Consumer medicine information

Priligy

Dapoxetine

BRAND INFORMATION

Brand name

Priligy

Active ingredient

Dapoxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Priligy.

What is in this leaflet

This leaflet answers some common questions about PRILIGY.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

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

What PRILIGY is used for

PRILIGY is a treatment for premature ejaculation (PE) in men 18 to 64 years old who have all of the following:

  • ejaculation in less than 2 minutes following vaginal penetration, on most occasions, with little stimulation and before the man wishes to; and
  • marked personal distress and interpersonal difficulty as a result of premature ejaculation (premature ejaculation troubles the man and his partner); and
  • poor control over ejaculation.

PRILIGY contains the active ingredient dapoxetine and is a type of drug called a selective serotonin reuptake inhibitor (SSRI) and it is also known as a urological medicine. PRILIGY increases your time to ejaculation and can improve your control over ejaculation and reduce your distress over how fast you ejaculate. This may improve your satisfaction with sexual intercourse.

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

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

Before you take PRILIGY

When you must not take it

Do not take PRILIGY if you have an allergy to:

  • any medicine containing dapoxetine
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

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

Do not take PRILIGY:

  • if you are taking a monoamine oxidase inhibitor (MAOI ) medicine used to treat depression, or have taken a MAOI within the last 14 days (see Taking other medicines for examples of MAOIs). Once you stop taking PRILIGY you will need to wait 7 days before taking an MAOI.
  • if you are taking thioridazine used to treat schizophrenia, or have taken thioridazine within the last 14 days. Once you stop taking PRILIGY you will need to wait 7 days before taking thioridazine.
  • if you are taking a serotonin reuptake inhibitor (such as a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA)), and certain other medicines and herbal products to treat depression or have taken these medicines within the last 14 days (see Taking other medicines for examples of serotonin reuptake inhibitors and other medicines used to treat depression). Once you stop taking PRILIGY you will need to wait 7 days before taking these medications/herbal products.
  • if you are taking certain medicines to treat fungal infections or medicines to treat HIV (see Taking other medicines for examples of these medicines).
  • if you have a history of mania or severe depression

Do not take PRILIGY if you have heart problems, such as heart failure or problems with the heart rhythm.

Do not take PRILIGY if you have moderate to severe liver problems.

Do not take PRILIGY if you are prone to fainting or passing out caused by a temporary drop in blood pressure (Syncope).

Do not take PRILIGY if you are under 18 years of age, or over 65 years of age. Safety and effectiveness in patients under 18 years or over 65 years have not been established.

Do not take PRILIGY if you are a woman. PRILIGY has been studied for use by men with premature ejaculation. Its safety in women has not been established.

This medicine contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

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

Before you start to take it

Before you start taking this medicine, your doctor should perform a test to make sure that your blood pressure doesn’t drop too much when you stand up from sitting or lying down.

Tell your doctor if:

  • you have any allergies to any other medicines, foods, preservatives or dyes
  • you have not been diagnosed with premature ejaculation
  • you use recreational drugs such as ecstasy or LSD (lysergic acid diethylamide). Taking PRILIGY with these drugs can cause serious reactions.
  • you take narcotics (strong pain medicines) or benzodiazepines such as Valium. These medicines can increase the drowsiness and dizziness of PRILIGY.
  • you consume alcohol. Alcohol can increase the risk of fainting and should be avoided while taking PRILIGY.
  • you are being treated for depression
  • you are currently using medications to treat fungal infections
  • you are currently taking medicine that thins your blood such as aspirin, anticoagulants such as warfarin, non-steroidal anti-inflammatory medicines (NSAIDs) such as ibuprofen, or medicine used to treat psychiatric conditions such as depression. Taking PRILIGY together with these medications can increase the risk of bleeding abnormalities.

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

  • history of dizziness from low blood pressure
  • heart and blood vessel problems
  • history of bleeding or blood clotting problems
  • depression
  • fainting (see Things to be careful of)
  • you have any thoughts of suicide or harming yourself.
    All thoughts of suicide must be taken seriously.
    Tell your doctor or a mental health professional immediately if you have any suicidal thoughts or other mental/mood changes.
  • psychiatric disorders, such as schizophrenia
  • history of mania (great excitement, hallucinations, difficulty in concentrating or staying still) or bipolar disorder (extreme mood swings between mania and depression) or develop these disorders
  • seizures (fits) or have uncontrolled epilepsy
  • moderate or severe liver problems
  • severe kidney problems
  • other forms of sexual problems such as erectile dysfunction. It is not known whether PRILIGY can worsen these conditions.
  • eye problems such as glaucoma, (high pressure in the eye )
  • HIV

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

Taking other medicines

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

Some medicines and PRILIGY may interfere with each other. These include:

  • monoamine oxidase inhibitors (MAOIs) used to treat depression, such as moclobemide, phenelzine and tranylcypromine.
  • medicines used to treat depression such as amitriptyline, citalopram, escitalopram, doxepin, fluoxetine, fluvoxamine, mianserin, mirtazapine, nortriptyline, paroxetine, sertraline, nefazodone, venlafaxine or vortioxetine.
  • triptans, medicines (used to treat migraine (e.g. sumatriptan,)
  • tramadol, used for pain
  • lithium, used for mood disorders
  • thioridazine used to treat schizophrenia.
  • linezolid, an antibiotic used to treat infection.
  • tryptophan, used to help your mood and help you sleep.
  • St John's wort (Hypericum perforatum), a herbal preparation

PRILIGY should not be taken with the above listed medicines/ herbal preparations or within 14 days of stopping these medicines.

Once you stop taking PRILIGY you will need to wait 7 days before taking these medicines/ herbal preparations.

Other medicines or food and PRILIGY may interfere with each other. These include:

  • medicines for mental health problems other than depression
  • medicines to thin your blood, such as warfarin
  • certain medicines for fungal infections, including ketoconazole, itraconazole and fluconazole
  • certain medicines for HIV, including ritonavir, saquinavir and atazanavir
  • certain medicines used to treat high blood pressure and chest pain (angina), enlarged prostate, or erectile dysfunction (impotence), as these medicines may lower your blood pressure, possibly upon standing
  • anti-inflammatory medicines such as ibuprofen or aspirin
  • certain antibiotics for treating infection, such as erythromycin, telithromycin and clarithromycin
  • aprepitant used to treat nausea
  • grapefruit. Do not drink grapefruit juice within 24 hours prior to taking PRILIGY
  • narcotics (strong pain medicines) or benzodiazepines such as valium. These medicines can increase the drowsiness and dizziness of PRILIGY.
  • alcohol. Alcohol can increase the risk of fainting and should be avoided while taking PRILIGY.

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

These medicines may be affected by PRILIGY or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Other medicines not listed here may be affected by PRILIGY or may affect how well it works. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take PRILIGY

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

How much to take

The recommended dose is a single tablet (30mg), taken when you need it, about 1 to 3 hours before sexual activity.

Do not take more than a single tablet in 24 hours.

How to take it

Swallow the tablets whole to avoid a bitter taste, with at least one full glass of water.

PRILIGY may be taken with or without food.

Avoid alcohol when taking PRILIGY.

Do not drink grapefruit juice within 24 hours prior to taking PRILIGY. Grapefruit juice can increase the level of this medicine in your body.

When to take it

Take the tablet when you need it about 1 to 3 hours before sexual activity.

PRILIGY should be taken as needed when sexual activity is anticipated. It is not intended for continuous daily use.

Do not take more than one tablet once every 24 hours due to increased risk of side effects and lack of additional benefit.

If you forget to take it

As PRILIGY is only taken when needed, it is not a problem if you forget to take it.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre on 13 11 26 (Australia) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much PRILIGY. Do this even if there are no signs of discomfort or poisoning.

Tell your doctor or pharmacist if you have taken more PRILIGY tablets than you should. You may feel sick or be sick. Symptoms of overdose in PRILIGY are drowsiness, nausea, vomiting, rapid heartbeat, tremor, agitation and dizziness. If you think that you have taken too much PRILIGY, you may need urgent medical attention.

While you are taking PRILIGY

WARNING: PRILIGY can make you faint or make you feel dizzy or light-headed.

To help lower the chance of this happening:

  • Take PRILIGY with at least one full glass of water.
  • Do not take PRILIGY if you are dehydrated (you do not have enough water in your body).
  • This can happen if:
    - You have not had water to drink in the past 4 to 6 hours
    - You have been sweating for a long time
    - You have an illness where you have a high temperature, diarrhoea or being sick
    - You have had alcohol
  • If you feel like you might faint (such as feeling sick, feeling dizzy, light-headed, feeling weak, confused, sweaty or an abnormal heart beat), or feel light-headed when you stand up, immediately lie down so your head is lower than the rest of your body or sit down with your head between your knees until you feel better. This will stop you from falling and hurting yourself if you do faint.
  • Do not stand up quickly after you have been sitting or lying down for a long time.
  • Do not drive or use any tools or machines if you feel faint when taking this medicine.
  • Tell your doctor if you faint when taking this medicine.

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking PRILIGY.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Keep all of your doctor's appointments so that your progress can be checked.

Talk to your doctor before you stop taking this medicine. You may have problems sleeping and feel dizzy after you stop taking it, even if you have not taken it every day.

Things you must not do

Do not take PRILIGY to treat any other complaints unless your doctor tells you to.

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

Things to be careful of

Be careful driving or operating machinery until you know how PRILIGY affects you. This medicine may cause dizziness, light-headedness, tiredness, drowsiness, fainting, having difficulty concentrating and blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Avoid alcohol while you are taking this medicine. The effects of alcohol, such as dizziness, drowsiness, slow reflexes or impaired judgement, may be increased if taken with PRILIGY.

Make sure you are not dehydrated (don't have enough water in your body). This can occur if you have not had anything to drink in the past 4-6 hours or you have been sweating for a long period or have an illness involving fever, diarrhoea or vomiting.

PRILIGY may cause fainting. To help lessen your chance of fainting or being injured by fainting:

  • Take PRILIGY with at least one full glass of water
  • If you begin to feel dizzy, light-headed, sweaty, shaky, clammy, nauseated, or otherwise unwell, lie down immediately so you don't get hurt falling from a fainting spell.
  • If you are sitting or lying down, do not stand up quickly after you take PRILIGY
  • If you experience any of these or similar effects, you should avoid driving and using machines.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking PRILIGY.

This medicine helps most people, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Stop taking PRILIGY and see your doctor right away if:

  • you have fits (seizures)
  • you faint or feel light-headed when you stand up
  • you notice any changes in your mood
  • you have any thoughts of suicide or harming yourself

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

  • nausea
  • headache
  • dizziness

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

  • fainting or feeling dizzy upon standing (see While you are taking PRILIGY)
  • increased blood pressure
  • trembling
  • tingling or numbness
  • blurred vision
  • eye pain
  • ringing in the ears
  • nasal congestion
  • diarrhoea, abdominal pain, dry mouth, vomiting, indigestion, intestinal gas, constipation, bloating
  • excessive sweating
  • fatigue, sleepiness and yawning
  • difficulty paying attention and feeling irritable
  • erectile dysfunction (difficulty getting or keeping an erection)
  • difficulty sleeping
  • anxiety, nervousness, decreased sexual desire, depression, indifference
  • abnormal dreams
  • unusual bruising and bleeding

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • Signs of allergy such as rash, itching or hives on the skin; shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using PRILIGY

Storage

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

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

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

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

Disposal

If your doctor tells you to stop taking this medicine, or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

PRILIGY 30 mg film-coated tablets are light grey, round and marked "30" inside a triangle on one side.

PRILIGY is supplied in blister packs containing 3 or 6 tablets.

Ingredients

PRILIGY contains 30 mg of dapoxetine (as hydrochloride) as the active ingredient.

It also contains:

  • lactose monohydrate
  • microcrystalline cellulose
  • croscarmellose sodium
  • colloidal anhydrous silica
  • magnesium stearate
  • hypromellose
  • titanium dioxide
  • iron oxide black
  • iron oxide yellow
  • triacetin

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

Supplier

PRILIGY is supplied in Australia by:

A. Menarini Australia Pty Ltd
Level 8, 67 Albert Ave
Chatswood NSW 2067
Medical Information: 1800 644 542

® PRILIGY is a registered trademark of Berlin-Chemie AG

Australian Registration Number:
AUST R 147946

This leaflet was revised in November 2022

For the most up to date version of this leaflet, please go to www.menarini.com.au/cmi

[vA10-0]

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Priligy

Active ingredient

Dapoxetine

Schedule

S4

 

1 Name of Medicine

Dapoxetine (as hydrochloride).

2 Qualitative and Quantitative Composition

Priligy is available as 30 mg tablets. Each Priligy 30 mg film-coated tablet contains 30 mg of dapoxetine base (as hydrochloride).

Excipient with known effect.

Contains lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Priligy 30 mg: light grey film-coated tablets debossed with "30" inside a triangle on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Priligy is indicated for the treatment of premature ejaculation (PE) in men 18 to 64 years of age, who have all of the following:
an intravaginal ejaculatory latency time (IELT) of less than two minutes; and
persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the patient wishes; and
marked personal distress or interpersonal difficulty as a consequence of PE; and
poor control over ejaculation.

4.2 Dose and Method of Administration

For oral use. Tablets should be swallowed whole to avoid the bitter taste. It is recommended that tablets be taken with at least one full glass of water. Priligy may be taken with or without food (see Section 5.2 Pharmacokinetic Properties).
Precautions to be taken before handling or administering the medicinal product.
Before treatment is initiated, see Section 4.4 Special Warnings and Precautions for Use regarding orthostatic hypotension.
Patients should be cautioned to avoid situations where injury could result should syncope or its prodromal symptoms such as dizziness or lightheadedness occur (see Section 4.4 Special Warnings and Precautions for Use). Priligy has minor or moderate influence on the ability to drive and use machines. Dizziness, disturbance in attention, syncope, blurred vision and somnolence have been reported in subjects receiving Priligy in clinical trials. Therefore, patients should be warned to avoid situations where injury could result, including driving or operating hazardous machinery.

Adult men (18 to 64 years of age).

Patients must not take more than one tablet once every 24 hours due to increased risk of side effects (see Boxed Warnings) and lack of additional benefit.
The recommended dose for all patients is 30 mg, taken as needed approximately 1 to 3 hours prior to sexual activity. Priligy is not intended for continuous daily use. Priligy should be taken only when sexual activity is anticipated.
The maximum recommended dosing frequency is once every 24 hours. Priligy may be taken with or without food (see Section 5.2 Pharmacokinetic Properties).
A careful appraisal of individual benefit risk of Priligy should be performed by the physician after the first four weeks of treatment (or at least after 6 doses of treatment) to determine whether continuing treatment with Priligy is appropriate.

Elderly (age 65 years and over).

Safety and efficacy of Priligy have not been established in patients age 65 years and over as limited data are available in this population (see Section 5.2 Pharmacokinetic Properties).

Children and adolescents.

Priligy should not be used in individuals below 18 years of age.

Patients with renal impairment.

No dose adjustment is required but caution is advised in patients with mild or moderate renal impairment. Priligy is not recommended for use in patients with severe renal impairment (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

No dose adjustment is required in patients with mild hepatic impairment. Priligy is contraindicated in patients with moderate and severe hepatic impairment (Child-Pugh class B and C) (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).

Known CYP2D6 poor metabolisers or patients treated with potent CYP2D6 inhibitors.

Caution is advised in patients known to be of CYP2D6 poor metaboliser genotype or in patients concomitantly treated with potent CYP2D6 inhibitors (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.2 Pharmacokinetic Properties).

Patients treated with moderate or potent inhibitors of CYP3A4.

Concomitant use of potent CYP3A4 inhibitors is contraindicated. Caution is advised when used concomitantly with moderate CYP3A4 inhibitors (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Priligy is contraindicated:
in patients with known hypersensitivity to dapoxetine hydrochloride or to any of the excipients listed, see Section 6.1 List of Excipients;
in patients with significant pathological cardiac conditions such as heart failure (NYHA class II-IV), conduction abnormalities such as AV block or sick sinus syndrome, significant ischemic heart disease or significant valvular disease, history of syncope;
in patients with a history of mania or severe depression;
for concomitant treatment with monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing treatment with an MAOI. Similarly, an MAOI should not be administered within 7 days after Priligy has been discontinued (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
for concomitant treatment with thioridazine, or within 14 days of discontinuing treatment with thioridazine. Similarly, thioridazine should not be administered within 7 days after Priligy has been discontinued (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
for concomitant treatment with serotonin reuptake inhibitors [selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs)] or other medicinal/ herbal products with serotonergic effects [e.g. L-tryptophan, triptans, tramadol, linezolid, lithium, St. John's wort (Hypericum perforatum)] or within 14 days of discontinuing treatment with these medicinal/ herbal products. Similarly these medicinal/ herbal products should not be administered within 7 days after Priligy has been discontinued (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
for concomitant treatment with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir, atazanavir, etc. (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions);
in patients with moderate and severe hepatic impairment.

4.4 Special Warnings and Precautions for Use

Patients must not take more than one tablet once every 24 hours due to increased risk of side effects (see Boxed Warnings) and lack of additional benefit.

General.

Priligy is only indicated in men with PE who meet all the criteria listed, see Section 4.1 Therapeutic Indications; Section 5.1 Pharmacodynamic Properties. Priligy should be administered only as on-demand treatment before anticipated sexual activity. Priligy should not be prescribed to men who have not been diagnosed with Premature Ejaculation. Safety has not been established and there are no data on the ejaculation-delaying effects in men without PE.

Use with recreational drugs.

Patients should be advised not to use Priligy in combination with recreational drugs. Recreational drugs with serotonergic activity such as ketamine, methylenedioxy methamphetamine (MDMA) and lysergic acid diethylamide (LSD) may lead to potentially serious reactions if combined with Priligy. These reactions include, but are not limited to, arrhythmia, hyperthermia, and serotonin syndrome. Use of Priligy with recreational drugs with sedative properties such as narcotics and benzodiazepines may further increase somnolence and dizziness.

Ethanol.

Patients should be advised not to use Priligy in combination with alcohol. Combining alcohol with Priligy may increase alcohol-related neurocognitive effects and may also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking Priligy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.7 Effects on Ability to Drive and Use Machines).

Syncope.

The number and percentage of subjects with syncope (characterized as loss of consciousness) was greater in Priligy treated subjects than in those who were treated with placebo. A dose response relationship for syncope is suggested based on subject incidence across all studies. In phase 3 studies involving 6081 randomized subjects, the frequency of syncope characterised as a loss of consciousness was 0.06% for Priligy 30 mg and 0.05% for placebo, compared with a higher rate of 0.23% for an unapproved dose (60 mg) and 0.64% for all phase 1 doses combined (30 mg to 240 mg) in phase 1 non-PE subjects studies. In phase 3 studies, three cases of syncope with bradycardia and sinus arrest (2 events, 5 seconds each; one event 28 seconds in duration) were observed during Holter monitor recording. Each subject spontaneously recovered normal sinus rhythm.
Possibly prodromal symptoms such as nausea, dizziness/ light-headedness, and diaphoresis were reported more frequently among patients treated with Priligy compared to placebo. In patients receiving 30 mg Priligy in phase 3 clinical trials, nausea was reported in 11.0%, dizziness in 5.8% and hyperhidrosis/ diaphoresis in 0.8%.
Syncope (characterized as loss of consciousness, with bradycardia or sinus arrest observed in patients wearing Holter monitors) in the clinical trials were considered vasovagal in etiology and the majority occurred during the first 3 hours after dosing, after the first dose, or associated with study related procedures in the clinic setting (such as blood draw and orthostatic manoeuvres and blood pressure measurements). Possible prodromal symptoms, such as nausea, dizziness, light-headedness, palpitations, asthenia, confusion and diaphoresis generally occurred within the first 3 hours following dosing and often preceded the syncope. Patients need to be made aware that they could experience syncope at any time with or without prodromal symptoms during their treatment with Priligy. Prescribers should counsel patients about the importance of maintaining adequate hydration and about how to recognize prodromal signs and symptoms to decrease the likelihood of serious injury associated with falls due to loss of consciousness. If the patient experiences possibly prodromal symptoms, the patient should immediately lie down so his head is lower than the rest of his body or sit down with his head between his knees until the symptoms pass, and be cautioned to avoid situations where injury could result, including driving or operating hazardous machinery, should syncope or other CNS effects occur (see Section 4.7 Effects on Ability to Drive and Use Machines).
Combining alcohol with Priligy may enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol with taking Priligy.

Cardiovascular disease.

Subjects with underlying cardiovascular disease were excluded from phase 3 clinical trials. The risk of adverse cardiovascular outcomes from syncope (cardiac syncope and syncope from other causes) is increased in patients with underlying structural cardiovascular disease (e.g. documented outflow obstruction, valvular heart disease, carotid stenosis and coronary artery disease). There are insufficient data to determine whether this increased risk extends to vasovagal syncope in patients with underlying disease.

Cardiac conduction.

Alteration in cardiac conduction was observed only in preclinical isolated in vitro/ ex vivo models, and not in whole animal testing. In clinical studies, supraventricular beats and arrhythmias were slightly higher on Priligy. A review of Holter data in over 3350 subjects in phase 3 clinical trials demonstrated asymptomatic nonsustained ventricular tachycardia occurring in 0.2%, 0.3%, and 0.3% of placebo, Priligy 30 mg and Priligy 60 mg dose groups, respectively. In addition, no effect on QTc prolongation was detected in two phase I thorough QT studies designed to investigate the effect of Priligy on cardiac repolarization.

Orthostatic hypotension.

Before treatment initiation, a careful medical examination including history of orthostatic events should be performed by the physician. An orthostatic test should be performed before initiating therapy (blood pressure and pulse rate, supine and standing).
In case of a history of documented or suspected orthostatic reaction, treatment with Priligy should be avoided.
Orthostatic hypotension has been reported in clinical trials. The prescriber should counsel the patient in advance that if he experiences possibly prodromal symptoms, such as light-headedness soon after standing, he should immediately lie down so his head is lower than the rest of his body or sit down with his head between his knees until the symptoms pass. The prescriber should also inform the patient not to rise quickly after prolonged lying or sitting.

Medicinal products with vasodilatation properties.

Priligy should be prescribed with caution in patients taking medicinal products with vasodilatation properties (such as alpha adrenergic receptor antagonists, nitrates) due to possible reduced orthostatic tolerance (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Moderate CYP3A4 inhibitors.

Caution is advised in all patients concomitantly treated with moderate CYP3A4 inhibitors. Unless the patient is known to be a CYP2D6 extensive metaboliser, caution is advised when used concomitantly with moderate CYP3A4 inhibitors (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Potent CYP2D6 inhibitors.

Caution is advised in patients taking potent CYP2D6 inhibitors or in patients known to be of CYP2D6 poor metaboliser genotype, as this may increase exposure levels, which may result in a higher incidence and severity of dose dependent adverse events (see Section 4.2 Dose and Method of Administration; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Suicide/ suicidal thoughts.

Antidepressants, including SSRIs have been shown to increase the risk compared to placebo of suicidal thinking and suicidality in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24. In clinical trials with Priligy for the treatment of premature ejaculation, there was no clear indication of treatment-emergent suicidality.

Mania.

Priligy should not be used in patients with a history of mania/ hypomania or bipolar disorder and should be discontinued in any patient who develops symptoms of these disorders.

Seizure.

Due to the potential of SSRIs to lower the seizure threshold, Priligy should be discontinued in any patient who develops seizures and avoided in patients with unstable epilepsy. Patients with controlled epilepsy should be carefully monitored.

Co-morbid depression and psychiatric disorders.

Men with underlying signs and symptoms of depression should be evaluated prior to treatment with Priligy to rule out undiagnosed depressive disorders. Concomitant treatment of Priligy with antidepressants, including SSRIs and SNRIs, is contraindicated (see Section 4.3 Contraindications). Discontinuation of treatment for ongoing depression or anxiety in order to initiate Priligy for the treatment of PE is not recommended. Priligy is not indicated for psychiatric disorders and should not be used in men with these disorders, such as schizophrenia, or in those suffering with co-morbid depression, as worsening of symptoms associated with depression cannot be excluded. This could be the result of underlying psychiatric disorder or might be a result of medicinal product therapy. Physicians should encourage patients to report any distressing thoughts or feelings at any time and if signs and symptoms of depression develop during treatment, Priligy should be discontinued.

Haemorrhage.

There have been reports of bleeding abnormalities with SSRIs. Caution is advised in patients taking Priligy, particularly in concomitant use with medicinal products known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants [TCAs], acetylsalicylic acid, nonsteroidal anti-inflammatory drugs [NSAIDs], anti-platelet agents) or anticoagulants (e.g. warfarin), as well as in patients with a history of bleeding or coagulation disorders (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in renal impairment.

Priligy is not recommended for use in patients with severe renal impairment and caution is advised in patients with mild or moderate renal impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Withdrawal effects.

Abrupt discontinuation of chronically administered SSRIs used to treat chronic depressive disorders has been reported to result in the following symptoms: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paraesthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania).
A double-blind clinical trial in subjects with PE designed to assess the withdrawal effects of 62 days of daily or as needed dosing with 60 mg Priligy showed mild withdrawal symptoms with a slightly higher incidence of insomnia and dizziness reported in subjects switched to placebo after daily dosing (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Consistent results were seen in a second double blind clinical trial with a 24 week treatment phase of 30 and 60 mg doses as needed followed by a 1 week withdrawal assessment period.

Eye disorders.

As with other SSRIs, the use of Priligy has been associated with ocular effects such as mydriasis and eye pain. Priligy should be used with caution in patients with raised intraocular pressure or those at risk of angle closure glaucoma.

Mood related adverse events.

In phase 3 studies, Priligy 30 mg was associated with a higher incidence of mood related AEs, such as insomnia (2.2%), anxiety (1.1%) euphoric mood (0.2%), and depression (0.2%) compared to placebo (1.5%, 0.5%, 0%, 0.3%, respectively). Men with psychiatric disorders such as depression and anxiety were excluded from phase 3 clinical studies. Priligy should not be used in men with concomitant psychiatric disorders, as it is unknown if the risk of these events and/or the underlying psychiatric condition could worsen (see Section 4.4 Special Warnings and Precautions for Use).

Other forms of sexual dysfunction.

In phase 3 studies, Priligy 30 mg was associated with a higher incidence of sexual AEs, such as erectile dysfunction (2.3%) and libido decreased (0.5%) compared to placebo (1.6% and 0.3%, respectively). Men with clinically significant erectile dysfunction and other sexual disorders were excluded from clinical studies. Caution should be used when prescribing Priligy to men with other forms of sexual dysfunction, as it is unknown if the sexual dysfunction could worsen. Before treatment, subjects with other forms of erectile dysfunction (ED), should be carefully investigated by physicians.
Priligy should not be used in men with erectile dysfunction (ED) who are using PDE5 inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Accidental injury.

In phase 3 studies, Priligy 30 mg was associated with a higher incidence of accidental injuries (2.7%) compared to placebo (1.8%). While some accidents were reported to be related to syncope occurrence, there was no clear correlation between accidental injury adverse events and events of dizziness or changes in alertness associated with Priligy administration. Patients should be cautioned to avoid situations where injury could result should syncope or symptoms such as dizziness occur (see Section 4.4 Special Warnings and Precautions for Use; Section 4.7 Effects on Ability to Drive and Use Machines; Section 4.2 Dose and Method of Administration).

Use in the elderly.

Safety and efficacy of Priligy have not been established in patients age 65 years and over as limited data are available in this population (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

Priligy should not be used in individuals below 18 years of age.

Lactose intolerance.

Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Effects on laboratory tests.

No available data.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Potential for interaction with monoamine oxidase inhibitors.

In patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued an SSRI and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Animal data on the effects of combined use of an SSRI and MAOIs suggest that these medicinal products may act synergistically to elevate blood pressure and evoke behavioural excitation. Therefore, Priligy should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, an MAOI should not be administered within 7 days after Priligy has been discontinued (see Section 4.3 Contraindications).

Potential for interaction with thioridazine.

Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias. Medicinal products such as Priligy that inhibit the CYP2D6 isoenzyme appear to inhibit the metabolism of thioridazine and the resulting elevated levels of thioridazine are expected to augment the prolongation of the QTc interval. Priligy should not be used in combination with thioridazine or within 14 days of discontinuing treatment with thioridazine. Similarly, thioridazine should not be administered within 7 days after Priligy has been discontinued (see Section 4.3 Contraindications).

Medicinal/ herbal products with serotonergic effects.

As with other SSRIs, co-administration with serotonergic medicinal/ herbal products (including MAOIs, L-tryptophan, triptans, tramadol, linezolid, SSRIs, SNRIs, lithium and St John's wort (Hypericum perforatum) preparations) may lead to an incidence of serotonin associated effects. Priligy should not be used concomitantly with other SSRIs, MAOIs, other serotonergic medicinal/ herbal products or within 14 days of discontinuing treatment with these medicinal/ herbal products. Similarly, these medicinal/ herbal products should not be administered within 7 days after Priligy has been discontinued (see Section 4.3 Contraindications).

CNS active medicinal products.

The use of Priligy in combination with CNS active medicinal products (e.g. antiepileptics, antidepressants, antipsychotics, anxiolytics, sedative hypnotics) has not been systematically evaluated in patients with premature ejaculation. Consequently, caution is advised if the concomitant administration of Priligy and such medicinal products is required.

Effects of co-administered medicinal products on dapoxetine hydrochloride.

In vitro studies in human liver, kidney, and intestinal microsomes indicate dapoxetine is metabolized primarily by CYP2D6, CYP3A4 and flavin monooxygenase 1 (FMO1). Therefore, inhibitors of these enzymes may reduce dapoxetine clearance.

CYP3A4 inhibitors: potent CYP3A4 inhibitors.

Administration of ketoconazole (200 mg twice daily for 7 days) increased the Cmax and AUCinf of dapoxetine (60 mg single dose) by 35% and 99%, respectively. Considering the contribution of both unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may be increased by approximately 25% and the AUC of the active fraction may be doubled if taken with potent CYP3A4 inhibitors.
The increases in the Cmax and AUC of the active fraction may be markedly increased in a part of the population which lack a functional CYP2D6 enzyme, i.e. CYP2D6 poor metabolisers, or in combination with potent inhibitors of CYP2D6.
Therefore, concomitant use of Priligy and potent CYP3A4 inhibitors, such as such as ketoconazole, itraconazole, ritonavir, saquinavir, telithromycin, nefazodone, nelfinavir and atazanavir, is contraindicated. Grapefruit juice is also a potent CYP3A4 inhibitor and should be avoided within 24 hours prior to taking Priligy (see Section 4.3 Contraindications).

CYP3A4 inhibitors: moderate CYP3A4 inhibitors.

Concomitant treatment with moderate CYP3A4 inhibitors (e.g. erythromycin, clarithromycin, fluconazole, amprenavir, fosamprenavir, aprepitant, verapamil, diltiazem) may also give rise to significantly increased exposure of dapoxetine and desmethyldapoxetine, especially in CYP2D6 poor metabolisers. The maximum dose of dapoxetine should be 30 mg if dapoxetine is combined with any of these drugs (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Potent CYP2D6 inhibitors.

The Cmax and AUCinf of dapoxetine (60 mg single dose) increased by 50% and 88%, respectively, in the presence of fluoxetine (60 mg/day for 7 days). Considering the contribution of both unbound dapoxetine and desmethyldapoxetine, the Cmax of the active fraction may be increased by approximately 50% and the AUC of the active fraction may be doubled if taken with potent CYP2D6 inhibitors. These increases in the Cmax and AUC of the active fraction are similar to those expected for CYP2D6 poor metabolisers and may result in a higher incidence and severity of dose dependent adverse events (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

PDE5 inhibitors.

Priligy should not be used in patients using PDE5 inhibitors due to possible reduced orthostatic tolerance (see Section 4.4 Special Warnings and Precautions for Use). The pharmacokinetics of dapoxetine (60 mg) in combination with tadalafil (20 mg) and sildenafil (100 mg) were evaluated in a single dose crossover study (C-2003-027). Tadalafil did not affect the pharmacokinetics of dapoxetine. Sildenafil caused slight changes in dapoxetine pharmacokinetics (22% increase in AUCinf and 4% increase in Cmax), which are not expected to be clinically significant. Concomitant use of Priligy with PDE5 inhibitors may result in orthostatic hypotension (see Section 4.4 Special Warnings and Precautions for Use). The efficacy and safety of Priligy in patients with both premature ejaculation and erectile dysfunction concomitantly treated with Priligy and PDE5 inhibitors have not been established.

Effects of dapoxetine hydrochloride on co-administered medicinal products.

Tamsulosin.

Concomitant administration of single or multiple doses of 30 mg or 60 mg Priligy to patients receiving daily doses of tamsulosin did not result in changes in the pharmacokinetics of tamsulosin. The addition of Priligy to tamsulosin did not result in a change in the orthostatic profile and there were no differences in orthostatic effects between tamsulosin combined with either 30 or 60 mg Priligy and tamsulosin alone. However, Priligy should be prescribed with caution in patients who use alpha adrenergic receptor antagonists due to possible reduced orthostatic tolerance (see Section 4.4 Special Warnings and Precautions for Use).

Medicinal products metabolized by CYP2D6.

Multiple doses of dapoxetine (60 mg/day for 6 days) followed by a single 50 mg dose of desipramine increased the mean Cmax and AUCinf of desipramine approximately 11% and 19%, respectively, compared to desipramine administered alone. Dapoxetine may give rise to a similar increase in the plasma concentrations of other drugs metabolized by CYP2D6. The clinical relevance is likely to be small.

Medicinal products metabolized by CYP3A4.

Multiple dosing of dapoxetine (60 mg/day for 6 days) decreased the AUCinf of midazolam (8 mg single dose) by approximately 20% (range -60 to +18%). The clinical relevance of the effect on midazolam is likely to be small in most patients. The increase in CYP3A activity may be of clinical relevance in some individuals concomitantly treated with a medicinal product mainly metabolized by CYP3A and with a narrow therapeutic window.

Medicinal products metabolized by CYP2C19.

Multiple dosing of dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics of a single 40 mg dose of omeprazole. Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C19 substrates.

Medicinal products metabolized by CYP2C9.

Multiple dosing of dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics of a single 5 mg dose of glyburide. Dapoxetine is unlikely to affect the pharmacokinetics of other CYP2C9 substrates.

Medicinal products metabolized by CYP1A and 2B6.

Repeated administration of dapoxetine induced CYP1A and 2B in laboratory animals. Dapoxetine may increase the clearance of substrates of CYP1A and 2B6.

PDE5 inhibitors.

In a single dose crossover study, dapoxetine (60 mg) did not affect the pharmacokinetics of tadalafil (20 mg) or sildenafil (100 mg).

Warfarin and medicinal products that are known to affect coagulation and/or platelet function.

There are no data evaluating the effect of chronic use of warfarin with Priligy; therefore, caution is advised when Priligy is used in patients taking warfarin chronically (see Section 4.4 Special Warnings and Precautions for Use). In a pharmacokinetic study, dapoxetine (60 mg/day for 6 days) did not affect the pharmacokinetics or pharmacodynamics (PT or INR) of warfarin following a single 25 mg dose.
There have been reports of bleeding abnormalities with SSRIs (see Section 4.4 Special Warnings and Precautions for Use).

Ethanol.

Coadministration of a single dose of ethanol, 0.5 g/kg (approximately 2 drinks), did not affect the pharmacokinetics of dapoxetine (60 mg single dose) or the pharmacokinetics of ethanol, however, Priligy in combination with ethanol increased somnolence and significantly decreased self-rated alertness. Pharmacodynamic measures of cognitive impairment (Digit Vigilance Speed, Digit Symbol Substitution Test) did not show a significant separation from placebo with either ethanol or Priligy alone but did show a statistically significant effect when Priligy was coadministered with ethanol versus ethanol alone. Concomitant use of alcohol and Priligy could increase the chance or severity of adverse reactions such as dizziness, drowsiness, slow reflexes, or altered judgment. Combining alcohol with Priligy may increase these alcohol related effects and may also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking Priligy (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effects on fertility were observed in male rats given dapoxetine HCl at up to 0.25% of the diet, corresponding to a dose of 158 mg/kg/day. Plasma concentrations of dapoxetine in the animals did not reach clinical levels. As such, the potential for effects on fertility in patients receiving Priligy is not known.
Fertility was unaffected in female rats given dapoxetine at up to 100 mg/kg/day by oral gavage, yielding exposure to dapoxetine (plasma AUC) marginally higher than that of men at the maximum recommended human dose of 60 mg/day.
(Category C)
Priligy is not indicated for use by women.
Dapoxetine was not teratogenic in rats at oral doses up to 100 mg/kg/day or in rabbits given up to 75 mg/kg/day during the period of organogenesis. Delayed ossification and an increased incidence of skeletal variations (extra ribs) were observed in fetuses at the highest doses tested, which were maternotoxic. Exposure to dapoxetine in rats (plasma AUC) was twice that of humans at the recommended clinical dose of 30 mg/day.
Dapoxetine and/or its metabolites cross the placenta in rats.
There are no adequate and well-controlled studies with dapoxetine in pregnant women. Neonates exposed to other SSRIs and SNRIs (serotonin and noradrenaline reuptake inhibitors) late in the third trimester have developed complications requiring prolonged hospitalisation, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyper-reflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.
There is no evidence to suggest that dapoxetine exposure has an effect on a partner's pregnancy based on limited observational data from the clinical trial database.
 Priligy is not indicated for use by women.
It is not known if either dapoxetine or its metabolites are excreted in human breast milk.

4.7 Effects on Ability to Drive and Use Machines

Dizziness, disturbance in attention, syncope, blurred vision and somnolence have been reported in subjects receiving dapoxetine in clinical trials. Therefore, patients should be warned to avoid situations where injury could result, including driving or operating hazardous machinery.
Combining alcohol with Priligy may increase alcohol related neurocognitive effects and may also enhance neurocardiogenic adverse events such as syncope, thereby increasing the risk of accidental injury; therefore, patients should be advised to avoid alcohol while taking Priligy (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.8 Adverse Effects (Undesirable Effects)

The safety of Priligy was evaluated in 6081 subjects with premature ejaculation who were randomised in five phase 3 double blind, placebo controlled clinical trials. Of these subjects, 1616 received Priligy 30 mg as needed and 1612 received placebo. A total of 241 subjects were exposed to Priligy 30 mg for > 121 days.
Syncope characterized as loss of consciousness with bradycardia or sinus arrest observed in patients wearing Holter monitors has been reported in clinical trials and is considered medicinal product related. The majority of cases occurred during the first 3 hours after dosing, after the first dose or associated with study related procedures in the clinic setting (such as blood draw and orthostatic manoeuvres and blood pressure measurements). Prodromal symptoms often preceded the syncope (see Section 4.4 Special Warnings and Precautions for Use).
The occurrence of syncope and possibly prodromal symptoms appears dose dependent as demonstrated by higher incidence among patients treated with higher than recommended doses in Phase 3 clinical trials.
Syncope and orthostatic hypotension has been reported in clinical trials (see Section 4.4 Special Warnings and Precautions for Use).
The most frequently reported AEs in subjects receiving Priligy included nausea, diarrhoea, dizziness and headache (Table 1). These AEs all occurred at higher frequency with doses of Priligy above 30 mg studied in phase 3 studies.
The most common adverse drug reactions (≥ 5%) reported during clinical trials at a dose of 30 mg Priligy were headache, dizziness and nausea. The most common events leading to discontinuation were nausea (0.9% of 30 mg Priligy treated subjects) and dizziness (0.7% of 30 mg Priligy treated subjects).
Adverse drug reactions reported by Priligy treated subjects in these trials are shown in Table 2.
Adverse drug reactions reported in the long-term open label extension trial were consistent with those reported in the double blind studies and no additional adverse drug reactions were reported.

Withdrawal effects.

Abrupt discontinuation of chronically administered SSRIs used to treat chronic depressive disorders has been reported to result in the following symptoms: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania.
Results of a safety study showed a slightly higher incidence of withdrawal symptoms of mild or moderate insomnia and dizziness in subjects switched to placebo after 62 days of daily dosing.

Postmarketing data.

No newly identified adverse drug reactions have been reported during postmarketing use of Priligy.

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

There have been no reports of overdose during clinical trials.
There were no unexpected adverse events in a clinical pharmacology study of Priligy with daily doses up to 240 mg (two 120 mg doses given 3 hours apart). In general, symptoms of overdose with SSRIs include serotonin mediated adverse reactions such as somnolence, gastrointestinal disturbances such as nausea and vomiting, tachycardia, tremor, agitation and dizziness.
In cases of overdose, standard supportive measures should be adopted as required. Due to high protein binding and large volume of distribution of dapoxetine hydrochloride, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for Priligy are known.
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.

Dapoxetine inhibits the serotonin transporter. The mechanism of action of dapoxetine in premature ejaculation is presumed to be linked to the inhibition of neuronal reuptake of serotonin and the subsequent potentiation of the neurotransmitter's action at pre- and post-synaptic receptors.
Human ejaculation is primarily mediated by the sympathetic nervous system. The ejaculatory pathway originates from a spinal reflex centre, mediated by the brain stem, which is influenced initially by a number of nuclei in the brain (medial preoptic and paraventricular nuclei). In the rat, dapoxetine inhibits the ejaculatory expulsion reflex by acting at a supraspinal level with the lateral paragigantocellular nucleus (LPGi) as a necessary brain structure for the effect. Postganglionic sympathetic fibres that innervate the seminal vesicles, vas deferens, prostate, bulbourethral muscles, and bladder neck cause them to contract in a coordinated fashion to achieve ejaculation. Dapoxetine modulates this ejaculatory reflex in rats, causing an increase in pudendal motoneuron reflex discharge (PMRD) latency.

Clinical trials.

The effectiveness of Priligy in the treatment of premature ejaculation (PE) was established in four double blind, placebo controlled clinical trials, in which a total of 1616 subjects were randomised to Priligy 30 mg and 1612 to placebo. All subjects were 18 years of age or older; 99% were < 64 years of age. All subjects were heterosexual males, in a stable relationship for at least 6 months, had PE defined by the DSM-IV-TR criteria and in two trials had at least moderate distress or interpersonal difficulty and had an intravaginal ejaculatory latency time (IELT; time from vaginal penetration to the moment of intravaginal ejaculation) of ≤ 2 minutes in a minimum of 75% of evaluable sexual intercourse events during the baseline period. Subjects with controlled hypertension (SBP < 180 mmHg, DBP < 100 mmHg) were included in phase 3 studies. Subjects with other forms of sexual dysfunction, including erectile dysfunction and those using other forms of pharmacotherapy for the treatment of PE or antidepressants were excluded from all studies.
In all studies, subjects were instructed to administer Priligy 1-3 hours prior to anticipated sexual activity and not to take more than one dose per 24 hours. Three of the studies were 12 weeks in duration (C-2002-012, C-2002-013, R096769-PRE-3003), and one study was 24 weeks of treatment followed by a one week assessment of possible withdrawal effects (R096769-PRE-3001).
In the analysis of the pooled studies, mean average IELT at week 12 (LPOCF) was significantly greater (p < 0.001) in the Priligy 30 mg (3.1 min) than in the placebo group (1.95 min) (Table 3). These results were similar to those seen in each phase 3 study, where mean average IELT at week 12 (LPOCF) was statistically greater for Priligy 30 mg compared to the placebo group. In the 12 week US studies that investigated Priligy 30 mg (C-2002-012 and C-2002-013), 1.1% of subjects withdrew due to lack of efficacy, 4.8% due to personal reasons, 4.0% due to adverse events, 4.6% due to withdrawal of consent, 6.3% due to lost to follow up, 1.3% due to noncompliance or a protocol violation and 0.6% due to other reasons. In the 12 week Pan-Asian study R096769-PRE-3003 that investigated Priligy 30 mg, 1.1% of subjects withdrew due to insufficient response, 9.9% due to personal reasons, 1.7% due to AEs, 0.8% due to lost to follow up, and 5.9% due to other reasons. In the 24 week EU study R096769-PRE-3001 that investigated Priligy 30 mg, 6.4% of subjects withdrew due to insufficient response, 14.4% due to personal reasons, 3.9% due to AEs, 5.7% due to lost to follow up and 12.4% due to other reasons.
In a representative study (R096769-PRE-3001) with the longest treatment duration (24 weeks), 1162 subjects were randomized, 385 to placebo, 388 to Priligy 30 mg as needed, and 389 to Priligy 60 mg as needed. The mean average IELT at baseline and study endpoint for placebo and 30 mg as needed treatment groups is shown in Figure 1. Increases in mean average IELT at the week 24 endpoint (LPOCF) were statistically significant (p < 0.001) in the Priligy group versus placebo. The magnitude of IELT prolongation was related to baseline IELT and was variable between individual subjects. The clinical relevance of Priligy treatment effects are described below in terms of patient reported response rates.
In addition to the primary endpoint of average IELT, meaningful treatment benefit to the patient in the above study was demonstrated using a definition of treatment response consisting of a composite of at least a 2-category increase in control over ejaculation (response options: very poor, poor, fair, good, and very good) plus at least a 1-category decrease in ejaculation related distress (response options: not at all, a little bit, moderately, quite a bit, and extremely). A greater percentage of subjects responded in the Priligy group versus placebo beginning at week 4 and up to and including week 24 (this was statistically significant; p = 0.003 for dapoxetine 30 mg versus placebo at week 16, all other comparisons p ≤ 0.001). Significant decrease in subject distress and significant improvement in subject satisfaction with sexual intercourse were also observed (response options: very poor, poor, fair, good, and very good). Improvements at weeks 12 and 24 (LPOCF) for the key secondary endpoints are presented in Table 4.
Other secondary patient reported outcome (PRO) endpoints were assessed in the clinical trials including clinical global impression of change in condition, CGIC, a commonly used measure in which patients assess the status of their condition. Patients were asked to compare their premature ejaculation from the start of the study, with response options ranging from much better to much worse. CGIC results by treatment group reported at the end of the above study are shown in Table 5.
Although Priligy 60 mg is not approved, this dose was used to test the withdrawal effects of chronic daily and as needed dosing of Priligy in the treatment of premature ejaculation in a placebo controlled, double blind, parallel group study in which 1238 subjects were randomized. Subjects diagnosed with PE based on the DSM-IV-TR without an IELT restriction received placebo or 60 mg Priligy either once daily or as needed for 62 days followed by a withdrawal assessment phase of 7 days of additional Priligy treatment or placebo. Withdrawal effects after abrupt cessation of therapy were measured using the Discontinuation Emergent Signs and Symptoms (DESS), a clinician rated instrument that queries for symptoms and signs associated with the discontinuation of serotonin reuptake inhibitor treatment. The DESS specifies a check list of 43 symptoms that are clinician rated as 1 of 4 categories (i.e. new symptom; old symptom, but worse; old symptom, but improved; and old symptom, but unchanged, or symptom not present). Those symptoms rated by the clinician as "new" or "old", "but worse" are counted as points indicative of a possible withdrawal effect. For each subject, discontinuation syndrome was defined as an increase in the weekly DESS score by at least 4 points from day 63 to day 70. In this study, there was no clear evidence of discontinuation (withdrawal) syndrome upon abrupt discontinuation of Priligy therapy. Consistent with the lack of discontinuation syndrome based on DESS, adverse event data showed little evidence of withdrawal symptoms. Similar results were seen in a second double blind clinical trial with a 24 week treatment phase of 30 and 60 mg doses as needed followed by a 1 week withdrawal assessment period.
In the two multidose phase 3 studies (C-2002-012 and C-2002-013) where the CYP2D6 metaboliser status was identified, a total of 120 poor metabolisers and 1598 extensive metabolisers were enrolled and treated with Priligy. No overall differences were seen in efficacy or safety between poor and extensive metabolisers.

5.2 Pharmacokinetic Properties

Absorption.

Dapoxetine is rapidly absorbed with maximum plasma concentrations (Cmax) occurring approximately 1-2 hours after tablet intake. The absolute oral bioavailability of dapoxetine is approximately 40% (range 15-76%). Following single oral doses of 30 mg and 60 mg in the fasted state, peak plasma concentration of dapoxetine were 297 nanogram/mL after 1.01 hours, and 498 nanogram/mL after 1.27 hours, respectively.
Ingestion of a high fat meal modestly reduced the Cmax (by 10%) and modestly increased the AUC (by 12%) of dapoxetine and slightly delayed the time for dapoxetine to reach peak concentrations; however, the extent of absorption was not affected by consumption of a high fat meal. These changes are not clinically significant. Priligy can be taken with or without food.

Distribution.

Greater than 99% of dapoxetine is bound in vitro to human plasma proteins. The active metabolite desmethyl dapoxetine is 98.5% protein bound. Dapoxetine appears to have a rapid distribution with a mean steady state volume of distribution of 162 L. Following intravenous administration in humans, mean estimated initial, intermediate, and terminal half-life values for dapoxetine were 0.10, 2.19, and 19.3 hours respectively.

Metabolism.

In vitro studies suggest that dapoxetine is cleared by multiple enzyme systems in the liver and kidneys, primarily CYP2D6, CYP3A4, and flavin monooxygenase 1 (FMO1). Following oral dosing in a clinical study designed to explore the metabolism of 14C-dapoxetine, dapoxetine was extensively metabolised to multiple metabolites primarily through the following biotransformational pathways: N-oxidation, N-demethylation, naphthyl hydroxylation, glucuronidation and sulfation. There was evidence of presystemic first-pass metabolism after oral administration.
Intact dapoxetine and dapoxetine-N-oxide were the major circulating species in the plasma. In vitro functional and binding studies showed that dapoxetine-N-oxide was only weakly active at the serotonin transporter. Additional metabolites include desmethyldapoxetine and didesmethyldapoxetine, which account for less than 3% of the circulating medicinal product-related material. In vitro functional studies indicate that desmethyldapoxetine is equipotent to dapoxetine and didesmethyldapoxetine has approximately 50% of the potency of dapoxetine. The unbound AUC of desmethyldapoxetine is ~40-50% of the free exposure of dapoxetine. The unbound (Cmax) of desmethyldapoxetine is estimated to be 15-20% of dapoxetine Cmax in the absence of intrinsic or extrinsic factors that may change exposure levels.

Excretion.

The metabolites of dapoxetine were primarily eliminated in the urine as conjugates. Unchanged active substance was not detected in the urine. Dapoxetine has a rapid elimination, as evidenced by a low concentration (less than 5% of peak) 24 hours after dosing. There was minimal accumulation of dapoxetine following daily dosing. The terminal half-life is approximately 19 hours following oral administration. The half-life of desmethyldapoxetine is similar to that of dapoxetine.

Special populations.

Race.

Analyses of single dose clinical pharmacology studies using 60 mg dapoxetine indicated no statistically significant differences between Caucasians, Blacks, Hispanics and Asians. A clinical study conducted to compare the pharmacokinetics of dapoxetine in Japanese and Caucasian subjects showed 10% to 20% higher plasma levels (AUC and peak concentration) of dapoxetine in Japanese subjects due to lower body weight. The slightly higher exposure is not expected to have a meaningful clinical effect.

Elderly (age 65 years and over).

Analyses of a single dose clinical pharmacology study using 60 mg dapoxetine showed that healthy elderly subjects had a slight increase in AUCinf, by approximately 12%, and a mean terminal half-life of approximately 26 hours. This slightly higher exposure and longer half-life is not expected to have a meaningful clinical effect.
The efficacy and safety has not been established in this population (see Section 4.2 Dose and Method of Administration).

Renal impairment.

In a single dose clinical pharmacology study using 60 mg dapoxetine, no correlation was noted between creatinine clearance and dapoxetine Cmax or AUCinf in subjects with mild (creatinine clearance 50 to 80 mL/min), moderate (creatinine clearance 30 to < 50 mL/min), and severe (creatinine clearance < 30 mL/min) renal impairment. Dapoxetine pharmacokinetics have not been evaluated in patients requiring renal dialysis. Limited data (n = 4) in subjects with severe renal impairment showed an approximate 100% increase in AUCinf when compared to those healthy subjects with no renal impairment (see Section 4.4 Special Warnings and Precautions For Use; Section 4.2 Dose and Method of Administration).

Hepatic impairment.

In patients with mild hepatic impairment, unbound Cmax of dapoxetine is decreased by 28% and unbound AUC is unchanged. The unbound Cmax and AUC of the active fraction (the sum of the unbound exposure of dapoxetine and desmethyldapoxetine) were decreased by 30% and 5%, respectively. In patients with moderate hepatic impairment, unbound Cmax of dapoxetine is essentially unchanged (decrease of 3%) and unbound AUC is increased by 66%. The unbound Cmax and AUC of the active fraction were essentially unchanged and doubled, respectively.
In patients with severe hepatic impairment, the unbound Cmax of dapoxetine was decreased by 42% but the unbound AUC was increased by approximately 223%. The Cmax and AUC of the active fraction had similar changes (decrease of 41% and increase of 241% respectively) (see Section 4.3 Contraindications; Section 4.2 Dose and Method of Administration).

CYP2D6 polymorphism.

In a single dose clinical pharmacology study using 60 mg dapoxetine, plasma concentrations in poor metabolisers of CYP2D6 were higher than in extensive metabolisers (approximately 31% higher for Cmax and 36% higher for AUCinf) of dapoxetine and 98% higher for Cmax and 161% higher for AUCinf of desmethyldapoxetine). The active fraction of dapoxetine may be increased by approximately 46% at Cmax and by approximately 90% for AUC. This increase may result in a higher incidence and severity of dose dependent adverse events (see Section 4.2 Dose and Method of Administration). The mean terminal half-life in poor metabolisers of CYP2D6 was approximately 22 hours, in comparison to a mean terminal half-life of approximately 19.5 hours, observed in extensive metabolisers of CYP2D6. The safety of dapoxetine in poor metabolisers of CYP2D6 is of particular concern with concomitant administration of other medicinal products that may inhibit the metabolism of dapoxetine such as moderate and potent CYP3A4 inhibitors (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
Plasma concentrations of dapoxetine and desmethyldapoxetine in CYP2D6 ultrarapid metabolisers are expected to be decreased.

5.3 Preclinical Safety Data

Carcinogenicity.

In studies with oral administration, dapoxetine was not carcinogenic to rats when administered daily for approximately two years at doses up to 225 mg/kg/day, yielding approximately three times the exposure to dapoxetine (plasma AUC) seen in human males given the recommended clinical dose of 30 mg. Dapoxetine also did not cause tumours in Tg.rasH2 mice when administered orally at the maximum possible doses of 100 mg/kg/day for 6 months and 200 mg/kg/day for 4 months. Exposure to dapoxetine in the mice at 100 mg/kg/day after 6 months administration was equivalent to that seen in humans at the 30 mg dose.
Daily topical dermal administration for 6 months to transgenic mice at 375, 750, or 1500 mg/kg/day produced some tumour promoter activity (papillomas at the application site) at 750 mg/kg/day or higher. Systemic exposure, to dapoxetine (plasma AUC) was approximately 2 to 3-fold that of males given the recommended clinical dose of 30 mg. The clinical relevance of this finding is unknown.

Genotoxicity.

Dapoxetine was not mutagenic in vitro in the bacterial Ames assay or the forward mutation test in mouse lymphoma cells. Dapoxetine was not clastogenic in the in vitro chromosomal aberration test in Chinese hamster ovary cell or the in vivo mouse micronucleus assay. The major human metabolite, dapoxetine N-oxide, was negative in tests for bacterial mutagenicity and in vitro clastogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, hypromellose, triacetin, titanium dioxide, iron oxide black, iron oxide 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

Priligy tablets should be stored below 25°C.

6.5 Nature and Contents of Container

Priligy Tablets are round, film-coated tablets and are available in packs of 3, 6 or 18 tablets. The 18 tablets pack size is not currently marketed.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Dapoxetine hydrochloride belongs to the pharmacotherapeutic group of selective serotonin reuptake inhibitors (SSRIs).
Dapoxetine hydrochloride is a white to slightly yellow powder. It is freely soluble in methanol, propylene glycol, some organic solvents (e.g. n, n-dimethylformamide) and slightly soluble in ethanol. The solubility of dapoxetine hydrochloride in aqueous media is a function of the pH (soluble at pH 3.9, sparingly soluble at pH 2.1 and insoluble at pH > 7.0).

Chemical structure.

Dapoxetine hydrochloride has the following chemical structure:

Chemical name.

The chemical name is (+)-(S)-N,N-dimethyl- (α)-[2-(1-naphthalenyloxy)ethyl]-benzenemethanamine hydrochloride.

Molecular formula.

C21H23NO.HCl.

Molecular mass.

MW: 341.88.

CAS number.

129938-20-1.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes