Optrex Sore Eye Drops

1. Name Of The Medicinal Product

Optrex Sore Eye Drops

2. Qualitative And Quantitative Composition

Active

Distilled Witch Hazel BPC l3%v/v

(Synonyms: Hamamelis Water, Witch Hazel)

3. Pharmaceutical Form

Eye Drops

4. Clinical Particulars

4.1 Therapeutic Indications

For the relief of minor eye irritations caused by dusty or smoky atmospheres, driving or close work.

4.2 Posology And Method Of Administration

For topical application into the eye.

For adults, children and the elderly:

Gently squeeze one or two drops into each eye.

Use as often as required.

4.3 Contraindications

Hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

For external use only.

Not suitable for use with hydrophilic (soft) contact lenses.

Keep all medicines out of the sight and reach of children.

Discard any eye drops remaining 28 days after opening the container.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant drug interactions known.

4.6 Pregnancy And Lactation

The safety of Optrex Sore Eyes Eye Drops during pregnancy and lactation has not been established but use during these periods is not considered to constitute a hazard.

4.7 Effects On Ability To Drive And Use Machines

No adverse effects known.

4.8 Undesirable Effects

Occasional hypersensitivity reactions.

4.9 Overdose

In view of the size of the container, overdosage should not be a problem and any treatment should only be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Hamamelis water has cooling and astringent properties.

5.2 Pharmacokinetic Properties

Not available.

5.3 Preclinical Safety Data

There are no preclinical safety data of relevance to the consumer.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Boric acid

Borax

Glycerin

Benzalkonium chloride

Purified water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

a)	Unopened:	36 months
b)	After first opening:	28 days

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Polyethylene bottle with a polyethylene dropper plug and a tamper evident polyethylene cap. Pack sizes of 10ml and 18ml.

6.6 Special Precautions For Disposal And Other Handling

None.

ADMINISTRATIVE DATA

7. Marketing Authorisation Holder

Optrex Limited

1 Thane Road West

Nottingham

NG2 3AA

8. Marketing Authorisation Number(S)

PL 00062/5003R

9. Date Of First Authorisation/Renewal Of The Authorisation

15 May 1987

10. Date Of Revision Of The Text

15/04/2008

Orelox Tablets 100mg

1. Name Of The Medicinal Product

Orelox^TM Tablets 100mg.

2. Qualitative And Quantitative Composition

Each Orelox tablet contains 130mg of cefpodoxime proxetil (equivalent to 100mg cefpodoxime).

3. Pharmaceutical Form

Tablet for oral use.

4. Clinical Particulars

4.1 Therapeutic Indications

Orelox is a bactericidal cephalosporin antibiotic active against a wide range of Gram-negative and Gram-positive organisms. It is indicated for the treatment of the following infections either before the infecting organism has been identified or when caused by bacteria of established sensitivity.

Upper respiratory tract infections caused by organisms sensitive to cefpodoxime, including sinusitis.

In tonsillitis and pharyngitis, Orelox should be reserved for recurrent or chronic infections, or for infections where the causative organism is known or suspected to be resistant to commonly used antibiotics.

Lower respiratory tract infections caused by organisms sensitive to cefpodoxime, including acute bronchitis, relapses or exacerbations of chronic bronchitis and bacterial pneumonia.

Upper and lower urinary tract infections caused by organisms sensitive to cefpodoxime including cystitis and acute pyelonephritis.

Skin and soft tissue infections caused by organisms sensitive to cefpodoxime such as abscesses, cellulitis, infected wounds, furuncles, folliculitis, paronychia, carbuncles and ulcers.

Gonorrhoea - uncomplicated gonococcal urethritis.

4.2 Posology And Method Of Administration

Route of administration: oral.

Adults:

Adults with normal renal function:

Upper respiratory tract infections: For upper respiratory tract infections caused by organisms sensitive to cefpodoxime, including sinusitis. In tonsillitis and pharyngitis, Orelox should be reserved for recurrent or chronic infections, or for infections where the causative organism is known or suspected to be resistant to commonly used antibiotics. Sinusitis: 200mg twice daily. Other upper respiratory tract infections: 100mg twice daily.

Lower respiratory tract infections: For lower respiratory tract infections caused by organisms sensitive to cefpodoxime, including acute bronchitis, relapses or exacerbations of chronic bronchitis and bacterial pneumonia: 100-200 mg twice daily, dependent on the severity of the infection.

Urinary tract infections:

Uncomplicated lower urinary tract infections: 100mg should be taken twice daily.

Uncomplicated upper urinary tract infections: 200mg should be taken twice daily.

Uncomplicated gonococcal urethritis: 200mg should be taken as a single dose.

Skin and soft tissue infections: 200mg should be taken twice daily.

Tablets should be taken during meals for optimum absorption.

Elderly:

It is not necessary to modify the dose in elderly patients with normal renal function.

Children:

Orelox Paediatric is available to treat infants (over 15 days old) and children. Please refer to the separate Summary of Product Characteristics for details.

Hepatic Impairment:

The dosage does not require modification in cases of hepatic impairment.

Renal Impairment:

The dosage of Orelox does not require modification if creatinine clearance exceeds 40 ml/min.

Below this value, pharmacokinetic studies indicate an increase in plasma elimination half-life and the maximum plasma concentrations, and hence the dosage should be adjusted appropriately.

CREATININE CLEARANCE (ML/MIN)
39 – 10	Unit dose1 administered as a single dose every 24 hours (i.e half of the usual adult dose).
< 10	Unit dose1 administered as a single dose every 48 hours (i.e quarter of the usual adult dose).
Haemodialysis Patients	Unit dose1 administered after each dialysis session.

NOTE:

¹The unit dose is either 100mg or 200mg, depending on the type of infection.

4.3 Contraindications

Hypersensitivity to cephalosporin antibiotics.

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

4.4 Special Warnings And Precautions For Use

Preliminary enquiry about allergy to penicillin is necessary before prescribing cephalosporins since cross allergy to penicillins occurs in 5-10% of cases.

Particular care will be needed in patients sensitive to penicillin: strict medical surveillance is necessary from the very first administration. Where there is doubt, medical assistance should be available at the initial administration, in order to treat any anaphylactic episode.

In patients who are allergic to other cephalosporins, the possibility of cross allergy to Orelox should be borne in mind. Orelox should not be given to those patients with a previous history of immediate type hypersensitivity to cephalosporins.

Hypersensitivity reactions (anaphylaxis) observed with beta-lactam antibiotics can be serious and occasionally fatal.

The onset of any manifestation of hypersensitivity indicates that treatment should be stopped.

Orelox is not the preferred antibiotic for the treatment of staphylococcal pneumonia and should not be used in the treatment of atypical pneumonia caused by organisms such as Legionella, Mycoplasma and Chlamydia.

In cases of severe renal insufficiency it may be necessary to reduce the dosage regimen dependent on the creatinine clearance.

Possible side effects include gastrointestinal disorders such as nausea, vomiting and abdominal pain. Antibiotics should always be prescribed with caution in patients with a history of gastrointestinal disease, particularly colitis. Orelox may induce diarrhoea, antibiotic associated colitis and pseudomembranous colitis. These side-effects, which may occur more frequently in patients receiving higher doses for prolonged periods, should be considered as potentially serious. The presence of C. difficile should be investigated. In all potential cases of colitis, the treatment should be stopped immediately. The diagnosis should be confirmed by sigmoidoscopy and specific antibiotic therapy (vancomycin) substituted if considered clinically necessary. The administration of products which cause faecal stasis must be avoided. Although any antibiotic may cause pseudomembranous colitis, the risk may be higher with broad-spectrum drugs, such as the cephalosporins.

As with all beta-lactam antibiotics, neutropenia, and more rarely agranulocytosis may develop, particularly during extended treatment. For cases of treatment lasting longer than 10 days, blood count should therefore be monitored, and treatment discontinued if neutropenia is found.

Cephalosporins may be absorbed onto the surface of red cell membranes and react with antibodies directed against the drug. This can produce a positive Coombs' test and very rarely, haemolytic anaemia. Cross-reactivity may occur with penicillin for this reaction.

Changes in renal function have been observed with antibiotics of the same class, particularly when given concurrently with potentially nephrotoxic drugs such as aminoglycosides and/or potent diuretics. In such cases, renal function should be monitored.

As with other antibiotics, the prolonged use of cefpodoxime proxetil may result in the overgrowth of non-susceptible organisms. With oral antibiotics the normal colonic flora may be altered, allowing overgrowth by clostridia with consequent pseudomembranous colitis. Repeated evaluation of the patient is essential and if superinfection occurs during therapy, appropriate measures should be taken.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No clinically significant drug interactions have been reported during the course of clinical studies.

Histamine H2-antagonists and antacids reduce the bioavailibility of cefpodoxime. Probenecid reduces the excretion of cephalosporins. Cephlasporins potentially enhance the anticoagulant effect of coumarins and reduce the contraceptive effect of oestrogens.

As with other cephalosporins, isolated cases showing development of a positive Coombs' test have been reported (see Precautions).

Studies have shown that bioavailability is decreased by approximately 30% when Orelox is administered with drugs which neutralise gastric pH or inhibit acid secretions. Therefore, such drugs as antacids of the mineral type and H₂ blockers such as ranitidine, which can cause an increase in gastric pH, should be taken 2 to 3 hours after Orelox administration.

The bioavailability increases if the product is administered during meals.

A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions or with copper sulphate test tablets, but not with tests based on enzymatic glucose oxidase reactions.

4.6 Pregnancy And Lactation

Studies carried out in several animal species have not shown any teratogenic or foetotoxic effects. However, the safety of cefpodoxime proxetil in pregnancy has not been established and, as with all drugs, it should be administered with caution during the early months of pregnancy.

Cefpodoxime is excreted in human milk. Either breastfeeding or treatment of the mother should be stopped.

4.7 Effects On Ability To Drive And Use Machines

Attention should be drawn to the risk of dizzy sensations.

4.8 Undesirable Effects

Possible side effects include gastrointestinal disorders such as diarrhoea and rarely antibiotic-associated colitis, including pseudomembranous colitis (see Section 4.4: Special Warnings and Precautions for Use), nausea, vomiting and abdominal pain and rash, urticaria and itching. Changes in renal function have been observed with antibiotics from the same group as Cefpodoxime, particularly when co-prescribed with aminoglycosides and/or potent diuretics.

Occasional cases have been reported of headaches, dizziness, tinnitus, parethesia, asthenia and malaise. Rare cases of allergic reactions include hypersensitivity mucocutaneous reactions, skin rashes and pruritus. Occasional cases of bullous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme have also been received. Transient moderate elevations of ASAT, ALAT and alkaline phosphatases and/or bilirubin have been reported. These laboratory abnormalities which may be explained by the infection, may rarely exceed twice the upper limit of the named range and elicit a pattern of liver injury, usually cholestatic and most often asymptomatic.Slight increases in blood urea and creatinine have also been reported. Exceptionally rare are the occurrence of liver damage and of haematological disorders such as reduction in haemoglobin, thrombocytosis, thrombocytopenia, leucopenia and eosinophilia. Haemolytic anaemia has extremely rarely been reported.

As with other β-lactam antibiotics, neutropenia and, more rarely, agranulocytosis may develop during treatment with Cefpodoxime, particularly if given over long periods.

As with other cephalosporins, there have been rare reports of anaphylactic reactions, bronchospasm, purpura and angiodema, serum-sickness-like reactions with rashes, fever and arthralgia.

4.9 Overdose

In the event of overdosage with Orelox, supportive and symptomatic therapy is indicated.

In cases of overdosage, particularly in patients with renal insufficiency, encephalopathy may occur. The encephalopathy is usually reversible once cefpodoxime plasma levels have fallen.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Orelox (Cefpodoxime proxetil) is a beta-lactam antibiotic, a 3rd generation oral cephalosporin. It is the prodrug of cefpodoxime.

Following oral administration, Orelox is taken up by the gastro-intestinal wall where it is rapidly hydrolysed to cefpodoxime, a bactericidal antibiotic, which is then absorbed systemically.

BACTERIOLOGY:

The mechanism of action of cefpodoxime is based on inhibition of bacterial cell wall synthesis. It is stable to numerous beta-lactamases.

Cefpodoxime has been shown to possess in vitro bactericidal activity against numerous Gram-positive and Gram-negative bacteria.

It is highly active against the Gram-positive organisms:

• Streptococcus pneumoniae

• Streptococci of Groups A (S. pyogenes), B (S. agalactiae), C, F and G

• Other streptococci (S. mitis, S. sanguis and S. salivarius)

• Corynebacterium diphtheriae

It is highly active against the Gram-negative organisms:

• Haemophilus influenzae (beta-lactamase and non beta-lactamase producing strains)

• Haemophilus para-influenzae (beta-lactamase and non beta-lactamase producing strains)

• Branhamella catarrhalis (beta-lactamase and non beta-lactamase producing strains)

• Neisseria meningitidis

• Neisseria gonorrhoeae

• Escherichia coli

• Klebsiella Spp. (K. pneumoniae; K. oxytoca)

• Proteus mirabilis

It is moderately active against meticillin-sensitive staphylococci, penicillinase and non-penicillinase producing strains (S. aureus and S. epidermidis).

In addition, as with many cephalosporins, the following are resistant to cefpodoxime: enterococci, meticillin-resistant staphylococci (S. aureus and S. epidermidis), Staphylococcus saprophyticus, Pseudomonas aeruginosa and Pseudomonas Spp., Clostridium difficile, Bacteroides fragilis and related species.

As with all antibiotics, whenever possible, sensitivity should be confirmed by in vitro testing.

5.2 Pharmacokinetic Properties

Orelox is taken up in the intestine and is hydrolysed to the active metabolite cefpodoxime. When cefpodoxime proxetil is administered orally to fasting subjects as a tablet corresponding to 100mg of cefpodoxime, 51.5% is absorbed and absorption is increased by food intake. The volume of distribution is 32.3 l and peak levels of cefpodoxime occur 2 to 3 hrs after dosing. The maximum plasma concentration is 1.2mg/l and 2.5mg/l after doses of 100mg and 200mg respectively. Following administration of 100mg and 200mg twice daily over 14.5 days, the plasma pharmacokinetic parameters of cefpodoxime remain unchanged.

Serum protein binding of cefpodoxime, 40% principally to albumin. This binding is non saturable in type.

Concentrations of cefpodoxime in excess of the minimum inhibitory levels (MIC) for common pathogens can be achieved in lung parenchyma, bronchial mucosa, pleural fluid, tonsils, interstitial fluid and prostate tissue.

As the majority of cefpodoxime is eliminated in the urine, the concentration is high. (Concentrations in 0-4, 4-8, 8-12 hr fractions after a single dose exceed MIC₉₀ of common urinary pathogens). Good diffusion of cefpodoxime is also seen into renal tissue, with concentrations above MIC₉₀ of the common urinary pathogens, 3-12hrs after an administration of a single 200mg dose (1.6-3.1µG/G). Concentrations of cefpodoxime in the medullary and cortical tissues is similar.

Studies in healthy volunteers show median concentrations of cefpodoxime in the total ejaculate 6-12hrs following administration of a single 200mg dose to be above the MIC₉₀ of N. gonorrhoeae.

The main route of excretion is renal, 80% is excreted unchanged in the urine, with an elimination half life of approx 2.4 hours.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The product contains magnesium stearate, carboxymethylcellulose calcium, hydroxypropylcellulose, sodium lauryl sulphate, lactose, ethyl alcohol and purified water. The coating contains titanium dioxide, talc and hydroxypropylmethylcellulose 6CP.

6.2 Incompatibilities

None reported during clinical studies.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store below 25°C.

6.5 Nature And Contents Of Container

Orelox tablets are supplied in blister packs of 10 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 04425/0252

9. Date Of First Authorisation/Renewal Of The Authorisation

12 February 2004

10. Date Of Revision Of The Text

8 October 2010

LEGAL CATEGORY

POM

Orphenadrine Hydrochloride 50mg / 5ml Oral Solution

1. Name Of The Medicinal Product

Orphenadrine Hydrochloride 50mg/5ml Oral Solution

2. Qualitative And Quantitative Composition

Orphenadrine hydrochloride 50mg/5ml

3. Pharmaceutical Form

Oral Solution

4. Clinical Particulars

4.1 Therapeutic Indications

Anticholinergic, for the treatment of all forms of Parkinsonism, including drug induced (neuroleptic syndrome)

4.2 Posology And Method Of Administration

Adults and the elderly:

Initially, 150mg daily in divided doses, increasing by 50mg every two or three days until maximum benefit is obtained. Optimal dosage is usually 250mg to 300mg daily in divided doses in idiopathic and post-encephalitic Parkinsonism; 100mg to 150mg daily in divided doses in arteriosclerotic parkinsonism; and 150mg to 300mg daily in divided doses in the neuroleptic syndrome.

Maximal dosage is 400mg daily in divided doses. The elderly may be more susceptible to side effects at doses which are clinically optimal.

Children:

Not recommended for use in children.

4.3 Contraindications

Hypersensitivity to orphenadrine or to any of the Excipients.

In patients with prostatic hypertrophy, tardive dyskinesia, porphyria, urinary retention and must also be used with caution in elderly men.

Also in patients with paralytic ileus or pyloric stenosis, where use may lead to obstruction.

Do not use in patients with glaucoma or too narrow an angle between iris and cornea, as it may raise intra-ocular pressure. Not indicated for use in patients at risk of developing hyperpyrexia.

4.4 Special Warnings And Precautions For Use

Use with caution in the elderly (see Section 4.2).

When used alone or with analgesics, pain or skeletal muscle spasms have been reported.

Use with caution in conditions characterised by tachycardia. Anti-muscarinic agents, such as orphenadrine, should be used with caution in patients with pre-existing tachycardia (e.g. in heart failure, thyrotoxicosis) as they may cause further acceleration of the heart rate.

Anti-muscarinic agents such as orphenadrine are not effective in the treatment of tardive dyskinesia which may be made worse, and should not be used in patients with this condition.

Care should be taken when using in patients with concomitant hypertension, cardiac, renal or hepatic dysfunction.

Use with caution in patients with micturition difficulties and in pregnancy and breastfeeding.

Avoid abrupt discontinuation of treatment. For some patients orphenadrine may be a drug of abuse.

Excipient Warnings

Orphenadrine Oral Solution 50mg/5ml contains methyl and propyl hydroxybenzoates (preservatives) which may cause allergic reactions (possibly delayed).

The product also contains liquid maltitol and sorbitol solution. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Effects may be enhanced by concomitant administration of anticholinergic drugs. May be provocation of dextropropoxyphene side effects during concurrent administration.

As with other similar agents, the anti-muscarinic effects of orphenadrine may be enhanced by the concomitant administration of other medications with anti-muscarinic properties, such as antihistamines, antispasmodics, tricyclic antidepressants, phenothiazines, dopaminergic anti parkinsonian drugs including amantadine, and anti-arrhythmics such as disopyramide.

Although the additional effects may be minor, there is the potential for the development of severe constipation and ileus, atropine-like psychoses and heat stroke.

Due to the anti-muscarinic effects of orphenadrine on the gastrointestinal tract, a reduction in gastric motility may occur which may affect the absorption of other orally administered drugs.

4.6 Pregnancy And Lactation

There is inadequate evidence of safety in human pregnancy, and, although it has been widely used for many years without apparent ill consequence, if considered necessary orphenadrine should be used with caution during pregnancy. Animal studies have not revealed any hazard.

It is probably excreted in milk during lactation. Although the quantity is unlikely to be significant at normal therapeutic doses, if considered necessary orphenadrine should be used with caution during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Orphenadrine may cause blurred vision or slight euphoria. If patients experience these side effects, driving or operating machinery is not recommended.

4.8 Undesirable Effects

System Organ Class	Common >1/100 <1/10	Uncommon >1/1000 <1/100	Rare >1/10,000 <1/1000
Immune system disorder		Hypersensitivity
Nervous system disorder	Dizziness, restlessness	Sedation, confusion, nervousness, hallucinations, convulsions, insomnia, euphoria, co-ordination disturbances, light-headedness	Memory disturbances
Eye disorders	Accommodation disorders
Cardiac disorders		Tachycardia
Gastrointestinal disorders	Dry mouth, nausea, gastrointestinal disturbances	Constipation
Renal and urinary disorders		Urinary retention

4.9 Overdose

Toxicity:

Adults: 2 –3 g can be fatal for an adult though patients have survived doses of 5 g and 7.5 g.

Children: A 23 month old had severe toxicity after ingesting 300mg.

Toxicity is mainly due to anticholinergic effects at autonomic nerve endings and in the brain.

Features:

Common: Nausea, vomiting, flushing, dilated pupils, dry mouth and tongue, hot dry skin, fever, sinus tachycardia, hypertension, ataxia, nystagmus, drowsiness, delirium, agitation and visual hallucinations.

Uncommon: Myoclonic jerking, coma, convulsions, cardiac conduction abnormalities and dysrhythmias, cardiovascular collapse, paralytic ileus, urinary retention.

Treatment:

Activated charcoal or gastric lavage may be of benefit if the patient presents within 1 hour of having taken a potentially toxic amount.

Forced diuresis, haemodialysis and haemoperfusion are of no benefit.

Observe the mildest cases for at least 6 hours.

Monitor for and treat the following as clinically indicated: Airway patency, arterial blood gases (hypoxia and/or hypercapnoea may require oxygen or ventilation to correct), hypothermia or hyperthermia, hypotension (intravascular volume expanders or dopamine may be required), skin blisters (treat as burns), convulsions or delirium (can be treated with diazepam).

Cardiac dysrhythmias: Resist the temptation to use antiarrythmic drugs. Correct hypoxia and administer sodium bicarbonate (even in the absence of acidosis).

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code – N04A B

Pharmacotherapeutic Group: Anti-Parkinson Drugs

Orphenadrine, which is a congener of diphenhydramine without sharing its soporific effect, is an anti-muscarinic agent. It also works has weak antihistaminic and local anaesthetic properties.

Orphenadrine is used as the hydrochloride in the symptomatic treatment of Parkinsonism. It is also used to alleviate the extrapyramidal syndrome induced by drugs such as the phenothiazine derivatives, but is of no value in tardive dyskinesia, which may be exacerbated.

5.2 Pharmacokinetic Properties

Orphenadrine is readily absorbed from the gastro-intestinal tract. It is rapidly distributed in tissues and most of a dose is metabolised to at least 8 metabolites and excreted in the urine along with a small proportion of unchanged drug. A half life of 14 hours has been reported.

5.3 Preclinical Safety Data

Orphenadrine is a drug on which extensive clinical experience has been obtained. Relevant information for the prescriber is provided elsewhere in the Summary of Product Characteristics.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Methyl hydroxybenzoate, propyl hydroxybenzoate, propylene glycol, liquid maltitol, sorbitol solution 70%, saccharin sodium, blackcurrant flavour, aniseed flavour, citric acid monohydrate, sodium citrate and purified water.

6.2 Incompatibilities

Incompatible with alkali, protect from light.

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

Store below 25°C and avoid exposure to direct sunlight. Only dispense in amber glass bottles.

6.5 Nature And Contents Of Container

Bottles: Amber (Type III) glass.

Closures: a) Aluminium, EPE wadded, roll-on pilfer-proof (ROPP) screw cap.

b) HDPE, EPE wadded, tamper evident screw cap.

c) HDPE, EPE wadded, tamper evident, child resistant closure.

Capacity: 150ml, 200ml or 500ml

6.6 Special Precautions For Disposal And Other Handling

Keep out of the reach of children.

Administrative Data

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd., Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK.

8. Marketing Authorisation Number(S)

PL 00427/0076

9. Date Of First Authorisation/Renewal Of The Authorisation

15.05.90/09.04.97/8.4.02

10. Date Of Revision Of The Text

23 Nov 2009

OxyNorm 50 mg / ml, solution for injection or infusion

OxyNorm 50 mg/ml, solution for injection or infusion

Oxycodone hydrochloride

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

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


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


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


• If any of the side effects become serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1. What OxyNorm injection is and what it is used for

2. Before you use OxyNorm injection

3. How to use OxyNorm injection

4. Possible side effects

5. How to store OxyNorm injection

6. Further information

What OxyNorm injection is and what it is used for

This injection has been prescribed for you by your doctor to relieve moderate to severe pain. It contains the active ingredient oxycodone which belongs to a group of medicines called strong analgesics or ‘painkillers’. The other ingredients are listed in section 6 of this leaflet.

Before you use OxyNorm injection

Do not use OxyNorm injection:

• if you are allergic (hypersensitive) to oxycodone, or any of the other ingredients of OxyNorm injection;


• if you have breathing problems, such as respiratory depression, chronic obstructive airways disease, chronic bronchial asthma or severe pulmonary disease, unless otherwise recommended by your doctor;


• if you have a head injury that causes a severe headache or makes you feel sick. This is because the injection may make these symptoms worse or hide the extent of the head injury;


• if you have a condition where the small bowel does not work properly (paralytic ileus) or you have severe pain in your abdomen;


• if you have a heart problem after long-term lung disease (cor pulmonale);


• if you have severe kidney problems or moderate to severe liver problems. If you have other long term kidney or liver problems you should only use OxyNorm injection if recommended by your doctor;


• if you have ongoing problems with constipation;


• if you are taking a type of medicine known as a monoamine oxidase inhibitor (examples include tranylcypromide, phenelzine, isocarboxazid, moclobemide and linezolid), or you have taken this type of medicine in the last two weeks.

Children and adolescents under 18 years old should not use the injection.

Take special care with OxyNorm injection

Before treatment with OxyNorm injection tell your doctor or pharmacist:

• if you have an under-active thyroid gland (hypothyroidism), as you may need a lower dose of OxyNorm injection;


• if you have a severe headache or feel sick as this may indicate that the pressure in your skull is increased;


• if you have low blood pressure (hypotension);


• if you have a mental disorder as a result of an infection (toxic psychosis);


• if you have inflammation of the pancreas (pancreatitis) or problems with your gall bladder;


• if you have inflammatory bowel disease;


• if you have prostate problems;


• if you have poor adrenal gland function;


• if you are or have ever been addicted to alcohol or drugs;


• if you have previously suffered from withdrawal symptoms such as agitation, anxiety, shaking or sweating upon stopping taking alcohol or drugs.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription. If you use OxyNorm injection with some other medicines, the effect of OxyNorm injection or the other medicines may be changed.

Tell your doctor or pharmacist:

• if you are taking medicines to help you sleep (for example tranquillisers, hypnotics or sedatives);


• if you have recently been given an anaesthetic;


• if you are taking medicines to treat depression;


• if you are taking medicines to treat psychiatric or mental disorders;


• if you are taking other strong analgesics or ‘painkillers’;


• if you are taking muscle relaxants;


• if you are taking medicines to treat high blood pressure;


• if you are taking a type of medicine known as a monoamine oxidase inhibitor (examples include tranylcypromide, phenelzine, isocarboxazid, moclobemide and linezolid), or you have taken this type of medicine in the last two weeks.

Using OxyNorm injection with alcohol

Drinking alcohol during your treatment with OxyNorm injection may make you sleepy. If you are affected you should avoid drinking alcohol.

Pregnancy and breastfeeding

Do not use OxyNorm injection if you are pregnant or breastfeeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

You may feel sleepy when you first start using OxyNorm injection, or when increasing to a higher dose. If you are affected you should not drive or use machinery.

Important information about some of the ingredients of OxyNorm injection

This injection contains less than 1 mmol sodium (23 mg) per 1 ml, i.e. it is essentially “sodium-free”.

How to use OxyNorm injection

A doctor or nurse will usually prepare and administer the injection for you. The injection should be used immediately after opening. The dose and how often the injection is given may be adjusted according to the severity of your pain.

The usual starting dose for adults over 18 years old is dependent upon how the injection is administered. The usual starting doses are as follows:

• As a single injection into a vein, the usual dose is 1 to 10 mg given slowly over 1 to 2 minutes. This can be repeated every 4 hours.


• As an infusion into a vein, the usual starting dose is 2 mg/hour.


• As a single injection through a fine needle into the tissue under the skin, the usual starting dose is 5 mg repeated at 4-hourly intervals if needed.


• As an infusion through a fine needle into the tissue under the skin, the usual starting dose is 7.5 mg/day.


• If given by patient controlled analgesia (PCA), the dose is worked out according to your weight (0.03 mg per kg of body weight). Your doctor or nurse will set a suitable frequency.

The dose recommended by the doctor should not be exceeded. Check with the doctor or pharmacist
if you are unsure.

If you find that you are still in pain whilst being given OxyNorm injection discuss this with your
doctor.

If you use more OxyNorm injection than you should, or if someone else uses your injection

Call your doctor or hospital straight away. People who have been given an overdose may feel very sleepy and sick. They may also have breathing difficulties leading to unconsciousness or even death and may need emergency treatment in hospital. When seeking medical attention make sure that you
take this leaflet and any remaining injection with you to show to the doctor.

If you stop using OxyNorm injection

You should not suddenly stop using this injection unless your doctor tells you to. If you want to stop using your injection, discuss this with your doctor first. They will tell you how to do this, usually by reducing the dose gradually so you do not experience unpleasant effects.

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

Possible side effects

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

All medicines can cause allergic reactions, although serious allergic reactions are rare. Tell your doctor immediately if you get any sudden wheeziness, difficulties in breathing, swelling of the eyelids, face or lips, rash or itching especially those covering your whole body.

As with all strong painkillers, there is a risk that you may become addicted or reliant on OxyNorm
injection.

Common side effects

(Probably affecting more than 1 in 100 people using OxyNorm injection)

Most people will have constipation when they use OxyNorm injection. Your doctor can prescribe a laxative to overcome this problem.

You may feel sick or vomit (be sick) when using this injection, this should normally wear off after a few days however your doctor can prescribe an anti-vomiting medicine if it continues to be a problem.

You may find that you feel more sleepy than normal when you start using your injection or when your dose is increased. This should wear off after a few days.

The following side effects have also been commonly reported in patients treated with OxyNorm injection:

• Dry mouth, loss of appetite, indigestion, abdominal pain or discomfort, diarrhoea.


• Headache, confusion, a feeling of unusual weakness, dizziness, a feeling of ‘faintness’ especially on standing up, anxiety, nervousness, twitching, difficulty in sleeping, abnormal thoughts or dreams.


• Difficulty in breathing or wheezing, shortness of breath, decreased cough reflex.


• Rash, itchy skin.


• Sweating, chills.

Uncommon side effects

(Probably affecting fewer than 1 in 100 people using OxyNorm injection)

• Difficulty in swallowing, belching, hiccups, wind, gastrointestinal disorders (e.g. upset stomach), changes in taste.


• A feeling of dizziness or ‘spinning’, hallucinations, mood changes, depression, a feeling of extreme happiness, restlessness, agitation, generally feeling unwell, loss of memory, shaking, difficulties with speech, reduced sensitivity to pain or touch, tingling in the hands or feet, seizures, fits or convulsions, blurred vision.


• Difficulty passing urine, impotence, decreased sexual drive, absence of menstrual periods.


• Fast, irregular heart beat, low blood pressure, flushing of the skin.


• Dehydration, thirst, swelling of the hands, ankles or feet.


• Dry skin, severe flaking or peeling of the skin.


• Redness of the face, reduction in size of the pupils in the eye, high temperature.


• Withdrawal symptoms such as agitation, anxiety, shaking or sweating upon stopping using OxyNorm injection.

If you need to have blood tests remind your doctor that you are using OxyNorm injection. This is important because OxyNorm injection may change the way your liver works and this could affect the results of some blood tests.

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

How to store OxyNorm injection

Keep out of the reach and sight of children. Accidental overdose by a child is dangerous and may be fatal.

Do not use OxyNorm injection after the expiry date which is stated on the ampoule label and carton. EXP 08 2010 means that you should not use the injection after the last day of that month i.e. August 2010.

There are no special precautions for storage prior to use however once the ampoule is opened the injection should be used immediately. Any unused portion should be discarded immediately.

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 OxyNorm injection contains

The active ingredient is oxycodone hydrochloride.

The other ingredients are:

• Citric acid monohydrate


• Sodium citrate


• Sodium chloride


• Hydrochloric acid, dilute


• Sodium hydroxide


• Water for injections

What OxyNorm injection looks like and the contents of the pack

OxyNorm
injection is a clear, colourless solution supplied in clear glass ampoules. The 50 mg/ml strength is available as 1 ml of solution (containing 50 mg of oxycodone hydrochloride).

Marketing Authorisation Holder and Manufacturer

OxyNorm
injection is made by

Hamol Ltd

1 Thane Road

Nottingham

NG90 2DB

UK

The marketing authorisation holder is

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

This leaflet is also available in large print, Braille or as an audio CD. To request a copy, please call the RNIB Medicine Information line (free of charge) on :

0800 198 5000

You will need to give details of the product name and reference number.

These are as follows:

Product name: OxyNorm solution for injection or infusion

Reference number: 16950/0155

This leaflet was last approved in March 2009.

OxyNorm, NAPP and the NAPP device (logo) are Registered Trade Marks.

© 2009 Napp Pharmaceuticals Limited

P0183-A UK AW R2V0 12-03-09

OxyContin tablets

OxyContin 5 mg, 10 mg, 20 mg, 40 mg and 80 mg, prolonged release tablets

Oxycodone hydrochloride

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

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


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


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


• If any of the side effects become serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

1. What OxyContin tablets are and what they are used for

2. Before you take OxyContin tablets

3. How to take OxyContin tablets

4. Possible side effects

5. How to store OxyContin tablets

6. Further information

What OxyContin tablets are and what they are used for

These tablets have been prescribed for you by your doctor to relieve moderate to severe pain over a period of 12 hours. They contain the active ingredient oxycodone which belongs to a group of medicines called strong analgesics or ‘painkillers’.

Before you take OxyContin tablets

Do not take OxyContin tablets if you:

• are allergic (hypersensitive) to oxycodone, or any of the other ingredients of the tablets (see section 6 ‘Further Information’);


• have breathing problems, such as chronic obstructive airways disease, severe bronchial asthma or respiratory depression. Your doctor will have told you if you have any of these conditions. Symptoms may include breathlessness, coughing or breathing more slowly or weakly than expected;


• have a head injury that causes a severe headache or makes you feel sick. This is because the tablets may make these symptoms worse or hide the extent of the head injury;


• have a condition where the small bowel does not work properly (paralytic ileus), your stomach empties more slowly than it should (delayed gastric emptying) or you have severe pain in your abdomen;


• have a heart problem after long-term lung disease (cor pulmonale);


• have severe kidney problems or moderate to severe liver problems. If you have other long-term kidney or liver problems you should only take these tablets if recommended by your doctor;


• have ongoing problems with constipation;


• are taking a type of medicine known as a monoamine oxidase inhibitor (examples include tranylcypromide, phenelzine, isocarboxazid, moclobemide and linezolid), or you have taken this type of medicine in the last two weeks;


• are under 18 years of age.

If you are going to have an operation, please tell the doctor at the hospital that you are taking these tablets.

Take special care with OxyContin tablets

Before treatment with these tablets tell your doctor or pharmacist if you:

• have an under-active thyroid gland (hypothyroidism), as you may need a lower dose;


• have a severe headache or feel sick as this may indicate that the pressure in your skull is increased;


• have low blood pressure (hypotension);


• have a mental disorder as a result of an infection (toxic psychosis);


• have inflammation of the pancreas (which causes severe pain in the abdomen and back) or problems with your gall bladder;


• have inflammatory bowel disease;


• have prostate problems;


• have poor adrenal gland function (your adrenal gland is not working properly which may cause symptoms including weakness, weight loss, dizziness, feeling or being sick);


• have breathing problems such as severe pulmonary disease. Your doctor will have told you if you have this condition. Symptoms may include breathlessness and coughing;


• have previously suffered from withdrawal symptoms such as agitation, anxiety, shaking or sweating, upon stopping taking alcohol or drugs.

These tablets should be avoided in patients with a history of, or present alcohol or drug abuse.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. If you take these tablets with some other medicines, the effect of these tablets or the other medicine may be changed.

These tablets must not be used together with a monoamine oxidase inhibitor, or if you have taken this type of medicine in the last two weeks (see section 2 “Do not take…”).

Tell your doctor or pharmacist if you are taking:

• medicines to help you sleep (for example tranquillisers, hypnotics or sedatives);


• medicines to treat depression;


• medicines to treat psychiatric or mental disorders (such as phenothiazines or neuroleptic drugs);


• other strong analgesics or painkillers;


• muscle relaxants;


• medicines to treat high blood pressure;


• quinidine (a medicine to treat a fast heart beat);


• cimetidine (a medicine for stomach ulcers, indigestion or heartburn);


• antifungal medicines (such as ketoconazole or voriconazole);


• antibiotics (such as erythromycin).

Also tell your doctor if you have recently been given an anaesthetic.

Taking OxyContin tablets with alcohol

These tablets should not be taken with alcohol. Alcohol use could increase serious side-effects of oxycodone, such as sleepiness, drowsiness and slow and shallow breathing.

Pregnancy and breastfeeding

Do not take these tablets if you are pregnant or breastfeeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

These tablets may cause a number of side effects such as drowsiness which could affect your ability to drive or use machinery (see section 4 for a full list of side effects). These are usually most noticeable when you first start taking the tablets, or when changing to a higher dose. If you are affected you should not drive or use machinery.

Important information about some of the ingredients of OxyContin tablets

These tablets contain lactose which is a form of sugar. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking these tablets.

How to take OxyContin tablets

Always take these tablets exactly as your doctor has told you. The label on your medicine will tell you how many tablets to take and how often.

Adults (over 18 years of age)

The usual starting dose is one 10 mg tablet every 12 hours. However, your doctor will prescribe the dose required to treat your pain. If you find that you are still in pain whilst taking these tablets discuss this with your doctor.

Do not exceed the dose recommended by your doctor. You should check with your doctor or pharmacist if you are not sure.

Swallow your tablets whole with water. Do not crush, dissolve or chew them.

These tablets should not be taken with alcoholic drinks.

OxyContin tablets are designed to work properly over 12 hours when swallowed whole. If a tablet is broken, crushed, dissolved or chewed, the entire 12-hour dose may be absorbed rapidly into your body. This can be dangerous, causing serious problems such as an overdose, which may be fatal.

You should take your tablets every 12 hours. For instance, if you take a tablet at 8 o’clock in the morning, you should take your next tablet at 8 o’clock in the evening.

You must only take the tablets by mouth. The tablets should never be crushed or injected as this may lead to serious side effects, which may be fatal.

Children

Children and adolescents under 18 years of age should not take the tablets.

If you take more OxyContin tablets than you should or if someone accidentally swallows your tablets

Call your doctor or hospital straight away. People who have taken an overdose may feel very sleepy, sick or dizzy, or have hallucinations. They may also have breathing difficulties leading to unconsciousness or even death and may need emergency treatment in hospital. When seeking medical attention make sure that you take this leaflet and any remaining tablets with you to show to the doctor.

If you forget to take your OxyContin tablets

If you remember within 4 hours of the time your tablet was due, take your tablet straight away. Take your next tablet at your normal time. If you are more than 4 hours late, please call your doctor or pharmacist for advice. Do not take a double dose to make up for a forgotten tablet.

If you stop taking OxyContin tablets

You should not suddenly stop taking these tablets unless your doctor tells you to. If you want to stop taking your tablets, discuss this with your doctor first. They will tell you how to do this, usually by reducing the dose gradually so you do not experience unpleasant effects. Withdrawal symptoms such as agitation, anxiety, palpitations, shaking or sweating may occur if you suddenly stop taking these tablets.

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

OxyContin tablets Side Effects

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

All medicines can cause allergic reactions, although serious allergic reactions are rare. Tell your doctor immediately if you get any sudden wheeziness, difficulties in breathing, swelling of the eyelids, face or lips, rash or itching especially those covering your whole body.

The most serious side effect is a condition where you breathe more slowly or weakly than expected (respiratory depression).

As with all strong painkillers, there is a risk that you may become addicted or reliant on these tablets.

Common side effects

(Probably affecting more than 1 in 100 people taking these tablets)

• Constipation (your doctor can prescribe a laxative to overcome this problem).


• Feeling or being sick (this should normally wear off after a few days, however your doctor can prescribe an anti-sickness medicine if it continues to be a problem).


• Drowsiness (this is most likely when you start taking your tablets or when your dose is increased, but it should wear off after a few days).


• Dry mouth, loss of appetite, indigestion, abdominal pain or discomfort, diarrhoea.


• Headache, confusion, a feeling of unusual weakness, dizziness, anxiety, nervousness, twitching, difficulty in sleeping, abnormal thoughts or dreams.


• Difficulty in breathing or wheezing, shortness of breath, decreased cough reflex.


• Rash, itchy skin.


• Sweating, chills.

Uncommon side effects

(Probably affecting fewer than 1 in 100 people taking these tablets)

• Difficulty in swallowing, belching, hiccups, wind, gastrointestinal disorders (e.g. upset stomach), changes in taste, tooth decay.


• A blockage in the flow of bile from the liver (cholestasis). This can cause itchy skin, yellow skin, very dark urine and very pale stools.


• A feeling of dizziness or ‘spinning’, a feeling of ‘faintness’ especially on standing up, hallucinations, mood changes, depression, a feeling of extreme happiness, restlessness, agitation, generally feeling unwell, loss of memory, shaking, difficulties with speech, reduced sensitivity to pain or touch, tingling or numbness, seizures, fits or convulsions, blurred vision.


• Difficulty in passing urine, impotence, decreased sexual drive, absence of menstrual periods.


• Fast, irregular heart beat, low blood pressure, flushing of the skin.


• Dehydration, thirst, swelling of the hands, ankles or feet.


• Dry skin, severe flaking or peeling of the skin.


• Redness of the face, reduction in size of the pupils in the eye, muscle spasm, high temperature.


• A need to take increasingly higher doses to obtain the same level of pain relief (tolerance).

Uncommonly, these tablets may affect the results of blood tests to check that your liver is working properly.

You may see the remains of the tablets in your faeces. This should not affect how the tablets work.

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

How to store OxyContin tablets

Keep out of the reach and sight of children. Accidental overdose by a child is dangerous and may be fatal.

Do not use any tablets after the expiry date which is stated on the blister and carton.

EXP 08 2020 means that you should not take the tablets after the last day of that month i.e. August 2020.

Do not store your tablets above 25°C.

Do not take your tablets if they are broken or crushed as this can be dangerous and can cause serious problems such as overdose.

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 OxyContin tablets contain

The active ingredient is oxycodone hydrochloride. Each tablet contains 5 mg, 10 mg, 20 mg, 40 mg or 80 mg of oxycodone hydrochloride.

The other ingredients are:

• Lactose monohydrate


• Povidone


• Ammoniomethacrylate polymer


• Sorbic acid


• Triacetin


• Stearyl alcohol


• Talc


• Magnesium stearate


• Hypromellose (E464)


• Titanium dioxide (E171)


• Macrogol

In addition, the tablet coatings contain the following:

5 mg - brilliant blue (E133)

10 mg – hydroxypropylcellulose

20 mg and 40 mg - polysorbate 80 (E433), and iron oxide (E172)

80 mg - hydroxypropylcellulose, iron oxide (E172), and indigo carmine (E132)

What OxyContin tablets look like and the contents of the pack

The tablets are marked OC on one side and the strength on the other (5, 10, etc). All strengths are round, bi-convex, film coated tablets.

The tablets are all film coated in the following colours: 5 mg - light blue, 10 mg - white, 20 mg - pink, 40 mg - yellow, 80 mg - green.

In each box there are 28 or 56 tablets.

Marketing Authorisation Holder and Manufacturer

The tablets are made by

Bard Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

for the marketing authorisation holder

Napp Pharmaceuticals Limited

Cambridge Science Park

Milton Road

Cambridge

CB4 0GW

UK

This leaflet is also available in large print, Braille or as an audio CD. To request a copy, please call the RNIB Medicine Information line (free of charge) on:

0800 198 5000

You will need to give details of the product name and reference number.

These are as follows:

Product name: OxyContin

Reference number: 16950/0123

This leaflet was last revised in April 2010.

OxyContin tablets are the subject of European Patents (UK) Numbers 0 253 104, 0 576 643 and European Patent Application 96102992.3.

OxyContin, NAPP and the NAPP device (logo) are Registered Trade Marks.

© 2009-2010 Napp Pharmaceuticals Limited

P0213-A R3V1 UK AW 26-04-10

Optivate

1. Name Of The Medicinal Product

Optivate^®, 100 IU/mL human factor VIII, a powder for solution.

2. Qualitative And Quantitative Composition

Optivate is a concentrate of human coagulation factor VIII with associated von Willebrand factor (VWF) (the natural stabiliser for FVIII). There are no added proteins as stabilisers. The product is obtained from blood from screened donors. These donors are selected from the USA.

Each vial contains nominally 250 IU, 500 IU or 1000 IU of human coagulation factor VIII. One mL of Optivate contains approximately 100 IU of human coagulation factor VIII after reconstitution with 2.5 mL (250 IU), 5 mL (500 IU) or 10 mL (1000 IU) of Sterilised Water for Injections, Ph.Eur..

The factor VIII potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of Optivate is approximately 800 IU/mg protein when VWF is discounted and approximately 43 IU/mg protein when the presence of VWF is considered in the calculation.

The product contains approximately 172 IU VWF:RCo per mL when reconstituted with Sterilised Water for Injections as described above.

The specific activity of Optivate is approximately 75 IU of VWF:RCo/mg protein.

The VWF potency (IU) is measured according to ristocetin cofactor activity (VWF:RCo) compared to the International Standard for von Willebrand factor concentrate (WHO).

The label on each vial states the assayed amounts of factor VIII and VWF ristocetin cofactor activities.

For a full list of excipients, see 6.1.

3. Pharmaceutical Form

Powder for solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency).

4.2 Posology And Method Of Administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.

The dosage and duration of the substitution therapy depend on the severity of the FVIII deficiency, on the location and extent of the bleeding and the patient's clinical condition.

Posology

On demand treatment

The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for factor VIII in plasma).

One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one mL of normal human plasma. The calculation of the required dosage of factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the plasma factor VIII activity by 2.2% - 2.7% of normal activity (2.2-2.7 IU/dL). The required dosage is determined using the following formula:

Required units =

body weight (kg)

x

desired factor VIII rise (%) (IU/dL)

x

0.4

The amount to be administered and the frequency of administration should always be orientated to the clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor VIII activity should not fall below the given plasma activity level (in % of normal; IU/dL) in the corresponding period. The following table can be used to guide dosing in bleeding episodes and surgery:

Degree of haemorrhage/Type of surgical procedure	Factor VIII level required (%) (IU/dL)	Frequency of doses (hours)/Duration of therapy (days)
Haemorrhage
Early haemarthrosis, muscle bleeding or oral bleeding	20-40	Repeat every 12 to 24 hours. At least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
More extensive haemarthrosis, muscle bleeding or haematoma.	30-60	Repeat infusion every 12 to 24 hours for 3-4 days or more until pain and acute disability are resolved.
Life threatening haemorrhages	60-100	Repeat infusion every 8 to 24 hours until threat resolved.
Surgery
Minor surgery Including tooth extraction	30-60	Every 24 hours, at least 1 day, until healing is achieved.
Major surgery	80-100 (pre- and postoperative)	Repeat infusion every 8 to 24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dL).

Prophylaxis

For long term prophylaxis against bleeding in patients with severe haemophilia A, the usual doses are 20 to 40 IU of factor VIII per kg body weight at intervals of 2 to 3 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable. Individual patients may vary in their response to factor VIII, achieving different levels of in vivo recovery and demonstrating different half-lives.

Paediatric patients

Optivate is indicated for use in children, including those less than 6 years of age. The usual dose is 17 to 30 IU/kg. This can be given up to 3 times a week to prevent bleeding. In the clinical trials the median doses in children

Patients should be monitored for the development of factor VIII inhibitors. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a factor VIII inhibitor is present. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of patients with haemophilia.

See also 4.4.

Method of administration

Dissolve the preparation as described in 6.6. The product should be administered via the intravenous route at a rate not exceeding 3 mL per minute (note that increasing the rate of administration may result in side effects).

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

As with any intravenous protein product, allergic type hypersensitivity reactions are possible. The product contains traces of human proteins other than factor VIII and VWF. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur, they should be advised to discontinue use of the product immediately and contact their physician.

In case of shock, standard medical treatment for shock should be implemented.

Standard measures are implemented to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for non-enveloped viruses HAV and parvovirus B19.

It is strongly recommended that every time that Optivate is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay. The risk of developing inhibitors is correlated to the exposure to anti-haemophilic factor VIII, this risk being highest within the first 20 exposure days. Rarely, inhibitors may develop after the first 100 exposure days.

Cases of recurrent inhibitor (low titre) have been observed after switching from one FVIII product to another in previously treated patients with more than 100 exposure days who have a previous history of inhibitor development. Therefore, it is recommended to monitor patients carefully for inhibitor occurrence following any product switch.

In general, all patients treated with human coagulation factor VIII should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests.

See also 4.8 Undesirable effects.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

No interactions of human coagulation factor VIII products with other medicinal products have been reported.

4.6 Pregnancy And Lactation

Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and lactation only if clearly indicated.

4.7 Effects On Ability To Drive And Use Machines

Optivate has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

The following adverse reactions have been reported from 96 patients in clinical studies. Approximately 10% of patients can be expected to experience adverse reactions on long-term treatment. Frequencies are defined as: very common (

MedDRA Standard System Organ Class	Adverse Reactions	Frequency
Nervous System Disorders	Headache	Common
Somnolence	Common
Ear and Labyrinth Disorders	Vertigo (dizziness)	Common
Skin and Subcutaneous Tissue Disorders	Rash	Common
Pruritus	Common
Musculoskeletal and Connective Tissue Disorders	Muscle and joint stiffness	Common
General Disorders and Administration Site Disorders	Infusion site erythema, rash, or pain	Common
Oedema peripheral	Common
Shivering (rigors)	Common
Fever (pyrexia)	Common

In post-marketing experience, the following additional undesirable effects have been reported: sneezing, cough, throat irritation, abdominal pain and malaise.

Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed infrequently, and may in some cases progress to severe anaphylaxis.

Patients with haemophilia A may develop neutralising antibodies (inhibitors) to factor VIII. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. One previously untreated patient (PUP) has been treated in the clinical development programme. Neither he nor any of the 95 previously treated patients (PTPs) in the clinical trials has developed inhibitors. The median number of exposure days in these patients was 97 days (range 2 to 408 days).

For information on viral safety see 4.4.

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group :

Antihaemorrhagics: blood coagulation factor VIII, ATC code: B02BD02.

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient's circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed. Haemophilia A is a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

In addition to its role as a factor VIII protecting protein, von Willebrand factor mediates platelet adhesion to sites of vascular injury and plays a role in platelet aggregation.

From clinical trial experience, young children using prophylactic Optivate experienced less bleeds than those only using it on demand. For doses in children see 4.2.

5.2 Pharmacokinetic Properties

The pharmacokinetics of Optivate have been evaluated in 15 patients with severe haemophilia A after bolus doses of 50 IU/kg. The mean results were as follows:

Non-compartmental terminal half-life	12.4 hours
95%CI	10.94-13.83 hours
Mean Residence Time	17.5 hours
95%CI	15.99-18.92 hours
Clearance	3.1 mL/kg/h
95%CI	2.71-3.51 mL/kg/h
Area under curve (AUC0-48h)	16.1 h.IU/mL
95%CI	13.97-18.28 h.IU/mL
Area under curve (AUC0-inf)	17.31 h.IU/mL
95%CI	14.98-19.65 h.IU/mL
Volume of distribution	53.4 mL/kg
95%CI	46.2-60.52 mL/kg
Alpha half-life	2.2 hours
95%CI	1.48-2.88 hours
Beta half-life	12.6 hours
95%CI	11.33-13.92 hours
Incremental recovery	2.5 IU/dL per IU/kg
95%CI	2.22-2.74 IU/dL per IU/kg

During the clinical trials, there were 309 assessments of incremental recovery, all based on the maximum FVIII:C in the first hour (ISTH 2001). These assessments have involved 27 batches of Optivate and 70 adults with severe haemophilia A. The overall values of incremental recovery were as follows:

Mean:	2.7 IU/dL per IU/kg
95%CI:	2.53-2.80 IU/dL per IU/kg
Median:	2.6 IU/dL per IU/kg.

5.3 Preclinical Safety Data

The factor VIII and von Willebrand factor in Optivate are normal constituents of human plasma and act in the same way as the endogenous proteins. Therefore, safety testing is not relevant.

However, an acute toxicity study and a repeated dose toxicity study in mice indicated that the Optivate formulation was not toxic, even at levels up to 20 times that likely to be used in man. In these studies, the various constituents of the product were administered to the test animals in different, greater, amounts for each excipient, compared to that in a clinical dose.

It is scientifically inappropriate to conduct genotoxicity or carcinogenicity studies with plasma coagulation factor VIII with or without its natural stabiliser, VWF.

6. Pharmaceutical Particulars

6.1 List Of Excipients

The reconstituted solution contains:

Sodium chloride

Sodium citrate

Calcium chloride

Polysorbate 20

Trehalose.

6.2 Incompatibilities

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

Only the recommended injection/infusion sets should be used because treatment failure can occur as a consequence of human plasma coagulation factor VIII adsorption to the internal surfaces of some infusion equipment.

6.3 Shelf Life

Unopened (at 2°C - 25°C, in the dark) 3 years.

6.4 Special Precautions For Storage

Store below 25°C. Do not freeze. Protect from light.

6.5 Nature And Contents Of Container

The product is presented as a 250 IU, 500 IU or 1000 IU presentation in Type I, Ph.Eur., glass vials. These vials are stoppered with a halobutyl rubber freeze-drying stopper under vacuum and then oversealed with a snap-off polypropylene cap and aluminium lacquered skirt.

Supplied with the product is a Transfer Device called Mix2Vial^TM to allow needle-free, easy and safe reconstitution of the product with the Sterilised Water for Injection, (Ph.Eur.).

6.6 Special Precautions For Disposal And Other Handling

Optivate should only be reconstituted with Water for Injections provided with the product. The 250 IU, 500 IU and 1000 IU presentations should be reconstituted using 2.5 mL, 5 mL and 10 mL Sterilised Water for Injections, Ph.Eur., respectively.

The container of Optivate and Water for Injections should be brought to between 20°C and 30°C prior to the removal of the flip-off closure from the product vial.

The Mix2Vial^TM Transfer Device is provided with the product for needle-free, easy and safe use.

The reconstitution is performed as follows:

Step 1: Remove the cap from the product vial and clean the top of the stopper with an alcohol swab. Repeat this step with the sterile water vial. Peel back the top of the Transfer Device package but leave the device in the package.

Step 2: Place the blue end of the Transfer Device on the water vial and push straight down until the spike penetrates the rubber stopper and snaps into place.

Remove the plastic outer packaging from the Transfer Device and discard it, taking care not to touch the exposed end of the device.

Step 3: Turn the water vial upside down with the Transfer Device still attached.

Place the clear end of the Transfer Device on the product vial and push straight down until the spike penetrates the rubber stopper and snaps into place.

Step 4: The sterile water will be pulled into the product vial by the vacuum contained within it. Gently swirl the vial to make sure the product is thoroughly mixed. Do not shake the vial. A clear or slightly pearl-like solution should be obtained, usually in about 2 to 2 ½ minutes (5 minutes maximum).

Step 5: Separate the empty water vial and blue part from the clear part by unscrewing anti-clockwise. Draw air into the syringe by pulling the plunger to the volume of water added. Connect the syringe to the white filter and push the air into the vial.

Step 6: Immediately invert the vial of solution which will be drawn into the syringe. Disconnect the filled syringe from the device. Follow normal safety practices to administer your medicine.

Note: If you have more than one vial to make up your dose, repeat Steps 1 through 6 withdrawing the solution in the vial into the same syringe.

The Transfer Device supplied with the product is sterile and cannot be used more than once. When the reconstitution process is complete, dispose of in the 'sharps box'.

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

The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Reconstituted products should be inspected visually for particulate matter and discolouration prior to administration.

7. Marketing Authorisation Holder

BPL, Bio Products Laboratory

Dagger Lane, Elstree, Herts, WD6 3BX

United Kingdom

Tel: +44 (0) 208 258 2200

Email: info@bpl.co.uk

8. Marketing Authorisation Number(S)

PL08801/0051

9. Date Of First Authorisation/Renewal Of The Authorisation

December 2004

10. Date Of Revision Of The Text

July 2009

Item code: OptSmPC5