tadalafil (20 mg) single-dose exposure (AUC) by 32% with a 30% reduction in Cmax. Although specific interactions have not been studied, other HIV protease inhibitors such as saquinavir, and other CYP3A4 inhibitors, such as erythromycin, clarithromycin, itraconazole and grapefruit juice should be co-administered with caution because they would be expected to increase plasma concentrations of tadalafil.
A selective CYP3A4 inducer, rifampicin (600 mg daily), reduced tadalafil single-dose exposure (AUC) by 88%, and Cmax by 46% relative to the AUC and Cmax values for tadalafil (10 mg) alone. This reduced exposure can be anticipated to decrease the efficacy of once-a-day-dosed tadalafil; the magnitude of decreased efficacy is unknown. It can be expected that concomitant administration of other CYP3A4 inducers such as phenobarbitone, phenytoin and carbamazepine would also decrease plasma concentrations of tadalafil.
Studies with the CYP3A4 probe substrates midazolam with tadalafil 10 mg and lovastatin with tadalafil 20 mg showed little alteration in the kinetics suggesting that tadalafil is unlikely to have interactions with CYP3A4 substrates.

Antacids (magnesium hydroxide/aluminium hydroxide).

Simultaneous administration of an antacid (magnesium hydroxide/aluminium hydroxide) and tadalafil reduced the apparent rate of absorption of tadalafil without altering exposure (AUC) to tadalafil (10 mg).

H2 antagonists.

An increase in gastric pH resulting from administration of nizatidine had no significant effect on tadalafil (10 mg) pharmacokinetics.

Potential for tadalafil to affect other drugs.

Nitrates.

In clinical pharmacology studies, tadalafil 10 mg was shown to potentiate the hypotensive effects of nitrates. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated. A placebo-controlled study was conducted to assess the degree of interaction between nitroglycerine and tadalafil. One hundred and fifty subjects received daily doses of tadalafil 20 mg for 7 days. On the 7th day, 0.4 mg sublingual nitroglycerine was given at various times following the daily dose of tadalafil. This interaction lasted for more than 24 hours and was no longer detectable when 48 hours had elapsed, see Section 4.3 Contraindications.

Recreational drugs called "poppers" or "amyl".

Due to the known interaction between tadalafil and nitrates or other nitric oxide donors on nitrogen monoxide/cGMP metabolism, patients must be expressly informed that they should never use recreational drugs called "poppers" or "amyl", typically taken through inhalation. These drugs represent various alkyl nitrites including amyl nitrite, butyl nitrite and isobutyl nitrite.

Antihypertensive agents.

Tadalafil has systemic vasodilatory properties and may augment the blood pressure-lowering effects of antihypertensive agents. Patients should be advised of this possibility. In a clinical pharmacology study measuring ambulatory blood pressure, when tadalafil (20 mg) was administered to 17 hypertensive patients treated with angiotensin II receptor blockers, ambulatory systolic blood pressure fell by 30 mmHg or more in 9 (53%) subjects on tadalafil treatment and in 5 (29%) subjects on placebo treatment, with a maximum fall of 57 mmHg following tadalafil compared to 37 mmHg following placebo. None of the decreases were associated with any hypotensive symptoms. Additionally, in patients taking multiple antihypertensive agents whose hypertension was not well controlled, greater reductions in blood pressure were observed. These reductions were not associated with hypotensive symptoms in the vast majority of patients. Appropriate clinical advice should be given to patients when they are treated with antihypertensive medications and tadalafil.
When initiating daily treatment with tadalafil, appropriate clinical considerations should be given to a possible dose adjustment of the antihypertensive therapy.
In other clinical pharmacology studies, tadalafil 10 mg was added to angiotensin converting enzyme (ACE) inhibitors (enalapril), beta blockers (metoprolol) or thiazide diuretics (bendrofluazide). Tadalafil 10 mg and 20 mg was added to calcium channel blockers (amlodipine) or alpha-blockers (tamsulosin). In all these studies, tadalafil did not produce a significant additional reduction in mean systolic or diastolic blood pressure. However, potentially significant blood pressure reductions occurred in some individuals. Analysis of phase 3 clinical trial data showed no difference in the overall incidence of adverse events in patients taking tadalafil with or without hypertensive medications.
Human platelets contain the PDE5 enzyme system. Tadalafil, in limited studies, did not affect platelet function in vivo. In in vitro studies tadalafil was shown to potentiate the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor).

Alpha blockers.

In two clinical pharmacology studies, no significant decreases in blood pressure were observed when tadalafil was co-administered to healthy subjects taking the selective alpha [1A]-adrenergic blocker, tamsulosin.
In three clinical pharmacology studies when tadalafil was co-administered to healthy subjects taking doxazosin (4-8 mg daily), an alpha [1]-adrenergic blocker, there was an augmentation of the blood-pressure-lowering effect of doxazosin. The number of patients with potentially clinically significant standing-blood-pressure decreases was greater for the combination. In these clinical pharmacology studies, there were symptoms associated with the decrease in blood pressure including syncope.
In patients on a stable dose of alpha-blocker therapy for BPH (tamsulosin, doxazosin, terazosin, alfuzosin or silodosin), a Phase 3 randomised, multicentre, double-blind, placebo-controlled, parallel design, 12 week study, assessed the potential for adverse hemodynamic effects from the coadministration of tadalafil 5 mg for once daily use. Subjects had a mean age of 67 years (59% > 65; 25% ≥ 75 years of age). In this study, there was no statistically significant difference in treatment-emergent dizziness.
Caution is advised when PDE5 inhibitors are coadministered with nonselective alpha (α1)-blockers. PDE5 inhibitors, including tadalafil, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, which may lead to symptomatic hypotension (e.g. fainting).
Consideration should be given to the following:
Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor. Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.
In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended dose.
In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.
Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

5-alpha reductase inhibitors.

