Physiotens

Physiotens

Moxonidine

Tablets

200 micrograms

300 micrograms

400 micrograms

What you should know about Physiotens

Please read this leaflet before you take your Physiotens. It gives you important information about your tablets. Please keep this leaflet safe. You may want to read it again. If you have any questions or you are not sure about anything, ask your doctor or a pharmacist.

What is Physiotens for ?

Physiotens reduces high blood pressure. Medicines which reduce blood pressure are known as anti-hypertensives.

Before taking your tablets

Please tell your doctor or a pharmacist before you start to take your tablets if you:

• have a heart complaint (for example, heart failure or abnormal rhythm);


• have a serious liver or kidney complaint;


• have ever had an allergic reaction to any of the ingredients; or


• have had attacks of angioneurotic oedema (a serious allergic reaction which causes swellings of the face or throat).

There is limited experience on the use of Physiotens by patients who:

• are pregnant, or think they might be;


• are breast-feeding;


• have leg pains caused by poor blood circulation;


• have Raynaud’s disease (poor circulation which makes the toes and fingers numb and pale);


• have Parkinson’s disease (a disease of the nerves which causes tremor, stiffness and shuffling);


• have epilepsy (fits);


• have glaucoma (swelling behind the eyes);


• are depressed; or


• are under 16 years old.

Tell your doctor if you think any of the above apply to you.

Some medicines can affect the way other medicines work. Before you start taking Physiotens, tell your doctor or a pharmacist if you are taking other medicines to reduce your blood pressure, antidepressants (tricyclic antidepressants such as imipramine and amitriptyline) or sleeping tablets (known as benzodiazepines). As we do not know whether alcohol affects the way Physiotens works, you shouldn’t drink alcohol while you are taking Physiotens.

How to take your tablets

Your treatment will normally start with one 200 microgram tablet each morning. After about three weeks, your doctor may increase this dose to 400 micrograms each day. After another three weeks, your doctor may need to increase this dose to 600 micrograms each day. Do not take 600 micrograms as one dose - take 300 micrograms in the morning and 300 micrograms in the evening. Physiotens is not recommended for children under 16.

Your doctor may tell you to take a lower dose than normal if you have a kidney complaint.

Take your tablets with a drink of water, before, during or after a meal.

Keep taking your tablets unless your doctor decides you should stop. If this happens, your doctor will tell you how to reduce your dose gradually. If you are taking more than one medicine for high blood pressure, your doctor will tell you which medicine to stop first so that your body can adjust gradually to the change.

If you miss a dose, ignore it and take the next dose at the normal time. Don’t take two doses together to make up for the one you have missed.

If someone takes an overdose (too many Physiotens tablets), call a doctor or go to the nearest hospital casualty department immediately. Show the pack to the doctor.

Physiotens Side Effects

You may have some of the following side effects when you first start to take Physiotens:

• A dry mouth


• Headaches


• General weakness


• Dizziness


• Feeling sick


• Difficulty sleeping


• Skin flushing

The side effects listed above will ease as your treatment continues. Sometimes, people who take Physiotens tablets complain of drowsiness. If you feel drowsy, don´t drive or use machinery.

Occasionally, people taking Physiotens may develop allergic skin reactions (rash, itching, inflamed or reddened skin) and very rarely angioedema (a serious allergic reaction which causes swelling of the face or throat). Please tell your doctor if you think you have these or any other side effects.

How to store your tablets

• Do not store your tablets above 25°C.


• Do not take the tablets after the expiry date printed on the carton.


• Keep all medicines where children cannot see or reach them.


• Take any tablets you haven’t used to a pharmacist.

These tablets are for you. Please do not give them to anyone else, even if they have the same symptoms as you.

What’s in your tablets ?

Each tablet contains 200 micrograms, 300 micrograms or 400 micrograms of moxonidine.

The tablets also contain lactose, crospovidone, povidone, magnesium stearate, hypromellose, ethylcellulose, talc, polyethylene glycol 6000, red ferric oxide (E171) and titanium dioxide (E172).

The 200 microgram tablets are round, pale pink and are marked 0.2. The 300 microgram tablets are round, pale red and are marked 0.3. The 400 microgram tablets are round, dull red and are marked 0.4.

Physiotens tablets come in packs of 28.

The marketing authorisation holder is :

Solvay Healthcare Ltd.

Southampton

SO18 3JD

UK

The tablets are made by :

Solvay Pharmaceuticals

01400 Châtillon-sur-Chalaronne

France

This leaflet was approved in May 2007.

Registered trademark

1056693 CL575

Physiotens Tablets 200 micrograms

1. Name Of The Medicinal Product

Physiotens^® Tablets 200 micrograms

Cynt Tablets 200 micrograms

Moxonidine 200 micrograms Tablets

2. Qualitative And Quantitative Composition

Each tablet contains 200 micrograms moxonidine.

Excipients:

95.8 mg lactose per tablet

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film coated tablets.

Light pink, round, biconvex, film-coated tablets imprinted '0.2' on one face.

4. Clinical Particulars

4.1 Therapeutic Indications

Mild to moderate essential or primary hypertension.

4.2 Posology And Method Of Administration

Adults (including the elderly):

Treatment should be started with 200 micrograms of Physiotens/Cynt/Moxonidine in the morning. The dose may be titrated after three weeks to 400 micrograms, given as one dose or as divided doses (morning and evening) until a satisfactory response has been achieved. If the response is still unsatisfactory after a further three weeks' treatment, the dosage can be increased up to a maximum of 600 micrograms in divided doses (morning and evening).

A single dose of 400 micrograms of Physiotens/Cynt/Moxonidine and a daily dose of 600 micrograms in divided doses (morning and evening) should not be exceeded.

In patients with moderate renal dysfunction (GFR above 30 ml/min, but below 60 ml/min), the single dose should not exceed 200 micrograms and the daily dose should not exceed 400 micrograms of moxonidine.

The tablets should be taken with a little liquid. As the intake of food has no influence on the pharmacokinetic properties of moxonidine, the tablets may be taken before, during or after the meal.

Paediatric population

Physiotens/Cynt/Moxonidine is not recommended for use in children and adolescents below 18 years due to lack of data on safety and efficacy.

4.3 Contraindications

Physiotens/Cynt/Moxonidine should not be used in cases of:

- hypersensitivity to the active substance or to any of the excipients

- sick sinus syndrome or sino-atrial block

- 2nd or 3rd degree atrioventricular block

- bradycardia (below 50 beats/minute at rest)

- severe heart failure (see Section 4.4)

- severe renal dysfunction (GFR <30 ml/min, serum creatinine concentration>160 µmol/l).

Physiotens/Cynt/Moxonidine should not be used because of lack of therapeutic experience in cases of:

- pregnancy or lactation (see Section 4.6)

- children and adolescents below 18 years of age.

4.4 Special Warnings And Precautions For Use

When moxonidine is used in patients with 1st degree AV block, special care should be exercised to avoid bradycardia.

When moxonidine is used in patients with severe coronary artery disease or unstable angina pectoris, special care should be exercised due to the fact that there is limited experience in this patient population.

Caution is advised in the administration of moxonidine to patients with renal impairment as moxonidine is excreted primarily via the kidneys. In these patients careful titration of the dose is recommended, especially at the start of therapy. Dosing should be initiated with 200 micrograms daily and can be increased to a maximum of 400 micrograms daily if clinically indicated and well tolerated.

If Moxonidine is used in combination with a beta-blocker and both treatments have to be discontinued, the beta-blocker should be discontinued first and then Moxonidine after a few days.

So far, no rebound-effect has been observed on the blood pressure after discontinuing the treatment with moxonidine. However, an abrupt discontinuance of the moxonidine treatment is not advisable; instead the dose should be reduced gradually over a period of two weeks.

Due to a lack of clinical data supporting the safety in patients with co-existing moderate heart failure, Physiotens/Cynt/Moxonidine must be used with caution in such patients.

Treatment with Physiotens/Cynt/Moxonidine should not be discontinued abruptly, but should be withdrawn gradually over a period of two weeks.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concurrent administration of other antihypertensive agents enhances the hypotensive effect of Physiotens/Cynt/Moxonidine.

Since tricyclic antidepressants may reduce the effectiveness of centrally acting antihypertensive agents, it is not recommended that tricyclic antidepressants be co- administered with moxonidine.

Moxonidine can potentiate the effect of tricyclic anti-depressants (avoid co-prescribing), tranquillisers, alcohol, sedatives and hypnotics.

Moxonidine moderately augmented the impaired performance in cognitive functions in subjects receiving lorazepam. Moxonidine may enhance the sedative effect of benzodiazepines when administered concomitantly.

Moxonidine is excreted through tubular excretion. Interaction with other agents that are excreted through tubular excretion cannot be excluded.

4.6 Pregnancy And Lactation

Pregnancy:

There are no adequate data from use of moxonidine in pregnant woman. Studies in animals have shown embryo-toxicological effects (see section 5.3). The potential risk for humans is unknown. Moxonidine should not be used during pregnancy unless clearly necessary.

Lactation:

Moxonidine is secreted in breast milk and should therefore not be used during breast -feeding.

If therapy with moxonidine is considered absolutely necessary, breast-feeding should be stopped.

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.

Somnolence and dizziness have been reported. This should be borne in mind when performing these tasks.

4.8 Undesirable Effects

Most frequent side effects reported by those taking moxonidine include dry mouth, dizziness, asthenia and somnolence. These symptoms often decrease after the first few weeks of treatment.

Undesirable Effects by System Organ Class (observed during placebo-controlled clinical trials with n=886 patients exposed to moxonidine resulted in frequencies below):

MedDRA system organ class	Very Common	Common	Uncommon
Cardiac disorders			Bradycardia
Ear and labyrinth disorders			Tinnitus
Nervous system disorders		Headache*, Dizziness/Vertigo, Somnolence	Syncope*
Vascular disorders			Hypotension* (including orthostatic)
Gastrointestinal disorders	Dry mouth	Diarrhoea, Nausea/Vomiting/Dyspepsia
Skin and subcutaneous tissue disorders		Rash/ Pruritus	Angioedema
General disorders and administration site reactions		Asthenia	Oedema
Musculoskeletal and connective tissue disorders		Back pain	Neck pain
Psychiatric disorders		Insomnia	Nervousness

* there was no increase in frequency compared to placebo

4.9 Overdose

Symptoms of overdose

In the few cases of overdose that have been reported, a dose of 19.6 mg was ingested acutely without fatality. Signs and symptoms reported included: headache, sedation, somnolence, hypotension, dizziness, asthenia, bradycardia, dry mouth, vomiting, fatigue and upper abdominal pain. In case of a severe overdose close monitoring of especially consciousness disturbances and respiratory depression is recommended.

In addition, based on a few high dose studies in animals, transient hypertension, tachycardia, and hyperglycaemia may also occur.

Treatment of overdose

No specific antidote is known. In case of hypotension, circulatory support such as fluids and dopamine administration may be considered. Bradycardia may be treated with atropine. α-Receptor antagonists may diminish or abolish the paradoxal hypertensive effects of a moxonidine overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Imidazoline receptor agonists, moxonidine, ATC code: C02AC05.

In different animal models, Physiotens/Cynt/Moxonidine has been shown to be a potent antihypertensive agent. Available experimental data convincingly suggest that the site of the antihypertensive action of Physiotens/Cynt/Moxonidine is the central nervous system (CNS). Within the brainstem, Physiotens/Cynt/Moxonidine has been shown to selectively interact with I₁-imidazoline receptors. These imidazoline-sensitive receptors are concentrated in the rostral ventrolateral medulla, an area critical to the central control of the peripheral sympathetic nervous system. The net effect of this interaction with the I₁-imidazoline receptor appears to result in a reduced activity of sympathetic nerves (demonstrated for cardiac, splanchnic and renal sympathetic nerves).

Physiotens/Cynt/Moxonidine differs from other available centrally acting antihypertensives by exhibiting only low affinity to central α₂-adrenoceptors as compared to I₁-imidazoline receptors; α₂-adrenoceptors are considered the molecular target via which sedation and dry mouth, the most common undesired side effects of centrally acting antihypertensives, are mediated.

In humans, Physiotens/Cynt/Moxonidine leads to a reduction of systemic vascular resistance and consequently in arterial blood pressure.

5.2 Pharmacokinetic Properties

Oral moxonidine treatment of rats and dogs resulted in rapid and almost complete absorption and peak plasma levels within <0.5 hours. Average plasma concentrations were comparable in both species after p.o. and i.v. administration. The elimination half-lives of radioactivity and unchanged compound were estimated to be 1-3 hours. Moxonidine and its two main metabolites (4,5-dehydromoxonidine and a guanidine derivative) was predominantly excreted in the urine. No indication of moxonidine cumulation was observed in either species during chronic toxicity studies after 52 weeks.

In humans, about 90% of an oral dose of moxonidine is absorbed; it is not subject to first-pass metabolism and its bio-availability is 88%. Food intake does not interfere with moxonidine pharmacokinetics. Moxonidine is 10-20% metabolised, mainly to 4,5-dehydromoxonidine and to a guanidine derivative by opening of the imidazoline ring. The hypotensive effect of 4,5-dehydromoxonidine is only 1/10, and that of the guanidine derivative is less than 1/100 of that of moxonidine. The maximum plasma levels of moxonidine are reached 30-180 minutes after the intake of a film-coated tablet.

Only about 7% of moxonidine is bound to plasma protein (Vd_ss=1.8 ± 0.4 l/kg). Moxonidine and its metabolites are eliminated almost entirely via the kidneys. More than 90% of the dose is eliminated via the kidneys in the first 24 hours after administration, while only about 1% is eliminated via the faeces. The cumulative renal excretion of unchanged moxonidine is about 50-75%.

The mean plasma elimination half-life of moxonidine is 2.2-2.3 hours, and the renal elimination half-life is 2.6-2.8 hours.

Pharmacokinetics in the elderly

Small differences between the pharmacokinetic properties of moxonidine in the healthy elderly and younger adults are unlikely to be clinically significant. As there is no accumulation of moxonidine, dosage adjustment is unnecessary provided renal function is normal.

Pharmacokinetics in children

No pharmacokinetic studies have been performed in children.

Pharmacokinetics in renal impairment

In moderately impaired renal function (GFR 30-60 ml/min), AUC increased by 85% and clearance decreased to 52%. In such patients the hypotensive effect of Physiotens/Cynt/Moxonidine should be closely monitored, especially at the start of treatment; additionally, single doses should not exceed 200 micrograms and the daily dose should not exceed 400 micrograms.

5.3 Preclinical Safety Data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Chronic oral treatment for 52 weeks of rats (with dosages of 0.12-4 mg/kg) and dogs (with dosages of 0.04-0.4 mg/kg) revealed significant effects of moxonidine only at the highest doses. Slight disturbances of electrolyte balance (decrease of blood sodium and increase of potassium, urea and creatinine) were found in the high dose rats and emesis and salivation only for the high dose dogs. In addition slight increases of liver weight were obvious for both high dose species.

Reproductive toxicity studies showed no effect on fertility and no teratogenic potential. Embryo-fetal toxicity was seen at doses associated with maternal toxicity.

Increased embryo-fetal loss and delayed fetal development were seen in rats with doses above 2 mg/kg/day and in rabbits with doses above 0.7 mg /kg/day. In a peri- and post natal study in rats reduced pup weight, viability and delayed development was noted with doses above 1 mg/kg/day.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose, povidone, crospovidone, magnesium stearate, hypromellose, ethylcellulose, polyethylene glycol 6000, talc, red ferric oxide, titanium dioxide.

6.2 Incompatibilities

No incompatibilities are known.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

The tablets are packed in blister strips of 14. The blister strips are made of PVC/PVdC or PVC film with covering Aluminium foil. Each carton contains 14, 28 or 84 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Solvay Healthcare Limited

Mansbridge Road

West End

Southampton

SO18 3JD

8. Marketing Authorisation Number(S)

PL 00512/0152

9. Date Of First Authorisation/Renewal Of The Authorisation

15 September 1997/ 5 April 2002

10. Date Of Revision Of The Text

July 2010

Pavacol-D

Pavacol-D

pholcodine

Read all of this leaflet carefully before you start taking this medicine.

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


• Ask your pharmacist if you need more information or advice.


• You must contact a doctor if your symptoms worsen or do not improve after 5 days.


• If you notice any side effects (see section 4) or any side effects not mentioned in this leaflet, talk to your doctor or pharmacist.

In this leaflet:

• 
  1. What Pavacol-D is and what it is used for
  


• 
  2. Before you take Pavacol-D
  


• 
  3. How you take Pavacol-D
  


• 
  4. Possible side effects
  


• 
  5. How to store Pavacol-D
  


• 
  6. Further information
  

What Pavacol-D is and what it is used for

Pavacol-D is a dark brown liquid that contains the active ingredient pholcodine. Pholcodine is one of a group of medicines called anti-tussives (help to prevent coughing).

Pavacol-D is a cough suppressant for relief of acute non-productive cough associated with upper respiratory tract infection.

For children aged 6 to 12 years: simple treatments should be tried first before you give this medicine. Further information on treating coughs and colds in children can be found at the end of this leaflet.

Before you take Pavacol-D

Do not give to children under 6 years of age.

You should not take Pavacol-D if you:

• are allergic to pholcodine or any other ingredients of Pavacol-D (these are listed in Section 6).


• have liver disease


• have a very serious breathing problem (ventilatory failure)


• have chronic bronchitis (inflammation of the airways)


• have bronchiectasis (abnormal widening of one or more airways)


• have or may have any problems with your airways such as chronic obstructive pulmonary disease (COPD), or other breathing problems


• are taking or have taken MAOIs in the last 2 weeks (MAOIs [monoamine oxidase inhibitors] are a type of antidepressant such as phenelzine, isocarboxazid, tranylcypromine or moclebemide).

Take special care with Pavacol-D and tell your doctor if you have any of the following conditions:

• kidney disease


• a history of drug abuse


• if you suffer from a chronic or persistent cough

Tell your doctor if you still have a cough after 5 days.

Ask a doctor before use if you suffer from a chronic or persistent cough, if you have asthma, are suffering from an acute asthma attack or where the cough is accompanied by excessive secretions.

Taking other medicines/alcohol

Do not take Pavacol-D if you are taking any other cough or cold medicines.

Tell you doctor or pharmacist about any other medicines, including medicines you are taking at the same time, particularly the following:

Antidepressants, antihistamines, sleeping tablets or sedatives strong painkillers, medicines to treat epilepsy, as Pavacol-D may make you feel more sleepy.

Avoid consumption of alcohol as this may also increase drowsiness if taken with Pavacol-D.

Also tell your doctor or pharmacist if you are taking any of the following medicines:

Diuretics (water tablets), antihypertensives (blood pressure tablets) as Pavacol-D can lower your blood pressure.

Tell your doctor or pharmacist if you are due to have or have recently had a general anaesthetic.

Pregnancy and breast-feeding

You should not take Pavacol-D during the first three months of pregnancy unless you doctor tells you to. Always speak to your doctor or pharmacist for advice before taking any medication.

Driving and using machines

Pavacol-D may cause sleepiness. Make sure you are not affected before you drive or operate machinery.

Important information about some of the ingredients of Pavacol-D

• If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking Pavacol-D.


• May have a mild laxative effect. Calorific value 2.6 kcal/g sorbitol.


• Pavacol-D also contains small amounts of ethanol (alcohol), less than 100 mg per 5 ml.


• The propyl and methyl hydroxybenzoates in Pavacol-D may cause allergic reactions (possibly delayed).

How you take Pavacol-D

Dosage

Adults and the elderly

One or two 5 ml spoonfuls as required. The dose may be increased to three 5 ml spoonfuls if necessary. No more than 60 ml (12 x 5 ml spoonfuls) should be taken in 24 hours.

Children

From 6 to 12 years: one 5 ml spoonful four to five times daily. No more than 25 ml (5 x 5 ml spoonfuls) should be taken in 24 hours.

Do not use for more than 5 days without the advice of a doctor.

Seek medical attention if the child's condition gets worse during treatment.

Do not give to children under 6 years of age.

Do not exceed the stated dose.

If you take more Pavacol-D than you should

Contact your doctor or go to your nearest hospital immediately. Symptoms of overdose include feeling sick, sleepiness, restlessness, excitement, co-ordination problems, and shallow breathing.

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

Pavacol-D Side Effects

Like all medicines, Pavacol-D can cause side-effects, although these do not affect everyone. If you experience any of the following stop taking Pavacol-D immediately and talk to your doctor or pharmacist.

• 
  sudden wheeziness
  


• 
  difficulty in breathing
  


• 
  severe allergic reactions including swelling of the eyelids, face or lips, rash or itching, especially affecting your whole body
  

The following side effects have also been reported occasionally:

• feeling sick (nausea)


• congestion (sputum retention)


• constipation


• mild laxative effect


• drowsiness


• dizziness


• excitation


• confusion


• vomiting

If any of the side effects becomes severe, or if you notice any side effects not listed in this leaflet, please tell you doctor or pharmacist.

How to store Pavacol-D

Pavacol-D should be kept out of the reach and sight of children.

Do not store above 25ºC and protect from light.

Do not use Pavacol-D after the expiry date as indicated on the box after "EXP". The expiry date refers to the last day of the month.

Medicines should not be disposed of via waste-water or with household waste. Ask your pharmacist what you should do with medications you no longer need. These measures will help protect the environment.

Further information

What Pavacol-D contains

The active substance is pholcodine 5 mg in 5 ml. The other ingredients are:

Tolu balsam, ethanol 96%, anise oil, clove oil, peppermint oil, capsicum tincture, strong ginger tincture, sorbitol solution, saccharin, sodium hydroxyethylcellulose, treacle flavour, caramel, menthol, methyl hydroxybenzoate, propyl hydroxybenzoate, and purified water.

What Pavacol-D looks like and contents of the pack

Pavacol-D is available as 50 ml, 100 ml, 150 ml, 250 ml, 300 ml, and 1000 ml round amber glass bottles with an aluminium cap.

Not all pack sizes may be marketed.

Treating cough and cold in children

It's normal for children to get 8 or more colds in a year. Gradually they build up immunity and get fewer colds. Most colds will get better within a few days and you may not need to do more than keep your child comfortable until they get over it. Because colds are caused by viruses, not bacteria, antibiotics don't help. Here are some simple steps to help your child who has a cough or cold:

• 
  1. If they are hot/feverish:
  

Increase the amount of fluid your child normally drinks. Lower their temperature with a paracetamol or ibuprofen medicine which has doses for children. (Paracetamol is not for children under 2 months. Ibuprofen is not for children under 3 months).

• 
  2. For coughs:
  

Although it is distressing to hear your child cough, in fact coughing serves a purpose. It helps clear phlegm on the chest or mucus from the nose. Give the child plenty or warm clear fluids to drink.

• 
  3. To help with breathing:
  

Plain saline nose drops, available from your pharmacy, can help babies with blocked noses who are having trouble feeding.

Marketing Authorisation Holder and Manufacturer

The product licence holder is:

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

United Kingdom

Pavacol-D is manufactured by:

William Ransom & Son plc

Stepfield

Witham

Essex

CM8 3AG

United Kingdom

This leaflet was last revised in May 2009

Pavacol-D is a registered trademark of Alliance Pharmaceuticals Limited. Alliance and associated devices are registered trademarks of Alliance Pharmaceuticals Limited.

© Alliance Pharmaceuticals Ltd 2009.

Pentasa Suppositories 1g

1. Name Of The Medicinal Product

PENTASA^® Suppositories 1g

2. Qualitative And Quantitative Composition

Each suppository contains mesalazine 1g

3. Pharmaceutical Form

Suppositories

Oblong, compressed white to light tan, speckled suppositories

4. Clinical Particulars

4.1 Therapeutic Indications

PENTASA Suppositories are indicated for the treatment of ulcerative proctitis.

4.2 Posology And Method Of Administration

Ulcerative Proctitis:

Usual adult dose: Acute treatment: 1 suppository daily for 2 to 4 weeks.

Maintenance treatment: 1 suppository daily.

Children: Not recommended.

Elderly Patients: The usual adult dose applies.

4.3 Contraindications

PENTASA is contraindicated in:

- patients with known sensitivity to salicylates

- children under the age of 15 years

- patients with severe liver and/or renal impairment

- patients allergic to any of the ingredients

4.4 Special Warnings And Precautions For Use

Serious blood dyscrasias have been reported rarely with mesalazine. Haematological investigations should be performed if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Treatment should be stopped if there is suspicion or evidence of blood dyscrasia.

Most patients who are intolerant or hypersensitive to sulphasalazine are able to use PENTASA without risk of similar reactions. However, caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates). Caution is recommended in patients with impaired liver function.

It is recommended that mesalazine is used with extreme caution in patients with mild to moderate renal impairment (see section 4.3).

If a patient develops dehydration while on treatment with mesalazine, normal electrolyte levels and fluid balance should be restored as soon as possible.

Mesalazine induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely. Treatment should be discontinued on suspicion or evidence of these reactions.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The concurrent use of mesalazine with other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions (see section 4.4).

Concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine or 6-mercaptopurine.

4.6 Pregnancy And Lactation

PENTASA should be used with caution during pregnancy and lactation and only if the potential benefit outweighs the possible hazards in the opinion of the physician.

Mesalazine is known to cross the placental barrier, but the limited data available on its use in pregnant women do not allow assessment of possible adverse effects. No teratogenic effects have been observed in animal studies.

Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA.

Mesalazine is excreted in breast milk. The mesalazine concentration in breast milk is lower than in maternal blood, whereas the metabolite, acetyl mesalazine appears in similar or increased concentrations. There is limited experience of the use of oral mesalazine in lactating women. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions like diarrhoea in the infant cannot be excluded.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects.

4.8 Undesirable Effects

Mesalazine may be associated with an exacerbation of the symptoms of colitis in those patients who have previously had such problems with sulphasalazine.

Undesirable effects are as follows:

Common	Gastrointestinal disorders:
(	Nausea, vomiting, diarrhoea, abdominal pain
	Skin disorders:
	Rash (including urticaria and erythematous rash)
	General:
	Headache
Rare	Blood disorders:
(	Leucopenia (including granulocytopenia), neutropenia, agranulocytosis, aplastic anaemia, thrombocytopenia
	Nervous system disorders:
	Peripheral neuropathy
	Cardiac disorders:
	Myocarditis, pericarditis
	Respiratory disorders:
	Allergic lung reactions (including dyspnoea, coughing, allergic alveolitis, pulmonary eosinophilia, pulmonary infiltration, pneumonitis)
	Gastrointestinal disorders:
	Pancreatitis, increased amylase
	Liver:
	Abnormalities of hepatic function and hepatotoxicity (including hepatitis, cirrhosis, hepatic failure)
	Urogenital:
	Abnormal renal function (including interstitial nephritis, nephrotic syndrome), urine discolouration (*see additional text)
	Collagen disorders:
	Lupus erythematosus-like reactions
Very rare	Blood disorders:
(<0.01% )	Anaemia, eosinophilia (as part of an allergic reaction) and pancytopenia
	Liver:
	Increased liver enzymes and bilirubin
	Skin disorders:
	Reversible alopecia, bullous skin reactions including erythema multiforme and Stevens-Johnson syndrome
	Musculo-skeletal disorders:
	Myalgia, arthralgia
	Allergic reactions:
	Hypersensitivity reactions, drug fever

*Renal failure has been reported. Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.

The mechanism of mesalazine induced myocarditis, pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of allergic origin.

Following rectal administration local reactions such as pruritus, rectal discomfort and urge may occur.

4.9 Overdose

Acute experience in animals:

Single oral doses of mesalazine of up to 5g/kg in pigs or a single intravenous dose of mesalazine at 920mg/kg in rats were not lethal.

Human experience:

No cases of overdose have been reported.

Management of overdose in man:

Symptomatic treatment at hospital. Close monitoring of renal function. Intravenous infusion of electrolytes may be used to promote diuresis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agents.

Mechanism of action and pharmacodynamic effects:

Mesalazine is recognised as the active moiety of sulphasalazine in the treatment of ulcerative colitis. It is thought to act locally on the gut wall in inflammatory bowel disease, although its precise mechanism of action has not been fully elucidated.

Increased leucocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4 and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. It is currently unknown which, if any of these mechanisms play a predominant role in the clinical efficacy of mesalazine.

5.2 Pharmacokinetic Properties

General characteristics of the active substance:

Disposition and local availability:

PENTASA suppositories are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. They are used to treat the rectum.

Biotransformation:

Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl mesalazine (acetyl mesalazine). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.

Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.

Absorption:

The absorption following rectal administration is low, but depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2g (1g x 2), approximately 10% of the dose is absorbed after administration of suppositories.

Distribution:

Mesalazine and acetyl mesalazine do not cross the blood brain barrier. Protein binding of mesalazine is approximately 50% and of acetyl mesalazine about 80%.

Elimination:

The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.

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 Ph. Eur.

Macrogol 6000 Ph. Eur.

Magnesium stearate Ph. Eur.

Talc Ph. Eur.

6.2 Incompatibilities

None known

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 25ºC. Store in the original package.

6.5 Nature And Contents Of Container

Double aluminium foil blister strips of 7 suppositories each.

Pack size: 28

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Ferring Pharmaceuticals Ltd.

The Courtyard

Waterside Drive

Langley

Berkshire SL3 6EZ

8. Marketing Authorisation Number(S)

PL 3194/0045

9. Date Of First Authorisation/Renewal Of The Authorisation

5^th December 2002

10. Date Of Revision Of The Text

February 2005

11. LEGAL CATEGORY

POM

Phenylephrine Injection BP 10 mg / ml

1. Name Of The Medicinal Product

Phenylephrine Injection BP 10 mg/ml

2. Qualitative And Quantitative Composition

Phenylephrine hydrochloride Ph Eur 1.0% w/v

3. Pharmaceutical Form

Sterile solution

4. Clinical Particulars

4.1 Therapeutic Indications

For the treatment of hypotensive states, e.g. circulatory failure, during spinal anaesthesia or drug-induced hypotension.

4.2 Posology And Method Of Administration

For subcutaneous, intramuscular, slow intravenous injection or intravenous infusion.

Adults

Phenylephrine injection may be administered subcutaneously or intramuscularly in a dosage of 2 to 5 mg with further doses of 1 to 10 mg if necessary according to response, or in a dose of 100 to 500 micrograms by slow intravenous injection as a 0.1% solution, repeated as necessary after at least 15 minutes.

Alternatively, 10 mg in 500 ml of glucose 5% injection or sodium chloride 0.9% injection may be infused intravenously, initially at a rate of up to 180 micrograms per minute, reduced according to response to 30-60 micrograms per minute.

Children

100 mcg/kg bodyweight subcutaneously or intramuscularly.

Elderly

There is no need for dosage reduction in the elderly.

4.3 Contraindications

Patients taking monoamine oxidase inhibitors, or within 14 days of ceasing such treatment. Severe hypertension and hyperthyroidism.

4.4 Special Warnings And Precautions For Use

Great care should be exercised in administering Phenylephrine Injection to patients with pre-existing cardiovascular disease such as ischaemic heart disease, arrhythmias, occlusive vascular disease including arteriosclerosis, hypertension or aneurysms. Anginal pain may be precipitated in patients with angina pectoris.

Care is also required when given to patients with diabetes mellitus or closed-angle glaucoma.

Keep all medicines out of the reach of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Phenylephrine may interact with cyclopropane and halothane and other halogenated inhalational anaesthetics, to induce ventricular fibrillation. An increased risk of arrhythmias may also occur if phenylephrine injection is given to patients receiving cardiac glycosides, quinidine or tricyclic antidepressants.

Phenylephrine may increase blood pressure and consequently reverse the action of many antihypertensive agents. Interactions of phenylephrine with alpha and beta receptor blocking drugs may be complex.

¹ Drugs which have an effect on α₁ adrenoreceptors could potentiate (such as ganisetron) or inhibit (such as doxazosin or buspirone) the vasopressive action of phenylephrine.

¹PL 06464/0902-0013; 17/04/09

4.6 Pregnancy And Lactation

The safety of phenylephrine during pregnancy and lactation has not been established. Administration of phenylephrine in late pregnancy or labour may cause foetal hypoxia and bradycardia. Excretion of phenylephrine in breast milk appears to be minimal.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Extravasation of Phenylephrine Injection may cause tissue necrosis. Phenylephrine will cause a rise in blood pressure with headache and vomiting and this may produce cerebral haemorrhage and pulmonary oedema. There may also be a reflex bradycardia or tachycardia, other cardiac arrhythmias, anginal pain, palpitations and cardiac arrest, hypotension with dizziness, and fainting and flushing may occur. Phenylephrine may induce difficulty in micturition and urinary retention, ²mydriasis, dyspnoea, altered metabolism including disturbances of glucose metabolism, sweating, hypersalivation, transient tingling and coolness of the skin and temporary fullness of the head. Phenylephrine is without significant stimulating effects on the central nervous system at usual doses.

²PL 06464/0902-0014; 11/05/2009

4.9 Overdose

Symptoms of overdosage include headache, vomiting, hypertension and reflex bradycardia and other cardiac arrhythmias.

Treatment should consist of symptomatic and supportive measures. The hypertensive effects may be treated with an alpha-adrenoceptor blocking drug, such as phentolamine, 5 to 60 mg i.v. over 10-30 minutes, repeated as necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Phenylephrine hydrochloride is a sympathomimetic agent with mainly direct effects on adrenergic receptors. It has predominantly alpha-adrenergic activity and is without significant stimulating effects on the central nervous system at usual doses. After injection it produces peripheral vasoconstriction and increased arterial pressure. It also causes reflex bradycardia.

5.2 Pharmacokinetic Properties

When injected subcutaneously or intramuscularly, phenylephrine takes 10 to 15 minutes to act. Subcutaneous and intramuscular injections are effective for up to about one and up to two hours respectively. Intravenous injections are effective for up to about 20 minutes. Phenylephrine is metabolised in the liver by monoamine oxidase. The metabolites, their route and rate of excretion have not been identified.

5.3 Preclinical Safety Data

³Phenylephrine has been used to induce cardiac myocyte hypertrophy in cultures of rat neonatal mycocytes at doses of 100 µM and 10 µM. To the best of our knowledge there have been no human studies associating therapeutic phenylephrine use with the development of cardiac myocyte hypertrophy.

³PL 06464/0902-0015; 17/12/2008

6. Pharmaceutical Particulars

6.1 List Of Excipients

N/1 Sodium Hydroxide for SP

N/1 Hydrochloric Acid for SP

Water for Injections Ph Eur

Sterile N/1 Sodium Hydroxide for SP

Sterile N/1 Hydrochloric Acid for SP

6.2 Incompatibilities

Phenylephrine Injection has been stated to be incompatible with alkalis, ferric salts, phenytoin sodium and oxidising agents.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Store at 2-25°C. Protect from light.

6.5 Nature And Contents Of Container

1 ml neutral glass ampoule with ceramic breakring.

Pack size: 6, 10 ampoules

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

Administrative Data

7. Marketing Authorisation Holder

Waymade Plc

Sovereign Medical

Sovereign House

Miles Gray Road

Basildon

Essex SS14 3FR

United Kingdom

8. Marketing Authorisation Number(S)

PL 06464/0902

9. Date Of First Authorisation/Renewal Of The Authorisation

17 November 1999

10. Date Of Revision Of The Text

May 2009

Pergoveris 150 IU / 75 IU powder and solvent for solution for injection

1. Name Of The Medicinal Product

Pergoveris 150 IU/75 IU powder and solvent for solution for injection.

2. Qualitative And Quantitative Composition

One vial contains 150 IU (equivalent to 11 micrograms) of follitropin alfa (r-hFSH) and 75 IU (equivalent to 3.0 micrograms) of lutropin alfa (r-hLH).

The reconstituted solution contains 150 IU r-hFSH and 75 IU r-hLH per milliliter. Follitropin alfa and lutropin alfa are produced in genetically engineered Chinese Hamster Ovary (CHO) cells.

Excipients: sucrose, disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for solution for injection.

Powder: white lyophilised pellet.

Solvent: clear colourless solution.

The pH of the reconstituted solution is 6.5 - 7.5.

4. Clinical Particulars

4.1 Therapeutic Indications

Pergoveris is indicated for the stimulation of follicular development in women with severe LH and FSH deficiency.

In clinical trials, these patients were defined by an endogenous serum LH level < 1.2 IU/l.

4.2 Posology And Method Of Administration

Treatment with Pergoveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems.

Pergoveris is intended for subcutaneous administration. The powder should be reconstituted immediately prior to use with the solvent provided.

In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of Pergoveris therapy is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotrophin (hCG). Pergoveris should be given as a course of daily injections. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time.

Treatment should be tailored to the individual patient's response as assessed by measuring follicle size by ultrasound and oestrogen response. A recommended regimen commences with one vial of Pergoveris daily. If less than one vial of Pergoveris daily is used, the follicular response may be unsatisfactory because the amount of lutropin alfa may be insufficient (see section 5.1).

If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7

When an optimal response is obtained, a single injection of 5,000 IU to 10,000 IU hCG should be administered 24-48 hours after the last Pergoveris injection. The patient is recommended to have coitus on the day of, and on the day following, hCG administration. Alternatively, intrauterine insemination (IUI) may be performed.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle.

In clinical trials, patients with severe FSH and LH deficiency were defined by an endogenous serum LH level <1.2 IU/l as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories. In these trials the ovulation rate per cycle was 70-75%.

4.3 Contraindications

Pergoveris is contraindicated in patients with:

• hypersensitivity to the active substances follitropin alfa and lutropin alfa or to any of the excipients

• case of tumours of the hypothalamus and pituitary gland

• ovarian enlargement or cyst not due to polycystic ovarian disease

• gynaecological haemorrhages of unknown aetiology

• ovarian, uterine or mammary carcinoma

Pergoveris must not be used when an effective response cannot be obtained, such as:

• primary ovarian failure

• malformations of sexual organs incompatible with pregnancy

• fibroid tumours of the uterus incompatible with pregnancy

4.4 Special Warnings And Precautions For Use

Pergoveris contains potent gonadotrophic substances capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management.

Gonadotrophin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of Pergoveris calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH/LH administration, with a poor response to FSH/LH in some patients. The lowest effective dose in relation to the treatment objective should be used in women.

Self-administration of Pergoveris should only be performed by patients who are well motivated, adequately trained and with access to expert advice.

The first injection of Pergoveris should be performed under direct medical supervision.

Patients with porphyria or a family history of porphyria should be closely monitored during treatment with Pergoveris. Deterioration or a first appearance of this condition may require cessation of treatment.

Pergoveris contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Pergoveris contains 30 mg of sucrose per dose. This should be taken into account in patients with diabetes mellitus.

Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for the following:

• hypothyroidism

• adrenocortical deficiency

• hyperprolactinemia and pituitary or hypothalamic tumours

Appropriate specific treatment should be given.

Patients undergoing stimulation of follicular growth are at an increased risk of developing hyperstimulation in view of possible excessive oestrogen response and multiple follicular development.

In clinical trials, lutropin alfa in combination with follitropin alfa has been shown to increase the ovarian sensitivity to gonadotropins. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments using a licensed follitropin alfa preparation.

Ovarian Hyperstimulation Syndrome (OHSS) is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.

The following symptomatology may be observed in severe cases of OHSS:

• abdominal pain

• abdominal distension

• severe ovarian enlargement

• weight gain

• dyspnoea

• oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea.

Clinical evaluation may reveal:

• hypovolaemia

• haemoconcentration

• electrolyte imbalances

• ascites

• haemoperitoneum

• pleural effusions

• hydrothorax

• acute pulmonary distress, and thromboembolic events.

Very rarely, severe OHSS may be complicated by pulmonary embolism, ischemic stroke and myocardial infarction.

Excessive ovarian response seldom gives rise to significant hyperstimulation unless hCG is administered to induce ovulation. Therefore in cases of ovarian hyperstimulation it is prudent to withhold hCG in such cases and advise the patient to refrain from coitus or use barrier methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after hCG administration.

To minimise the risk of OHSS or of multiple pregnancy (see below), ultrasound scans as well as oestradiol measurements are recommended. In anovulation the risk of OHSS is increased by a serum oestradiol level> 900 pg/ml (3,300 pmol/l) and by the presence of more than 3 follicles of 14 mm or more in diameter.

Adherence to recommended Pergoveris and FSH dosage and regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see below).

OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses.

If severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing. The patient should be hospitalised and specific therapy for OHSS started.

This syndrome occurs with higher incidence in patients with polycystic ovarian disease.

In patients undergoing induction of ovulation, the incidence of multiple pregnancies and births is increased compared with natural conception. The majority of multiple conceptions are twins. To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended.

The patients should be advised of the potential risk of multiple births before starting treatment.

The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than in the normal population.

When risk of OHSS or multiple pregnancies is assumed, treatment discontinuation should be considered.

Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after IVF was reported to be 2 to 5%, as compared to 1 to 1.5% in the general population.

There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established whether or not treatment with gonadotrophins increases the baseline risk of these tumours in infertile women.

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies.

In women with generally recognised risk factors for thrombo-embolic events, such as personal or family history, treatment with gonadotrophins may further increase the risk. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thrombo-embolic events.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Pergoveris should not be administered as a mixture with other medicinal products, in the same injection, except follitropin alfa.

4.6 Pregnancy And Lactation

Pergoveris should not be used during pregnancy or lactation.

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

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Nervous system disorders	Very Common ( Common (	Headache Somnolence
Respiratory, thoracic and mediastinal disorders	Very rare (<1/10,000)	Exacerbation or worsening of asthma
Gastrointestinal disorders	Common (	Abdominal pain and gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal cramps and bloating
Vascular disorders	Very rare (<1/10,000)	Thromboembolism, usually associated with severe ovarian hyperstimulation syndrome (OHSS)
General disorders and administration site conditions	Very Common (	Mild to severe injection site reaction (pain, redness, bruising, swelling and/or irritation at the site of injection)
Immune system disorders	Very rare (<1/10,000)	Mild systemic allergic reactions (e.g. mild forms of erythema, rash, facial swelling, urticaria, oedema, difficulty breathing). Serious cases of allergic reactions, including anaphylactic reactions, have also been reported.
Reproductive system and breast disorders	Very Common (	Ovarian cysts
	Common (	Breast pain, pelvic pain, mild to moderate OHSS
	Uncommon (	Severe OHSS
	Rare (	Ovarian torsion, a complication of OHSS

4.9 Overdose

The effects of an overdose of Pergoveris are unknown.Nevertheless one could expect ovarian hyperstimulation syndrome to occur, which is further described in section 4.4.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Gonadotrophins, ATC code: G03GA05 / G03GA07.

Pergoveris is a preparation of follicle stimulating hormone and luteinising hormone produced by genetically engineered Chinese Hamster Ovary (CHO) cells.

In clinical trials the efficacy of the combination of follitropin alfa and lutropin alfa has been demonstrated in women with hypogonadotropic hypogonadism.

In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of lutropin alfa is an increase in oestradiol secretion by the follicles, the growth of which is stimulated by FSH.

In one clinical study of women with hypogonadotrophic hypogonadism and an endogenous serum LH concentration below 1.2 IU/L the appropriate dose of r-hLH (lutropin alfa) was investigated. A dose of 75 IU r-hLH daily (in combination with 150 IU follitropin alfa (r-hFSH)) resulted in adequate follicular development and oestrogen production. A dose of 25 IU r-hLH daily (in combination with 150 IU follitropin alfa) resulted in insufficient follicular development. Therefore, administration of less than one vial of Pergoveris daily may provide too little LH-activity to ensure adequate follicular development.

5.2 Pharmacokinetic Properties

Follitropin alfa and lutropin alfa have shown the same pharmacokinetic profile as follitropin alfa and lutropin alfa separately.

Follitropin alfa

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine.

Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin alfa accumulates 3-fold achieving asteady

Lutropin alfa

Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life of approximately one hour and eliminated from the body with a terminal half-life of about 10-12 hours. The steady state volume of distribution is around 10-14 l. Lutropin alfa shows linear pharmacokinetics, as assessed by AUC which is directly proportional to the dose administered. Total clearance is around 2 l/h, and less than 5% of the dose is excreted in the urine. The mean residence time is approximately 5 hours.

Following subcutaneous administration, the absolute bioavailability is approximately 60%; the terminal half-life is slightly prolonged. The lutropin alfa pharmacokinetics following single and repeated administration of lutropin alfa are comparable and the accumulation ratio of lutropin alfa is minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder:

Sucrose

Polysorbate 20

Methionine

Disodium phosphate dihydrate

Sodium dihydrogen phosphate monohydrate

Phosphoric acid, concentrated for pH adjustment

Sodium hydroxide for pH adjustment

Solvent:

Water for Injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf Life

3 years.

For immediate and single use following first opening and reconstitution.

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

Powder: 3 ml vials (Type I glass) with a stopper (bromobutyl rubber) and aluminium flip-off cap.

1 vial contains 11 micrograms r-hFSH and 3 micrograms r-hLH.

Solvent: 3 ml vials (Type I glass) with a Teflon coated rubber stopper and aluminium flip-off cap.

1 vial of solvent contains 1 ml of water for injections.

The medicinal product is supplied in pack sizes of 1, 3 and 10 vials with the corresponding number of 1, 3 and 10 vials of solvent.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For single use only.

Pergoveris must be reconstituted with the solvent before use.

The reconstituted solution should not be administered if it contains particles or is not clear.

Pergoveris may be mixed with follitropin alfa and co-administered as a single injection.

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

7. Marketing Authorisation Holder

Merck Serono Europe Limited

56 Marsh Wall

London E14 9TP

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/07/396/001

EU/1/07/396/002

EU/1/07/396/003

9. Date Of First Authorisation/Renewal Of The Authorisation

25 June 2007

10. Date Of Revision Of The Text

July 2009