Volsaid Retard 75 mg & 100mg tablets

1. Name Of The Medicinal Product

VOLSAID RETARD 75

VOLSAID RETARD 100

2. Qualitative And Quantitative Composition

Each 75mg modified-release tablet contains 75mg diclofenac sodium.

Each 100mg modified-release tablet contains 100mg diclofenac sodium.

For excipients see section 6.1

3. Pharmaceutical Form

Modified-release tablet

75mg: White, triangular tablet. One side is marked "DIC 75" and the reverse side is plain.

100mg: Pale red, round, biconvex tablet. One side is marked "DIC 100" and the reverse side is plain.

4. Clinical Particulars

4.1 Therapeutic Indications

Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) recommended for the treatment of:

- rheumatoid arthritis, osteoarthritis and ankylosing spondylitis

- acute gout

- low back pain

- the relief of pain in fractures

- acute musculo-skeletal disorders and trauma including periarthritis (particularly frozen shoulder), bursitis, tendinitis, tenosynovitis, dislocations, sprains and strains

- the control of pain and inflammation in orthopaedic, dental and other minor surgery

4.2 Posology And Method Of Administration

Route of Administration

For oral administration

Dosage Recommendations

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.4).

Adults

One 100mg tablet to be taken once a day or one 75mg tablet to be taken once or twice a day, swallowed whole, preferably with or after food.

Children

Diclofenac sodium is not suitable for use in children.

The Elderly

The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used and for the shortest possible duration. The patient should be monitored regularly for GI bleeding during NSAID therapy.

4.3 Contraindications

Hypersensitivity to diclofenac sodium or to any of the excipients.

Active, or history of recurrent peptic ulcer/haemorrhage (two or more distinct episodes of proven ulceration or bleeding.

NSAIDs are contraindicated in patients who have previously shown hypersensitivity reactions (e.g., asthma, rhinitis, angioedema, urticaria), in response to aspirin, ibuprofen or other non-steroidal anti-inflammatory drugs.

Porphyria.

Severe heart failure, hepatic failure and renal failure (see section 4.4).

During the last trimester of pregnancy (see section 4.6).

History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see section 4.2, and GI and cardiovascular risks below).

The use of Volsaid with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).

Elderly

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal (see section 4.2).

Respiratory disorders

Caution is required if administered to patients suffering from, or with a previous history of bronchial asthma since NSAIDs have been reported to precipitate bronchospasm in such patients.

Cardiovascular, Renal and Hepatic Impairment

The administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Patients at greatest risk of this reaction are those with impaired renal function, cardiac impairment, liver dysfunction, those taking diuretics and the elderly. Renal function should be monitored in these patients (see also section 4.3). On stopping diclofenac, effects on renal function are usually reversible.

Diclofenac should be stopped if liver function tests show abnormalities that persist or worsen, or if liver disease develops or if other symptoms such as eosinophilia or rash occur.

Diclofenac sodium may trigger an attack in patients with hepatic porphyria.

Monitoring of renal function, hepatic function (elevation of liver enzymes may occur) and blood counts should be performed on long-term NSAID patients, as a precautionary measure.

Cardiovascular and cerebrovascular effects

Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high dose (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).

Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with diclofenac after careful consideration. Similar consideration should be made before initiating longer-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking).

Gastrointestinal bleeding, ulceration and perforation

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at any time during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving diclofenac, the treatment should be withdrawn.

NSAIDs should be given with care in patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease, haematemesis, melaena, haematological abnormalities, or bleeding diathesis) as these conditions may be exacerbated (see section 4.8).

SLE and mixed connective tissue disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis (see section 4.8).

Dermatological

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first appearance of skin rash, mucosal lesions, or any signs of hypersensitivity.

Impaired female fertility

The use of Volsaid may impair female fertility and is not recommended in women attempting to conceive. In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of Volsaid should be considered.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Care should be taken in patients treated with any of the drugs mentioned below because, as with other NSAIDs, diclofenac sodium has the potential to induce the following interactions.

Other analgesics including cyclooxygenase-2 selective inhibitors

Avoid concomitant use of two or more NSAIDs (including aspirin) as this may increase the risk of adverse effects (see section 4.4).

Anti-hypertensives

Reduced anti-hypertensive effect.

Diuretics

Reduced diuretic effect. Diuretics can increase the risk of nephrotoxicity of NSAIDs. Increased serum potassium levels may result when diclofenac is given concomitantly with potassium-sparing diuretics. Serum potassium levels should therefore be monitored.

Cardiac Glycosides

NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.

Lithium

Decreased elimination of lithium.

Methotrexate

Decreased elimination of methotrexate. Methotrexate and NSAIDs should only be administered within 24 hours of each other if given with extreme caution.

Ciclosporin

Increased risk of nephrotoxicity. Ciclosporin may increase the bioavailability of diclofenac.

Quinolone Antibiotics

Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.

Anticoagulants

Care is required when giving anticoagulants with NSAIDs as diclofenac may reversibly inhibit platelet aggregation. NSAIDs may enhance the effects of anti-coagulants, such as warfarin. Monitoring is recommended to ensure the desired response to the anticoagulants is maintained.

Oral Hypoglycaemic Agents

It has been reported that hypo- and hyperglycaemic effects have occurred rarely when diclofenac and oral antidiabetic agents have been given together and adjustment of the hypoglycaemic may be required.

Inhibition of metabolism of sulfonylurea drugs, prolonged half-life and increased risk of hypoglycaemia have also been reported.

Aminoglycosides

Reduction in renal function in susceptible individuals, decreased elimination of aminoglycosides and increased plasma concentrations have been reported.

Probenecid

Reduction in metabolism and elimination of NSAID and metabolites occurs with probenecid.

Mifepristone

NSAIDs should not be used for 8 to 12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone.

Corticosteroids

Increased risk of gastrointestinal ulceration or bleeding. (See section 4.4).

Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs)

Increased risk of gastrointestinal bleeding (see section 4.4).

Tacrolimus

Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus.

Zidovudine

Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

4.6 Pregnancy And Lactation

Congenital abnormalities have been reported in association with NSAID administration in man; however, these are low in frequency and do not appear to follow any discernible pattern. In view of the known effects of NSAIDs on the foetal cardiovascular system (risk of closure of the ductus arteriosus), use in the last trimester is contraindicated. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child (see section 4.3). NSAIDs should not be used during the first two trimesters of pregnancy or labour unless the potential benefit to the patient outweighs the potential risk to the foetus.

In limited studies so far available, NSAIDs can appear in breast milk in very low concentrations. NSAIDs should, if possible, be avoided when breastfeeding.

See section 4.4 Special warnings and precautions for use, regarding female fertility.

4.7 Effects On Ability To Drive And Use Machines

Undesirable effects such as dizziness, drowsiness, fatigue, visual disturbances and headaches are possible after taking NSAIDs. If affected, patients should not drive or operate machinery.

4.8 Undesirable Effects

Gastrointestinal

The most commonly observed adverse events are gastrointestinal in nature. Peptic ulcers, perforation or GI bleeding, sometimes fatal, particularly in the elderly, may occur (see section 4.4). Nausea, vomiting, diarrhoea, constipation, anorexia, dyspepsia, flatulence and abdominal pain, melaena, haematemesis, ulcerative stomatitis, glossitis, oesophageal lesions, aphthous stomatitis, exacerbation of colitis and Crohn's disease (See section 4.4) have been reported following administration. Less frequently, gastritis has been observed. Pancreatitis has been reported very rarely.

Cardiovascular

Oedema, hypertension and cardiac failure have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of diclofenac, particularly at high doses (150mg daily) and in long term treatment may be associated with a small increased risk of arterial thromobotic events (for example myocardial infarction or stroke) (see section 4.4).

Hypersensitivity Reactions

Hypersensitivity reactions have been reported following treatment with NSAIDs. These may consist of:

- non-specific allergic reactions and anaphylaxis

- respiratory tract reactivity comprising of asthma, aggravated asthma, bronchospasm or dyspnoea

- assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and more rarely Stevens-Johnson syndrome, Lyell's syndrome, eczema, erythroderma, hair loss, exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

Other adverse reactions reported less commonly include:

Neurological and Special Senses

Visual disturbances, optic neuritis, headache, paraesthesia, reports of aseptic meningitis (especially in patients with existing auto-immune disorders, such as systemic lupus erythematosus, mixed connective tissue disease), with symptoms such as stiff neck, headache, nausea, vomiting, fever or disorientation, (see section 4.4), depression, confusion, hallucinations, tinnitus, vertigo, dizziness, malaise, fatigue, drowsiness, tiredness, impaired hearing, anorexia, insomnia, convulsions, irritability, anxiety, psychotic reactions, tremors, memory disturbance, disturbance of vision, nightmares and taste alterations.

Dermatological Reaction

Bullous reactions including Stevens Johnson Syndrome and Toxic Epidermal Necrolysis (very rare). Photosensitivity

Renal

Nephrotoxicity in various forms, including interstitial nephritis, nephrotic syndrome, and renal failure. Occasional effects on the kidney include acute renal insufficiency, urinary abnormalities (e.g., haematuria, proteinuria) and papillary necrosis.

Hepatic

Effects on the liver include occasional reports of elevation of serum aminotransferase enzymes (ALT, ST) and rarely abnormal liver function, hepatitis and jaundice.

Haematological Reactions

Thrombocytopenia, neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia and leucopenia..

Other rarely reported reactions include hypotension, hypertension, palpitation, impotence and chest pain.

4.9 Overdose

Symptoms

Symptoms include headache, nausea, vomiting, epigastric pain, gastrointestinal bleeding, rarely diarrhoea, excitation, coma, drowsiness, dizziness, tinnitus, fainting, occasionally convulsions, hypotension and respiratory depression. In cases of significant poisoning acute renal failure and liver damage are possible.

Management

Patients should be treated symptomatically as required.

Within one hour of ingestion of a potentially toxic amount, activated charcoal should be considered. Alternatively in adults gastric lavage should be considered within one hour of ingestion of a potentially life-threatening overdose.

Good urine output should be ensured.

Renal and liver function should be closely monitored.

Patients should be observed for at least four hours after ingestion of potentially toxic amounts.

Frequent or prolonged convulsions should be treated with intravenous diazepam.

The correction of severe electrolyte abnormalities may need to be considered.

Other measures may be indicated by the patient's clinical condition.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. It is an inhibitor of prostaglandin synthetase.

5.2 Pharmacokinetic Properties

This extended release diclofenac formulation is designed to release diclofenac over a period of time. Following a pharmacokinetic study with the 100mg tablet in volunteers, it was found that the average time to reach maximum plasma concentration was 6.05 hours.

The average elimination half-life was found to be 6.75 hours. The average maximum plasma concentrations were found to be 262ng/ml.

a) General Characteristics of the Active Substance

Diclofenac sodium is almost totally absorbed after oral administration, and it is subject to significant first-pass metabolism with only approximately 60% of an oral dose reaching the systemic circulation.

Diclofenac sodium is highly protein bound (> 99%). It is mainly excreted in the form of metabolites via the urine but also in the bile.

The main metabolite has a minimal anti-inflammatory activity compared to the parent drug.

b) Characteristics in Patients

Plasma concentrations of unchanged diclofenac are not reported to be significantly affected by age, renal or hepatic impairment. The metabolite concentrations may be increased by severe renal impairment.

5.3 Preclinical Safety Data

There is no preclinical data available that is of relevance to the prescriber.

6. Pharmaceutical Particulars

6.1 List Of Excipients

For Uncoated Tablets :

Talc

Ethylcellulose

Magnesium stearate

Povidone

Stearic acid

For Coating:

Hypromellose (E.464)

Ethylcellulose

Diethyl phthalate

Macrogol 4000

Titanium dioxide (E171)

In Addition for 100 mg :

Red iron oxide (E.172)

Yellow iron oxide (E.172)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Do not store above 25^°C. Store in the original package. Keep container in the outer carton.

6.5 Nature And Contents Of Container

The modified-release tablets are enclosed in blisters composed of 250µm PVC coated with 40gm^-2 PVdC and 25µm aluminium coated with 20gm^-2 PVdC.

The blisters are boxed in cardboard cartons containing 28, 30, 50, 56, 60, 84, 100, 250, 500 and 1000 modified-release tablets and a user leaflet.

6.6 Special Precautions For Disposal And Other Handling

Not applicable

7. Marketing Authorisation Holder

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK8 3GY

United Kingdom

8. Marketing Authorisation Number(S)

75mg tablets: PL 8829/0045

100mg tablets: PL 8829/0046

9. Date Of First Authorisation/Renewal Of The Authorisation

8^th January 2002

10. Date Of Revision Of The Text

30/01/2010

11. LEGAL CATEGORY

POM

Strepsils Strawberry Sugar Free Lozenges (Reckitt Benckiser Healthcare (UK) Ltd)

1. Name Of The Medicinal Product

Strepsils Strawberry Sugar Free Lozenges

2. Qualitative And Quantitative Composition

Amylmetacresol BP 0.6mg/lozenge

2,4-Dichlorobenzyl alcohol 1.2mg/lozenge

For excipients, see 6.1

3. Pharmaceutical Form

Lozenge

4. Clinical Particulars

4.1 Therapeutic Indications

As an antiseptic for the relief of sore throat and its associated pain.

4.2 Posology And Method Of Administration

For oral administration

Adults and children (over 6 years old)

One lozenge to be dissolved slowly in the mouth every 2-3 hours up to a maximum of 12 lozenges in 24 hours.

Not suitable for children under 6 years.

Elderly

There is no need for dosage reduction in the elderly

4.3 Contraindications

Strepsils Strawberry Sugar Free Lozenges are contraindicated in persons who have previously shown hypersensitivity to any of the ingredients.

4.4 Special Warnings And Precautions For Use

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

Not to be given to children under 6 years.

If symptoms persist consult your doctor.

Warning: Do not exceed the stated dose.

Consult your doctor if symptoms persist or are accompanied by a high fever or headache.

Contains isomaltitol and maltitol syrup, which may have a mild laxative effect if several are taken a day. 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

None known.

4.6 Pregnancy And Lactation

The product is not contraindicated during pregnancy and lactation. However, as with all medicines during this period, caution should be exercised.

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 nature and presentation of Strepsils Strawberry Sugar Free Lozenges, accidental or deliberate overdosage is highly unlikely.

Overdosage should not present a problem other than gastrointestinal discomfort. Treatment should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

2,4-Dichlorobenzyl alcohol and amylmetacresol have antiseptic properties.

5.2 Pharmacokinetic Properties

No data available.

5.3 Preclinical Safety Data

There are no preclinical data available specific to the product.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Flav P Strawberry Flavour

Ponceau 4R (E124)

Saccharin sodium Ph Eur (E954)

Tartaric acid Ph Eur

Isomalt (Isomaltitol E953)

Maltitol syrup (E965)

6.2 Incompatibilities

Not applicable

6.3 Shelf Life

3 years

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

The lozenges are contained in a strip pack containing either 6, 8, 12, 16, 20, 24, 32 or 36 lozenges packed into a cardboard carton.

The lozenges are contained in a strip pack containing 8 lozenges packed into a wrap around cardboard carton with tamper-evident seal.

Not all pack sizes may be marketed

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Ltd

Slough

SL1 3UH

8. Marketing Authorisation Number(S)

PL 00063/0395

9. Date Of First Authorisation/Renewal Of The Authorisation

6^th April 2010

10. Date Of Revision Of The Text

April 2010.

Stamaril

1. Name Of The Medicinal Product

STAMARIL (or local trade name)

Powder and solvent for suspension for injection in pre-filled syringe.

Yellow fever vaccine (Live).

2. Qualitative And Quantitative Composition

After reconstitution, 1 dose (0.5 ml) contains:

Yellow fever virus¹ 17 D-204 strain (live, attenuated) ........................... not less than 1000 LD₅₀ units²

¹ produced in specified pathogen-free chick embryos

² The statistically determined lethal dose in 50% of animals tested

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and solvent for suspension for injection.

The powder is beige to orange beige; the solvent is clear and colourless.

4. Clinical Particulars

4.1 Therapeutic Indications

STAMARIL is indicated for active immunization against yellow fever in persons:

• travelling to, passing through or living in an endemic area,

• travelling to any country that requires an International Certificate of Vaccination for entry (which may or may not depend on the previous itinerary).

• handling potentially infectious materials (e.g. laboratory personnel).

See sections 4.2, 4.3 and 4.4 regarding the minimum age for vaccination of children under special circumstances and guidance for vaccination of other specific patient populations.

In order to comply with vaccine regulations and to be officially recognised, yellow fever vaccines must be administered in an approved World Health Organization (WHO) vaccination centre and registered on an International Certificate of Vaccination. This certificate is valid for 10 years from the 10th day after vaccination and immediately after re-vaccination.

4.2 Posology And Method Of Administration

Posology

Primary vaccination

Adults and children aged 9 months and over: A single dose of 0.5 ml of reconstituted vaccine.

Children under 9 months of age: The vaccine must not be given to children less than 6 months old (see section 4.3). Vaccination against yellow fever is not usually recommended in children aged from 6 months up to 9 months except in specific circumstances and in accordance with available official recommendations (see section 4.4), in which case the dose is the same as in older children and adults.

The vaccine should be given at least 10 days before entering an endemic area since protective immunity may not be achieved until at least this time has elapsed.

Elderly

The dose is the same as for adults. However due to a higher risk of yellow fever vaccine-associated severe and potentially fatal disease in persons from 60 years of age, the vaccine should only be given when it is considered that there is a considerable and unavoidable risk of acquiring yellow fever infection (see sections 4.4 and 4.8).

Re-vaccination

Re-vaccination with one dose of 0.5 ml is recommended every 10 years in persons considered to be at risk of exposure.

International Health Regulations require re-vaccination, using the same dose as for primary vaccination, at intervals of 10 years in order to retain a valid certificate.

Method of administration

It is preferable that the vaccine is injected by the subcutaneous route

Intramuscular injection may be performed if this is in accordance with applicable official recommendations.

For intramuscular use the recommended injection sites are the anterolateral aspect of the thigh in the infants and toddlers (6 months up to 2 years of age) and the deltoid muscle in older children and adults.

DO NOT INJECT INTRAVASCULARLY

See section 6.6. for instructions on reconstitution

4.3 Contraindications

• Hypersensitivity reaction to eggs, chicken proteins or to any component of STAMARIL

• Serious hypersensitivity reactions (e.g., anaphylaxis) after a previous dose of any yellow fever vaccine.

• Immunosuppression, whether congenital, idiopathic or as a result of treatment with systemic steroids (greater than the standard dose of topical or inhaled steroids), radiotherapy or cytotoxic drugs.

• History of thymus dysfunction (including thymoma, thymectomy)

• Symptomatic HIV infection

• Asymptomatic HIV infection when accompanied by evidence of impaired immune function (see section 4.4).

• Age less than 6 months (see sections 4.2 and 4.4).

• Current severe febrile illness.

4.4 Special Warnings And Precautions For Use

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of anaphylaxis or other severe hypersensitivity reaction following administration of the vaccine.

STAMARIL should be administered only to persons who are/will be at risk of infection with yellow fever virus or who must be vaccinated to comply with international health regulations. Before considering administration of yellow fever vaccine, care should be taken to identify those who might be at increased risk of adverse reactions following vaccination (see section 4.3 and below).

Yellow fever vaccine associated neurotropic disease

Very rarely, yellow fever vaccine-associated neurotropic disease (YEL-AND) has been reported following vaccination, with sequelae or with fatal outcome in some cases (see section 4.8). Clinical features have appeared within one month of vaccination and include high fever with headache that may progress to include one or more of the following: confusion, encephalitis/encephalopathy, meningitis, focal neurological deficits, or Guillain Barré syndrome. To date, those affected have been primary vaccinees. The risk appears to be higher in those aged over 60 years, although cases have been also reported in younger persons or following transmission from nursing mothers to the infants.

Yellow fever vaccine-associated viscerotropic disease

Very rarely, yellow fever vaccine-associated viscerotropic disease (YEL-AVD) resembling fulminant infection by wild-type virus has been reported following vaccination (see section 4.8). The clinical presentation may include fever, fatigue, myalgia, headache, hypotension, progressing to one or more of metabolic acidosis, muscle and liver cytolysis, lymphocytopenia and thrombocytopenia, renal failure and respiratory failure. The mortality rate has been around 60%. To date, all cases of YEL-AVD have been in primary vaccinees with onset within 10 days of vaccination. The risk appears to be higher in those aged over 60 years although cases have also been reported in younger persons. Disease of the thymus gland has also been recognised as a potential risk factor (see section 4.3 and section 4.8).

Immunosuppressed persons

STAMARIL must not be administered to immunosuppressed persons (see section 4.3).

If the immunosuppression is temporary, vaccination should be delayed until the immune function has recovered. In patients who have received systemic corticosteroids for 14 days or more, it is advisable to delay vaccination until at least one month after completing the course.

• HIV infection

STAMARIL must not be administrated to persons with symptomatic HIV infection or with asymptomatic HIV infection when accompanied by evidence of impaired immune function (see section 4.3). However, there are insufficient data at present to determine the immunological parameters that might differentiate persons who could be safely vaccinated and who might mount a protective immune response from those in whom vaccination could be both hazardous and ineffective. Therefore, if an asymptomatic HIV-infected person cannot avoid travel to an endemic area available official guidance should be taken into account when considering the potential risks and benefits of vaccination.

• Children born to HIV positive mothers

Children aged at least 6 months (see sections 4.2 and 4.3 and below) may be vaccinated if it is confirmed that they are not infected with HIV.

HIV infected children aged at least 6 months who are potentially in need of protection against yellow fever should be referred to a specialist paediatric team for advice on whether or not to vaccinate.

Age

• Children aged 6 to 9 months

STAMARIL must not be administered to children before the age of 6 months (see section 4.3). Children aged from 6 months up to 9 months should only be vaccinated under special circumstances (e.g. during major outbreaks) and on the basis of current official advice.

• Persons aged 60 years and older

Some serious and potentially fatal adverse reactions (including systemic and neurological reactions persisting more than 48 hours, YEL-AVD and YEL-AND) appear to occur at higher frequencies after the age of 60 years. Therefore, the vaccine should only be given to those who have a considerable risk of acquiring yellow fever (see above and section 4.8).

Because intramuscular injection can cause injection site haematoma, STAMARIL should not be given by the intramuscular route to persons with any bleeding disorder, such as haemophilia or thrombocytopenia, or to persons on anticoagulant therapy. The subcutaneous route of administration should be used instead.

Patients with rare hereditary problems of fructose intolerance should not take this vaccine.

Transmission

There are very few reports suggesting that transmission of Yellow Fever vaccine virus may occur from nursing mothers, who received Yellow Fever vaccine postpartum, to the infant. Following transmission the infants may develop yellow fever vaccine associated neurotropic disease (YEL-AND) from which the infants recover (see section 4.6).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

STAMARIL must not be mixed with any other vaccine or medicinal product in the same syringe.

If there is a need to administer another injectable vaccine(s) at the same time as STAMARIL each vaccine should be injected into a separate site (and preferably a separate limb).

STAMARIL may be administered at the same time as measles vaccine if this is in accordance with official recommendations.

STAMARIL may be administered at the same time as vaccines containing typhoid Vi capsular polysaccharide and/or inactivated hepatitis A virus.

STAMARIL must not be administered to persons who are receiving immunosuppressant therapy (e.g., cytotoxic agents, systemic steroids, greater than standard dose of topical or inhaled steroids or other agents). See section 4.3.

4.6 Pregnancy And Lactation

Pregnancy

No animal reproduction studies have been conducted with STAMARIL and the potential risk for humans is unknown. Data on a limited number of exposed pregnancies indicate no adverse effects of STAMARIL on pregnancy or the health of the fetus/newborn child. Nevertheless, STAMARIL should be given to pregnant women only when clearly needed and only after careful consideration of the potential risks and benefits.

Lactation

As there is a probable risk of transmission of the vaccine virus strain to the infants from breast-feeding mothers, STAMARIL should not be given to nursing mothers unless when clearly needed such as during an outbreak control, and following an assessment of the risks and benefits (see section 4.4.).

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive or use machine have been performed.

4.8 Undesirable Effects

Data from clinical studies

Across clinical studies, the most common adverse reactions occurring after vaccine administration were local reactions, reported in approximately 16% of subjects.

The following adverse events are from one clinical study in which 106 healthy adult subjects received STAMARIL. .

The adverse events are ranked under headings of frequency, using the following convention:

• Very common:

• Common:

• Uncommon:

Nervous system disorders
Very common:	Headache
Gastro-intestinal system disorders
Common:	Nausea, Diarrhoea, Vomiting
Uncommon:	Abdominal pain
Musculo-skeletal and connective tissue disorders
Common:	Myalgia
Uncommon:	Arthralgia
General disorders and administration site conditions
Very common:	Local reactions (including pain, redness, haematoma, induration, swelling)
Common:	Pyrexia, Asthenia

Data from post-marketing experience

The following additional adverse events have been reported during post marketing experience with STAMARIL. They are based on spontaneous reporting therefore the frequencies are unknown.

Blood and lymphatic system disorders

Lymphadenopathy

Immune system disorders

Anaphylaxis, angioedema.

Nervous system disorders

Cases of neurotropic disease (known as YEL-AND), some of which have had a fatal outcome, have been reported following yellow fever vaccination (see section 4.4). YEL-AND may manifest as high fever with headache that may progress to include one or more of confusion, lethargy, encephalitis, encephalopathy and meningitis (see section 4.4).

Other neurological signs and symptoms have been reported and include convulsion, Guillain-Barré syndrome and focal neurological deficits.

Skin and subcutaneous tissue disorders

Rash, Urticaria

General disorders and administration site conditions

Cases of viscerotropic disease (known as YEL-AVD and formerly described as “Febrile Multiple Organ-System Failure”) have been reported following yellow fever vaccination some of which have been fatal (see section 4.4). YEL-AVD may manifest as fever, fatigue, myalgia, headache and hypotension progressing to one or more of metabolic acidosis, muscle and liver cytolysis, lymphocytopenia and thrombocytopenia, renal and respiratory failure.

Additional information on special population

Congenital or acquired immunodeficiency has been identified as a risk factor for neurotropic disease (See sections 4.3 and 4.4).

Age of more than 60 years (see section 4.4) has been identified as a risk factor for YEL-AVD and YEL-AND. A medical history of thymic disease (see sections 4.3 and 4.4) has been identified as a risk factor for YEL-AVD.

4.9 Overdose

No case of overdose has been reported.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Yellow Fever Vaccine (Live)

ATC code: J07B L1

STAMARIL is a live attenuated yellow fever virus vaccine. As with other live attenuated viral vaccines, there is a sub-clinical infection in healthy recipients that results in the production of specific B and T cells and the appearance of specific circulating antibody.

Protective immunity appears from about 10 days after injection. Although International Health Regulations require re-vaccination at intervals of 10 years in order to retain a valid certificate, some degree of immunity likely persists for more than 10 years.

5.2 Pharmacokinetic Properties

No pharmacokinetic studies have been performed.

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder:

Lactose

Sorbitol E420

L-histidine hydrochloride

L-alanine

Sodium chloride

Potassium chloride

Disodium phosphate

Monopotassium phosphate

Calcium chloride

Magnesium sulphate

Solvent:

Sodium chloride

Water for injections.

6.2 Incompatibilities

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

6.3 Shelf Life

3 years.

After reconstitution, the medicinal product must be used immediately.

6.4 Special Precautions For Storage

Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the vial in the outer carton in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature And Contents Of Container

Powder in vial (type I glass), with a stopper (chlorobutyl) and a flip-off cap (aluminium) + 0.5 ml of solvent in a pre-filled syringe (type I glass), with a plunger-stopper (halobutyl), and an attached needle and needle-shield (natural rubber or polyisoprene)– pack size of 1, 10 or 20.

Powder in vial (type I glass), with a stopper (chlorobutyl) and a flip-off cap (aluminium) + 0.5 ml of solvent in a pre-filled syringe (type I glass), with a plunger-stopper (halobutyl), and a tip-cap (chlorobromobutyl or styrene - butadiene) – pack size of 1, 10.

Powder in vial (type I glass), with a stopper (chlorobutyl) and a flip-off cap (aluminium) + 0.5 ml of solvent in a pre-filled syringe (type I glass), with a plunger-stopper (halobutyl) and a tip cap (chlorobromobutyl or styrene - butadiene) with 1 or 2 separate needles attached in the blister– pack size of 1 and 10.

Not all pack sizes or presentations may be marketed.

6.6 Special Precautions For Disposal And Other Handling

For syringe without attached needle only: After removing the syringe tip cap, the needle should be firmly placed on the tip of the syringe and secured by rotating a quarter of a turn (90°).

The powder is reconstituted by adding the solvent provided in the pre-filled syringe to the vial. The vial is shaken and, after complete dissolution, the suspension obtained is withdrawn into this same syringe for injection.

Before administration, the reconstituted vaccine should be shaken vigorously.

Use immediately after reconstitution.

After reconstitution the suspension is beige to pink beige.

Contact with disinfectants is to be avoided since they may inactivate the virus.

Any unused product or waste material should be disposed of, preferably by heat inactivation or incineration, in accordance with local requirements.

7. Marketing Authorisation Holder

Sanofi Pasteur MSD Limited

Mallards Reach

Bridge Avenue

Maidenhead

Berkshire SL6 1QP

8. Marketing Authorisation Number(S)

PL 6745/0087

9. Date Of First Authorisation/Renewal Of The Authorisation

03/09/2007

10. Date Of Revision Of The Text

11/2010

Primacor

milrinone lactate

Dosage Form: Injection

200 MCG/ML IN 5% DEXTROSE INJECTION

Primacor Description

Primacor, brand of milrinone lactate injection, is a member of a class of bipyridine inotropic/vasodilator agents with phosphodiesterase inhibitor activity, distinct from digitalis glycosides or catecholamines. Primacor (milrinone lactate) is designated chemically as 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile lactate and has the following structure:

Milrinone is an off-white to tan crystalline compound with a molecular weight of 211.2 and an empirical formula of C12H9N3O. It is slightly soluble in methanol, and very slightly soluble in chloroform and in water. As the lactate salt, it is stable and colorless to pale yellow in solution. Primacor is available as sterile aqueous solutions of the lactate salt of milrinone for infusion intravenously.

Pre-Mix Flexible Containers:The Flexible Containers provide two ready-to-use dilutions of milrinone in volumes of 100 mL and 200 mL of 5% Dextrose Injection. Each mL contains milrinone lactate equivalent to 200 mcg milrinone. The nominal concentration of lactic acid is 0.282 mg/mL. Each mL also contains 49.4 mg dextrose, anhydrous, USP. The pH is adjusted to between 3.2 and 4.0 with lactic acid or sodium hydroxide. The flexible plastic container is comprised of polyvinyl chloride with a foil overwrap. Water can permeate the plastic into the overwrap, but the amount is insufficient to significantly affect the pre-mix solution.

Primacor - Clinical Pharmacology

Primacor is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines.

Primacor, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that Primacor is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as do the digitalis glycosides.

Clinical studies in patients with congestive heart failure have shown that Primacor produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that Primacor produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Primacor also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug.

Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL.

In addition to increasing myocardial contractility, Primacor improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation.

The acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients, with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related.

PHARMACOKINETICS

Following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, Primacor had a volume of distribution of 0.38 liters/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. Following intravenous infusions of 0.20 mcg/kg/min to 0.70 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent.

Primacor has been shown (by equilibrium dialysis) to be approximately 70% bound to human plasma protein.

The primary route of excretion of Primacor in man is via the urine. The major urinary excretions of orally administered Primacor in man are milrinone (83%) and its 0-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of Primacor is approximately 0.3 liters/min, indicative of active secretion.

Pharmacodynamics

In patients with heart failure due to depressed myocardial function, Primacor produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. Additionally, there is no increased effect on myocardial oxygen consumption. In uncontrolled studies, hemodynamic improvement during intravenous therapy with Primacor was accompanied by clinical symptomatic improvement, but the ability of Primacor to relieve symptoms has not been evaluated in controlled clinical trials. The great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of the initiation of therapy.

In studies in congestive heart failure patients, Primacor when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.50 mcg/kg/min, and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. Mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). A smaller number of patients have received infusions of Primacor for periods up to 72 hours without evidence of tachyphylaxis.

The duration of therapy should depend upon patient responsiveness.

Primacor has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation, it is possible that Primacor may increase ventricular response rate because of its slight enhancement of AV node conduction. In these cases, digitalis should be considered prior to the institution of therapy with Primacor.

Improvement in left ventricular function in patients with ischemic heart disease has been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia.

The steady-state plasma milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.50 mcg/kg/min are approximately 200 ng/mL. Near maximum favorable effects of Primacor on cardiac output and pulmonary capillary wedge pressure are seen at plasma milrinone concentrations in the 150 ng/mL to 250 ng/mL range.

Indications and Usage for Primacor

Primacor is indicated for the short-term intravenous treatment of patients with acute decompensated heart failure. Patients receiving Primacor should be observed closely with appropriate electrocardiographic equipment. The facility for immediate treatment of potential cardiac events, which may include life threatening ventricular arrhythmias, must be available. The majority of experience with intravenous Primacor has been in patients receiving digoxin and diuretics. There is no experience in controlled trials with infusions of Primacor for periods exceeding 48 hours.

Contraindications

Primacor is contraindicated in patients who are hypersensitive to it.

Warnings

Whether given orally or by continuous or intermittent intravenous infusion, Primacor has not been shown to be safe or effective in the longer (greater than 48 hours) treatment of patients with heart failure. In a multicenter trial of 1088 patients with Class III and IV heart failure, long-term oral treatment with Primacor was associated with no improvement in symptoms and an increased risk of hospitalization and death. In this study, patients with Class IV symptoms appeared to be at particular risk of life-threatening cardiovascular reactions. There is no evidence that Primacor given by long-term continuous or intermittent infusion does not carry a similar risk.

The use of Primacor both intravenously and orally has been associated with increased frequency of ventricular arrhythmias, including nonsustained ventricular tachycardia. Long-term oral use has been associated with an increased risk of sudden death. Hence, patients receiving Primacor should be observed closely with the use of continuous electrocardiographic monitoring to allow the prompt detection and management of ventricular arrhythmias.

Precautions

General

Primacor should not be used in patients with severe obstructive aortic or pulmonic valvular disease in lieu of surgical relief of the obstruction. Like other inotropic agents, it may aggravate outflow tract obstruction in hypertrophic subaortic stenosis.

Supraventricular and ventricular arrhythmias have been observed in the high-risk population treated. In some patients, injections of Primacor and oral Primacor have been shown to increase ventricular ectopy, including nonsustained ventricular tachycardia. The potential for arrhythmia, present in congestive heart failure itself, may be increased by many drugs or combinations of drugs. Patients receiving Primacor should be closely monitored during infusion.

Primacor produces a slight shortening of AV node conduction time, indicating a potential for an increased ventricular response rate in patients with atrial flutter/fibrillation which is not controlled with digitalis therapy.

During therapy with Primacor, blood pressure and heart rate should be monitored and the rate of infusion slowed or stopped in patients showing excessive decreases in blood pressure.

If prior vigorous diuretic therapy is suspected to have caused significant decreases in cardiac filling pressure, Primacor should be cautiously administered with monitoring of blood pressure, heart rate, and clinical symptomatology.

There is no experience in controlled trials with infusions of milrinone for periods exceeding 48 hours. Cases of infusion site reaction have been reported with intravenous milrinone therapy (seeADVERSE REACTIONS). Consequently,careful monitoring of the infusion site should be maintainedto avoid possible extravasation.

Use in Acute Myocardial Infarction

No clinical studies have been conducted in patients in the acute phase of post myocardial infarction. Until further clinical experience with this class of drugs is gained, Primacor is not recommended in these patients.

Laboratory Tests

Fluid and Electrolytes

Fluid and electrolyte changes and renal function should be carefully monitored during therapy with Primacor. Improvement in cardiac output with resultant diuresis may necessitate a reduction in the dose of diuretic. Potassium loss due to excessive diuresis may predispose digitalized patients to arrhythmias. Therefore, hypokalemia should be corrected by potassium supplementation in advance of or during use of Primacor.

Drug Interactions

No untoward clinical manifestations have been observed in limited experience with patients in whom Primacor was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.

Chemical Interactions

There is an immediate chemical interaction which is evidenced by the formation of a precipitate when furosemide is injected into an intravenous line of an infusion of Primacor. Therefore, furosemide should not be administered in intravenous lines containing Primacor.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Twenty-four months of oral administration of Primacor to mice at doses up to 40 mg/kg/day (about 50 times the human oral therapeutic dose in a 50 kg patient) was unassociated with evidence of carcinogenic potential. Neither was there evidence of carcinogenic potential when Primacor was orally administered to rats at doses up to 5 mg/kg/day (about 6 times the human oral therapeutic dose) for twenty-four months or at 25 mg/kg/day (about 30 times the human oral therapeutic dose) for up to 18 months in males and 20 months in females. Whereas the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system, results from the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis indicated an absence of mutagenic potential. In reproductive performance studies in rats, Primacor had no effect on male or female fertility at oral doses up to 32 mg/kg/day.

Animal Toxicity

Oral and intravenous administration of toxic dosages of Primacor to rats and dogs resulted in myocardial degeneration/fibrosis and endocardial hemorrhage, principally affecting the left ventricular papillary muscles. Coronary vascular lesions characterized by periarterial edema and inflammation have been observed in dogs only. The myocardial/endocardial changes are similar to those produced by beta-adrenergic receptor agonists such as isoproterenol, while the vascular changes are similar to those produced by minoxidil and hydralazine. Doses within the recommended clinical dose range (up to 1.13 mg/kg/day) for congestive heart failure patients have not produced significant adverse effects in animals.

Pregnancy Category C

Oral administration of Primacor to pregnant rats and rabbits during organogenesis produced no evidence of teratogenicity at dose levels up to 40 mg/kg/day and 12 mg/kg/day, respectively. Primacor did not appear to be teratogenic when administered intravenously to pregnant rats at doses up to 3 mg/kg/day (about 2.5 times the maximum recommended clinical intravenous dose) or pregnant rabbits at doses up to 12 mg/kg/day, although an increased resorption rate was apparent at both 8 mg/kg/day and 12 mg/kg/day (intravenous) in the latter species. There are no adequate and well-controlled studies in pregnant women. Primacor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Caution should be exercised when Primacor is administered to nursing women, since it is not known whether it is excreted in human milk.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Use in Elderly Patients

There are no special dosage recommendations for the elderly patient. Ninety percent of all patients administered Primacor in clinical studies were within the age range of 45 to 70 years, with a mean age of 61 years. Patients in all age groups demonstrated clinically and statistically significant responses. No age-related effects on the incidence of adverse reactions have been observed. Controlled pharmacokinetic studies have not disclosed any age-related effects on the distribution and elimination of Primacor.

Adverse Reactions

Cardiovascular Effects

In patients receiving Primacor in Phase II and III clinical trials, ventricular arrhythmias were reported in 12.1%: Ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1% and ventricular fibrillation, 0.2% (2 patients experienced more than one type of arrhythmia). Holter recordings demonstrated that in some patients injection of Primacor increased ventricular ectopy, including nonsustained ventricular tachycardia. Life-threatening arrhythmias were infrequent and when present have been associated with certain underlying factors such as preexisting arrhythmias, metabolic abnormalities (e.g. hypokalemia), abnormal digoxin levels and catheter insertion. Primacor was not shown to be arrhythmogenic in an electrophysiology study. Supraventricular arrhythmias were reported in 3.8% of the patients receiving Primacor. The incidence of both supraventricular and ventricular arrhythmias has not been related to the dose or plasma milrinone concentration.

Other cardiovascular adverse reactions include hypotension, 2.9% and angina/chest pain, 1.2%.

In the post marketing experience, there have been rare cases of "torsades de pointes" reported.

CNS Effects

Headaches, usually mild to moderate in severity, have been reported in 2.9% of patients receiving Primacor.

Other Effects

Other adverse reactions reported, but not definitely related to the administration of Primacor include hypokalemia, 0.6%; tremor, 0.4%; and thrombocytopenia, 0.4%.

Post-Marketing Adverse Event Reports

In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with Primacor:

Isolated spontaneous reports of bronchospasm and anaphylactic shock.

Liver function test abnormalities and skin reactions such as rash.

Administration site conditions: Infusion site reaction.

Overdosage

Doses of Primacor may produce hypotension because of its vasodilator effect. If this occurs, administration of Primacor should be reduced or temporarily discontinued until the patient's condition stabilizes. No specific antidote is known, but general measures for circulatory support should be taken.

Primacor Dosage and Administration

Primacor (milrinone lactate) should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines:

LOADING DOSE

50 mcg/kg: Administer slowly over 10 minutes

Note: Primacor Flexible Containers (200 mcg/mL in 5% Dextrose Injection) are for intravenous infusion only and should not be used for a loading dose. Dosage recommendations using a 1mg/mL concentration of milrinone are included for informational purposes only. The loading dose should be administered using a milrinone 1mg/mL vial.

The table below shows the loading dose in milliliters (mL) of milrinone (1mg/mL) by patient body weight (kg).

Loading Dose (mL) Using 1 mg/mL Concentration

Patient Body Weight (kg)
kg	30	40	50	60	70	80	90	100	110	120
mL	1.5	2.0	2.5	3.0	3.5	4.0	4.5	5.0	5.5	6.0

The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL (seeMaintenance Dosefor diluents) may simplify the visualization of the injection rate.

MAINTENANCE DOSE

	Infusion Rate	Total Daily Dose (24 Hours)
Minimum	0.375 mcg/kg/min	0.59 mg/kg	Administer as a
Standard	0.50 mcg/kg/min	0.77 mg/kg	continuous
Maximum	0.75 mcg/kg/min	1.13 mg/kg	intravenous infusion

The infusion rate should be adjusted according to hemodynamic and clinical response. Patients should be closely monitored. In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure.

Note: See"Dosage Adjustment in Renally Impaired Patients."Dosage may be titrated to the maximum hemodynamic effect and should not exceed 1.13 mg/kg/day. Duration of therapy should depend upon patient responsiveness.

The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table.

Note:Primacor supplied in 100 mL and 200 mL Flexible Containers (200 mcg/mL in 5% Dextrose Injection) need not be diluted prior to use.

Primacor Infusion Rate (mL/hr) Using 200 mcg/mL Concentration

Maintenance Dose	Patient Body Weight (kg)
(mcg/kg/min)	30	40	50	60	70	80	90	100	110	120
0.375	3.4	4.5	5.6	6.8	7.9	9.0	10.1	11.3	12.4	13.5
0.400	3.6	4.8	6.0	7.2	8.4	9.6	10.8	12.0	13.2	14.4
0.500	4.5	6.0	7.5	9.0	10.5	12.0	13.5	15.0	16.5	18.0
0.600	5.4	7.2	9.0	10.8	12.6	14.4	16.2	18.0	19.8	21.6
0.700	6.3	8.4	10.5	12.6	14.7	16.8	18.9	21.0	23.1	25.2
0.750	6.8	9.0	11.3	13.5	15.8	18.0	20.3	22.5	24.8	27.0

When administering Primacor (milrinone lactate) by continuous infusion, it is advisable to use a calibrated electronic infusion device.

The Flexible Container has a concentration of milrinone equivalent to 200 mcg/mL in 5% Dextrose Injection. To use the Flexible Container, tear the overwrap at the notch and remove the Pre-Mix solution container. Squeeze the container firmly to check for leaks. Discard the container if leaks are found since the sterility of the product could be affected. Do not add supplementary medication. To prepare the container for administration of Primacor intravenously, use aseptic techniques.

1)

The flow control clamp of the administration set is closed.

2)

The cover of the outlet port at the bottom of the container is removed.

3)

Noting the full directions on the administration set carton, the piercing pin of the set is inserted into the port with a twisting motion until it is firmly seated.

4)

The container is suspended on the hanger.

5)

The drip chamber is squeezed and released to establish the fill level.

6)

The flow control clamp is opened to expel air from the set, and then closed.

7)

The set is attached to the venipuncture device, primed, and if not indwelling, the venipuncture is performed.

8)

The rate of administration is controlled with the flow control clamp. WARNING- DO NOT USE IN SERIES CONNECTIONS. Caution: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present.

Dosage Adjustment in Renally Impaired Patients

Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of Primacor. Reductions in infusion rate may be necessary in patients with renal impairment. For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table:

Creatinine Clearance (mL/min/1.73m2)	Infusion Rate (mcg/kg/min)
5	0.20
10	0.23
20	0.28
30	0.33
40	0.38
50	0.43

How is Primacor Supplied

Primacor Flexible Containers (200 mcg/mL in 5% Dextrose Injection) are supplied:

100 mL (200 mcg/mL) NDC 0024-1203-11 in 5% Dextrose Injection single units.

200 mL (200 mcg/mL) NDC 0024-1203-22 in 5% Dextrose Injection single units.

Exposure of pharmaceutical products to heat should be minimized. Avoid excessive heat. Protect from freezing. It is recommended that the Flexible Containers be stored at room temperature, 25 C (77 F), however, brief exposure up to 40 C (104 F) does not adversely affect the product.

Manufactured by:

Hospira Inc.

Lake Forest, IL 60045

Manufactured for:

sanofi-aventis U.S. LLC

Bridgewater, NJ 08807

Revised March 2007B

©2007 sanofi-aventis U.S. LLC

Primacor  milrinone lactate  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0024-1203 Route of Administration INTRAVENOUS DEA Schedule

INGREDIENTS Name (Active Moiety) Type Strength milrinone lactate (milrinone) Active 200 MICROGRAM  In 1 MILLILITER Dextrose, Anhydrous Inactive 49.4 MILLIGRAM  In 1 MILLILITER lactic acid Inactive 0.282 MILLIGRAM  In 1 MILLILITER Water Inactive

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 0024-1203-01 100 mL (MILLILITER) In 1 CONTAINER None 2 0024-1203-02 200 mL (MILLILITER) In 1 CONTAINER None

Revised: 02/2008sanofi-aventis U.S. LLC

More Primacor resources

• Primacor Side Effects (in more detail)
• Primacor Dosage
• Primacor Use in Pregnancy & Breastfeeding
• Primacor Drug Interactions
• Primacor Support Group
• 0 Reviews for Primacor - Add your own review/rating

• Primacor Concise Consumer Information (Cerner Multum)


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• Primacor MedFacts Consumer Leaflet (Wolters Kluwer)


• Primacor I.V. Concise Consumer Information (Cerner Multum)

Compare Primacor with other medications

• Heart Failure

Viridal Duo 40 micrograms / ml,Powder and Solvent for Solution for Injection.

1. Name Of The Medicinal Product

Viridal Duo 40 microgram/ml, Powder and Solvent for Solution for Injection

2. Qualitative And Quantitative Composition

Alprostadil 40 micrograms (used as a 1:1 clathrate complex with alfadex)

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Powder and Solvent for Solution for Injection.

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

4. Clinical Particulars

4.1 Therapeutic Indications

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

Treatment of erectile dysfunction in adult males.

4.2 Posology And Method Of Administration

The drug solution should be prepared shortly before the injection.

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

Unused solution must be discarded immediately.

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

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

Dosage for injection in the clinic

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

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

Dosage for self-injection therapy at home

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

Follow-up

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

4.3 Contraindications

Hypersensitivity to the active substances or to any other ingredients.

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

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

4.4 Special Warnings And Precautions For Use

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

Sexual stimulation and intercourse can lead to cardiac and/or pulmonary events in patients with coronary heart disease, congestive heart failure or pulmonary disease.

Viridal Duo should be used with care in these patient groups and patients should be examined and cleared for stress resistance by a cardiologist before treatment.

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

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

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

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

Other intracavernous drugs e.g. smooth muscle relaxing agents or alpha-adrenergic blocking agents may lead to prolonged erection and must not be used concomitantly.

The effects of a combination therapy of alprostadil with oral, intraurethral or topical medicinal products for erectile dysfunction are currently unknown.

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

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

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

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

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

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

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

Viridal Duo does not interfere with ejaculation and fertility.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

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

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

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

4.6 Pregnancy And Lactation

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

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

Undesirable effects frequencies are defined as:

Very common (

Common (

Uncommon (

Rare (

Very rare (< 1/10,000).

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

General disorders and administration site condition

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

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

Reproductive system and breast disorders

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

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

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

Cardiac disorders

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

Immune system disorders

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

4.9 Overdose

Symptoms

Full rigid erections lasting more than four hours.

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

Treatment strategy

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

If the erection has lasted less than six hours:

− observation of the erection because spontaneous flaccidity frequently occurs.

If the erection has lasted longer than six hours:

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

or

− aspiration of blood from the cavernous body.

Accidental systemic injection of high doses

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

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC Code: Other urologicals G04BX 05

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

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

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

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

5.2 Pharmacokinetic Properties

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

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

Metabolism

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

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

Excretion

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

5.3 Preclinical Safety Data

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

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

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

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

Mutagenicity studies with alprostadil alfadex revealed no risk of mutagenicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Powder for injection:

Lactose monohydrate

Alfadex

Diluent:

Sodium chloride

Water for injection.

6.2 Incompatibilities

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

6.3 Shelf Life

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

Shelf life after reconstitution: for immediate use only.

6.4 Special Precautions For Storage

Do not store above 25°C.

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

6.5 Nature And Contents Of Container

Administration devices:

1 reusable injector (starter kit)

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

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

1 alcohol swab to be obtained for each injection.

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

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

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

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

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

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

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

Unused solution must be discarded immediately.

Advice

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

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

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

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

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

Disposal of cartridge: no special requirements.

7. Marketing Authorisation Holder

UCB Pharma Limited

208 Bath Road

Slough

Berkshire

SL1 3WE

United Kingdom

8. Marketing Authorisation Number(S)

PL 00039/0753

9. Date Of First Authorisation/Renewal Of The Authorisation

3^rd September 2010

10. Date Of Revision Of The Text