In a 26 week clinical trial that compared tadalafil 5 mg coadministered with finasteride 5 mg to placebo plus finasteride 5 mg for the early relief of BPH symptoms, no new adverse reactions were identified. However, as a formal pharmacokinetic drug-drug interaction study evaluating the effects of tadalafil and 5-alpha reductase inhibitors (5-ARIs) has not been performed, caution should be exercised when tadalafil is co-administered with 5-ARIs'.

Alcohol.

Tadalafil did not affect alcohol concentrations, and alcohol did not affect tadalafil concentrations. At high doses of alcohol (0.7 g/kg), the addition of tadalafil 20 mg did not induce statistically significant mean blood pressure decreases. In some subjects, postural dizziness and orthostatic hypotension were observed. When tadalafil was administered with lower doses of alcohol (0.6 g/kg), hypotension was not observed and dizziness occurred with similar frequency to alcohol alone.

Aspirin.

Tadalafil (10 mg) did not potentiate the increase in bleeding time caused by aspirin.

Warfarin.

In a crossover study, 12 healthy volunteers received a single dose of warfarin 25 mg after taking tadalafil 10 mg or placebo once daily for 6 days. Tadalafil reduced the exposure (AUC) to R- and S-warfarin by 11% and 13%, respectively, but did not alter the effect of warfarin on prothrombin time (PT). The clinical implications of these findings are unclear. The possibility of an increase or decrease in PT and/or international normalised ratio (INR) should be considered when patients begin taking or cease taking tadalafil.

Ethinyloestradiol.

Tadalafil has been demonstrated to produce an increase in the oral bioavailability of ethinyloestradiol; a similar increase may be expected with oral administration of terbutaline, although the clinical consequence of this is uncertain.

Theophylline.

Tadalafil (10 mg) had no clinically significant effect on the pharmacokinetics or pharmacodynamics of theophylline (CYP1A2 substrate). The only pharmacodynamic effect was a small (3.5 bpm) increase in heart rate.

Riociguat.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There were no effects on fertility, reproductive performance or reproductive organ morphology in male or female rats given oral doses of tadalafil up to 400 mg/kg/day (systemic exposure ca 13 (males) or 25 (females) times that expected at the maximum recommended dose of 20 mg taken once daily, based on AUC for unbound drug at steady state). However, regression of the seminiferous tubular epithelium of the testes resulting in oligospermia or aspermia in the epididymides was observed in dogs treated for 6 or 12 months with oral tadalafil doses ≥ 25 mg/kg/day. The no-observed-effect level for these effects in the 6-month dog study was 10 mg/kg/day. At this dose, systemic exposure to tadalafil, based on unbound drug concentrations, was similar to that expected in humans taking the maximum recommended dose of 20 mg tadalafil daily. Similar findings were not observed in rats and mice, see Section 5.1 Pharmacodynamic Properties.
(Category B1)
Tadalafil is not intended for use by women.
Studies in rats have shown that tadalafil and/or its metabolites cross the placenta and distribute to the foetus. No evidence of embryofoetal toxicity or teratogenicity was observed in pregnant rats or mice given oral doses of tadalafil up to 1000 mg/kg/day. These doses were associated with systemic exposure to tadalafil ca 12-14-fold that expected at the maximum recommended dose of 20 mg taken once daily, based on AUC for unbound drug at steady state. Increased postnatal pup mortality was observed in rats after oral treatment with tadalafil doses ≥ 60 mg/kg/day during gestation and lactation. The no-effect dose of 30 mg/kg/day was associated with systemic exposure ca 10-fold that expected in humans at the maximum recommended dose of 20 mg tadalafil taken once daily, based on AUC for unbound drug at steady state.
There are no studies of tadalafil in pregnant women.
 Tadalafil is not intended for use by women.
Tadalafil and/or its metabolites are excreted in the milk of lactating rats at concentrations up to 2.4-fold higher than the maximal maternal plasma concentration. Increased postnatal pup mortality was observed in rats after treatment with oral tadalafil doses ≥ 60 mg/kg/day during gestation and lactation, see Section 4.6 Fertility, Pregnancy, and Lactation.
There are no human data on the excretion of tadalafil into breast milk or on the safety of tadalafil exposure in infants.

4.7 Effects on Ability to Drive and Use Machines

The frequency of reports of dizziness in placebo and tadalafil arms in clinical trials was similar, except in patients over 75 years of age receiving tadalafil 5 mg once a day for the treatment of benign prostatic hyperplasia in whom dizziness was reported more frequently. Patients should be aware of how they react to tadalafil before driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

An adverse event is defined as any untoward medical occurrence in a patient administered tadalafil that first occurred or worsened in severity after baseline and which does not necessarily have to have a causal relationship with tadalafil treatment. An adverse drug reaction is an adverse event where a causal relationship between tadalafil treatment and an adverse event is at least a reasonable possibility.

Erectile dysfunction (ED) clinical trials.

On-demand dosing (10 mg or 20 mg).

In six placebo-controlled Phase 3 clinical trials, five of 12 weeks duration and one of 24 weeks duration, tadalafil was administered in doses of 10 and 20 mg to over 700 subjects (ages 25 to 80 years). The discontinuation rate due to adverse events in tadalafil-treated patients (2.5%) was not significantly different, although was numerically greater, than placebo-treated patients (1.3%). In these studies, the adverse events reported with tadalafil were generally mild or moderate. In these controlled phase 3 clinical trials, the following adverse events were reported during 12 weeks of treatment in patients receiving 10 mg and 20 mg doses of tadalafil compared to placebo. See Table 1.

Adverse drug reactions reported by < 2% of patients treated with tadalafil 10 mg or 20 mg in phase 3 studies.

Frequency estimate: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1000 to < 1/100), Rare (≥ 1/10,000 to < 1/1000), Very Rare (< 1/10,000) and Not known (events not reported in registration trials cannot be estimated from post-marketing spontaneous reports).

Nervous system.

Rare: transient amnesia(a).
(a) Frequency based upon events reported in erectile dysfunction placebo-controlled clinical trials in patients treated with tadalafil on demand and daily dosing with doses within the currently approved dosing range for tadalafil.

Eye disorders.

Uncommon: ocular hyperaemia; eye pain; eyelid oedema, rare: changes in colour vision.

Ear and labyrinth disorders.

Uncommon: sudden decrease or loss of hearing(b).
(b) Sudden decrease or loss of hearing has been reported in a small number of postmarketing and clinical trial cases with the use of all PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the ear and labyrinth 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 tadalafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea.

Vascular disorders.

Common: fatigue; uncommon: oedema peripheral.

Gastrointestinal disorders.

Common: nausea, vomiting.
Once-a-day dosing (2.5 mg or 5 mg). In four placebo-controlled Phase 3 clinical trials, three of 12 weeks duration and one of 24 weeks duration, tadalafil was administered in doses of 2.5 and 5 mg to more than 600 subjects (ages 24 to 82 years of age). The discontinuation rate due to adverse events in tadalafil-treated patients (3.55%) was not significantly different from placebo-treated patients (2.52%). The adverse events reported with tadalafil were generally mild or moderate in severity. In these controlled phase 3 clinical trials, the following adverse events were reported during 12 weeks of treatment in patients receiving 2.5 mg and 5 mg doses of tadalafil compared to placebo (see Table 2):

Adverse drug reactions reported by < 2% of patients treated with tadalafil 2.5 mg or 5 mg in phase 3 studies.

Frequency estimate: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1000 to < 1/100), Rare (≥ 1/10,000 to < 1/1000), Very Rare (< 1/10,000) and Not known (events not reported in registration trials cannot be estimated from post-marketing spontaneous reports).

Respiratory, thoracic and mediastinal disorders.

Common: nasal congestion, uncommon: dyspnoea.

Vascular disorders.

Common: flushing.

Nervous system.

Rare: transient amnesia(c).
(c) Frequency based upon events reported in erectile dysfunction placebo-controlled clinical trials in patients treated with tadalafil on demand and daily dosing with doses within the currently approved dosing range for tadalafil.
A slightly higher incidence of ECG abnormalities, primarily sinus bradycardia, has been reported in patients treated with tadalafil once a day as compared with placebo. Most of these ECG abnormalities were not associated with adverse reactions.

Lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) clinical trials.

In four placebo-controlled Phase 3 clinical trials of 12 weeks duration, enrolling patients of various ages (range 45-92 years), tadalafil was administered in doses of 5 mg to over 700 patients with BPH and BPH/ED. The discontinuation rate due to adverse events in tadalafil-treated patients (3.1%) was higher than placebo-treated patients (1.5%), with headache being the most frequently reported AE leading to discontinuation in the tadalafil 5 mg group (0.7%). The adverse events reported with tadalafil were generally mild or moderate in severity. In these controlled phase 3 clinical trials, the following adverse events were reported in patients receiving 5 mg doses of tadalafil compared to placebo (see Table 3):

Adverse drug reactions reported by < 1% of patients treated with tadalafil 5 mg in phase 3 studies.

Frequency estimate: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1000 to < 1/100), Rare (≥ 1/10,000 to < 1/1000), Very Rare (< 1/10,000) and Not known (events not reported in registration trials cannot be estimated from postmarketing spontaneous reports).

Nervous system.

