Enbrel 25mg solution for injection in pre-filled syringe

Enbrel 25 mg solution for injection in pre-filled syringe

Etanercept

Read all (both sides) of this leaflet carefully before you start using this medicine.

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


• Your doctor will also give you a Patient Alert Card, which contains important safety information that you need to be aware of before and during treatment with Enbrel.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you or a child in your care. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours or those of the child you are caring for.


• If you are concerned about any side effect, or if you notice any side effects that are not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

Information in this leaflet is organised under the following 7 sections:

1. What Enbrel is and what it is used for

2. Before you use Enbrel

3. How to use Enbrel

4. Possible side effects

5. How to store Enbrel

6. Further information

7. Instructions for preparing and giving an injection of Enbrel (See overleaf)

What Enbrel Is And What It Is Used For

Enbrel is a medicine that is made from two human proteins. It blocks the activity of another protein in the body that causes inflammation. Enbrel works by reducing the inflammation associated with certain diseases.

In adults (aged 18 and over), Enbrel can be used for moderate or severe rheumatoid arthritis, psoriatic arthritis, severe ankylosing spondylitis and moderate or severe psoriasis – in each case usually when other widely used treatments have not worked well enough or are not suitable for you.

For rheumatoid arthritis, Enbrel is usually used in combination with methotrexate, although it may also be used alone if treatment with methotrexate is unsuitable for you. Whether used alone or in combination with methotrexate, Enbrel can slow down the damage to your joints caused by the rheumatoid arthritis and improve your ability to do normal daily activities.

For psoriatic arthritis patients with multiple joint involvement, Enbrel can improve your ability to do normal daily activities. For patients with multiple symmetrical painful or swollen joints (e.g., hands, wrists and feet), Enbrel can slow down the structural damage to those joints caused by the disease.

Enbrel is also prescribed for the treatment of the following diseases in children and adolescents:

• Polyarticular juvenile idiopathic arthritis (a type of juvenile arthritis that affects many joints) in patients from the age of 4 years who have had an inadequate response to (or are unable to take) methotrexate.


• Severe psoriasis in patients from the age of 8 years who have had an inadequate response to (or are unable to take) phototherapies or other systemic therapies.

Before You Use Enbrel

Do not use Enbrel

• 
  Allergy: Do not use Enbrel if you, or the child you are caring for, are allergic to etanercept or any of the other ingredients of Enbrel. If you or the child experience allergic reactions such as chest tightness, wheezing, dizziness or rash, do not inject more Enbrel, and contact your doctor immediately.


• 
  Serious blood infection: Do not use Enbrel if you or the child have, or are at risk of developing a serious blood infection called sepsis. If you are not sure, please contact your doctor.


• 
  Infections: Do not use Enbrel if you or the child have an infection of any kind. If you are not sure, please talk to your doctor.

Take special care with Enbrel

• 
  Allergic reactions: If you or the child experience allergic reactions such as chest tightness, wheezing, dizziness or rash, do not inject more Enbrel, and contact your doctor immediately.


• 
  Infections/surgery: If you or the child develop a new infection, or are about to have any major surgery, your doctor may wish to monitor the treatment with Enbrel.


• 
  Infections/diabetes: Tell your doctor if you or the child have a history of recurrent infections or suffer from diabetes or other conditions that increase the risk of infection.


• 
  Infections/monitoring: Tell your doctor of any recent travel outside the European region. If you or the child develop symptoms of an infection such as fever, chills or cough, notify your doctor immediately. Your doctor may decide to continue to monitor you or the child for the presence of infections after you or the child stop using Enbrel.


• 
  Tuberculosis: As cases of tuberculosis have been reported in patients treated with Enbrel, your doctor will check for signs and symptoms of tuberculosis before starting Enbrel. This may include a thorough medical history, a chest X-ray and a tuberculin test. The conduct of these tests should be recorded on the Patient Alert Card. It is very important that you tell your doctor if you or the child have ever had tuberculosis, or have been in close contact with someone who has had tuberculosis. If symptoms of tuberculosis (such as persistent cough, weight loss, listlessness, mild fever), or any other infection appear during or after therapy, tell your doctor immediately.


• 
  Hepatitis B: Your doctor may decide to test for the presence of hepatitis B infection before you or the child begin treatment with Enbrel.


• 
  Hepatitis C: Tell your doctor if you or the child have hepatitis C. Your doctor may wish to monitor the treatment with Enbrel in case the infection worsens.


• 
  Blood disorders: Seek medical advice immediately if you or the child have any signs or symptoms such as persistent fever, sore throat, bruising, bleeding or paleness. Such symptoms may point to the existence of potentially life-threatening blood disorders, which may require discontinuation of Enbrel.


• 
  Nervous system and eye disorders: Tell your doctor if you or the child have multiple sclerosis, optic neuritis (inflammation of the nerves of the eyes) or transverse myelitis (inflammation of the spinal cord). Your doctor will determine if Enbrel is an appropriate treatment.


• 
  Congestive heart failure: Tell your doctor if you or the child have a history of congestive heart failure, because Enbrel needs to be used with caution under these circumstances.


• 
  Cancer: Tell your doctor if you have or have ever had lymphoma (a type of blood cancer) or any other cancer before you are given Enbrel.
  
  Patients with severe rheumatoid arthritis, who have had the disease for a long time, may be at higher than average risk of developing lymphoma.
  
  Children and adults taking Enbrel may have an increased risk of developing lymphoma or another cancer.
  
  Some children and teenage patients who have received Enbrel or other medicines that work the same way as Enbrel have developed cancers, including unusual types, which sometimes resulted in death.
  
  Some patients receiving Enbrel have developed skin cancers called non-melanoma skin cancer. Tell your doctor if you or the child develop any change in the appearance of the skin or growths on the skin.


• 
  Vaccinations: If possible, children should be up to date with all vaccinations before using Enbrel. Some vaccines, such as oral polio vaccine, should not be given while using Enbrel. Please consult your doctor before you or the child receive any vaccines.


• 
  Chickenpox: Tell your doctor if you or the child are exposed to chickenpox when using Enbrel. Your doctor will determine if preventive treatment for chickenpox is appropriate.


• 
  Latex: The needle cover is made from latex (dry natural rubber). Contact your doctor before using Enbrel if the needle cover will be handled by, or Enbrel will be given to, someone with a known or possible hypersensitivity (allergy) to latex.


• 
  Alcohol abuse: Enbrel should not be used for the treatment of hepatitis related to alcohol abuse. Please tell your doctor if you or the child in your care have a history of alcohol abuse.


• 
  Wegener’s granulomatosis: Enbrel is not recommended for the treatment of Wegener’s granulomatosis, a rare inflammatory disease. If you or the child in your care have Wegener’s granulomatosis, talk to your doctor.


• 
  Anti-diabetic medicines: Tell your doctor if you or the child have diabetes or are taking medicines to treat diabetes. Your doctor may decide if you or the child need less anti-diabetic medicine while taking Enbrel.

Using other medicines

Tell the doctor or pharmacist if you or the child are taking or have recently taken any other medicines (including anakinra, abatacept or sulfasalazine), even those not prescribed by the doctor. You or the child should not use Enbrel with medicines that contain the active substance anakinra or abatacept.

Taking Enbrel with food and drink

Enbrel can be taken with or without food or drink.

Pregnancy and breast-feeding

The effects of Enbrel in pregnant women are not known, and so the use of Enbrel during pregnancy is not recommended. Women using Enbrel should not become pregnant. If the patient becomes pregnant, you should consult the patient's doctor.

Women using Enbrel should not breast-feed, since it is not known if Enbrel passes into human breast milk.

Driving and using machines

The use of Enbrel is not expected to affect the ability to drive or use machines.

How To Use Enbrel

Always use Enbrel exactly as the doctor has told you. You should check with the doctor or pharmacist if you are not sure.

If you feel that the effect of Enbrel is too strong or too weak, talk to your doctor or pharmacist.

Dosing for adult patients (aged 18 years or over)

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

The usual dose is 25 mg given twice a week or 50 mg once a week as an injection under the skin. However, your doctor may determine an alternative frequency at which to inject Enbrel.

Plaque psoriasis

The usual dose is 25 mg twice a week or 50 mg once a week.

Alternatively, 50 mg may be given twice a week for up to 12 weeks, followed by 25 mg twice a week or 50 mg once a week.

Your doctor will decide how long you should take Enbrel and whether retreatment is needed based on your response. If Enbrel has no effect on your condition after 12 weeks, your doctor may tell you to stop taking this medicine.

Dosing for children and adolescents

The appropriate dose and frequency of dosing for the child or adolescent will depend on body weight and disease. This is a single-use syringe for patients weighing 62.5 kg or more. 25 mg vials are available for paediatric use from which doses less than 25 mg can be administered. The doctor will provide you with detailed directions for preparing and measuring the appropriate dose.

For polyarticular juvenile idiopathic arthritis in patients from the age of 4 years, the usual dose is 0.4 mg of Enbrel per kg bodyweight (up to a maximum of 25 mg), and should be given twice weekly.

For psoriasis in patients from the age of 8 years, the usual dose is 0.8 mg of Enbrel per kg bodyweight (up to a maximum of 50 mg), and should be given once weekly. If Enbrel has no effect on the child’s condition after 12 weeks, your doctor may tell you to stop using this medicine.

Method and route of administration

Enbrel is administered by an injection under the skin (by subcutaneous injection).

Enbrel can be taken with or without food or drink.

Detailed instructions on how to inject Enbrel are provided in section 7, “INSTRUCTIONS FOR PREPARING AND GIVING AN INJECTION OF ENBREL”. Do not mix the Enbrel solution with any other medicine.

To help you remember, it may be helpful to write in a diary which day(s) of the week Enbrel should be used.

If you use more Enbrel than you should

If you have used more Enbrel than you should (either by injecting too much on a single occasion or by using it too frequently), talk to a doctor or pharmacist immediately. Always have the outer carton of the medicine with you, even if it is empty.

If you forget to inject Enbrel

If you forget a dose, you should inject it as soon as you remember, unless the next scheduled dose is the next day; in which case you should skip the missed dose. Then continue to inject the medicine on the usual day(s). If you do not remember until the day that the next injection is due, do not take a double dose (two doses on the same day) to make up for a forgotten dose.

If you stop using Enbrel

Your symptoms may return upon discontinuation.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Possible Side Effects

Like all medicines, Enbrel can cause side effects, although not everybody gets them.

Other side effects that are not listed in this leaflet may occur. If you are concerned about any side effect, or if you notice any side effects that are not listed in this leaflet, please tell your doctor or pharmacist.

Allergic reactions

If any of the following happen, do not inject more Enbrel. Tell your doctor immediately, or go to the casualty department at your nearest hospital.

• Trouble swallowing or breathing


• Swelling of the face, throat, hands, or feet


• Feeling nervous or anxious, throbbing sensations, sudden reddening of the skin and/or a warm feeling


• Severe rash, itching, or hives (elevated patches of red or pale skin that often itch)

Serious allergic reactions are rare. However, any of the above symptoms may indicate an allergic reaction to Enbrel, so you should seek immediate medical attention.

Serious side effects

If you notice any of the following, you or the child may need urgent medical attention.

• Signs of serious infections, such as high fever that may be accompanied by cough, shortness of breath, chills, weakness, or a hot, red, tender, sore area on the skin or joints


• Signs of blood disorders, such as bleeding, bruising, or paleness


• Signs of nerve disorders, such as numbness or tingling, changes in vision, eye pain, or onset of weakness in an arm or leg


• Signs of worsening heart failure, such as fatigue or shortness of breath with activity, swelling in the ankles, a feeling of fullness in the neck or abdomen, night-time shortness of breath or coughing, bluish colour of the nails or the lips

These are rare or uncommon side effects, but are serious conditions (some of which may rarely be fatal). If these signs occur, tell your doctor immediately, or visit the casualty department at your nearest hospital.

The frequency of possible side effects listed below is defined using the following convention:

• Very common (affects more than 1 user in 10)


• Common (affects 1 to 10 users in 100)


• Uncommon (affects 1 to 10 users in 1,000)


• Rare (affects 1 to 10 users in 10,000)


• Very rare (affects less than 1 user in 10,000)


• Not known (frequency cannot be estimated from the available data)

The side effects listed below are those that have been seen in adult patients. The side effects seen in children and adolescents are similar to those seen in adults.

• 
  Very common: Infections (including colds, sinusitis, bronchitis, urinary tract infections and skin infections); injection site reactions (including bleeding, bruising, redness, itching, pain, and swelling). Reactions at the injection site are very common, but do not occur as often after the first month of treatment. Some patients have developed a reaction at an injection site that was used before.


• 
  Common: allergic reactions; fever; itching; antibodies directed against normal tissue (autoantibody formation).


• 
  Uncommon: serious infections (including pneumonia, deep skin infections, joint infections, blood infection, and infections at various sites); low blood platelet count; skin cancer (excluding melanoma); localised swelling of the skin (angioedema); hives (elevated patches of red or pale skin that often itch); eye inflammation; psoriasis (new or worsening); rash; inflammation or scarring of the lungs.


• 
  Rare: serious allergic reactions (including severe localised swelling of the skin and wheezing); lymphoma (a type of blood cancer); combined low platelet, red, and white blood cell count; nervous system disorders (with signs and symptoms similar to those of multiple sclerosis or inflammation of the nerves of the eyes or spinal cord); tuberculosis; worsening congestive heart failure; seizures; lupus or lupus-like syndrome (symptoms may include persistent rash, fever, joint pain, and tiredness); inflammation of the blood vessels; low red blood cell count, low white blood cell count, low neutrophil (a type of white blood cell) count; elevated liver blood tests; skin rash, which may lead to severe blistering and peeling of the skin.


• 
  Very rare: failure of the bone marrow to produce crucial blood cells.


• 
  Not known: leukaemia (cancer affecting the blood and bone marrow); excessive activation of white blood cells associated with inflammation (macrophage activation syndrome).

How To Store Enbrel

Keep out of the reach and sight of children.

Do not use Enbrel after the expiry date which is stated on the carton and pre-filled syringe after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2° – 8°C). Do not freeze.

Keep the pre-filled syringes in the outer carton in order to protect from light.

After taking a syringe from the refrigerator, wait approximately 15-30 minutes to allow the Enbrel solution in the syringe to reach room temperature. Do not warm in any other way. Immediate use is then recommended.

Inspect the solution in the syringe. Only inject the solution in the syringe if it is clear, colourless or pale yellow, and free from easily visible particles. If it is not, use a different syringe, then contact your pharmacist for assistance.

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 Enbrel contains

The active substance in Enbrel is etanercept. Each pre-filled syringe contains 0.5 ml of solution, providing 25 mg of etanercept.

The other ingredients are sucrose, sodium chloride, L-arginine hydrochloride, sodium phosphate monobasic dihydrate and sodium phosphate dibasic dihydrate, and water for injections.

What Enbrel looks like and contents of the pack

Enbrel is supplied as a pre-filled syringe containing a clear, colourless or pale yellow solution for injection (solution for injection). Each pack contains 4, 8 or 24 pre-filled syringes and 8, 16 or 48 alcohol swabs. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Wyeth Europa Ltd.

Huntercombe Lane South

Taplow

Maidenhead

Berkshire

SL6 0PH

United Kingdom

Manufacturer:

Wyeth Pharmaceuticals

New Lane

Havant

Hampshire

PO9 2NG

United Kingdom

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder.

United Kingdom

Wyeth Pharmaceuticals

Tel:+ 44 845 367 0098

This leaflet was last approved in 07/2010

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

Instructions For Preparing And Giving An Injection Of Enbrel

This section is divided into the following subsections:

Introduction

Step 1: Setting up for an injection

Step 2: Choosing an injection site

Step 3: Injecting the Enbrel solution

Step 4: Disposing of supplies

Introduction

The following instructions explain how to prepare and inject Enbrel. Please read the instructions carefully and follow them step by step. You will be instructed by your doctor or his/her assistant on the techniques of self-injection or on giving an injection to a child. Do not attempt to administer an injection until you are sure that you understand how to prepare and give the injection.

The Enbrel solution should not be mixed with any other medicine before use.

Step 1: Setting up for an injection

1. Select a clean, well-lit, flat working surface.

2. Take the Enbrel carton containing the pre-filled syringes out of the refrigerator and place it on the flat work surface. Remove one pre-filled syringe and one alcohol swab and place them on the work surface. Do not shake the pre-filled syringe of Enbrel. Place the carton containing any remaining pre-filled syringes back into the refrigerator. Please see section 5 for instructions on how to store Enbrel. If you have any questions about storage, contact your doctor, nurse, or pharmacist for further instructions.

3. You should allow 15 to 30 minutes for the Enbrel solution in the syringe to reach room temperature. Do NOT remove the needle cover while allowing it to reach room temperature. Waiting until the solution reaches room temperature may make the injection more comfortable for you. Do not warm Enbrel in any other way (for example, do not warm it in a microwave or in hot water).

4. Assemble the additional supplies you will need for your injection. These include an alcohol swab and a cotton ball or gauze.

5. Wash your hands with soap and warm water.

6. Inspect the solution in the syringe. Only inject the solution in the syringe if it is clear, colourless or pale yellow, and free from easily visible particles. If it is not, use a different syringe, then contact your pharmacist for assistance.

Step 2: Choosing an injection site

1. The three recommended injection sites for Enbrel using a pre-filled syringe include: (1) the front of the middle thighs; (2) the abdomen, except for the 5 cm area right around the navel; and (3) the outer area of the upper arms (see Diagram 1). If you are self injecting, you should not use the outer area of the upper arms.

2. A different site should be used for each new injection. Each new injection should be given at least 3 cm from an old site. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid areas with scars or stretch marks. (It may be helpful to keep notes on the location of the previous injections.)

3. If you or the child have psoriasis, you should try not to inject directly into any raised, thick, red, or scaly skin patches (“psoriasis skin lesions”).

Step 3: Injecting the Enbrel solution

1. Wipe the site where Enbrel is to be injected with an alcohol swab, using a circular motion. Do NOT touch this area again before giving the injection.

2. Pick up the pre-filled syringe from the flat work surface. Remove the needle cover by firmly pulling it straight off the syringe (see Diagram 2). Be careful not to bend or twist the cover during removal to avoid damage to the needle.

When you remove the needle cover, there may be a drop of liquid at the end of the needle; this is normal. Do not touch the needle or allow it to touch any surface. Do not touch or bump the plunger. Doing so could cause the liquid to leak out.

3. When the cleaned area of skin has dried, pinch and hold it firmly with one hand. With the other hand, hold the syringe like a pencil.

4. With a quick, short motion, push the needle all the way into the skin at an angle between 45° and 90° (see Diagram 3). With experience, you will find the angle that is most comfortable for you or the child. Be careful not to push the needle into the skin too slowly, or with great force.

5. When the needle is completely inserted into the skin, release the skin that you are holding. With your free hand, hold the syringe near its base to stabilise it. Then push the plunger to inject all of the solution at a slow, steady rate (see Diagram 4).

6. When the syringe is empty, pull the needle out of the skin, being careful to keep it at the same angle as inserted. There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site for 10 seconds. Do not rub the injection site. If needed, you may cover the injection site with a bandage.

Step 4: Disposing of supplies

• The pre-filled syringe is for single-use administration only. The syringe and needle should NEVER be re-used. NEVER re-cap a needle. Dispose of the needle and syringe as instructed by your doctor, nurse or pharmacist.

If you have any questions, please talk to a doctor, nurse or pharmacist who is familiar with Enbrel.

Doc ID:61174 (Taken from Doc ID: 61173 and annex)

Erythromycin 250mg Tablets

1. Name Of The Medicinal Product

Erythromycin Tablets BP 250mg

2. Qualitative And Quantitative Composition

Erythromycin 250mg

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Gastro-resistant tablets;

Reddish orange coloured round biconvex tablets, plain on both sides. They are made Gastro-resistant by enteric coating.

4. Clinical Particulars

4.1 Therapeutic Indications

For the prophylaxis and treatment of infections caused by Erythromycin-sensitive organisms.

Erythromycin is highly effective in the treatment of a great variety of clinical infections such as:

1. Upper respiratory tract infections: Tonsillitis, peritonsillar abscess, pharyngitis, laryngitis, sinusitis, secondary infections in influenza and common colds.

2. Lower respiratory tract infections: Tracheitis, acute and chronic bronchitis, pneumonia (lobar pneumonia, bronchopneumonia, primary atypical pneumonia), bronchiectasis, Legionnaire's disease

3. Ear infections: Otitis media and otitis externa, mastoiditis.

4. Eye infections: Blepharitis

5. Oral infections: Gingivitis, Vincent's angina

6. Skin and soft tissue infections: Boils and carbuncles, paronychia, abscesses, pustular acne, impetigo, cellulitis, erysipelas

7. Gastro-intestinal infections: cholecystitis, staphylococcal enterocolitis

8. Prophylaxis: pre- and post- operative trauma, burns, rheumatic fever

9. Other infections: osteomyelitis, urethritis, gonorrhoea, syphilis, lymphogranuloma venereum, diphtheria, prostatitis, scarlet fever

Note: Erythromycin has also proved to be of value in endocarditis and septicaemia, but in these conditions initial administration of erythromycin lactobionate by the intravenous route is advisable.

4.2 Posology And Method Of Administration

Adults and older children: Usual dosage is one tablet every four to six hours. This may be increased to 4g per day unusually severe infection.

4.3 Contraindications

Known hypersensitivity to erythromycin. Erythromycin is contraindicated in patients taking simvastatin, tolterodine, mizolastine, amisulpride, astemizole, terfenadine, and cisapride or pimozide.

Erythromycin is contraindicated with ergotamine and dihydroergotamine.

4.4 Special Warnings And Precautions For Use

Erythromycin is excreted principally by the liver, so caution should be exercised in administering the antibiotic to patients with impaired hepatic function or concomitantly receiving potentially hepatotoxic agents. Hepatic dysfunction including increased liver enzymes and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with erythromycin.

There have been reports suggesting erythromycin does not reach the foetus in adequate concentrations to prevent congenital syphilis. Infants born to women treated during pregnancy with oral erythromycin for early syphilis should be treated with an appropriate penicillin regimen.

There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.

Erythromycin interferes with the fluorometric determination of urinary catecholamines.

As with other broad-spectrum antibiotics, pseudomembranous colitis has been reported rarely with erythromycin.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with lovastatin.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use of erythromycin with simvastatin, tolterodine, mizolastine, amisulpride, terfenadine or astemizole is likely to result in an enhanced risk of cardio toxicity with these drugs. The concomitant use of erythromycin with either simvastatin, tolterodine, mizolastine, amisulpride, astemizole or terfenadine is therefore contra-indicated.

The metabolism of terfenadine and astemizole is significantly altered when either are taken concomitantly with erythromycin. Rare cases of serious cardio-vascular events have been observed, including torsades de pointes, other ventricular arrhythmias and cardiac arrest. Death has been reported with the terfenadine/erythromycin combination.

Elevated cisapride levels have been reported in patients receiving erythromycin and cisapride concomitantly. This may result in QT prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes.

Similar effects have been observed with concomitant administration of pimozide and clarithromycin, another macrolide antibiotic.

Concurrent use of erythromycin and ergotamine or dihydroergotamine has been associated in some patients with acute ergot toxicity, characterised by the rapid development of severe peripheral vasospasm and dysaesthesia.

Increases in serum concentrations of the following drugs metabolised by the cytochrome P450 system may occur when administered concurrently with erythromycin: alfentanil, astemizole, bromocriptine, carbamazepine, cyclosporin, digoxin, dihydroergotamine, disopyramide, ergotamine, hexobarbitone, midazolam, phenytoin, quinidine, tacrolimus, terfenadine, theophylline, triazolam, valproate, and warfarin. Appropriate monitoring should be undertaken and dosage should be adjusted as necessary.

Erythromycin has been reported to decrease the clearance of zopiclone and thus may increase the pharmacodynamic effects of this drug.

When oral erythromycin is given concurrently with theophylline, there is also a significant decrease in erythromycin serum concentrations. The decrease could result in subtherapeutic concentrations of erythromycin.

4.6 Pregnancy And Lactation

Erythromycin has been in widespread use for a number of years without apparent ill consequence. Animal studies have shown no hazard.

Erythromycin has been reported to cross the placental barrier in humans, but foetal plasma levels are generally low.

Erythromycin is excreted in breast milk, therefore, caution should be exercised when erythromycin is administered to a nursing mother.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Occasional side effects such as nausea, abdominal discomfort, vomiting and diarrhoea may be experienced. Reversible hearing loss associated with doses of erythromycin usually greater than 4g per day has been reported. Allergic reactions are rare and mild, although anaphylaxis has occurred. Skin reactions ranging from mild eruptions to erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have rarely been reported. There are no reports implicating erythromycin products with abnormal tooth development, and only rare reports of damage to the blood, kidneys or central nervous system.

Cardiac arrhythmias have been very rarely reported in patients receiving erythromycin therapy. There have been isolated reports of chest pain, dizziness and palpitations; however, a cause and effect relationship has not been established.

Symptoms of hepatitis, hepatic dysfunction and/or abnormal liver function test results may occur.

4.9 Overdose

Symptoms: hearing loss, severe nausea, vomiting and diarrhoea.

Treatment: gastric lavage, general supportive measures.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Macrolides- ATC Code: J01FA01

Erythromycin exerts its antimicrobial action by binding to the 50S ribosomal sub-unit of susceptible microorganisms and suppresses protein synthesis. Erythromycin is usually active against most strains of the following organisms both in vitro and in clinical infections:

Gram-positive bacteria - Listeria monocytogenes, Corynebacterium diphtheriae (as an adjunct to antitoxin), Staphylococci spp, Streptococci spp (including Enterococci).

Gram-negative bacteria - Haemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, Legionella pneumophila, Moraxella (Branhamella) catarrhalis, Bordetella pertussis, Campylobacter spp.

Mycoplasma - Mycoplasma pneumoniae, Ureaplasma urealyticum

Other organisms - Treponema pallidum, Chlamydia spp, Clostridia spp, L-forms, the agents causing trachoma and lymphogranuloma venereum

Note: The majority of strains of Haemophilus influenzae are susceptible to the concentrations reached after ordinary doses.

5.2 Pharmacokinetic Properties

Absorption and Fate

Erythromycin is adversely affected by gastric acid. For this reason erythromycin tablets are enteric coated.

It is absorbed from the small intestine. It is widely distributed throughout body tissues. Little metabolism occurs and only about 5% is eliminated in the urine. It is excreted principally by the liver.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Maize Starch

Croscarmellose Sodium Type A

Povidone

Talc

Magnesium Stearate (E572)

Sub coat:

Hypromellose (E464)

Macrogol 6000

Erythrosine (E127)

Talc

Enteric coat:

Methacrylic Acid ethylacrylate Copolymer (1:1) dispersion 30%

Macrogol 6000

Talc

Polysorbate 80 (E433)

Erythrosine (E127)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Do not store above 25°C.

(a) Tablet container: Keep the container tightly closed. Store in the original container.

(b) Blister: Store in the original container.

(c) Bag: Keep container in the outer carton.

6.5 Nature And Contents Of Container

Tablet container:

Nature: Polypropylene tamper evident tablet container with polyethylene cap.

Contents: 21, 100, 250, 500 and 1000 tablets

Blister:

Nature: 250 um PVC/20 um aluminium blister packs

Contents: 28, 56, 84 and 100 tablets.

Bag:

Nature: Polyethylene sealed bag

Contents: 5,000 and 10,000 tablets.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

Nothing stated.

7. Marketing Authorisation Holder

Milpharm Limited,

Ares,

Odyssey Business Park,

West End Road,

South Ruislip HA4 6QD,

United Kingdom

8. Marketing Authorisation Number(S)

PL 16363/0019

9. Date Of First Authorisation/Renewal Of The Authorisation

05/02/2009

10. Date Of Revision Of The Text

19/03/2009

Erythrocin 250 Tablets

1. Name Of The Medicinal Product

Erythrocin 250

2. Qualitative And Quantitative Composition

		mg / tablet
Active:	Erythromycin as erythromycin stearate	250

3. Pharmaceutical Form

Film coated tablet

4. Clinical Particulars

4.1 Therapeutic Indications

For the prophylaxis and treatment of infections caused by erythromycin-sensitive organisms.

Erythromycin is highly effective in the treatment of a great variety of clinical infections such as:

1. Upper Respiratory Tract infections: tonsillitis, peritonsillar abscess, pharyngitis, laryngitis, sinusitis, secondary infections in influenza and common colds

2. Lower Respiratory Tract infections: tracheitis, acute and chronic bronchitis, pneumonia (lobar pneumonia, bronchopneumonia, primary atypical pneumonia), bronchiectasis, Legionnaire's disease

3. Ear infection: otitis media and otitis externa, mastoiditis

4. Oral infections: gingivitis, Vincent's angina

5. Eye infections: blepharitis

6. Skin and soft tissue infections: boils and carbuncles, paronychia, abscesses, pustular acne, impetigo, cellulitis, erysipelas

7. Gastrointestinal infections: cholecystitis, staphylococcal enterocolitis

8. Prophylaxis: pre- and post- operative trauma, burns, rheumatic fever

9. Other infections: osteomyelitis, urethritis, gonorrhoea, syphilis, lymphogranuloma venereum, diphtheria, prostatitis, scarlet fever

4.2 Posology And Method Of Administration

For oral administration

Adults and children over 8 years: For mild to moderate infections 2g daily in divided doses. Up to 4g daily in severe infections.

Elderly: No special dosage recommendations.

Note: For younger children, infants and babies, Erythroped, erythromycin ethylsuccinate suspensions, are normally recommended. The recommended dose for children age 2-8 years, for mild to moderate infections, is 1 gram daily in divided doses. The recommended dose for infants and babies, for mild to moderate infections, is 500 mg daily in divided doses. For severe infections doses may be doubled.

4.3 Contraindications

Known hypersensitivity to erythromycin.

Erythromycin is contraindicated in patients taking astemizole, terfenadine, cisapride or pimozide.

Erythromycin is contraindicated with ergotamine and dihydroergotamine.

4.4 Special Warnings And Precautions For Use

Erythromycin is excreted principally by the liver, so caution should be exercised in administering the antibiotic to patients with impaired hepatic function or concomitantly receiving potentially hepatotoxic agents. Hepatic dysfunction including increased liver enzymes and/or cholestatic hepatitis, with or without jaundice, has been infrequently reported with erythromycin.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening (see section.4.8). Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents including erythromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C. difficile. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

There have been reports suggesting erythromycin does not reach the foetus in adequate concentrations to prevent congenital syphilis. Infants born to women treated during pregnancy with oral erythromycin for early syphilis should be treated with an appropriate penicillin regimen.

There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis.

Erythromycin interferes with the fluorometric determination of urinary catecholamines.

Rhabdomyolysis with or without renal impairment has been reported in seriously ill patients receiving erythromycin concomitantly with statins.

There have been reports of infantile hypertrophic pyloric stenosis (IHPS) occurring in infants following erythromycin therapy. In one cohort of 157 newborns who were given erythromycin for pertussis prophylaxis, seven neonates (5%) developed symptoms of non-bilious vomiting or irritability with feeding and were subsequently diagnosed as having IHPS requiring surgical pyloromyotomy. Since erythromycin may be used in the treatment of conditions in infants which are associated with significant mortality or morbidity (such as pertussis or chlamydia), the benefit of erythromycin therapy needs to be weighed against the potential risk of developing IHPS. Parents should be informed to contact their physician if vomiting or irritability with feeding occurs.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Increases in serum concentrations of the following drugs metabolised by the cytochrome P450 system may occur when administered concurrently with erythromycin: acenocoumarol, alfentanil, astemizole, bromocriptine, carbamazepine, cilostazol, cyclosporin, digoxin, dihydroergotamine, disopyramide, ergotamine, hexobarbitone, methylprednisolone, midazolam, omeprazole, phenytoin, quinidine, rifabutin, sildenafil, tacrolimus, terfenadine, theophylline, triazolam, valproate, vinblastine, and antifungals e.g fluconazole, ketoconazole and itraconazole. Appropriate monitoring should be undertaken and dosage should be adjusted as necessary. Particular care should be taken with medications known to prolong the QTc interval of the electrocardiogram.

Drugs that induce CYP3A4 (such as rifampicin, phenytoin, carbamazepine, phenobarbital, St John's Wort) may induce the metabolism of erythromycin. This may lead to sub-therapeutic levels of erythromycin and a decreased effect. The induction decreases gradually during two weeks after discontinued treatment with CYP3A4 inducers. Erythromycin should not be used during and two weeks after treatment with CYP3A4 inducers.

HMG-CoA Reductase Inhibitors: erythromycin has been reported to increase concentrations of HMG-CoA reductase inhibitors (e.g. lovastatin and simvastatin). Rare reports of rhabdomyolysis have been reported in patients taking these drugs concomitantly.

Contraceptives: some antibiotics may in rare cases decrease the effect of contraceptive pills by interfering with the bacterial hydrolysis of steroid conjugates in the intestine and thereby reabsorption of unconjugated steroid. As a result of this plasma levels of active steroid may decrease.

Antihistamine H1 antagonists: care should be taken in the coadministration of erythromycin with H1 antagonists such as terfenadine, astemizole and mizolastine due to the alteration of their metabolism by erythromycin.

Erythromycin significantly alters the metabolism of terfenadine, astemizole and pimozide when taken concomitantly. Rare cases of serious, potentially fatal, cardiovascular events including cardiac arrest, torsade de pointes and other ventricular arrhythmias have been observed (see sections 4.3 and 4.8).

Anti-bacterial agents: an in vitro antagonism exists between erythromycin and the bactericidal beta-lactam antibiotics (e.g. penicillin, cephalosporin). Erythromycin antagonises the action of clindamycin, lincomycin and chloramphenicol. The same applies for streptomycin, tetracyclines and colistin.

Protease inhibitors: in concomitant administration of erythromycin and protease inhibitors, an inhibition of the decomposition of erythromycin has been observed.

Oral anticoagulants: there have been reports of increased anticoagulant effects when erythromycin and oral anticoagulants (e.g. warfarin) are used concomitantly.

Triazolobenzodiazepines (such as triazolam and alprazolam) and related benzodiazepines: erythromycin has been reported to decrease the clearance of triazolam, midazolam, and related benzodiazepines, and thus may increase the pharmacological effect of these benzodiazepines.

Post-marketing reports indicate that co-administration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterised by vasospasm and ischaemia of the central nervous system, extremities and other tissues (see section 4.3).

Elevated cisapride levels have been reported in patients receiving erythromycin and cisapride concomitantly. This may result in QTc prolongation and cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes. Similar effects have been observed with concomitant administration of pimozide and clarithromycin, another macrolide antibiotic.

Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy. There have been published reports suggesting when oral erythromycin is given concurrently with theophylline there is a significant decrease in erythromycin serum concentrations. This decrease could result in sub-therapeutic concentrations of erythromycin.

There have been post-marketing reports of colchicine toxicity with concomitant use of erythromycin and colchicine.

Hypotension, bradyarrhythmias and lactic acidosis have been observed in patients receiving concurrent verapamil, a calcium channel blocker.

Cimetidine may inhibit the metabolism of erythromycin which may lead to an increased plasma concentration.

Erythromycin has been reported to decrease the clearance of zopiclone and thus may increase the pharmacodynamic effects of this drug.

4.6 Pregnancy And Lactation

There are no adequate and well-controlled studies in pregnant women. However, observational studies in humans have reported cardiovascular malformations after exposure to medicinal products containing erythromycin during early pregnancy.

Erythromycin has been reported to cross the placental barrier in humans, but foetal plasma levels are generally low.

Erythromycin is excreted in breast milk, therefore, caution should be exercised when erythromycin is administered to a nursing mother.

4.7 Effects On Ability To Drive And Use Machines

None reported

4.8 Undesirable Effects

Blood and lymphatic system disorders:

Eosinophilia.

Cardiac disorders

QTc interval prolongation, torsades de pointes, palpitations, and cardiac rhythm disorders including ventricular tachyarrhythmias.

Ear and labyrinth disorders

Deafness, tinnitus

There have been isolated reports of reversible hearing loss occurring chiefly in patients with renal insufficiency or high doses.

Gastrointestinal disorders

The most frequent side effects of oral erythromycin preparations are gastrointestinal and are dose-related. The following have been reported:

upper abdominal discomfort, nausea, vomiting, diarrhoea, pancreatitis, anorexia, infantile hypertrophic pyloric stenosis.

Pseudomembranous colitis has been rarely reported in association with erythromycin therapy (see section 4.4).

General disorders and administration site conditions

Chest pain, fever, malaise.

Hepatobiliary disorders

Cholestatic hepatitis, jaundice, hepatic disfunction, hepatomegaly, hepatic failure, hepatocellular hepatitis (see section 4.4).

Immune system disorders

Allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis have occurred.

Investigations

Increased liver enzyme values.

Nervous system disorders

There have been isolated reports of transient central nervous system side effects including confusion, seizures and vertigo; however, a cause and effect relationship has not been established.

Psychiatric disorders

Hallucinations

Renal and urinary disorders

Interstitial nephritis

Skin and subcutaneous tissue disorders

Skin eruptions, prurituls, urticaria, exanthema, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Vascular disorders

Hypotension.

4.9 Overdose

Symptoms: hearing loss, severe nausea, vomiting and diarrhoea.

Treatment: gastric lavage, general supportive measures.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: J01FA01

Erythromycin exerts its antimicrobial action by binding to the 50S ribosomal sub-unit of susceptible microorganisms and suppresses protein synthesis. Erythromycin is usually active against most strains of the following organisms both in vitro and in clinical infections:

Gram positive bacteria - Listeria monocytogenes, Corynebacterium diphtheriae (as an adjunct to antitoxin), Staphylococci spp, Streptococci spp (including Enterococci).

Gram negative bacteria - Haemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, Legionella pneumophila, Moraxella (Branhamella) catarrhalis, Bordetella pertussis, Campylobacter spp.

Mycoplasma - Mycoplasma pneumoniae, Ureaplasma urealyticum.

Other organisms - Treponema pallidum, Chlamydia spp, Clostridia spp, L-forms, the agents causing trachoma and lymphogranuloma venereum.

Note: The majority of strains of Haemophilus influenzae are susceptible to the concentrations reached after ordinary doses.

5.2 Pharmacokinetic Properties

Peak blood levels normally occur within one hour of dosing of erythromycin ethylsuccinate granules. The elimination half life is approximately two hours. Doses may be administered two, three or four times a day.

Erythromycin ethylsuccinate is less susceptible than erythromycin to the adverse effect of gastric acid. It is absorbed from the small intestine. It is widely distributed throughout body tissues. Little metabolism occurs and only about 5% is excreted in the urine. It is excreted principally by the liver.

5.3 Preclinical Safety Data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Povidone

Maize starch

Magnesium hydroxide

Polacrilin potassium

Polyethylene glycol 8000

Polyethylene glycol 400

Hydroxypropyl methyl cellulose

Sorbic acid.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

60 months.

6.4 Special Precautions For Storage

None stated.

6.5 Nature And Contents Of Container

High density polyethylene bottle with urea cap with 100 tablets, securitainer or snap-secure container with 50, 100 or 1000 tablets. Blister packs containing 28 tablets: PVC, heat sealed with 20 micron hard tamper aluminium foil.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Amdipharm plc

Regency House

Miles Gray Road

Basildon

Essex

SS14 3AF

8. Marketing Authorisation Number(S)

PL 20072/0036

9. Date Of First Authorisation/Renewal Of The Authorisation

16/06/97

10. Date Of Revision Of The Text

October 2010

11. LEGAL CATEGORY

POM

Eporatio 20,000 IU

1. Name Of The Medicinal Product

Eporatio 20,000 IU/1 ml solution for injection in pre

2. Qualitative And Quantitative Composition

One pre-filled syringe contains 20,000 international units (IU) (166.7 µg) epoetin theta in 1 ml solution for injection corresponding to 20,000 IU (166.7 µg) epoetin theta per ml.

Epoetin theta (recombinant human erythropoietin) is produced in Chinese Hamster Ovary Cells (CHO

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Solution for injection (injection) in pre

The solution is clear and colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

- Treatment of symptomatic anaemia associated with chronic renal failure in adult patients.

- Treatment of symptomatic anaemia in adult cancer patients with non-myeloid malignancies receiving chemotherapy.

4.2 Posology And Method Of Administration

Special requirements

Epoetin theta treatment should be initiated by physicians experienced in the above-mentioned indications.

Routes of administration

The solution can be administered subcutaneously (SC) or intravenously (IV). Subcutaneous use is preferable in patients who are not undergoing haemodialysis, in order to avoid puncturing peripheral veins. If epoetin theta is substituted for another epoetin, the same route of administration should be used. Epoetin theta should be administered by the subcutaneous route to cancer patients with non

Posology

Symptomatic anaemia associated with chronic renal failure

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician's evaluation of the individual patient's clinical course and condition is necessary. Epoetin theta should be administered either subcutaneously or intravenously in order to increase haemoglobin level to not greater than 12 g/dl (7.45 mmol/l).

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.45 mmol/l) should be avoided; guidance for appropriate dose adjustment if haemoglobin values exceeding 12 g/dl (7.45 mmol/l) are observed are described below.

A rise in haemoglobin of greater than 2 g/dl (1.24 mmol/l) over a four week period should be avoided. If the rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) in 4 weeks or the haemoglobin value exceeds 12 g/dl (7.45 mmol/l), the dose should be reduced by 25 to 50%. It is recommended that haemoglobin be monitored every two weeks until levels have stabilised and periodically thereafter. If the haemoglobin level continues to increase, therapy should be interrupted until the haemoglobin level begins to decrease, at which point therapy should be restarted at a dose approximately 25% below the previously administered dose.

In the presence of hypertension or existing cardiovascular, cerebrovascular or peripheral vascular diseases, the increase in haemoglobin and the target haemoglobin value should be determined individually taking into account the clinical picture.

Treatment with epoetin theta is divided into two stages.

Correction phase

Subcutaneous administration: The initial posology is 20 IU/kg body weight 3 times per week. The dose may be increased after 4 weeks to 40 IU/kg, 3 times per week, if the increase in haemoglobin is not adequate (< 1 g/dl [0.62 mmol/l] within 4 weeks). Further increases of 25% of the previous dose may be made at monthly intervals until the individual target haemoglobin level is obtained.

Intravenous administration: The initial posology is 40 IU/kg body weight 3 times per week. The dose may be increased after 4 weeks to 80 IU/kg, 3 times per week, and by further increases of 25% of the previous dose at monthly intervals, if needed.

For both routes of administration, the maximum dose should not exceed 700 IU/kg body weight per week.

Maintenance phase

The dose should be adjusted as necessary to maintain the individual target haemoglobin level between 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l), whereby a haemoglobin level of 12 g/dl (7.45 mmol/l) should not be exceeded. If a dose adjustment is required to maintain the desired haemoglobin level, it is recommended that the dose be adjusted by approximately 25%.

Subcutaneous administration: The weekly dose can be given as one injection per week or three times per week.

Intravenous administration: Patients who are stable on a three times weekly dosing regimen may be switched to twice-weekly administration.

If the frequency of administration is changed, haemoglobin level should be monitored closely and dose adjustments may be necessary.

The maximum dose should not exceed 700 IU/kg body weight per week.

If epoetin theta is substituted for another epoetin, haemoglobin level should be monitored closely and the same route of administration should be used.

Patients should be monitored closely to ensure that the lowest approved dose of epoetin theta is used to provide adequate control of the symptoms of anaemia.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

Epoetin theta should be administered by the subcutaneous route to patients with anaemia (e.g. haemoglobin concentration

Due to intra-patient variability, occasional individual haemoglobin values for a patient above and below the desired haemoglobin level may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the haemoglobin target range of 10 g/dl (6.21 mmol/l) to 12 g/dl (7.45 mmol/l). A sustained haemoglobin level of greater than 12 g/dl (7.45 mmol/l) should be avoided; guidance for appropriate dose adjustment if haemoglobin values exceeding 12 g/dl (7.45 mmol/l) are observed are described below.

The recommended initial dose is 20,000 IU, independent of bodyweight, given once-weekly. If, after 4 weeks of therapy, the haemoglobin value has increased by at least 1 g/dl (0.62 mmol/l), the current dose should be continued. If the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l) a doubling of the weekly dose to 40,000 IU should be considered. If, after an additional 4 weeks of therapy, the haemoglobin increase is still insufficient an increase of the weekly dose to 60,000 IU should be considered.

The maximum dose should not exceed 60,000 IU per week.

If, after 12 weeks of therapy, the haemoglobin value has not increased by at least 1 g/dl (0.62 mmol/l), response is unlikely and treatment should be discontinued.

If the rise in haemoglobin is greater than 2 g/dl (1.24 mmol/l) in 4 weeks or the haemoglobin level exceeds 12 g/dl (7.45 mmol/l), the dose should be reduced by 25 to 50%. Treatment with epoetin theta should be temporarily discontinued if haemoglobin levels exceed 13 g/dl (8.07 mmol/l). Therapy should be reinitiated at approximately 25% lower than the previous dose after haemoglobin levels fall to 12 g/dl (7.45 mmol/l) or below.

Therapy should be continued up to 4 weeks after the end of chemotherapy.

Patients should be monitored closely to ensure that the lowest approved dose of epoetin theta is used to provide adequate control of the symptoms of anaemia.

Special populations

Paediatric patients

There is no experience in children and adolescents.

Method of administration

The solution can be administered subcutaneously or intravenously. Subcutaneous use is preferable in patients who are not undergoing haemodialysis, in order to avoid puncturing peripheral veins. If epoetin theta is substituted for another epoetin, the same route of administration should be used. In cancer patients with non

Subcutaneous injections should be given into the abdomen, arm or thigh.

Eporatio is supplied in a single use pre-filled syringe. The solution should be visually inspected prior to use. Only clear, colourless solutions without particles should be used. The solution for injection should not be shaken. It should be allowed to reach a comfortable temperature (15 °C

Eporatio must not be mixed with other medicinal products (see section 6.2).

The injection sites should be rotated and the injection performed slowly to avoid discomfort at the site of injection.

4.3 Contraindications

- Hypersensitivity to the active substance, other epoetins and derivatives or to any of the excipients.

- Uncontrolled hypertension.

4.4 Special Warnings And Precautions For Use

General

Supplementary iron therapy is recommended for all patients with serum ferritin values below 100 µg/l or with transferrin saturation below 20%. To ensure effective erythropoiesis, iron status has to be evaluated for all patients prior to and during treatment.

Non-response to therapy with epoetin theta should prompt a search for causative factors. Deficiencies of iron, folic acid or vitamin B₁₂ reduce the effectiveness of epoetins and should therefore be corrected. Intercurrent infections, inflammatory or traumatic episodes, occult blood loss, haemolysis, aluminium intoxication, underlying haematological diseases or bone marrow fibrosis may also compromise the erythropoietic response. A reticulocyte count should be considered as part of the evaluation.

Pure red cell aplasia (PRCA)

If typical causes of non-response are excluded, and the patient has a sudden drop in haemoglobin associated with reticulocytopenia, an examination of anti-erythropoietin antibodies and the bone marrow for diagnosis of pure red cell aplasia should be considered. Discontinuation of treatment with epoetin theta should be taken into account.

PRCA caused by neutralising anti-erythropoietin antibodies has been reported in association with erythropoietin therapy. These antibodies have been shown to cross-react with all epoetins, and patients suspected or confirmed to have neutralising antibodies to erythropoietin should not be switched to epoetin theta (see section 4.8).

Hypertension

Patients on epoetin theta therapy can experience an increase in blood pressure or aggravation of existing hypertension particularly during the initial treatment phase.

Therefore, in patients treated with epoetin theta, special care should be taken to monitor closely and control blood pressure. Blood pressure should be controlled adequately before initiation and during therapy to avoid acute complications, such as hypertensive crisis with encephalopathy-like symptoms (e.g. headaches, confused state, speech disturbances, impaired gait) and related complications (seizures, stroke), which may also occur in individual patients with otherwise normal or low blood pressure. If these reactions occur, they require the immediate attention of a physician and intensive medical care. Particular attention should be paid to sudden sharp migraine-like headaches as a possible warning signal.

Increases in blood pressure may require treatment with antihypertensive medicinal products or a dose increase of existing antihypertensive medicinal products. In addition, a reduction of the administered dose of epoetin theta needs to be considered. If blood pressure values remain high, temporary interruption of epoetin theta therapy may be required. Once hypertension has been controlled with more intensified therapy, epoetin theta therapy should be re-started at a reduced dose.

Misuse

Misuse of epoetin theta by healthy persons may lead to an excessive increase in haemoglobin and haematocrit. This may be associated with life-threatening cardiovascular complications.

Special populations

Due to limited experience, the efficacy and safety of epoetin theta could not be assessed in patients with impaired liver function or homozygous sickle cell anaemia.

In clinical trials, patients over 75 years of age had a higher incidence of serious and severe adverse events irrespective of a causal relationship to treatment with epoetin theta. Furthermore, deaths were more frequent in this patient group compared to younger patients.

Laboratory monitoring

It is recommended that haemoglobin measurement, a complete blood count and platelet count be performed regularly.

Symptomatic anaemia associated with chronic renal failure

The use of epoetin theta in nephrosclerotic patients not yet undergoing dialysis should be defined individually, as a possible accelerated progression of renal failure cannot be ruled out with certainty.

During haemodialysis, patients treated with epoetin theta may require increased anticoagulation treatment to prevent clotting of the arterio-venous shunt.

In patients with chronic renal failure, the maintenance haemoglobin concentration should not exceed the upper limit of the target haemoglobin concentration recommended in section 4.2. In clinical trials, an increased risk of death and serious cardiovascular events was observed when epoetins were administered to target a haemoglobin level in excess of 12 g/dl (7.45 mmol/l). Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when the haemoglobin concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

Effect on tumour growth

Epoetins are growth factors that primarily stimulate red blood cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells. As with all growth factors, there is a concern that epoetins could stimulate the growth of any type of malignancy (see section 5.1).

In several controlled studies, epoetins have not been shown to improve overall survival or decrease the risk of tumour progression in patients with anaemia associated with cancer. In controlled clinical studies, use of epoetins has shown:

	- shortened time to tumour progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a haemoglobin level in excess of 14 g/dl (8.69 mmol/l),
	- shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a haemoglobin value of 12
	- increased risk of death when administered to target a haemoglobin value of 12 g/dl (7.45 mmol/l) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy.

Epoetins are not indicated for use in this patient population.

In view of the above, in some clinical situations blood transfusion should be the preferred treatment for the management of anaemia in patients with cancer. The decision to administer recombinant erythropoietins should be based on a benefit-risk assessment with the participation of the individual patient, which should take into account the specific clinical context. Factors that should be considered in this assessment should include the type of tumour and its stage, the degree of anaemia, life

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, i.e. essentially 'sodium-free'.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interaction studies have been performed.

4.6 Pregnancy And Lactation

For epoetin theta no clinical data on exposed pregnancies are available. Animal studies with other epoetins do not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

It is unknown whether epoetin theta is excreted in human breast milk, but data in neonates show no absorption or pharmacological activity of erythropoietin when given together with breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with epoetin theta should be made taking into account the benefit of breast-feeding to the child and the benefit of epoetin theta therapy for the woman.

4.7 Effects On Ability To Drive And Use Machines

Epoetin theta has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

The safety of epoetin theta has been evaluated based on results from clinical studies including 972 patients.

Approximately 9% of patients can be expected to experience an adverse reaction. The most frequent undesirable effects are hypertension, influenza-like illness and headache.

Adverse reactions listed below are classified according to System Organ Class. Frequency groupings are defined according to the following convention:

Very common:
Common:
Uncommon:
Rare:
Very rare:	< 1/10,000;
Not known:	cannot be estimated from the available data.

System organ class	Adverse reaction	Frequency
Symptomatic anaemia associated with chronic renal failure	Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy
Blood and lymphatic system disorders	Thromboembolic events	—	Not known
Shunt thrombosis	Common	—
Immune system disorders	Hypersensitivity reactions	Not known
Nervous system disorders	Headache	Common
Vascular disorders	Hypertension	Common
Hypertensive crisis	Common	—
Skin and subcutaneous tissue disorders	Skin reactions	Common
Musculoskeletal and connective tissue disorders	Arthralgia	—	Common
General disorders and administration site conditions	Influenza-like illness	Common

Shunt thrombosis may occur, especially in patients who have a tendency to hypotension or whose arterio-venous fistulae exhibit complications (e.g. stenoses, aneurisms) (see section 4.4).

One of the most frequent adverse reactions during treatment with epoetin theta is an increase in blood pressure or aggravation of existing hypertension particularly during the initial treatment phase. Hypertension occurs in chronic renal failure patients more often during the correction phase than during the maintenance phase. Hypertension can be treated with appropriate medicinal products (see section 4.4).

Hypertensive crisis with encephalopathy-like symptoms (e.g. headaches, confused state, speech disturbances, impaired gait) and related complications (seizures, stroke) may also occur in individual patients with otherwise normal or low blood pressure (see section 4.4).

Skin reactions such as rash, pruritus or injection site reactions may occur.

Symptoms of influenza-like illness such as fever, chills and asthenic conditions have been reported.

Certain adverse reactions have not yet been observed with epoetin theta, but are generally accepted as being attributable to epoetins:

In isolated cases in patients with chronic renal failure, neutralising anti-erythropoietin antibody-mediated PRCA associated with therapy with other epoetins has been reported. If PRCA is diagnosed, therapy with epoetin theta must be discontinued and patients should not be switched to another recombinant epoetin (see section 4.4).

4.9 Overdose

The therapeutic margin of epoetin theta is very wide. In the case of overdose, polycythaemia can occur. In the event of polycythaemia, epoetin theta should be temporarily withheld.

If severe polycythaemia occurs, conventional methods (phlebotomy) may be indicated to reduce the haemoglobin level.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other anti-anaemic preparations, ATC code: B03XA01

Mechanism of action

Human erythropoietin is an endogenous glycoprotein hormone that is the primary regulator of erythropoiesis through specific interaction with the erythropoietin receptor on the erythroid progenitor cells in the bone marrow. It acts as a mitosis-stimulating factor and differentiation hormone. The production of erythropoietin primarily occurs in and is regulated by the kidney in response to changes in tissue oxygenation. Production of endogenous erythropoietin is impaired in patients with chronic renal failure and the primary cause of their anaemia is erythropoietin deficiency. In patients with cancer receiving chemotherapy the aetiology of anaemia is multifactorial. In these patients, erythropoietin deficiency and a reduced response of erythroid progenitor cells to endogenous erythropoietin both contribute significantly towards their anaemia.

Epoetin theta is identical in its amino acid sequence and similar in its carbohydrate composition (glycosylation) to endogenous human erythropoietin.

Preclinical efficacy

The biological efficacy of epoetin theta has been demonstrated after intravenous and subcutaneous administration in various animal models in vivo (mice, rats, dogs). After administration of epoetin theta, the number of erythrocytes, the haematocrit values and reticulocyte counts increase.

Clinical efficacy and safety

Symptomatic anaemia associated chronic renal failure

Data from correction phase studies in 284 chronic renal failure patients show that the haemoglobin response rates (defined as haemoglobin levels above 11 g/dl at two consecutive measurements) in the epoetin theta group (88.4% and 89.4% in studies in patients on dialysis and not yet undergoing dialysis, respectively) were comparable to epoetin beta (86.2% and 81.0%, respectively). The median time to response was similar in the treatment groups with 56 days in haemodialysis patients and 49 days in patients not yet undergoing dialysis.

Two randomised controlled studies were conducted in 270 haemodialysis patients and 288 patients not yet undergoing dialysis, who were on stable treatment with epoetin beta. Patients were randomised to continue their current treatment or to be converted to epoetin theta (same dose as epoetin beta) in order to maintain their haemoglobin levels. During the evaluation period (weeks 15 to 26), the mean and median level of haemoglobin in patients treated with epoetin theta was virtually identical to their baseline haemoglobin level. In these two studies, 180 haemodialysis patients and 193 patients not undergoing dialysis were switched from maintenance phase treatment with epoetin beta to treatment with epoetin theta for a period of six months showing stable haemoglobin values and a similar safety profile as epoetin beta. In the clinical studies, patients not yet undergoing dialysis (subcutaneous administration) discontinued the study more frequently than haemodialysis patients (intravenous administration) as they had to terminate the study when starting dialysis.

In two long-term studies, the efficacy of epoetin theta was evaluated in 124 haemodialysis patients and 289 patients not yet undergoing dialysis. The haemoglobin levels remained within the desired target range and epoetin theta was well tolerated over a period of up to 15 months.

In the clinical studies, pre-dialysis patients were treated once-weekly with epoetin theta, 174 patients in the maintenance phase study and 111 patients in the long-term study.

Symptomatic anaemia in cancer patients with non-myeloid malignancies receiving chemotherapy

409 cancer patients receiving chemotherapy were included in two prospective, randomised double

Effect on tumour growth

Erythropoietin is a growth factor that primarily stimulates red cell production. Erythropoietin receptors may be expressed on the surface of a variety of tumour cells.

Survival and tumour progression have been examined in five large controlled studies involving a total of 2,833 patients, of which four were double-blind placebo-controlled studies and one was an open-label study. Two of the studies recruited patients who were being treated with chemotherapy. The target haemoglobin concentration in two studies was> 13 g/dl; in the remaining three studies it was 12

Data from three placebo-controlled clinical studies in 586 anaemic cancer patients conducted with epoetin theta, showed no negative effect of epoetin theta on survival. During the studies, mortality was lower in the epoetin theta group (6.9%) compared to placebo (10.3%).

A systematic review has also been performed involving more than 9,000 cancer patients participating in 57 clinical trials. Meta-analysis of overall survival data produced a hazard ratio point estimate of 1.08 in favour of controls (95% CI: 0.99, 1.18; 42 trials and 8,167 patients). An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06; 35 trials and 6,769 patients) was observed in patients treated with recombinant human erythropoietin. There is therefore consistent evidence to suggest that there may be significant harm to patients with cancer who are treated with recombinant human erythropoietin. The extent to which these outcomes might apply to the administration of recombinant human erythropoietin to patients with cancer, treated with chemotherapy to achieve haemoglobin concentrations less than 13 g/dl, is unclear because few patients with these characteristics were included in the data reviewed.

5.2 Pharmacokinetic Properties

General

The pharmacokinetics of epoetin theta have been examined in healthy volunteers, in patients with chronic renal failure and in cancer patients receiving chemotherapy. The pharmacokinetics of epoetin theta are independent of age or gender.

Subcutaneous administration

Following subcutaneous injection of 40 IU/kg body weight epoetin theta at three different sites (upper arm, abdomen, thigh) in healthy volunteers, similar plasma level profiles were observed. The extent of absorption (AUC) was slightly greater after injection in the abdomen in comparison to the other sites. The maximum concentration is reached after an average of 10 to 14 hours and the average terminal half-life ranges from approximately 22 to 41 hours.

Average bioavailability of epoetin theta after subcutaneous administration is approximately 31% compared with intravenous administration.

In pre-dialysis patients with chronic renal failure following subcutaneous injection of 40 IU/kg body weight, the protracted absorption results in a concentration plateau, whereby the maximum concentration is reached after an average of approximately 14 hours. The terminal half-life is higher than after intravenous administration, with an average of 25 hours after single dosing and 34 hours in steady state after repeated dosing three times weekly, without leading to an accumulation of epoetin theta.

In cancer patients receiving chemotherapy, after repeated subcutaneous administration of 20,000 IU epoetin theta once-weekly, the terminal half-life is 29 hours after the first dose and 28 hours in steady state. No accumulation of epoetin theta was observed.

Intravenous administration

In patients with chronic renal failure undergoing haemodialysis, the elimination half-life of epoetin theta is 6 hours after single dosing and 4 hours in steady state after repeated intravenous administration of 40 IU/kg body weight epoetin theta three times weekly. No accumulation of epoetin theta was observed. Following intravenous administration, the volume of distribution approximates to total blood volume.

5.3 Preclinical Safety Data

Non-clinical data with epoetin theta reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated-dose toxicity.

Non-clinical data with other epoetins reveal no special hazard for humans based on conventional studies of genotoxicity and toxicity to reproduction.

In reproductive toxicity studies performed with other epoetins, effects interpreted as being secondary to decreased maternal body weight were observed at doses sufficiently in excess to the recommended human dose.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium dihydrogen phosphate dihydrate

Sodium chloride

Polysorbate 20

Trometamol

Hydrochloric acid (6 M) (for pH adjustment)

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store in a refrigerator (2 °C – 8 °C).

Do not freeze.

Keep the pre-filled syringe in the outer carton in order to protect from light.

For the purpose of ambulatory use, the patient may remove the product from the refrigerator and store it at a temperature not above 25 °C for a single period of up to 7 days without exceeding the expiry date. Once removed from the refrigerator, the medicinal product must be used within this period or disposed of.

6.5 Nature And Contents Of Container

1 ml of solution in a pre-filled syringe (type I glass) with a tip cap (bromobutyl rubber), a plunger stopper (teflonised chlorobutyl rubber), an injection needle (stainless steel) and with or without a pre

Pack sizes of 1, 4 and 6 pre-filled syringes with or without safety device.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The pre

Any unused product or waste material should be disposed of in accordance with local requirements.

7. Marketing Authorisation Holder

ratiopharm GmbH

Graf-Arco-Straße 3

89079 Ulm

Germany

info@ratiopharm.de

8. Marketing Authorisation Number(S)

EMEA/H/C/0010350000/21

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 29 October 2009

10. Date Of Revision Of The Text

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.