Viridal Duo 10 micrograms / ml,Powder and Solvent for Solution for Injection

1. Name Of The Medicinal Product

Viridal Duo 10 micrograms/ml, Powder and Solvent for Solution for Injection.

2. Qualitative And Quantitative Composition

Alprostadil 10 micrograms (used as a 1:1 clathrate complex with alfadex).

For a full list of excipients see section 6.1

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Double chamber glass cartridge containing lyophilised powder and solvent for reconstitution (0.9% w/v sodium chloride solution).

The powder is white and odourless, and the isotonic sodium chloride solution is clear. The powder dissolves immediately to yield a clear solution.

4. Clinical Particulars

4.1 Therapeutic Indications

As an adjunct to the diagnostic evaluation of erectile dysfunction in adult males.

Treatment of erectile dysfunction in adult males.

4.2 Posology And Method Of Administration

The drug solution should be prepared shortly before the injection.

Prior to injection the needle should be screwed onto the tip of the injector. After disinfecting the tip of the cartridge with one of the alcohol swabs, the cartridge should then be inserted into the injector. By screwing the thread part clockwise, the cartridge is fixed in the injector. Then, the dry substance, which is inside the front chamber of the cartridge, is reconstituted with 1 ml sterile sodium chloride solution 0.9% in the bottom chamber. While holding the device in a vertical position with the needle upwards, the thread part should be screwed slowly until it will not go any further. The solvent will by-pass the upper stopper into the front chamber and dissolve the dry substance within a few seconds. As soon as the dry substance is reconstituted, the larger external and the smaller inner protective cap have to be removed from the needle. The air should then be expelled out of the cartridge and the prescribed dose adjusted precisely.

Unused solution must be discarded immediately.

Viridal Duo is injected into either the right or the left cavernous body of the penile shaft. Once the needle is in the cavernous body, the injection should be done within 5 to 10 seconds and is very easy without much resistance if the needle is in the correct position.

The development of an erection will start approximately 5 – 15 minutes after the injection.

Dosage for injection in the clinic

Injections for diagnostic evaluation and dose titration must be performed by the attending physician. He will determine an individual dose suitable to produce an erectile response for diagnostic purposes.

The recommended starting dose is 2.5 mcg Viridal Duo in patients with primary psychogenic or neurogenic origin of erectile dysfunction. In all other patients with erectile dysfunction 5 mcg Viridal Duo should be used as a starting dose. Dose adjustments may be performed in increments of about 2.5 mcg to 5 mcg Viridal Duo. Most of the patients require between 10 and 20 mcg per injection. Some patients may need to be titrated to higher doses. Doses exceeding 20 mcg should be prescribed with particular care in patients with cardiovascular risk factors. The dose per injection should never exceed 40 mcg.

Dosage for self-injection therapy at home

Before starting treatment at home, each patient or the patient's partner has to be taught by a physician how to prepare the drug and perform the injection. In no cases should the injection therapy be started without precise instructions by the physician. The patient should only use his optimum individual dosage, which has been pre-determined by his physician using the above-mentioned procedure. This dose should allow the patient to have an erection at home, which should not last longer than one hour. If he experiences prolonged erections beyond 2 hours but less than 4 hours, the patient is recommended to contact his physician to re-establish the dose of the drug. Maximum injection frequency recommended is 2 or 3 times a week with an interval of at least 24 hours between the injections.

Follow-up

After the first injections and at regular intervals, e.g. every three months, the physician should re-evaluate the patient. Any local adverse reaction, e.g. haematoma, fibrosis or nodules should be noted and controlled. Following discussion with the patient, an adjustment of dosage may be necessary.

4.3 Contraindications

Hypersensitivity to the active substances or to any other ingredients.

Patients with diseases causing priapism e.g. sickle-cell disease, leukaemia and multiple myeloma or patients with anatomical deformation of the penis as cavernosal fibrosis or Peyronie's disease. Patients with penis implants should not use Viridal Duo.

Viridal Duo should not be used in men for whom sexual activity is contraindicated.

4.4 Special Warnings And Precautions For Use

The physician should carefully select patients suitable for self-injection therapy.

Sexual stimulation and intercourse can lead to cardiac and/or pulmonary events in patients with coronary heart disease, congestive heart failure or pulmonary disease. Viridal Duo should be used with care in these patient groups and patients should be examined and cleared for stress resistance by a cardiologist before treatment.

Viridal Duo should be used with care in patients who have experienced transient ischaemic attacks.

Patients who experience a prolonged erection lasting longer than four hours should contact their physician immediately. Therefore it is recommended that the patient has an emergency telephone number of his attending physician or of a clinic experienced in therapy of erectile dysfunction. Prolonged erection may damage penile erectile tissue and lead to irreversible erectile dysfunction.

A benefit-risk evaluation is neccesary before using Viridal Duo in patients with pre-existing scarring, e.g. nodules of the cavernous body or pre-existing penile deviation or Peyronie's disease or clinically relevant phimosis, e.g. phimosis with risk of paraphimosis these patients should be treated with particular care, e.g. more frequent re-evaluation of the patient's condition.

Patients who have to be treated with alpha-adrenergic drugs due to prolonged erections (see: overdose) may in the case of concomitant therapy with monoamino-oxidase-inhibitors, develop a hypertensive crisis.

Other intracavernous drugs e.g. smooth muscle relaxing agents or alpha-adrenergic blocking agents may lead to prolonged erection and must not be used concomitantly. The effects of a combination therapy of alprostadil with oral, intraurethral or topical medicinal products for erectile dysfunction are currently unknown.

Patients with blood clotting disorders or patients on therapy influencing blood clotting parameters should be carefully selected for treatment by the treating physician and treated with special care, e.g. monitoring of the clotting parameters, patients should be thoroughly educated by the prescriber about the associated risks and advised to exercise sufficient manual pressure on the injection site. This is because of the increased risk of bleeding.

To prevent abuse, self-injection therapy with Viridal Duo should not be used by patients with drug addiction and/or disturbances of psychological or intellectual development.

In cases of excessive use, e.g. higher frequencies than recommended, an increased risk of penile scarring cannot be excluded.

Use of intracavernous alprostadil offers no protection from the transmission of sexually transmitted diseases. Individuals who use alprostadil should be counselled about the protective measures that are necessary to guard against the spread of sexually transmitted diseases, including the human immunodeficiency virus (HIV). In some patients, injection of Viridal Duo can induce a small amount of bleeding at the injection site. In patients infected with blood borne diseases, this could increase the transmission of such diseases to the partner. For this reason we recommend that a condom is used for intercourse after injecting Viridal Duo.

Viridal Duo is for intracavernous injection. Subcutaneous injection or injections at areas of the penis other than the cavernous body should be avoided.

The injection should be performed under hygienic conditions to avoid infections. In any condition that precludes safe self-injection like poor manual dexterity, poor visual acuity or morbid obesity, the partner should be trained in the injection technique and should perform the injection.

Up to now, there is no clinical experience in patients under 18 and over 75 years of age.

Viridal Duo does not interfere with ejaculation and fertility.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of smooth muscle relaxing drugs like papaverine or other drugs inducing erection like alpha-adrenergic blocking agents may lead to prolonged erection and should not be used in parallel with Viridal Duo.

Risks exist when using alpha-adrenergic drugs to terminate prolonged erections in patients with cardiovascular disorders or receiving MAO inhibitors.

The effects of blood pressure lowering and vasodilating drugs may be increased.

4.6 Pregnancy And Lactation

The natural amount of PGE1 present in the sperm may be increased by the PGE1 present in Viridal Duo. In case the partner is pregnant, a condom should be used in order to avoid irritation of the vagina and a risk for the foetus.

4.7 Effects On Ability To Drive And Use Machines

Viridal Duo may rarely induce a transient drop of blood pressure with subsequent impairment of reactivity that could interfere with patient's ability to drive or operate machinery.

4.8 Undesirable Effects

Undesirable effects frequencies are defined as:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000).

During administration of Viridal Duo the following undesirable effects may be observed:

General disorders and administration site condition

Common: burning sensation during injection and after the injection, sensation of tension in the penis and pain of mostly mild intensity at the site of injection.

Uncommon: spotlike haemorrhage/ spotlike bruises at the site of puncture, haemosiderin deposits, reddening and swellings at the site of injection, swellings of the preputium or the glans, and headache.

Reproductive system and breast disorders

Common: fibrotic alterations (e.g. fibrotic nodules, plaques at the site of injection or in the corpus cavernosum) can occur during long-term treatment.

Uncommon: fibrotic alterations associated with slight penile axis deviations. Prolonged erections of more than 4 hours' duration are uncommon (mainly seen during dose titration).

Rare: fibrotic changes of the cavernous body during a long term treatment lasting up to 4 years.

Cardiac disorders

Rare: circulatory effects such as short periods of hypotension and/or vertigo or dizziness.

Immune system disorders

Rare: allergic reactions ranging from cutaneous hypersensitivity such as rash, erythema, urticaria to anaphylactic/anaphylactoid reactions.

4.9 Overdose

Symptoms

Full rigid erections lasting more than four hours.

If the patient experiences a prolonged erection, he is advised to contact his attending physician or a urologic clinic nearby immediately.

Treatment strategy

Treatment of prolonged erection should be done by a physician experienced in the field of erectile dysfunction. If prolonged erection occurs, the following is recommended:

If the erection has lasted less than six hours:

− observation of the erection because spontaneous flaccidity frequently occurs.

If the erection has lasted longer than six hours:

− cavernous body injection of alpha-adrenergic substances (e.g. phenylephrine or epinephrine (adrenaline)). Risks exist when using drugs in patients with cardiovascular disorders or receiving MAO inhibitors. All patients should be monitored for cardiovascular effects when these drugs are used to terminate prolonged erections.

or

− aspiration of blood from the cavernous body.

Accidental systemic injection of high doses

Single dose rising tolerance studies in healthy volunteers indicated that single intravenous doses of alprostadil from 1 to 120 mcg were well tolerated. Starting with a 40 mcg bolus intravenous dose, the frequency of drug-related adverse events increased in a dose-dependent manner, characterised mainly by facial flushing.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: Other urologicals G04BX 05

Alprostadil [Prostaglandin E₁ (PGE₁)], the active ingredient of Viridal Duo, is an endogenous compound derived from the essential fatty acid dihomogammalinolenic acid. Alprostadil is a potent smooth muscle relaxant that produces vasodilation and occurs in high concentrations in the human seminal fluid. Pre-contracted isolated preparations of the human corpus cavernosum, corpus spongiosum and cavernous artery were relaxed by alprostadil, while other prostanoids were less effective. Alprostadil has been shown to bind to specific receptors in the cavernous tissue of human and non-human primates.

The binding of alprostadil to its receptors is accompanied by an increase in intracellular cAMP levels. Human cavernosal smooth muscle cells respond to alprostadil by releasing intracellular calcium. Since relaxation of smooth muscle is associated with a reduction of the cytoplasmic free calcium concentration, this effect may contribute to the relaxing activity of this prostanoid.

Intracavernous injection of alprostadil in healthy monkeys resulted in penile elongation and tumescence without rigidity. The cavernous arterial blood flow was increased for a mean duration of 20 min. In contrast, intracavernous application of alprostadil to rabbits and dogs caused no erectile response.

Systemic intravascular administration of alprostadil leads to a vasodilation and reduction of systemic peripheral vascular resistance. A decrease in blood pressure can be observed after administration of high doses. Alprostadil has also been shown in animal and in vitro tests to reduce platelet reactivity and neutrophil activation. Additional alprostadil activity has been reported: increase in fibrinolytic activity of fibroblasts, improvement of erythrocyte deformability and inhibition of erythrocyte aggregation; inhibition of the proliferative and mitotic activity of non-striated myocytes; inhibition of cholesterol synthesis and LDL-receptor activity; and an increase in the supply of oxygen and glucose to ischaemic tissue along with improved tissue utilisation of these substrates.

5.2 Pharmacokinetic Properties

After reconstitution, alprostadil (PGE₁) dissociates from the α-cyclodextrin clathrate, and the two components have independent fates.

In symptomatic volunteers, systemic mean endogenous PGE₁ venous plasma concentrations measured before intracavernous injection are approximately 1pg/ml. After injection of 20 mcg of alprostadil, the PGE₁ venous plasma concentrations increase rapidly to concentrations of about 10-20 pg/ml. The PGE₁ plasma concentrations return to concentrations close to the baseline within a few minutes. Approximately 90% of PGE₁ found in plasma is protein-bound.

Metabolism

Enzymatic oxidation of the C15-hydroxy group and reduction of the C13,14 double bond produce the primary metabolites, 15-keto-PGE₁, PGE_o (13,14-dihydro-PGE₁) and 15-keto-PGE_o. Only PGE_o and 15-keto-PGE_o have been detected in human plasma. Unlike the 15-keto metabolites, which are less pharmacologically active than the parent compound, PGE_o has a potency similar to that of PGE₁ in most respects.

In symptomatic volunteers, the mean endogenous PGE_o venous plasma concentrations measured before an intracavernous injection are approximately 1 pg/ml. After the injection of 20 mcg of alprostadil, the PGE_o plasma concentrations increase to concentrations of about 5 pg/ml.

Excretion

After further degradation of the primary metabolites by beta and omega oxidation, the resulting, more polar metabolites are excreted primarily with the urine (88%) and the faeces (12% ) and there is no evidence of tissue retention of PGE₁ or its metabolites.

5.3 Preclinical Safety Data

Studies on local tolerance following single and repeated intracavernous injections of alprostadil or alprostadil alfadex in rabbits and/or monkeys, in monkeys up to 6 months with daily injection revealed in general good local tolerance. Possible adverse effects like haematomas and inflammations are more likely related to the injection procedure.

Within the 6 months study in male monkeys, there were no adverse effects of alprostadil alfadex on male reproductive organs.

Alprostadil did not cause any adverse effects on fertility or general reproductive performance in male and female rats treated with 40-200 mcg/kg/day. The high dose of 200 mcg/kg/day is about 300 times the maximum recommended human dose on a body weight basis (MHRD < 1 mcg/kg).

Alprostadil was not fetotoxic or teratogenic at doses up to 5000 mcg/kg/day (7500 times the MHRD) in rats, 200 mcg/kg/day (300 times the MHRD) in rabbits and doses up to 20 mcg/kg/day (30 times the MHRD) in guinea pigs or monkeys.

Mutagenicity studies with alprostadil alfadex revealed no risk of mutagenicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder for injection:

Lactose monohydrates

Alfadex

Diluent:

Sodium chloride

Water for injection.

6.2 Incompatibilities

It is not intended that this medicinal product be mixed with other medicinal products, therefore, in the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Shelf life for the product as packaged for sale: 4 years.

Shelf life after reconstitution: for immediate use only.

6.4 Special Precautions For Storage

Do not store above 25°C.

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

Administration devices

1 reusable injector (starter kit)

1 double chamber cartridge with dry substance and 1 ml 0.9% sterile sodium chloride solution

1 injection needle 29G x ½ (0.33 mm x 12.7 mm)

1 alcohol swab to be obtained for each injection

1. Cartons containing one colourless glass double-chamber cartridge, one injection needle 29 G x ½ (0.33 mm x 12.7 mm) and one reusable injector (starter kit).

2. Cartons containing two colourless glass double-chamber cartridges, two injection needles 29 G x ½ (0.33 mm x 12.7 mm) and one reusable injector (starter kit).

3. Cartons containing one, two or six colourless glass double-chamber cartridges and corresponding number of injection needles 29 G x ½ (0.33 mm x 12.7 mm) without reusable injector.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Fix the injection needle onto the front part of the injector.

Disinfect the tip of the cartridge with one of the alcohol swabs. Insert the cartridge into the re-usable injector and fix it by screwing the thread part. Dissolve the drug substance in the front chamber of the cartridge by completely screwing the thread-part into the injector thus moving both rubber stoppers to the top of the cartridge and allowing the solvent in to the bottom chamber to reach the dry substance via the bypass of the cartridge. Shake slightly until a clear solution is produced.

Expel the air and adjust the prescribed dosage precisely prior to intracavernous injection.

After preparation of the solution, the injection must be performed using aseptic procedures into either the left or right cavernous body of the penile shaft. Care should be taken not to inject into penile vessels or nerves on the upper side of the penis and into the urethra on the under side. The injection should be completed within 5 to 10 seconds and manual pressure should be applied to the injection site for 2 to 3 minutes.

Unused solution must be discarded immediately.

Advice

The content of the front chamber of the cartridge consists of a white, dry powder, which forms a compact layer, approximately 8 mm in height. The layer may show cracks and crumble slightly.

In case of damage to the cartridge, the usually dry content of the front chamber becomes moist and sticky and extensively loses volume. Viridal Duo must not be used in this case.

The bottom chamber contains the clear, colourless sodium chloride solvent solution.

The dry substance dissolves immediately after addition of the sodium chloride solution. Initially after reconstitution the solution may appear slightly opaque due to the presence of bubbles. This is of no relevance and disappears within a short time to give a clear solution.

Disposal of needle: disable needle then dispose of in a sharps container.

Disposal of cartridge: no special requirements.

7. Marketing Authorisation Holder

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00039/0751

9. Date Of First Authorisation/Renewal Of The Authorisation

3^rd September 2010

10. Date Of Revision Of The Text

Vertab SR

VERTAB SR 240 Tablets

VERAPAMIL HYDROCHLORIDE

Please read this leaflet carefully before you start taking your tablets.

• Keep this leaflet. You may need to read it again.


• This leaflet provides some useful information for you about your medicine.


• If you have any questions or are not sure about anything ask your doctor or pharmacist.

REMEMBER: This medicine has been prescribed for you. Do not pass it to others. It may harm, them, even if their symptoms are the same as yours.

In this leaflet:

• 1. What Vertab SR 240 Tablets are and what they are used for


• 2. Before you take Vertab SR 240 Tablets


• 3. How to take Vertab SR 240 Tablets


• 4. Possible side effects


• 5. How to store Vertab SR 240 Tablets


• 6. Further information

What Vertab Sr 240 Tablets Are And What They Are Used For

The name of your medicine is: Vertab SR 240 Tablets

Vertab SR 240 Tablets belong to a group of medicines called calcium channel blockers. Calcium channel blockers change the amount of calcium getting into the muscle cell in your heart and blood vessels. This can change the strength and speed with which your heart beats. It also opens up the blood vessels so blood can be pumped around the body more easily. This helps more oxygen to get to your heart muscle and can lower your blood pressure.

Vertab SR 240 Tablets are indicated for the treatment of mild to moderate hypertension (high blood pressure) and the treatment and prevention of angina pectoris (chest pain).

Before You Take Vertab Sr 240 Tablets

If you are unsure if any of the lists applies to you, ask your doctor before you start to take your tablets.

Do not take Vertab SR 240 Tablets:

• If you have hypersensitivity to Verapamil Hydrochloride or to any of the other ingredients of Vertab SR 240 Tablets (listed in section 6 - Further information).


• If you are having a cardiogenic shock (a sudden and rapid fall in blood pressure).


• If you are having or have recently had a heart attack particularly if a slow heart beat, low blood pressure or left ventricular failure of the heart are involved.


• If you have second or third degree atrioventricular block or sino-atrial block (a disorder where parts of the heart may beat at the wrong time causing the heart not to pump blood around the body very well).


• If you have sick sinus syndrome (a heart beat disorder).


• If you have heart failure that is not currently being treated.


• If you have severe bradycardia (a condition where the heart beats at less than 50 beats per minute).


• If you have low blood pressure where the higher blood pressure reading is below 90.


• This medicine is for adults only. It should not be given to children under the age of 12.

Take special care with Vertab SR 240 Tablets:

Consult your doctor or pharmacist if:

• You suffer or you have ever suffered in the past from low blood pressure, from a condition known as "heart failure", an abnormally slow or irregular heart beat, or any other cardiac problem including Wolff-Parkinson-White syndrome.


• You suffer or you have ever suffered in the past from kidney or liver disorders. These above mentioned medical conditions may mean that your doctor will need to monitor you more closely.


• You are planning to have medical or dental surgery. This medicine may affect the anaesthetics or other treatments used.

Taking other medicines:

Please inform your doctor or pharmacist if you are taking or have recently taken any of the following medicines, even those not prescribed:

• Digoxin (used to treat certain heart conditions, such as heart failure)


• Beta-blockers or any other treatment for heart diseases and high blood pressure


• Anti-arrhythmic agents (used to steady an irregular heart beat)


• Carbamazepine, Phenytoin, Phenobarbital (usually used in epilepsy)


• Ciclosporin (normally used following organ transplants to help prevent rejection)


• Theophylline (used for breathing difficulties e.g. asthma)


• Rifampicin (antibiotic action for treatment of various infections such as tuberculosis (TB))


• Lithium (used for psychiatric conditions)


• Cimetidine (used for stomach disorders e.g. ulcers)

Taking Vertab SR 240 Tablets with food and drink:

Vertab SR 240 Tablets will increase the time your body takes to get rid of alcohol. This means that you may not have to drink as much for your blood alcohol level to be above the legal limit to drive. It will also take you longer to sober up.

Do not drink products containing grapefruit juice at the same time as you take this medicine.

Pregnancy and breast-feeding:

Consult your doctor or pharmacist if you are pregnant, trying to become pregnant, or breast-feeding.

Driving and using machines:

Vertab SR 240 Tablets can make some people feel dizzy especially when first starting to take the tablets. Do not drive, operate machinery or do anything that requires you to be alert, until you know how the tablets affect you.

Important information about some of the ingredients of Vertab SR 240 Tablets:

This medicinal product contains 36 mg sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

How To Take Vertab Sr 240 Tablets

Always take Vertab SR 240 Tablets exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

The tablets should not be chewed. They should be swallowed whole with a glass of water.

• 
  For treatment of hypertension: The usual dosage is one tablet per day. Some patients may need to take two tablets per day (one in the morning and one in the evening with about 12 hours between doses). Do not take more than two tablets per day.


• 
  For the treatment and prevention of angina pectoris: The usual dose is one tablet twice daily.

If you take more Vertab SR 240 Tablets than you should

In case of an overdose, contact your nearest hospital casualty department or tell your doctor immediately.

If you forget to take Vertab SR 240 Tablets

If you forget to take a dose, take it as soon as you remember, unless it is almost time for your next dose. If it is, do not take the missed dose at all. Never double-up on a dose to make up for the one you have missed.

If you have trouble remembering to take your tablets, tell your doctor or your pharmacist. If you take too many tablets by mistake, any side effects (see below) may be worse than usual; in this case see your doctor.

If you stop taking Vertab SR 240 Tablets

It is important that you continue taking the tablets until your doctor tells you to stop. Do not stop because you feel better. If you stop taking the tablets too soon your condition may get worse.

Vertab SR Side Effects

Vertab SR 240 is generally well tolerated. Side effects are usually mild and transient.

In rare cases people may have an allergic reaction to Verapamil Hydrochloride.

You should tell your doctor immediately if you have any unexpected wheezing or difficulty in breathing, if you have a Quincke's oedema (swelling of the face with itching), swelling of the mouth, lips, or tongue, or if you develop a skin rash, pruritus (itching), or severe skin rash with blistering and peeling of the skin.

If you experience the following side effects you should tell your doctor immediately:

• If you develop yellowing of the skin or eyes, a fever or tenderness around the middle.


• If you have bradycardia (slow heart beats), arrhythmia (irregular heart rhythm), palpitations (awareness of an irregular or rapid heart beat), chest pains for the first time or chest pains that become more frequent, dizziness, weakness or confusion, swollen ankles, feeling faint or breathless or a burning sensation in the feet, which may become hot and throbbing.


• Hypotension (abnormally low blood pressure)

Do not stop taking the tablets, but tell your doctor if you get any of the following:

Digestive effects such as constipation, nausea (feeling sick) or vomiting, headache, flushing, fatigue, pins and needles, muscle and joint pain.

Swelling of the breasts (gynaecomastia), which is usually seen in elderly male patients, and spreading of the gums over the teeth can occur with long term treatment. These effects are very rare and resolve on stopping treatment. You should tell your doctor if these side effects appear.

If you think your medicine may be causing any problems, even if they are not described in this leaflet, tell your doctor or pharmacist.

How To Store Vertab Sr 240 Tablets

Keep out of the reach and sight of children.

Check the expiry date on the label. Do not use the tablets if the date has passed.

You should store the tablets at or below 25°C.

In case of visible signs of deterioration, you should discard the package.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Vertab SR 240 Tablets contain:

The active substance is: Verapamil Hydrochloride 240mg.

The other ingredients are: Core: Sodium alginate, Microcrystalline cellulose, Povidone, Hypromellose, Colloidal anhydrous silica, Magnesium stearate. Coating: Hypromellose, Titanium dioxide, Macrogol, Yellow Lake E-104, Blue Lake E-132 and Carnauba wax.

What Vertab SR 240 Tablets look like and content of the pack:

This medicine can be identified as modified release, light-green film-coated, capsule-shaped, scored tablets.

Vertab SR 240 Tablets are supplied in packs of 28 tablets.

The Manufacturer/Holder of Marketing Authorisation is:

Dexcel - Pharma Ltd

1 Cottesbrooke Park

Heartlands Business Park

Daventry

Northamptonshire

NN11 8YL

England

Distributed by:

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK8 3GY

United Kingdom

Date upon which the leaflet was last revised:


February 2009

CP0032/1

1290360114-E

Volibris

1. Name Of The Medicinal Product

5 mg film-coated tablets

Volibris

10 mg film-coated tablets

Volibris

2. Qualitative And Quantitative Composition

5 mg film-coated tablets

Each tablet contains 5 mg of ambrisentan.

10 mg film-coated tablets

Each tablet contains 10 mg of ambrisentan.

Excipients

5 mg film-coated tablets

Each tablet contains lactose monohydrate (approximately 95 mg), Lecithin (Soya) (E322) (approximately 0.25 mg) and Allura red AC Aluminium Lake (E129) (approximately 0.11 mg).

10 mg film-coated tablets

Each tablet contains lactose monohydrate (approximately 90 mg), Lecithin (Soya) (E322) (approximately 0.25 mg) and Allura red AC Aluminium Lake (E129) (approximately 0.45 mg).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

5 mg film-coated tablets

Pale-pink, square, convex, film-coated tablet with "GS" debossed on one side and "K2C" on the other side.

10 mg film-coated tablets

Deep-pink, oval, convex, film-coated tablet with "GS" debossed on one side and "KE3" on the other side.

4. Clinical Particulars

4.1 Therapeutic Indications

Volibris is indicated for the treatment of patients with pulmonary arterial hypertension (PAH) classified as WHO functional class II and III, to improve exercise capacity (see section 5.1). Efficacy has been shown in idiopathic PAH (IPAH) and in PAH associated with connective tissue disease.

4.2 Posology And Method Of Administration

Treatment must be initiated by a physician experienced in the treatment of PAH.

Posology

Volibris is to be taken orally at a dose of 5 mg once daily.

Some additional efficacy has been observed with 10 mg Volibris in patients with class III symptoms, however an increase in peripheral oedema has also been observed. Patients with PAH associated with connective tissue disease may require 10 mg Volibris for optimal efficacy. Confirm that the 5 mg dose is well tolerated before considering an increase in dose to 10 mg Volibris in these patients (see sections 4.4 and 4.8).

Limited data suggest that the abrupt discontinuation of Volibris is not associated with rebound worsening of PAH.

When co-administered with cyclosporine A, the dose of ambrisentan should be limited to 5 mg once daily and the patient should be carefully monitored (see sections 4.5 and 5.2).

Children and adolescents

Volibris is not recommended for use in patients below 18 years of age due to a lack of data on safety and efficacy.

Elderly

No dose adjustment is required in patients over the age of 65 (see section 5.2).

Patients with renal impairment

No dose adjustment is required in patients with renal impairment (see section 5.2). There is limited experience with Volibris in individuals with severe renal impairment (creatinine clearance <30 ml/min); initiate therapy cautiously in this subgroup and take particular care if the dose is increased to 10 mg Volibris.

Patients with hepatic impairment

Volibris has not been studied in individuals with severe hepatic impairment (with or without cirrhosis). Since the main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile, hepatic impairment would be expected to increase exposure (C_max and AUC) to ambrisentan. Therefore Volibris should not be initiated in patients with severe hepatic impairment, or clinically significant elevated hepatic aminotransferases (greater than 3 times the Upper Limit of Normal (>3xULN); see sections 4.3 and 4.4).

Method of administration

It is recommended that the tablet is swallowed whole and it can be taken with or without food.

4.3 Contraindications

• Hypersensitivity to the active substance, to soya, or to any of the excipients (see sections 4.4 and 6.1).

• Pregnancy (see section 4.6).

• Women of child-bearing potential who are not using reliable contraception (see sections 4.4 and 4.6).

• Lactation (see section 4.6).

• Severe hepatic impairment (with or without cirrhosis) (see section 4.2).

• Baseline values of hepatic aminotransferases (aspartate aminotransferases (AST) and/or alanine aminotransferases (ALT)) >3xULN (see sections 4.2 and 4.4).

4.4 Special Warnings And Precautions For Use

Volibris has not been studied in a sufficient number of patients to establish the benefit/risk balance in WHO functional class I PAH.

The efficacy of Volibris as monotherapy has not been established in patients with WHO functional class IV PAH. Therapy that is recommended at the severe stage of the disease (e.g. epoprostenol) should be considered if the clinical condition deteriorates.

Liver function

Liver function abnormalities have been associated with PAH. Cases consistent with autoimmune hepatitis, including possible exacerbation of underlying autoimmune hepatitis, hepatic injury and hepatic enzyme elevations potentially related to therapy have been observed with Volibris. Therefore hepatic aminotransferases (ALT and AST) should be evaluated prior to initiation of Volibris and treatment should not be initiated in patients with baseline values of ALT and/or AST >3xULN (see section 4.3).

Patients should be monitored for signs of hepatic injury and monthly monitoring of ALT and AST is recommended. If patients develop sustained, unexplained, clinically significant ALT and/or AST elevation, or if ALT and/or AST elevation is accompanied by signs or symptoms of hepatic injury (e.g. jaundice), Volibris therapy should be discontinued.

In patients without clinical symptoms of hepatic injury or of jaundice, re-initiation of Volibris may be considered following resolution of hepatic enzyme abnormalities. The advice of a hepatologist is recommended.

Haemoglobin concentration

Reductions in haemoglobin concentrations and haematocrit have been associated with ERAs including Volibris (see section 4.8). Most of these decreases were detected during the first 4 weeks of treatment and haemoglobin generally stabilised thereafter.

Initiation of Volibris is not recommended for patients with clinically significant anaemia. It is recommended that haemoglobin and/or haematocrit levels are measured during treatment with Volibris, for example at 1 month, 3 months and periodically thereafter in line with clinical practice. If a clinically significant decrease in haemoglobin or haematocrit is observed, and other causes have been excluded, dose reduction or discontinuation of treatment should be considered.

Fluid retention

Peripheral oedema has been observed with ERAs including ambrisentan. Most cases of peripheral oedema in clinical studies with ambrisentan were mild to moderate in severity, although it appeared to occur with greater frequency and severity in patients 65 years. Peripheral oedema was reported more frequently with 10 mg ambrisentan (see section 4.8).

Post-marketing reports of fluid retention occurring within weeks after starting ambrisentan have been received and, in some cases, have required intervention with a diuretic or hospitalisation for fluid management or decompensated heart failure. If patients have pre-existing fluid overload, this should be managed as clinically appropriate prior to starting ambrisentan.

If clinically significant fluid retention develops during therapy with ambrisentan, with or without associated weight gain, further evaluation should be undertaken to determine the cause, such as ambrisentan or underlying heart failure, and the possible need for specific treatment or discontinuation of ambrisentan therapy.

Women of child-bearing potential

Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-treatment pregnancy test is negative and reliable contraception is practiced. If there is any doubt on what contraceptive advice should be given to the individual patient, consultation with a gynaecologist should be considered. Monthly pregnancy tests during treatment with Volibris are recommended (see sections 4.3 and 4.6).

Pulmonary veno-occlusive disease

Cases of pulmonary oedema have been reported with vasodilating agents, such as endothelin receptor antagonists, when used in patients with pulmonary veno-occlusive disease. Consequently, if PAH patients develop acute pulmonary oedema when treated with ambrisentan, the possibility of pulmonary veno-occlusive disease should be considered.

Concomitant use with other medicinal products

Rifampicin: Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin (see sections 4.5 and 5.2).

Excipients

Volibris tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Volibris tablets contain the azo colouring agent Allura red AC Aluminium Lake (E129), which can cause allergic reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ambrisentan does not inhibit or induce phase I or II drug metabolizing enzymes at clinically relevant concentrations in in vitro and in vivo non-clinical studies, suggesting a low potential for ambrisentan to alter the profile of medicinal products metabolized by these pathways.

The potential for ambrisentan to induce CYP3A4 activity was explored in healthy volunteers with results suggesting a lack of inductive effect of ambrisentan on the CYP3A4 isoenzyme.

Co-administration of ambrisentan with a phosphodiesterase inhibitor, either sildenafil or tadalafil (both substrates of CYP3A4) in healthy volunteers did not significantly affect the pharmacokinetics of the phosphodiesterase inhibitor or ambrisentan (see section 5.2).

Steady state administration of ketoconazole (a strong inhibitor of CYP3A4) did not result in a clinically significant increase in exposure to ambrisentan (see section 5.2).

Ambrisentan had no effects on the steady state pharmacokinetics and anti-coagulant activity of warfarin in a healthy volunteer study (see section 5.2). Warfarin also had no clinically significant effects on the pharmacokinetics of ambrisentan. In addition, in patients, ambrisentan had no overall effect on the weekly warfarin-type anticoagulant dose, prothrombin time (PT) and international normalized ratio (INR).Steady-state co-administration of ambrisentan and cyclosporine A resulted in a 2-fold increase in ambrisentan exposure in healthy volunteers. This may be due to the inhibition by cyclosporine A of transporters and metabolic enzymes involved in the pharmacokinetics of ambrisentan. Therefore the dose of ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine A (see section 4.2). Multiple doses of ambrisentan had no effect on cyclosporine A exposure, and no dose adjustment of cyclosporine A is warranted.

Co-administration of rifampicin (an inhibitor of OATP, a strong inducer of CYP3A and 2C19, and inducer of P-gp and uridine-diphospho-glucuronosyltransferases [UGTs]) was associated with a transient (approximately 2-fold) increase in ambrisentan exposure following initial doses in healthy volunteers. However, by day 8, steady state administration of rifampicin had no clinically relevant effect on ambrisentan exposure. Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin (see sections 4.4 and 5.2).

In a clinical study in healthy volunteers, steady-state dosing with ambrisentan 10 mg once daily did not significantly affect the single-dose pharmacokinetics of the ethinyl estradiol and norethindrone components of a combined oral contraceptive (see section 5.2). Based on this pharmacokinetic study, ambrisentan would not be expected to significantly affect exposure to oestrogen- or progestogen- based contraceptives.

The efficacy and safety of Volibris when co-administered with other treatments for PAH (e.g. prostanoids and phosphodiesterase type V inhibitors) has not been specifically studied in controlled clinical trials in PAH patients (see section 5.1). Therefore, caution is recommended in the case of co-administration.

Effect of ambrisentan on xenobiotic transporters

In vitro, ambrisentan has no inhibitory effect on the P-glycoprotein (Pgp)-mediated efflux of digoxin and is a weak substrate for Pgp-mediated efflux. Additional in vitro studies in rat and human hepatocytes showed that ambrisentan did not inhibit sodium-taurocholate co-transporter (NTCP), organic anion export pump (OATP), bile salt export pump (BSEP) and multi-drug resistance protein isoform-2 (MRP2). In vitro studies in rat hepatocytes also showed that ambrisentan has no inductive effects on Pgp, BSEP or MRP2.

Steady-state administration of ambrisentan in healthy volunteers had no clinically relevant effects on the single-dose pharmacokinetics of digoxin, a substrate for Pgp (see section 5.2).

4.6 Pregnancy And Lactation

Pregnancy

Volibris is contraindicated in pregnancy (see section 4.3). Animal studies have shown that ambrisentan is teratogenic. There is no experience in humans.

Volibris treatment must not be initiated in women of child-bearing potential unless the result of a pre-treatment pregnancy test is negative and reliable contraception is practiced. Monthly pregnancy tests during treatment with Volibris are recommended.

Women receiving Volibris must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs (see sections 4.3, 4.4 and 5.3).

Lactation

It is not known whether ambrisentan is excreted in human breast milk. The excretion of ambrisentan in milk has not been studied in animals. Therefore lactation is contraindicated in patients taking Volibris (see section 4.3).

Male fertility

The development of testicular tubular atrophy in male animals has been linked to the chronic administration of ERAs, including ambrisentan (see section 5.3). The effect on male human fertility is not known. Chronic administration of ambrisentan was not associated with a change in plasma testosterone in clinical studies.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable Effects

Experience from clinical studies

Safety of Volibris has been evaluated in clinical trials of more than 483 patients with PAH (see section 5.1). Adverse drug reactions (ADR) identified from 12 week placebo controlled clinical trial data are listed below by system organ class and frequency. With longer observation in uncontrolled studies (mean observation of 79 weeks), the safety profile was similar to that observed in the short term studies. Frequencies are defined as: very common ( 1/10); common ( 1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000). For dose-related adverse reactions the frequency category reflects the higher dose of Volibris. Frequency categories do not account for other factors including varying study duration, pre-existing conditions and baseline patient characteristics. Adverse reaction frequency categories assigned based on clinical trial experience may not reflect the frequency of adverse events occurring during normal clinical practice. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Cardiac disorders
Palpitation	Common
Blood and lymphatic system disorders
Anaemia (decreased haemoglobin, decreased haematocrit)	Common
Nervous system disorders
Headache (including sinus headache, migraine)1	Very common
Respiratory, thoracic and mediastinal disorders
Upper respiratory (e.g. nasal2, sinus) congestion, sinusitis, nasopharyngitis, rhinitis	Common
Gastrointestinal disorders
Abdominal pain	Common
Constipation	Common
Vascular disorders
Flushing	Common
General disorders and administration site conditions
Peripheral oedema, fluid retention3	Very common
Chest pain/discomfort	Common
Immune system disorders
Hypersensitivity reactions (e.g. angioedema, rash, pruritus)	Uncommon

¹ The frequency of headache appeared higher with 10 mg Volibris.

² The incidence of nasal congestion was dose related during Volibris therapy.

³ Peripheral oedema was reported more frequently with 10 mg Volibris. In clinical studies peripheral oedema was reported more commonly and tended to be more severe in patients 65 years (see section 4.4).

Laboratory abnormalities

Decreased haemoglobin (see section 4.4).

The frequency of decreased haemoglobin (anaemia) was higher with 10 mg Volibris. Across the 12 week placebo controlled Phase III clinical studies, mean haemoglobin concentrations decreased for patients in the Volibris groups and were detected as early as week 4 (decrease by 0.83 g/dl); mean changes from baseline appeared to stabilise over the subsequent 8 weeks. A total of 17 patients (6.5%) in the Volibris treatment groups had decreases in haemoglobin of 15% from baseline and which fell below the lower limit of normal.

Post-marketing data

In addition to adverse reactions identified from clinical studies, the following adverse reactions were identified during post-approval use of Volibris. Frequencies are defined as: common (

Nervous system disorders
Dizziness	Not known
Cardiac disorders
Cardiac failure4	Not known
Vascular disorders
Syncope, hypotension	Not known
Respiratory, thoracic and mediastinal disorders
Dyspnoea5	Not known
Gastrointestinal disorders
Syncope, hypotension	Not known
Hepatobiliary disorders
Hepatic transaminases increased	Common
Hepatic injury (see section 4.4)6	Uncommon
Autoimmune hepatitis (see section 4.4) 6	Uncommon

⁴Most of the reported cases of cardiac failure were associated with fluid retention.

⁵Cases of worsening dyspnoea of unclear aetiology have been reported shortly after starting Volibris therapy.

⁶Cases of autoimmune hepatitis, including cases of exacerbation of autoimmune hepatitis, and hepatic injury have been reported during ambrisentan therapy.

4.9 Overdose

There is no experience in PAH patients of Volibris at daily doses greater than 10 mg. In healthy volunteers, single doses of 50 and 100 mg (5 to 10 times the maximum recommended dose) were associated with headache, flushing, dizziness, nausea and nasal congestion.

Due to the mechanism of action, an overdose of Volibris could potentially result in hypotension (see section 5.3). In the case of pronounced hypotension, active cardiovascular support may be required. No specific antidote is available.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other anti-hypertensives, ATC code: C02KX02.

Mechanism of action

Ambrisentan is an orally active, propanoic acid-class, ERA selective for the endothelin A (ET_A) receptor. Endothelin plays a significant role in the pathophysiology of PAH.

− Ambrisentan is a potent (Ki 0.016 nM) and highly selective ET_A antagonist (approximately 4000-fold more selective for ET_A as compared to ET_B).

− Ambrisentan blocks the ET_A receptor subtype, localized predominantly on vascular smooth muscle cells and cardiac myocytes. This prevents endothelin-mediated activation of second messenger systems that result in vasoconstriction and smooth muscle cell proliferation.

− The selectivity of ambrisentan for the ET_A over the ET_B receptor is expected to retain ET_B receptor mediated production of the vasodilators nitric oxide and prostacyclin.

Efficacy

Two randomised, double-blind, multi-centre, placebo controlled, Phase 3 pivotal studies were conducted (ARIES-1 and 2). ARIES-1 included 201 patients and compared Volibris 5 mg and 10 mg with placebo. ARIES-2 included 192 patients and compared Volibris 2.5 mg and 5 mg with placebo. In both studies, Volibris was added to patients' supportive/background medication, which could have included a combination of digoxin, anticoagulants, diuretics, oxygen and vasodilators (calcium channel blockers, ACE inhibitors). Patients enrolled had IPAH or PAH associated with connective tissue disease. The majority of patients had WHO functional Class II (38.4%) or Class III (55.0%) symptoms. Patients with pre-existent hepatic disease (cirrhosis or clinically significantly elevated aminotransferases) and patients using other targeted therapy for PAH (e.g. prostanoids) were excluded. Haemodynamic parameters were not assessed in these studies.

The primary endpoint defined for the Phase 3 studies was improvement in exercise capacity assessed by change from baseline in 6 minute walk distance (6MWD) at 12 weeks. In both studies, treatment with Volibris resulted in a significant improvement in 6MWD for each dose of Volibris.

The placebo-adjusted improvement in mean 6MWD at week 12 compared to baseline was 30.6 m (95% CI: 2.9 to 58.3; p=0.008) and 59.4 m (95% CI: 29.6 to 89.3; p<0.001) for the 5 mg group, in ARIES 1 and 2 respectively. The placebo-adjusted improvement in mean 6MWD at week 12 in patients in the 10 mg group in ARIES-1 was 51.4 m (95% CI: 26.6 to 76.2; p <0.001).

A pre-specified combined analysis of the Phase 3 studies (ARIES-C) was conducted. The placebo-adjusted mean improvement in 6MWD was 44.6 m (95% CI: 24.3 to 64.9; p<0.001) for the 5 mg dose, and 52.5 m (95% CI: 28.8 to 76.2; p<0.001) for the 10 mg dose.

In ARIES-2, Volibris (combined dose group) significantly delayed the time to clinical worsening of PAH compared to placebo (p<0.001), the hazard ratio demonstrated a 80% reduction (95% CI: 47% to 92%). The measure included: death, lung transplantation, hospitalisation for PAH, atrial septostomy, addition of other PAH therapeutic agents and early escape criteria. A statistically significant increase (3.41 ± 6.96) was observed for the combined dose group in the physical functioning scale of the SF-36 Health Survey compared with placebo (-0.20 ± 8.14, p=0.005). Treatment with Volibris led to a statistically significant improvement in Borg Dyspnea Index (BDI) at week 12 (placebo-adjusted BDI of -1.1 (95% CI: -1.8 to -0.4; p=0.019; combined dose group)).

Long term data

Patients enrolled into ARIES 1 and 2 were eligible to enter a long term open label extension study ARIES E (n=383).

The effect of Volibris on the outcome of the disease is unknown. The observed probability of survival at 1 year for subjects receiving Volibris (combined Volibris dose group) was 95% and at 2 years was 84%.

In an open label study (AMB222), Volibris was studied in 36 patients to evaluate the incidence of increased serum aminotransferase concentrations in patients who had previously discontinued other ERA therapy due to aminotransferase abnormalities. During a mean of 53 weeks of treatment with Volibris, none of the patients enrolled had a confirmed serum ALT >3xULN that required permanent discontinuation of treatment. Fifty percent of patients had increased from 5 mg to 10 mg Volibris during this time.

The cumulative incidence of serum aminotransferase abnormalities >3xULN in all Phase 2 and 3 studies (including respective open label extensions) was 17 of 483 subjects over a mean exposure duration of 79.5 weeks. This is an event rate of 2.3 events per 100 patient years of exposure for Volibris.

Other clinical information

An improvement in haemodynamic parameters was observed in patients with PAH after 12 weeks (n=29) in a Phase 2 study (AMB220). Treatment with Volibris resulted in an increase in mean cardiac index, a decrease in mean pulmonary artery pressure, and a decrease in mean pulmonary vascular resistance.

No clinically meaningful effects on the pharmacokinetics of ambrisentan or sildenafil were seen during a drug-drug interaction study in healthy volunteers, and the combination was well tolerated. The number of patients who received concomitant Volibris and sildenafil in ARIES-E and AMB222 was 22 patients (5.7%) and 17 patients (47%), respectively. No additional safety concerns were identified in these patients.

5.2 Pharmacokinetic Properties

Absorption

Ambrisentan is absorbed rapidly in humans. After oral administration, maximum plasma concentrations (C_max) of ambrisentan typically occur around 1.5 hours post-dose under both fasted and fed conditions. C_max and area under the plasma concentration-time curve (AUC) increase dose proportionally over the therapeutic dose range. Steady-state is generally achieved following 4 days of repeat dosing.

A food-effect study involving administration of ambrisentan to healthy volunteers under fasting conditions and with a high-fat meal indicated that the C_max was decreased 12% while the AUC remained unchanged. This decrease in peak concentration is not clinically significant, and therefore ambrisentan can be taken with or without food.

Distribution

Ambrisentan is highly plasma protein bound. The in vitro plasma protein binding of ambrisentan was, on average, 98.8% and independent of concentration over the range of 0.2 – 20 microgram/ml. Ambrisentan is primarily bound to albumin (96.5%) and to a lesser extent to alpha₁-acid glycoprotein.

The distribution of ambrisentan into red blood cells is low, with a mean blood:plasma ratio of 0.57 and 0.61 in males and females, respectively.

Metabolism

Ambrisentan is a non-sulphonamide (propanoic acid) ERA.

Ambrisentan is glucuronidated via several UGT isoenzymes (UGT1A9S, UGT2B7S and UGT1A3S) to form ambrisentan glucuronide (13%). Ambrisentan also undergoes oxidative metabolism mainly by CYP3A4 and to a lesser extent by CYP3A5 and CYP2C19 to form 4-hydroxymethyl ambrisentan (21%) which is further glucuronidated to 4-hydroxymethyl ambrisentan glucuronide (5%). The binding affinity of 4-hydroxymethyl ambrisentan for the human endothelin receptor is 65-fold less than ambrisentan. Therefore at concentrations observed in the plasma (approximately 4% relative to parent ambrisentan), 4-hydroxymethyl ambrisentan is not expected to contribute to pharmacological activity of ambrisentan.

In vitro data have shown that at therapeutic concentrations, ambrisentan does not inhibit UGT1A1, UGT1A6, UGT1A9, UGT2B7 or cytochrome P450 enzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Additional in vitro studies showed that ambrisentan does not inhibit NTCP, OATP or BSEP. Furthermore, ambrisentan does not induce MRP2, Pgp or BSEP.

The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics and pharmacodynamics of a single dose of warfarin (25 mg), as measured by PT and INR, were investigated in 20 healthy volunteers. Ambrisentan did not have any clinically relevant effects on the pharmacokinetics or pharmacodynamics of warfarin. Similarly, co-administration with warfarin did not affect the pharmacokinetics of ambrisentan (see section 4.5).

The effect of 7-day dosing of sildenafil (20 mg three times daily) on the pharmacokinetics of a single dose of ambrisentan, and the effects of 7-day dosing of ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of sildenafil were investigated in 19 healthy volunteers. With the exception of a 13% increase in sildenafil C_max following co-administration with ambrisentan, there were no other changes in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and ambrisentan. This slight increase in sildenafil C_max is not considered clinically relevant (see section 4.5).

The effects of steady-state ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of tadalafil, and the effects of steady-state tadalafil (40 mg once daily) on the pharmacokinetics of a single dose of ambrisentan were studied in 23 healthy volunteers. Ambrisentan did not have any clinically relevant effects on the pharmacokinetics of tadalafil. Similarly, co-administration with tadalafil did not affect the pharmacokinetics of ambrisentan (see section 4.5).

The effects of repeat dosing of ketoconazole (400 mg once daily) on the pharmacokinetics of a single dose of 10 mg ambrisentan were investigated in 16 healthy volunteers. Exposures of ambrisentan as measured by AUC_(0-inf) and C_max were increased by 35% and 20%, respectively. This change in exposure is unlikely to be of any clinical relevance and therefore Volibris may be co-administered with ketoconazole.

The effects of repeat dosing of cyclosporine A (100 – 150 mg twice daily) on the steady-state pharmacokinetics of ambrisentan (5 mg once daily), and the effects of repeat dosing of ambrisentan (5 mg once daily) on the steady-state pharmacokinetics of cyclosporine A (100 – 150 mg twice daily) were studied in healthy volunteers. The C_max and AUC(0-) of ambrisentan increased (48% and 121%, respectively) in the presence of multiple doses of cyclosporine A. Based on these changes, the dose of ambrisentan should be limited to 5 mg once daily when co-administered with cyclosporine A (see section 4.2). However, multiple doses of ambrisentan had no clinically relevant effect on cyclosporine A exposure, and no dose adjustment of cyclosporine A is warranted.

The effects of acute and repeat dosing of rifampicin (600 mg once daily) on the steady-state pharmacokinetics of ambrisentan (10 mg once daily) were studied in healthy volunteers. Following initial doses of rifampicin, a transient increase in ambrisentan AUC(0–) (121% and 116% after first and second doses of rifampicin, respectively) was observed, presumably due to a rifampicin-mediated OATP inhibition. However, there was no clinically relevant effect on ambrisentan exposure by day 8, following administration of multiple doses of rifampicin. Patients on ambrisentan therapy should be closely monitored when starting treatment with rifampicin (see sections 4.4 and 4.5).

The effects of repeat dosing of ambrisentan (10 mg) on the pharmacokinetics of single dose digoxin were studied in 15 healthy volunteers. Multiple doses of ambrisentan resulted in slight increases in digoxin AUC_0-last and trough concentrations, and a 29% increase in digoxin C_max. The increase in digoxin exposure observed in the presence of multiple doses of ambrisentan was not considered clinically relevant, and no dose adjustment of digoxin is warranted (see section 4.5).

The effects of 12 days dosing with ambrisentan (10 mg once daily) on the pharmacokinetics of a single dose of oral contraceptive containing ethinyl estradiol (35 μg) and norethindrone (1 mg) were studied in healthy female volunteers. The Cmax and AUC(0–

Elimination

Ambrisentan and its metabolites are eliminated primarily in the bile following hepatic and/or extra-hepatic metabolism. Approximately 22% of the administered dose is recovered in the urine following oral administration with 3.3% being unchanged ambrisentan. Plasma elimination half-life in humans ranges from 13.6 to 16.5 hours.

Special populations

Based on the results of a population pharmacokinetic analysis in healthy volunteers and patients with PAH, the pharmacokinetics of ambrisentan were not significantly influenced by gender or age (see section 4.2).

Renal impairment

Ambrisentan does not undergo significant renal metabolism or renal clearance (excretion). In a population pharmacokinetic analysis, creatinine clearance was found to be a statistically significant covariate affecting the oral clearance of ambrisentan. The magnitude of the decrease in oral clearance is modest (20-40%) in patients with moderate renal impairment and therefore is unlikely to be of any clinical relevance. However, caution should be used in patients with severe renal impairment (see section 4.2).

Hepatic impairment

The main routes of metabolism of ambrisentan are glucuronidation and oxidation with subsequent elimination in the bile and therefore hepatic impairment would be expected to increase exposure (C_max and AUC) of ambrisentan. In a population pharmacokinetic analysis, the oral clearance was shown to be decreased as a function of increasing bilirubin levels. However, the magnitude of effect of bilirubin is modest (compared to the typical patient with a bilirubin of 0.6 mg/dl, a patient with an elevated bilirubin of 4.5 mg/dl would have approximately 30% lower oral clearance of ambrisentan). The pharmacokinetics of ambrisentan in patients with severe hepatic impairment (with or without cirrhosis) has not been studied. Therefore Volibris should not be initiated in patients with severe hepatic impairment or clinically significant elevated hepatic aminotransferases (>3xULN) (see sections 4.3 and 4.4).

5.3 Preclinical Safety Data

Due to the class primary pharmacologic effect, a large single dose of ambrisentan (i.e. an overdose) could lower arterial pressure and have the potential for causing hypotension and symptoms related to vasodilation.

Ambrisentan was not shown to be an inhibitor of bile acid transport or to produce overt hepatotoxicity.

Inflammation and changes in the nasal cavity epithelium have been seen in rodents after chronic administration at exposures below the therapeutic levels in humans. In dogs, slight inflammatory responses were observed following chronic high dose administration of ambrisentan at exposures greater than 20–fold that observed in patients.

Nasal bone hyperplasia of the ethmoid turbinates has been observed in the nasal cavity of rats treated with ambrisentan, at exposure levels 3-fold the clinical AUC. Nasal bone hyperplasia has not been observed with ambrisentan in mice or dogs. In the rat, hyperplasia of nasal turbinate bone is a recognised response to nasal inflammation, based on experience with other compounds.

Ambrisentan was clastogenic when tested at high concentrations in mammalian cells in vitro. No evidence for mutagenic or genotoxic effects of ambrisentan were seen in bacteria or in two in vivo rodent studies.

There were no treatment-related increases in the incidence of tumours in 2 year oral studies in rats and mice.

Testicular tubular atrophy, which was occasionally associated with aspermia, was observed in oral repeat dose toxicity and fertility studies with male rats and mice without safety margin. The testicular changes were not fully recoverable during the off-dose periods evaluated. However no testicular changes were observed in dog studies of up to 39 weeks duration at an exposure 35–fold that seen in humans based on AUC. In male rats, there were no effects of ambrisentan on sperm motility at all doses tested (up to 300 mg/kg/day). A slight (<10%) decrease in the percentage of morphologically normal sperms was noted at 300 mg/kg/day but not at 100 mg/kg/day (>9-fold clinical exposure at 10 mg/day). The effect of ambrisentan on male human fertility is not known.

Ambrisentan has been shown to be teratogenic in rats and rabbits. Abnormalities of the lower jaw, tongue, and/or palate were seen at all doses tested. In addition, interventricular septal defects, trunk vessel defects, thyroid and thymus abnormalities, ossification of the basisphenoid bone and increased incidence of left umbilical artery were seen in the rat study. Teratogenicity is a suspected class effect of ERAs.

Administration of ambrisentan to female rats from late-pregnancy through lactation caused adverse events on maternal behaviour, reduced pup survival and impairment of the reproductive capability of the offspring (with observation of small testes at necropsy), at exposure 3-fold the AUC at the maximum recommended human dose.

6. Pharmaceutical Particulars

6.1 List Of Excipients

5 mg film-coated tablets

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

5 mg film-coated tablets

Film coat

Polyvinyl alcohol (Partially Hydrolysed)

Talc (E553b)

Titanium dioxide (E171)

Macrogol / PEG 3350

Lecithin (Soya) (E322)

Allura red AC Aluminium Lake (E129)

10 mg film-coated tablets

Tablet core

Lactose monohydrate

Microcrystalline cellulose

Croscarmellose sodium

Magnesium stearate

10 mg film-coated tablets

Film coat

Polyvinyl alcohol (Partially Hydrolysed)

Talc (E553b)

Titanium dioxide (E171)

Macrogol / PEG 3350

Lecithin (Soya) (E322)

Allura red AC Aluminium Lake (E129)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

PVC/PVDC/aluminium foil blisters. Pack sizes of 10 or 30 film-coated tablets. Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Glaxo Group Ltd

Greenford

Middlesex

UB6 0NN

United Kingdom

8. Marketing Authorisation Number(S)

5 mg film-coated tablets

EU/1/08/451/001

EU/1/08/451/002

10 mg film-coated tablets

EU/1/08/451/003

EU/1/08/451/004

9. Date Of First Authorisation/Renewal Of The Authorisation

21/04/2008

10. Date Of Revision Of The Text

18/08/2011

Detailed information on this medicinal product is available on the website of the European Medicines

Viread 245 mg film-coated tablets

1. Name Of The Medicinal Product

Viread 245 mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 245 mg of tenofovir disoproxil (as fumarate), equivalent to 300 mg of tenofovir disoproxil fumarate, or 136 mg of tenofovir.

Excipient(s):

Each tablet contains 164 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet.

Light blue, almond-shaped, film-coated tablets, of dimensions 16.8 mm x 10.3 mm, debossed on one side with “GILEAD” and “4331” and on the other side with “300”.

4. Clinical Particulars

4.1 Therapeutic Indications

HIV-1 infection

Viread is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected adults aged 18 years and over.

The demonstration of the benefit of Viread in HIV-1 infection is based on results of one study in treatment-naïve patients, including patients with a high viral load (> 100,000 copies/ml) and studies in which Viread was added to stable background therapy (mainly tritherapy) in antiretroviral pre-treated patients experiencing early virological failure (< 10,000 copies/ml, with the majority of patients having < 5,000 copies/ml).

The choice of Viread to treat antiretroviral-experienced patients with HIV-1 infection should be based on individual viral resistance testing and/or treatment history of patients.

Hepatitis B infection

Viread is indicated for the treatment of chronic hepatitis B (see section 5.1) in adults with:

• compensated liver disease, with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis

• decompensated liver disease (see sections 4.4, 4.8 and 5.1).

4.2 Posology And Method Of Administration

Therapy should be initiated by a physician experienced in the management of HIV infection and/or treatment of chronic hepatitis B.

Posology

Adults: The recommended dose of Viread for the treatment of HIV or for the treatment of chronic hepatitis B is 245 mg (one tablet) once daily taken orally with food.

Chronic hepatitis B: The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:

- In HBeAg positive patients without cirrhosis, treatment should be administered for at least 6-12 months after HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection) is confirmed or until HBs seroconversion or there is loss of efficacy (see section 4.4). Serum ALT and HBV DNA levels should be followed regularly after treatment discontinuation to detect any late virological relapse.

- In HBeAg negative patients without cirrhosis, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.

If a patient misses a dose of Viread, the patient should take Viread with food as soon as possible and resume their normal dosing schedule. If a patient misses a dose of Viread and it is almost time for their next dose, the patient should not take the missed dose and simply resume the usual dosing schedule.

If the patient vomits within 1 hour of taking Viread, another tablet should be taken. If the patient vomits more than 1 hour after taking Viread they do not need to take another dose.

Special populations

Elderly: No data are available on which to make a dose recommendation for patients over the age of 65 years (see section 4.4).

Renal insufficiency: Tenofovir is eliminated by renal excretion and the exposure to tenofovir increases in patients with renal dysfunction. There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with moderate and severe renal impairment (creatinine clearance < 50 ml/min) and long-term safety data has not been evaluated for mild renal impairment (creatinine clearance 50-80 ml/min). Therefore, in patients with renal impairment tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. Dose interval adjustments are recommended for patients with creatinine clearance < 50 ml/min.

Mild renal impairment (creatinine clearance 50-80 ml/min): Limited data from clinical studies support once daily dosing of tenofovir disoproxil fumarate in patients with mild renal impairment.

Moderate renal impairment (creatinine clearance 30-49 ml/min): Administration of 245 mg tenofovir disoproxil (as fumarate) every 48 hours is recommended based on modelling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring haemodialysis, but has not been confirmed in clinical studies. Therefore, clinical response to treatment and renal function should be closely monitored in these patients (see sections 4.4 and 5.2).

Severe renal impairment (creatinine clearance < 30 ml/min) and haemodialysis patients: Adequate dose adjustments cannot be applied due to lack of alternative tablet strengths, therefore use in this group of patients is not recommended. If no alternative treatment is available, prolonged dose intervals may be used as follows:

Severe renal impairment: 245 mg tenofovir disoproxil (as fumarate) may be administered every 72-96 hours (dosing twice a week).

Haemodialysis patients: 245 mg tenofovir disoproxil (as fumarate) may be administered every 7 days following completion of a haemodialysis session*.

These dose adjustments have not been confirmed in clinical studies. Simulations suggest that the prolonged dose interval is not optimal and could result in increased toxicity and possibly inadequate response. Therefore clinical response to treatment and renal function should be closely monitored (see sections 4.4 and 5.2).

* Generally, once weekly dosing assuming three haemodialysis sessions per week, each of approximately 4 hours duration or after 12 hours cumulative haemodialysis.

No dosing recommendations can be given for non-haemodialysis patients with creatinine clearance < 10 ml/min.

Hepatic impairment: No dose adjustment is required in patients with hepatic impairment (see sections 4.4 and 5.2).

If Viread is discontinued in patients with chronic hepatitis B with or without HIV co-infection, these patients should be closely monitored for evidence of exacerbation of hepatitis (see section 4.4).

Paediatric population: Viread is not recommended for use in children.

The clinical data available in HIV-1 infected adolescents are inadequate to support the use of tenofovir disoproxil fumarate in this population (see sections 4.4 and 5.1) and no data are currently available in younger children.

No data are currently available in paediatric patients infected with chronic hepatitis B.

Method of administration

Viread tablets should be taken once daily, orally with food.

In exceptional circumstances in patients having particular difficulty in swallowing, Viread can be administered following disintegration of the tablet in at least 100 ml of water, orange juice or grape juice.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

General: HIV antibody testing should be offered to all HBV infected patients before initiating tenofovir disoproxil fumarate therapy (see below Co-infection with HIV-1 and hepatitis B).

Patients must be advised that tenofovir disoproxil fumarate has not been proven to prevent the risk of transmission of HIV or HBV to others through sexual contact or contamination with blood. Appropriate precautions must continue to be used.

Viread contains lactose monohydrate. Consequently, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Co-administration of other medicinal products:

- Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate.

- Viread should not be administered concomitantly with adefovir dipivoxil.

- Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended. Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.

Triple therapy with nucleosides/nucleotides: There have been reports of a high rate of virological failure and of emergence of resistance at an early stage in HIV patients when tenofovir disoproxil fumarate was combined with lamivudine and abacavir as well as with lamivudine and didanosine as a once daily regimen.

Renal function: Tenofovir is principally eliminated via the kidney. Renal failure, renal impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with the use of tenofovir disoproxil fumarate in clinical practice (see section 4.8).

Renal safety with tenofovir has only been studied to a very limited degree in patients with impaired renal function (creatinine clearance < 80 ml/min).

It is recommended that creatinine clearance is calculated in all patients prior to initiating therapy with tenofovir disoproxil fumarate and renal function (creatinine clearance and serum phosphate) is also monitored every four weeks during the first year, and then every three months. In patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil, consideration should be given to more frequent monitoring of renal function.

Patients with creatinine clearance < 50 ml/min, including haemodialysis patients: There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in patients with impaired renal function. Therefore, tenofovir disoproxil fumarate should only be used if the potential benefits of treatment are considered to outweigh the potential risks. In patients with severe renal impairment (creatinine clearance < 30 ml/min) and in patients who require haemodialysis use of tenofovir is not recommended. If no alternative treatment is available, the dosing interval must be adjusted and renal function should be closely monitored (see sections 4.2 and 5.2).

If serum phosphate is < 1.5 mg/dl (0.48 mmol/l) or creatinine clearance is decreased to < 50 ml/min in any patient receiving tenofovir disoproxil fumarate, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8, proximal tubulopathy). Consideration should also be given to interrupting treatment with tenofovir disoproxil fumarate in patients with creatinine clearance decreased to < 50 ml/min or decreases in serum phosphate to < 1.0 mg/dl (0.32 mmol/l).

Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored weekly.

Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicinal products which are secreted by the same renal pathway, including the transport proteins human organic anion transporter (hOAT) 1 and 3 or MRP 4 (e.g. cidofovir, a known nephrotoxic medicinal product). These renal transport proteins may be responsible for tubular secretion and in part, renal elimination of tenofovir and cidofovir. Consequently, the pharmacokinetics of these medicinal products which are secreted by the same renal pathway including transport proteins hOAT 1 and 3 or MRP 4 might be modified if they are co-administered. Unless clearly necessary, concomitant use of these medicinal products which are secreted by the same renal pathway is not recommended, but if such use is unavoidable, renal function should be monitored weekly (see section 4.5).

Bone effects: In HIV infected patients, in a 144-week controlled clinical study that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz in antiretroviral-naïve patients, small decreases in bone mineral density (BMD) of the hip and spine were observed in both treatment groups. Decreases in BMD of spine and changes in bone biomarkers from baseline were significantly greater in the tenofovir disoproxil fumarate treatment group at 144 weeks. Decreases in BMD of hip were significantly greater in this group until 96 weeks. However, there was no increased risk of fractures or evidence for clinically relevant bone abnormalities over 144 weeks.

Bone abnormalities (infrequently contributing to fractures) may be associated with proximal renal tubulopathy (see section 4.8).

If bone abnormalities are suspected or detected then appropriate consultation should be obtained.

Paediatric population: Viread may cause a reduction in BMD. The effects of tenofovir disoproxil fumarate-associated changes in BMD on long-term bone health and future fracture risk are currently unknown (see section 5.1).

Liver disease: Safety and efficacy data are very limited in liver transplant patients.

There are limited data on the safety and efficacy of tenofovir disoproxil fumarate in HBV infected patients with decompensated liver disease and who have a Child-Pugh-Turcotte (CPT) score > 9. These patients may be at higher risk of experiencing serious hepatic or renal adverse reactions. Therefore, hepatobiliary and renal parameters should be closely monitored in this patient population.

Exacerbations of hepatitis:

Flares on treatment: Spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients (see section 4.8). In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.

Flares after treatment discontinuation: Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy. Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported. Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation.

Liver flares are especially serious, and sometimes fatal in patients with decompensated liver disease.

Co-infection with hepatitis C or D: There are no data on the efficacy of tenofovir in patients co-infected with hepatitis C or D virus.

Co-infection with HIV-1 and hepatitis B: Due to the risk of development of HIV resistance, tenofovir disoproxil fumarate should only be used as part of an appropriate antiretroviral combination regimen in HIV/HBV co-infected patients. Patients with pre-existing liver dysfunction including chronic active hepatitis have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. However, it should be noted that increases of ALT can be part of HBV clearance during therapy with tenofovir, see above Exacerbations of hepatitis.

Lactic acidosis: Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues. The preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, a class effect of nucleoside analogues, is low for tenofovir disoproxil fumarate. However, as tenofovir is structurally related to nucleoside analogues, this risk cannot be excluded. Early symptoms (symptomatic hyperlactataemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely.

Lipodystrophy: Combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long-term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and protease inhibitors and lipoatrophy and nucleoside reverse transcriptase inhibitors has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Tenofovir is structurally related to nucleoside analogues hence the risk of lipodystrophy cannot be excluded. However, 144-week clinical data from antiretroviral-naïve HIV infected patients indicate that the risk of lipodystrophy was lower with tenofovir disoproxil fumarate than with stavudine when administered with lamivudine and efavirenz.

Mitochondrial dysfunction: Nucleoside and nucleotide analogues have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or postnatally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactataemia, hyperlipasaemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Osteonecrosis: Although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Elderly: Tenofovir disoproxil fumarate has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Interaction studies have only been performed in adults.

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low.

Concomitant use not recommended:

Viread should not be administered concomitantly with other medicinal products containing tenofovir disoproxil fumarate.

Viread should not be administered concomitantly with adefovir dipivoxil.

Didanosine: Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see section 4.4 and Table 1).

Renally eliminated medicinal products: Since tenofovir is primarily eliminated by the kidneys, co-administration of tenofovir disoproxil fumarate with medicinal products that reduce renal function or compete for active tubular secretion via transport proteins hOAT 1, hOAT 3 or MRP 4 (e.g. cidofovir) may increase serum concentrations of tenofovir and/or the co-administered medicinal products.

Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product. Some examples include, but are not limited to, aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2 (see section 4.4).

Given that tacrolimus can affect renal function, close monitoring is recommended when it is co-administered with tenofovir disoproxil fumarate.

Other interactions:

Interactions between tenofovir disoproxil fumarate and protease inhibitors and antiretroviral agents other than protease inhibitors are listed in Table 1 below (increase is indicated as “↑”, decrease as “

Table 1: Interactions between tenofovir disoproxil fumarate and other medicinal products

Medicinal product by therapeutic areas (dose in mg)	Effects on drug levels Mean percent change in AUC, Cmax, Cmin	Recommendation concerning co-administration with tenofovir disoproxil fumarate 300 mg
ANTI-INFECTIVES
Antiretrovirals
Protease inhibitors
Atazanavir/Ritonavir (300 q.d./100 q.d./300 q.d.)	Atazanavir: AUC: Cmax: Cmin: Tenofovir: AUC: ↑ 37% Cmax: ↑ 34% Cmin: ↑ 29%	No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).
Lopinavir/Ritonavir (400 b.i.d./100 b.i.d./300 q.d.)	Lopinavir/ritonavir: No significant effect on lopinavir/ritonavir PK parameters. Tenofovir: AUC: ↑ 32% Cmax: ↔ Cmin: ↑ 51%	No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).
Darunavir/Ritonavir (300/100 b.i.d./300 q.d.)	Darunavir: No significant effect on darunavir/ritonavir PK parameters. Tenofovir: AUC: ↑ 22% Cmin: ↑ 37%	No dose adjustment is recommended. The increased exposure of tenofovir could potentiate tenofovir associated adverse events, including renal disorders. Renal function should be closely monitored (see section 4.4).
NRTIs
Didanosine	Co-administration of tenofovir disoproxil fumarate and didanosine results in a 40-60% increase in systemic exposure to didanosine that may increase the risk for didanosine-related adverse reactions. Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported. Co-administration of tenofovir disoproxil fumarate and didanosine at a dose of 400 mg daily has been associated with a significant decrease in CD4 cell count, possibly due to an intracellular interaction increasing phosphorylated (i.e. active) didanosine. A decreased dosage of 250 mg didanosine co-administered with tenofovir disoproxil fumarate therapy has been associated with reports of high rates of virological failure within several tested combinations for the treatment of HIV-1 infection.	Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended (see section 4.4).
Adefovir dipivoxil	AUC: ↔ Cmax: ↔	Tenofovir disoproxil fumarate should not be administered concurrently with adefovir dipivoxil (see section 4.4).
Entecavir	AUC: ↔ Cmax: ↔	No clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was co-administered with entecavir.

Studies conducted with other medicinal products: There were no clinically significant pharmacokinetic interactions when tenofovir disoproxil fumarate was co-administered with emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, saquinavir (ritonavir boosted), methadone, ribavirin, rifampicin, tacrolimus, or the hormonal contraceptive norgestimate/ethinyl oestradiol.

Tenofovir disoproxil fumarate must be taken with food, as food enhances the bioavailability of tenofovir (see section 5.2).

4.6 Pregnancy And Lactation

Pregnancy

A moderate amount of data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformations or foetal/neonatal toxicity associated with tenofovir disoproxil fumarate.

Animal studies do not indicate reproductive toxicity (see section 5.3).

The use of tenofovir disproxil fumurate may be considered during pregnancy, if necessary.

Breast-feeding

Tenofovir has been shown to be excreted in human milk. There is insufficient information on the effects of tenofovir in newborns/infants. Viread should not be used during breast-feeding.

As a general rule, it is recommended that HIV and HBV infected women do not breast-feed their infants in order to avoid transmission of HIV and HBV to the infant.

Fertility

No human data on the effect of tenofovir disoproxil fumarate are available. Animal studies do not indicate harmful effects of tenofovir disoproxil fumarate on fertility.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil fumarate.

4.8 Undesirable Effects

a. Summary of the safety profile

HIV-1 and hepatitis B: In patients receiving tenofovir disoproxil fumarate, rare events of renal impairment, renal failure and proximal renal tubulopathy (including Fanconi syndrome) sometimes leading to bone abnormalities (infrequently contributing to fractures) have been reported. Monitoring of renal function is recommended for patients receiving Viread (see section 4.4).

HIV-1: Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events. Approximately 1% of tenofovir disoproxil fumarate-treated patients discontinued treatment due to the gastrointestinal events.

Lactic acidosis, severe hepatomegaly with steatosis and lipodystrophy are associated with tenofovir disoproxil fumarate (see sections 4.4 and 4.8c).

Co-administration of Viread and didanosine is not recommended as this may result in an increased risk of adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported (see section 4.4).

Hepatitis B: Approximately one quarter of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate, most of which are mild. In clinical trials of HBV infected patients, the most frequently occurring adverse reaction to tenofovir disoproxil fumarate was nausea (5.4%).

Acute exacerbation of hepatitis has been reported in patients on treatment as well as in patients who have discontinued hepatitis B therapy (see section 4.4).

b. Tabulated summary of adverse reactions

Assessment of adverse reactions for tenofovir disoproxil fumarate is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in Table 2.

HIV-1 clinical studies: Assessment of adverse reactions from HIV-1 clinical study data is based on experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-naïve patients received treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks.

Hepatitis B clinical studies: Assessment of adverse reactions from HBV clinical study data is primarily based on experience in two double-blind comparative controlled studies in which 641 patients with chronic hepatitis B and compensated liver disease received treatment with tenofovir disoproxil 245 mg (as fumarate) daily (n = 426) or adefovir dipivoxil 10 mg daily (n = 215) for 48 weeks.

Continued treatment with tenofovir disoproxil fumarate for up to 144 weeks in these studies did not reveal any new adverse reactions and no change in the tolerability profile (nature or severity of adverse events).

Patients with decompensated liver disease: The safety profile of tenofovir disoproxil fumarate in patients with decompensated liver disease was assessed in a double-blind active controlled study (GS-US-174-0108) in which patients received treatment with tenofovir disoproxil fumarate (n = 45) or emtricitabine plus tenofovir disoproxil fumarate (n = 45) or entecavir (n = 22) for 48 weeks.

In the tenofovir disoproxil fumarate treatment arm, 7% of patients discontinued treatment due to an adverse event; 9% of patients experienced a confirmed increase in serum creatinine of

Hepatocellular carcinoma was diagnosed in 3 patients in the tenofovir disoproxil fumarate group and two patients in the tenofovir disoproxil fumarate group died during the study.

The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (

Table 2: Tabulated summary of adverse reactions associated with tenofovir disoproxil fumarate based on clinical study and post-marketing experience

Frequency	Tenofovir disoproxil fumarate
Metabolism and nutrition disorders:
Very common:	hypophosphataemia1
Uncommon:	hypokalaemia1
Rare:	lactic acidosis3
Nervous system disorders:
Very common:	dizziness
Common:	headache
Gastrointestinal disorders:
Very common:	diarrhoea, vomiting, nausea
Common:	abdominal pain, abdominal distension, flatulence
Uncommon:	pancreatitis3
Hepatobiliary disorders:
Common:	increased transaminases
Rare:	hepatic steatosis3, hepatitis
Skin and subcutaneous tissue disorders:
Very common:	rash
Rare:	angioedema
Musculoskeletal and connective tissue disorders:
Uncommon:	rhabdomyolysis1, muscular weakness1
Rare:	osteomalacia (manifested as bone pain and infrequently contributing to fractures)1, 2, myopathy1
Renal and urinary disorders:
Uncommon:	increased creatinine
Rare:	acute renal failure, renal failure, acute tubular necrosis, proximal renal tubulopathy (including Fanconi syndrome), nephritis (including acute interstitial nephritis)2, nephrogenic diabetes insipidus
General disorders and administration site conditions:
Very common:	asthenia
Common:	fatigue

¹ This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil fumarate in the absence of this condition.

² This adverse reaction was identified through post-marketing surveillance but not observed in randomised controlled clinical trials or the tenofovir disoproxil fumarate expanded access program. The frequency category was estimated from a statistical calculation based on the total number of patients exposed to tenofovir disoproxil fumarate in randomised controlled clinical trials and the expanded access program (n = 7,319).

³ See section c. Description of selected adverse reactions for more details.

c. Description of selected adverse reactions

HIV-1 and hepatitis B:

Renal impairment: As Viread may cause renal damage monitoring of renal function is recommended (see sections 4.4 and 4.8a).

HIV-1:

Interaction with didanosine: Co-administration of tenofovir disoproxil fumarate and didanosine is not recommended as it results in a 40-60% increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.

Lipids, lipodystrophy and metabolic abnormalities: Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (see section 4.4).

Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump) (see section 4.4).

In a 144-week controlled clinical study in antiretroviral-naïve patients that compared tenofovir disoproxil fumarate with stavudine in combination with lamivudine and efavirenz, patients who received tenofovir disoproxil had a significantly lower incidence of lipodystrophy compared with patients who received stavudine. The tenofovir disoproxil fumarate arm also had significantly smaller mean increases in fasting triglycerides and total cholesterol than the comparator arm.

Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).

Osteonecrosis: Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Lactic acidosis and severe hepatomegaly with steatosis: Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactataemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels (see section 4.4).

Hepatitis B:

Exacerbations of hepatitis during treatment: In studies with nucleoside-naïve patients, on-treatment ALT elevations > 10 times ULN (upper limit of normal) and > 2 times baseline occurred in 2.6% of tenofovir disoproxil fumarate-treated patients. ALT elevations had a median time to onset of 8 weeks, resolved with continued treatment, and, in a majority of cases, were associated with a ₁₀ copies/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment (see section 4.4).

Exacerbations of hepatitis after discontinuation of treatment: In HBV infected patients,