Rare: transient amnesia(c).
(c) Frequency based upon events reported in erectile dysfunction placebo-controlled clinical trials in patients treated with tadalafil on demand and daily dosing with doses within the currently approved dosing range for tadalafil.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea.
Elderly. Data in patients over 65 years of age receiving tadalafil in clinical trials, either for the treatment of erectile dysfunction or the treatment of benign prostatic hyperplasia, are limited.
In clinical trials for the treatment of benign prostatic hyperplasia, involving 74 patients aged ≥ 75 years receiving tadalafil 5 mg taken once a day for 12 weeks, dizziness (4.8%) and diarrhoea (7.1%) were reported more frequently in patients aged ≥ 75 years compared with patients aged < 75 years (dizziness, 1.1%; diarrhoea 1.1%). The adverse event rate for patients ≥ 75 years receiving tadalafil was 32.1%, compared to 26.8% in patients < 75 years and 19.4% in patients ≥ 75 years receiving placebo (p = 0.043).
In all BPH, studies a total of 62 patients aged ≥ 75 years were exposed to tadalafil 5 mg for ≥ 12 months. Of these, 8.8% reported an SAE and 9.8% discontinued due to an adverse event which was more frequent compared to patients < 75 years (3.2% reported an SAE and 6.7% discontinued due to an adverse event, see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties, Clinical trials.

Adverse drug reactions identified from spontaneous post marketing surveillance.

Body as a whole.

Uncommon: hypersensitivity reactions including rash and urticaria.
Rare: facial oedema.
Frequency not known: Stevens-Johnson syndrome and exfoliative dermatitis.

Cardiac disorders(d).

Uncommon: palpitations, tachycardia, chest pain.
Rare: myocardial infarction.
Frequency not known: unstable angina pectoris, ventricular arrhythmia, sudden cardiac death.
(d) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to determine whether these events are related directly to these factors, to tadalafil, to sexual activity, or to a combination of these or other factors.

Vascular disorders.

Uncommon: hypotension (more commonly reported when tadalafil is given to patients who are already taking antihypertensive agents), hypertension.

Gastrointestinal.

Common: abdominal pain, diarrhoea in the elderly (aged 65 years).
Uncommon: gastroesophageal reflux.

Skin and subcutaneous tissue.

Uncommon: hyperhidrosis (sweating).

Eye disorders.

Uncommon: blurred vision.
Rare: visual field defect.
Frequency not known: non-arteritic anterior ischemic optic neuropathy (NAION), retinal vascular occlusion, central serous chorioretinopathy (CSCR).
Non-arteritic anterior ischemic 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 tadalafil. Most, but not all of these patients had underlying anatomic or vascular risk factors for development of 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. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient's underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Urogenital system.

Rare: prolonged erections.
Frequency not known: priapism, spontaneous penile erection.

Nervous system.

Very common: headache.
Common: dizziness.
Rare: stroke(e), migraine, syncope, transient ischemic attacks(e).
Frequency not known: seizures.
(e) Most of the patients in whom these events have been reported had pre-existing cardiovascular risk factors. However, it is not possible to determine whether these events are related directly to these factors, to tadalafil, to sexual activity, or to a combination of these or other factors.

Respiratory system.

Uncommon: epistaxis.

Ear and labyrinth disorders.

Very rare: sudden decrease or loss of hearing(f).
(f) Sudden decrease or loss of hearing has been reported in a small number of post-marketing and clinical trial cases with the use of all PDE5 inhibitors, including tadalafil. In some of the cases, medical conditions and other factors were reported that may have also played a role in the ear and labyrinth 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 tadalafil, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors.

Immune system disorders.

Rare: angioedema.

Reproductive system.

Rare: penile haemorrhage and haematospermia.

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

Single doses of up to 500 mg of tadalafil have been given to healthy subjects and multiple daily doses of up to 100 mg have been given to patients. Adverse events were similar to those seen at lower doses. In cases of overdose, standard supportive measures should be adopted as required. Haemodialysis contributes negligibly to tadalafil elimination.
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.

Tadalafil is a reversible inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5) in the smooth muscle of the corpus cavernosum, the prostate, the bladder and their vascular supply.
In the corpus cavernosum, when sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. Tadalafil has no effect in the treatment of erectile dysfunction in the absence of sexual stimulation.
In the smooth muscle of the prostate, bladder and their vascular supply, the effect of PDE5 inhibition on cGMP concentration results in vascular relaxation and increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced. These vascular effects may be complemented by inhibition of bladder afferent nerve activity and smooth muscle relaxation of the prostate and bladder.
Studies in vitro have shown that tadalafil inhibits PDE5 more potently than other PDEs. PDE5 is an enzyme found in the smooth muscle of the corpus cavernosum, prostate, bladder, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung and cerebellum. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE1, PDE2, PDE4, and PDE7 enzymes which are found in the heart, brain, blood vessels, liver, leukocytes, skeletal muscle and other organs. Tadalafil is > 10,000-fold more potent for PDE5 than for PDE3, an enzyme found in the heart and blood vessels. This selectivity for PDE5 over PDE3 is important because PDE3 is an enzyme involved in cardiac contractility. Additionally, tadalafil is approximately 700-fold more potent for PDE5 than for PDE6, an enzyme which is found in the retina and is responsible for phototransduction. Tadalafil is also > 9,000-fold more potent for PDE5 than for PDE8, 9 and 10 and 14-fold more potent for PDE5 than for PDE11. The tissue distribution and physiological effects of the inhibition of PDE8 through PDE11 have not been elucidated.

Studies of tadalafil on vision.

In a study to assess the effects of tadalafil on vision, no impairment of colour discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test. This finding is consistent with the low affinity of tadalafil for PDE6 compared to PDE5. In addition, no effects were observed on visual acuity, electroretinograms, intraocular pressure or pupillometry. Across all clinical studies, reports of changes in colour vision were rare, see Section 4.8 Adverse Effects (Undesirable Effects).

Studies of tadalafil on blood pressure and heart rate.

Tadalafil administered to healthy subjects produced no significant difference compared to placebo in supine systolic and diastolic blood pressure (mean maximal decrease of 1.6/0.8 mmHg, respectively), in standing systolic and diastolic blood pressure (mean maximal decrease of 0.2/4.6 mmHg, respectively) and no significant change in heart rate. Larger effects were recorded among subjects receiving concomitant nitrates, see Section 4.3 Contraindications.

Studies on spermatogenesis.

Three studies were conducted in men to assess the potential effect on spermatogenesis of tadalafil 10 mg (one 6-month study) and 20 mg (one 6-month and one 9-month study) administered daily. There were no adverse effects on sperm morphology or sperm motility in any of the three studies. In the study of 10 mg tadalafil for 6 months and the study of 20 mg tadalafil for 9 months, results showed a decrease in mean sperm concentrations relative to placebo. This effect was not seen in the study of 20 mg tadalafil taken for 6 months. In all 3 studies, there were no statistically significant differences between the placebo and tadalafil groups for mean total sperm counts. In addition, there was no adverse effect on mean concentrations of reproductive hormones, testosterone, luteinising hormone or follicle stimulating hormone with either 10 or 20 mg of tadalafil compared to placebo.

Study on QT.

The effect of a single 100 mg dose of tadalafil on the QT interval was evaluated at the time of peak tadalafil concentration in a randomised, double-blinded, placebo, and active (intravenous ibutilide)-controlled crossover study in 90 healthy males aged 18 to 53 years. The mean change in QTc (Fridericia QT correction) for tadalafil, relative to placebo, was 3.5 milliseconds (two-sided 90% CI = 1.9, 5.1). The mean change in QTc (Individual QT correction) for tadalafil, relative to placebo, was 2.8 milliseconds (two sided 90% CI = 1.2, 4.4). A 100 mg dose of tadalafil (5 times the highest recommended dose) was chosen because this dose yields exposures covering those observed upon coadministration of tadalafil with potent CYP3A4 inhibitors or those observed in renal impairment. In this study, the mean increase in heart rate associated with a 100 mg dose of tadalafil compared to placebo was 3.1 beats per minute.

Clinical trials.

On-demand dosing for the treatment of erectile dysfunction (ED). Tadalafil when taken on demand up to once daily, is effective in improving erectile function in men with erectile dysfunction (ED). In clinical studies assessing patients' ability to engage in successful and satisfying sexual activity, tadalafil demonstrated highly statistically significant improvement compared to placebo. Additionally, partners of patients on tadalafil had statistically significant greater satisfaction with sexual activity compared to partners of patients on placebo.
Tadalafil at doses of 2 to 100 mg has been evaluated in 16 clinical studies involving 3250 patients. Tadalafil 10 mg and/or 20 mg, taken on demand up to once daily, was compared to placebo in 6 primary efficacy studies (5 in a general ED population, 1 in patients with diabetes). Seven hundred and twenty four (724) patients received tadalafil 10 mg or 20 mg and 379 patients received placebo in these randomised, double-blinded, parallel group studies. Patients were free to choose the time interval between dose administration and the time of sexual attempts. Food and alcohol intake were not restricted. The studies were designed in this manner in order to allow for convenience and dosing flexibility for the patient and partner.
Several assessment instruments were used to evaluate the effect of tadalafil on erectile function. Global Assessment Questions (GAQ) were asked to determine whether the treatment improved patients' erections. During clinical studies, patients and partners completed sexual encounter profile (SEP) diaries assessing erectile function and sexual satisfaction of each sexual attempt. The International Index of Erectile Function (IIEF), a recall questionnaire, was also completed by patients. The IIEF provides global measures of erectile function and sexual satisfaction, as well as severity of ED.
In all primary efficacy studies, tadalafil demonstrated consistent and statistically significant improvement compared to placebo in all primary and secondary endpoints evaluated. In each primary efficacy study, a significant treatment effect was declared only if there was a statistically significant improvement on all three co-primary measures: 1) the IIEF Erectile Function Domain; 2) SEP Question 2 (assessing the ability to penetrate the partner's vagina); and 3) SEP Question 3 (assessing the ability to maintain the erection). The treatment effect did not diminish over time. Overall, tadalafil consistently showed efficacy in a broad and representative population that included patients with ED of various severities (mild, moderate, severe), aetiologies (including patients with diabetes), ages (21 to 86 years), ethnicities and durations of ED. In the five primary efficacy studies of general populations, 81% of patients reported that tadalafil 20 mg improved their erections compared to 35% of patients on placebo. Also, patients with ED in all severity categories reported improved erections while taking tadalafil 20 mg (86%, 83% and 72% for mild, moderate and severe, respectively) compared to patients on placebo (45%, 42% and 19% for mild, moderate and severe, respectively). Tadalafil showed statistically significant improvement in patients' ability to achieve an erection sufficient for sexual intercourse and maintain the erection for successful intercourse as measured by the SEP diaries. In the primary efficacy studies, 75% of intercourse attempts were successful in patients taking tadalafil 20 mg compared to 32% of patients on placebo. This finding was confirmed by partner SEP responses. Tadalafil also demonstrated statistically significant improvement in erectile function as measured by the IIEF Erectile Function Domain. Additionally, in the primary efficacy studies, approximately 60% of patients taking tadalafil 20 mg achieved normal erectile function during treatment. Patients with ED in all severity categories improved into the normal range (defined by IIEF).

Patient confidence and sexual satisfaction.

The IIEF also measures patients' confidence that they can attain and keep an erection sufficient for sexual intercourse. Tadalafil statistically significantly improved patient confidence. Analysis of the Intercourse Satisfaction and Overall Satisfaction domains of the IIEF showed that tadalafil treatment provided statistically significant enhancement of sexual satisfaction measured by both domains. Additionally, tadalafil improved the proportion of sexual encounters that were satisfying for both the patient and the partner.

Efficacy in ED patients with diabetes mellitus.

Tadalafil is effective in treating ED in patients with diabetes. Patients with diabetes (n = 451) were included in all primary efficacy studies, one of which specifically assessed tadalafil only in ED patients with Type 1 or Type 2 diabetes. Tadalafil produced statistically significant improvement in erectile function and sexual satisfaction. In these studies, 68% of patients with diabetes taking tadalafil 20 mg reported improved erections.

Period of responsiveness.

The diary data from 11 previous efficacy studies in the general ED population was combined to define the period of responsiveness. There were 321, 1143, and 638 patients in the 10 mg, 20 mg tadalafil and placebo group, respectively. The response appeared as early as < 1 hour. At 24 hours, 71% and 72% of attempts at sexual intercourse were successful with 10 mg (n = 76) and 20 mg (n = 366) tadalafil, respectively. The success rate at 36 hours was 72% and 75% with 10 mg (n = 34) and 20 mg (n = 129) tadalafil, respectively. The success rate with placebo was 44% (n = 135) and 47% (n = 46) at 24 and 36 hours post-dose, respectively. Therefore, tadalafil demonstrated statistically significant improvement in erectile function and the ability to have successful sexual intercourse up to 36 hours following dosing, as well as patients' ability to attain and maintain erections for successful intercourse compared to placebo as early as 16 minutes following dosing.
Once-a-day dosing for the treatment of erectile dysfunction (ED). Tadalafil at doses of 2.5, 5, and 10 mg taken once a day was initially evaluated in 3 clinical studies involving 853 patients of various ages (range 21-82 years) and ethnicities, with erectile dysfunction of various severities (mild, moderate, severe) and aetiologies. The majority of the patients in these 3 initial studies were responders to previous on-demand treatment with PDE5 inhibitors. In the two primary efficacy studies of general populations, 76 and 85% of patients reported that tadalafil 5 mg taken once a day improved their erections as compared to 29 and 30% with placebo. Also, patients with erectile dysfunction in all severity categories reported improved erections while taking tadalafil once a day. In the two primary efficacy studies of general populations, the mean per-subject proportion of successful intercourse attempts in tadalafil 5 mg-treated patients was 57% and 67% compared to 31% and 37% with placebo.
Tadalafil 5 mg significantly improves erectile function over the 24-hour period between the doses.
In a subsequent study, 217 patients who were treatment naive were randomised to tadalafil 5 mg once a day vs. placebo. The mean per-subject proportion of successful sexual intercourse attempts was 68% in tadalafil 5 mg treated patients compared to 52% for patients on placebo.
Once-a-day dosing for the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Tadalafil was studied in men with moderate or severe lower urinary tract symptoms associated with benign prostatic hyperplasia in 4 randomised, multi-national, double-blind, placebo-controlled, parallel-design primary efficacy and safety studies of 12 weeks duration, enrolling 1500 patients of various ages (range 45-92 years, mean 63.1 years) including 74 patients ≥ 75 years randomised to tadalafil 5 mg for 12 weeks. Patients with unstable angina, myocardial infarction or coronary intervention within 90 days, stroke in past 6 months, current treatment with nitrates, heart failure (New York Heart Association Class 2 or Class 3 or greater, dependent on study), uncontrolled diabetes (glycosylated HbA1c greater than 9%), or uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg) were not enrolled in the LUTS/BPH clinical trials.
Other patients excluded from the studies included:
Infectious, neurological, anatomical or malignant bladder or urethral conditions such as urinary tract infection, interstitial cystitis, urethral stricture or intravesical median lobe, recent urinary retention, Parkinson's disease, multiple sclerosis, and pelvic radiotherapy.
Pelvic surgery or any other pelvic procedure or recent instrumentation of the lower urinary tract such as prostatectomy, penis implant, bowel resection or cystoscopy or prostate biopsy.
Lower urinary tract trauma or bladder stones within 6 months of screening.
Angina requiring treatment with short or long acting nitrates.
Bladder post void residual volume (PVR) ≥ 300 mL.
Severe renal or hepatic impairment.
Receiving androgens, antiandrogens or approved or experimental pharmacologic BPH, overactive bladder (OAB), or ED therapies, including alpha blockers, 5-alpha reductase inhibitors (5-ARIs), antimuscarinics phosphodiesterase type 5 (PDE5) inhibitors, or herbal preparations.
The primary efficacy endpoint that evaluated the effect of tadalafil for the signs and symptoms of BPH was the International Prostate Symptom Score (IPSS), a four week recall questionnaire that was administered at the beginning and end of a placebo run-in period and subsequently at follow-up visits after randomisation. The IPSS assesses the severity of irritative (frequency, urgency, nocturia) and obstructive symptoms (incomplete emptying, stopping and starting, weak stream, and pushing or straining), with scores ranging from 0 to 35; higher numeric scores representing greater severity. Maximum urinary flow rate (Qmax), an objective measure of urine flow, was assessed as a secondary efficacy endpoint in Study LVHJ and as a safety endpoint in Study LVHK.
In each of the individual studies, patients treated with tadalafil 5 mg had statistically significantly greater decrease in total IPSS as compared to placebo after 12 weeks of treatment. Data for each study are shown in Table 4.
The improvement in total IPSS in the tadalafil group compared to placebo occurred as early as 1 week in the integrated data from Studies LVHJ and LVID.
In the long-term open-label extension phase of the controlled study LVHG, in which patients received tadalafil 5 mg for up to 1 year after the 12-week double-blind treatment period, the improvement in total IPSS induced by tadalafil at week 12 of double-blind treatment was maintained over 1 year.
For the Benign Prostatic Hyperplasia Impact Index (BII), the key secondary efficacy measure, tadalafil 5 mg demonstrated statistical superiority over placebo in improving the BII in each of the 4 studies. No adjustments for multiple comparisons were included in Study LVHG.
In Study LVHJ, the effect of tadalafil 5 mg once daily on maximum urinary flow rate (Qmax) was evaluated as a secondary efficacy endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (tadalafil 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.
In Study LVHK, the effect of tadalafil 5 mg once daily on Qmax was evaluated as a safety endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (tadalafil 5 mg: 1.6 mL/sec, placebo: 1.1 mL/sec); however, these changes were not significantly different between groups.
The number of patients aged 75 years or older who received tadalafil 5 mg for more than 12 weeks in studies supporting the LUTS/BPH indication is limited. In the four primary efficacy and safety studies a total of 74 patients aged ≥ 75 years were exposed to tadalafil 5 mg for 12 weeks. In all BPH studies, a total of 62 patients aged ≥ 75 years were exposed to tadalafil 5 mg for ≥ 12 months.
The change from baseline to endpoint in IPSS for patients aged ≥ 75 years is shown in Table 5. In each study, no statistically significant difference was observed between tadalafil 5 mg and placebo with respect to baseline to endpoint change in total IPSS among patients aged ≥ 75 years. In addition, in the integrated analysis of the 4 studies, the percentage of patients aged ≥ 75 years achieving at least a 25% decrease in total IPSS was similar on tadalafil 5 mg and placebo (53.6 versus 48.4%) and this difference was not statistically significant (relative benefit of 1.11, 95% CI 0.83, 1.48), see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects).
Once-a-day dosing for the treatment of erectile dysfunction (ED) and the treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Tadalafil 5 mg once daily resulted in statistically significant improvements in both BPH symptoms (as measured by the total IPSS) and erectile function (as measured by the EF domain of the IIEF questionnaire) in patients with both conditions. This was demonstrated in one of the placebo-controlled, double-blind, parallel-arm efficacy and safety studies which specifically assessed the efficacy and safety of tadalafil for once a day use in this population (Study LVHR). In this erectile dysfunction and benign prostatic hyperplasia study, tadalafil 5 mg demonstrated statistical superiority over placebo for total IPSS (mean treatment difference, -2.3; p < 0.001) and for the International Index of Erectile Function Erectile Function (IIEF EF) domain score (mean treatment difference, 4.7; p < 0.001). Patients treated with tadalafil 5 mg had statistically significant improvements versus placebo in both lower urinary tract symptoms and erectile function after 12 weeks of treatment. The mean per-subject proportion of successful sexual intercourse attempts in this study was 71.9% for tadalafil 5 mg patients compared to 48.3% patients on placebo.
In this study, the effect of tadalafil 5 mg once daily on Qmax was evaluated as a safety endpoint. Mean Qmax increased from baseline in both the treatment and placebo groups (tadalafil 5 mg: 1.6 mL/sec, placebo: 1.2 mL/sec); however, these changes were not significantly different between groups.

5.2 Pharmacokinetic Properties

Absorption.

Tadalafil is rapidly absorbed after oral administration and the mean maximum observed plasma concentration (Cmax) is achieved at a median time of 2 hours after dosing. There is no clinically relevant effect of food on the rate and extent of absorption of tadalafil, thus, tadalafil may be taken with or without food. The time of dosing (morning versus evening) has no clinically relevant effects on the rate and extent of absorption. The absolute bioavailability of oral tadalafil has not been established. The mean bioavailability of the tadalafil 20 mg tablet has been estimated to be 88% relative to an oral suspension dosage form.

Distribution.

The mean volume of distribution after oral dosing is approximately 63 L. At therapeutic concentrations, 94% of tadalafil in plasma is bound to proteins. Protein binding is not affected by impaired renal function. Less than 0.0005% of the administered dose appears in the semen of healthy subjects.

Metabolism.

Tadalafil is metabolised mainly (> 80%) by the cytochrome P450 (CYP) 3A4 isoform, with minor contributions by CYPs 2C8, 2C9, 2C19 and 2D6 (< 20% collectively). The major circulating metabolite is the methylcatechol glucuronide. This metabolite is at least 13,000-fold less potent than tadalafil for PDE5. Consequently, it is not expected to be clinically active at observed metabolite concentrations.

Excretion.

The mean oral clearance for tadalafil is 2.5 L/hr and the mean half-life is 17.5 hours in healthy subjects. Tadalafil is excreted predominantly as inactive metabolites, mainly in the faeces (approximately 61% of the dose) and to a lesser extent in the urine (approximately 36% of the dose).
Tadalafil pharmacokinetics in healthy subjects are linear with respect to time and dose. Over a dose range of 2.5 to 20 mg, exposure (AUC) increases proportionally with dose. Steady-state plasma concentrations are attained within 5 days of once-a-day dosing.
Pharmacokinetics determined with a population approach in patients with erectile dysfunction are similar to pharmacokinetics in subjects without erectile dysfunction. See Table 6.

Pharmacokinetics in special populations.

Elderly.

Healthy elderly subjects (65 years or over) had a lower clearance of tadalafil, resulting in a half-life of 22 hours and 25% higher exposure (AUC), relative to healthy subjects aged 19 to 45 years (half-life of 16-17 hours). This effect does not appear to warrant a dose adjustment, see Section 4.2 Dose and Method of Administration, Elderly patients. The half-life of tadalafil in the elderly increases the period after the last dose of tadalafil during which nitrates should be avoided, see Section 4.3 Contraindications.

Renal impairment.

In subjects with renal insufficiency, including those on haemodialysis, tadalafil exposure (AUC) was higher than in healthy subjects. Therefore, the recommended starting dose of tadalafil in patients with mild (creatinine clearance 51 to 80 mL/min) or moderate (creatinine clearance 31 to 50 mL/min) renal impairment is 10 mg for on-demand dosing for the treatment of erectile dysfunction. For patients with severe (creatinine clearance ≤ 30 mL/min) renal impairment, 10 mg is the maximum recommended dose for on-demand dosing for the treatment of erectile dysfunction, see Section 4.2 Dose and Method of Administration.
A single dose study in 8 men suffering from End Stage Renal Disease who were stable on haemodialysis showed 3-4 fold increase in AUC and 2-2.5 fold increase in Cmax in tadalafil levels. The half-life of the drug is also prolonged.

Hepatic impairment.

Tadalafil exposure (AUC) in subjects with mild and moderate hepatic impairment (Child-Pugh Class A and B) is comparable to exposure in healthy subjects. No controlled data are available in patients with severe hepatic impairment (Child-Pugh Class C). Once-a-day administration has not been evaluated in patients with hepatic insufficiency. If tadalafil is prescribed, a careful individual benefit/risk evaluation should be undertaken by the prescribing physician. Once a day dosing is not recommended for patients with severe hepatic impairment, see Section 4.4 Special Warnings and Precautions for Use.

Patients with diabetes.

Tadalafil exposure (AUC) in patients with diabetes was approximately 19% lower than the AUC value for healthy subjects. This difference in exposure does not warrant a dose adjustment.

5.3 Preclinical Safety Data

Genotoxicity.

Tadalafil was not mutagenic or genotoxic in in vitro bacterial and mammalian cell assays, and in in vitro human lymphocytes and in vivo rat micronucleus assays.

Carcinogenicity.

Oral administration of tadalafil at doses of 400 mg/kg/day for up to two years in mice resulted in increased development of hepatocellular adenomas in males but not in females. Tadalafil also caused hepatocellular microsomal enzyme induction in rodents and it is possible that this could lead to an increased incidence of hepatocellular neoplasms. However, hepatic microsomal enzyme induction is a common non-genotoxic biologic effect associated with hepatocellular tumour formation in rodents and is not considered relevant to human cancer risk. The no effect dose of 60 mg/kg/day was associated with systemic exposure to tadalafil approximately 5 to 7-fold that expected in men taking the maximum recommended dose of 20 mg daily, based on unbound drug concentrations.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tadalafil Sandoz tablets also contain the following excipients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sorbitan stearate.
Tadalafil Sandoz 5 mg tablets also contain Opadry II complete film-coating system 32K520007 Yellow.
Tadalafil Sandoz 10 mg tablets also contain Opadry II complete film-coating system 32K520017 Yellow.
Tadalafil Sandoz 20 mg tablets also contain Opadry II complete film-coating system 32K520009 Yellow.

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 the original package.

6.5 Nature and Contents of Container

Tadalafil Sandoz 20 mg tablets are presented in PVC/PE/PVdC-Alu blister packs of 4 and 8 tablets per carton.
Tadalafil Sandoz 10 mg tablets are presented in PVC/PE/PVdC-Alu blister packs of 4 tablets per carton.
Tadalafil Sandoz 5 mg tablets are presented in PVC/PE/PVdC-Alu blister packs of 28 tablets per carton.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical name.

Pyrazino[1', 2':1, 6]pyrido[3, 4-b]indole-1, 4-dione, 6-(1, 3-benzodioxol-5-yl)-2, 3, 6, 7, 12, 12a-hexahydro-2-methyl-, (6R, 12aR).

Molecular formula.

C22H19N3O4.

Molecular weight.

389.41.

Characteristics.

Tadalafil is a crystalline solid that is practically insoluble in water and very slightly soluble in ethanol.

CAS number.

171596-29-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes