Minodiab 5

1. Name Of The Medicinal Product

Minodiab 5 mg Tablets

2. Qualitative And Quantitative Composition

Glipizide 5.0 mg

3. Pharmaceutical Form

White biconvex tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

Glipizide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

4.2 Posology And Method Of Administration

Route of administration Oral

As for any hypoglycaemic agent, dosage must be adapted for each individual case.

Short term administration of glipizide may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

In general, glipizide should be given shortly before a meal to achieve the greatest reduction in post-prandial hyperglycaemia.

Initial Dose

The recommended starting dose is 5 mg, given before breakfast or the midday meal. Mild diabetics, geriatric patients or those with liver disease may be started on 2.5 mg.

Titration

Dosage adjustments should ordinarily be in increments of 2.5 to 5 mg, as determined by blood glucose response. At least several days should elapse between titration steps. The maximum recommended single dose is 15 mg. If this is not sufficient, splitting the daily dosage may prove effective. Doses above 15 mg should ordinarily be divided.

Maintenance

Some patients may be effectively controlled on a once-a-day regimen. Total daily dosage above 15 mg should ordinarily be divided.

The maximum recommended daily dosage is 20 mg.

Use in Children

Safety and effectiveness in children have not been established.

Use in Elderly and in High Risk Patients

In elderly patients, debilitated or malnourished patients and patients with an impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycaemic reactions (see Initial Dose and Special Warnings and Special Precautions for Use sections).

Patients Receiving Other Oral Hypoglycaemic Agents

As with other sulphonylurea class hypoglycaemics, no transition period is necessary when transferring patients to glipizide. Patients should be observed carefully (1-2 weeks) for hypoglycaemia when being transferred from longer half-life sulphonylureas (e.g. chlorpropamide) to glipizide due to potential overlapping of drug effect.

4.3 Contraindications

Glipizide is contraindicated in patients with:

1. Hypersensitivity to glipizide, other sulphonylureas or sulphonamides, or any excipients in the tablets;

2. Insulin-dependent diabetes, diabetic ketoacidosis, diabetic coma;

3. Severe renal or hepatic insufficiency;

4. Patients treated with miconazole (see 4.5 Interactions);

5. Pregnancy and lactation

4.4 Special Warnings And Precautions For Use

G6PD-deficiency: Since glipizide belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD-deficiency. Treatment of patients with G6PD-deficiency with sulfonylurea agents can lead to haemolytic anaemia and a non-sulfonylurea alternative should be considered.

Hypoglycaemia

All sulphonylurea drugs are capable of producing severe hypoglycaemia. Renal or hepatic insufficiency may cause elevated blood levels of glipizide and the latter may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycaemic reactions. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycaemic action of glucose-lowering drugs.

Hypoglycaemia may be difficult to recognise in the elderly, and in people who are taking beta-adrenergic blocking drugs (see interactions). Hypoglycaemia is more likely to occur when caloric- intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

Loss of control of blood glucose

When a patient stabilised on a diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue glipizide and administer insulin.

The effectiveness of any oral hypoglycaemic drug, including glipizide, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Renal and Hepatic Disease

The pharmacokinetics and/or pharmacodynamics of glipizide may be affected in patients with impaired renal or hepatic function. If hypoglycaemia should occur in such patients, it may be prolonged and appropriate management should be instituted.

Information for Patients

Patients should be informed of the potential risks and advantages of glipizide and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of urine and/or blood glucose.

The risks of hypoglycaemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained.

Laboratory Tests

Blood and urine glucose should be monitored periodically. Measurement of glycosylated haemoglobin may be useful.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The following products are likely to increase the hypoglycaemic effect:

- Contraindicated combinations

Miconazole: increase in hypoglycaemic effect, possibly leading to symptoms of hypoglycaemia or even coma.

- Inadvisable combinations

Nonsteroidal anti-inflammatory agents (NSAIDS) e.g. phenylbutazone: increase in hypoglycaemic effect of sulphonylureas (displacement of sulphonylurea binding to plasma proteins and/or decrease in sulphonylurea elimination).

Alcohol: increase in hypoglycaemic reaction which can lead to hypoglycaemic coma.

- Combinations requiring precaution

Fluconazole: increase in the half-life of the sulphonylurea, possibly giving rise to symptoms of hypoglycaemia.

Voriconazole: Although not studied, voriconazole may increase the plasma levels of sulfonylureas, (e.g. tolbutamide, glipizide and glyburide) and therefore cause hypoglycaemia. Careful monitoring of blood glucose is recommended during co-administration.

Salicylates (acetylsalicylic acid): increase in hypoglycaemic effect by high doses of acetylsalicylic acid (hypoglycaemic action of the acetylsalicylic acid).

Beta-blockers: all beta-blockers mask some of the symptoms of hypoglycaemia, i.e. palpitations and tachycardia. Most non cardioselective beta-blockers increase the incidence and severity of hypoglycaemia.

Angiotensin converting enzyme inhibitors: the use of angiotensin converting enzyme inhibitors may lead to an increased hypoglycaemic effect in diabetic patients treated with sulphonylureas.

Cimetidine: the use of cimetidine may be associated with a reduction in post prandial blood glucose in patients treated with glipizide.

The hypoglycaemic action of sulphonylureas in general may also be potentiated by monoamine oxidase inhibitors and drugs that are highly protein bound, such as sulfonamides, chloramphenicol, probenecid, coumarins and fibrates.

When such drugs are administered to (or withdrawn from) a patient receiving glipizide, the patient should be observed closely for hypoglycaemia (or loss of control).

The following products could lead to hyperglycaemia:

- Inadvisable combinations

Danazol: diabetogenic effect of danazol. If it cannot be avoided, warn the patient and step up self monitoring of blood glucose and urine. Possibly adjust the dosage of antidiabetic agent during treatment with danazol and after its discontinuation.

- Combinations requiring precaution

Phenothiazines (e.g. chlorpromazine) at high doses (> 100 mg per day of chlorpromazine): elevation in blood glucose (reduction in insulin release).

Corticosteroids: elevation in blood glucose.

Sympathomimetics (e.g. ritodrine, salbutamol, terbutaline): elevation in blood glucose due to beta-2-adrenoceptor stimulation. Progestogens: diabetogenic effects of high-dose progestogens. Warn the patient and step up self-monitoring of blood glucose and urine. Possibly adjust the dosage of antidiabetic agent during treatment with the neuroleptics, corticoids or progestogen and after discontinuation.

Other drugs that may produce hyperglycaemia and lead to a loss of control include the thiazides and other diuretics, thyroid products, oestrogens, oral contraceptives, phenytoin, nicotinic acid, calcium channel blocking drugs, and isoniazid.

When such drugs are withdrawn from a patient receiving glipizide, the patient should be observed closely for hypoglycaemia.

4.6 Pregnancy And Lactation

Pregnancy

Glipizide is contraindicated in pregnancy.

Glipizide was found to be mildly fetotoxic in rat reproductive studies. No teratogenic effects were found in rat or rabbit studies.

Prolonged severe hypoglycaemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulphonylurea drug at the time of delivery.

Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Lactation

No data are available on secretion into breast milk. Therefore glipizide is contraindicated in lactation.

4.7 Effects On Ability To Drive And Use Machines

The effect of glipizide on the ability to drive or operate machinery has not been studied. However, there is no evidence to suggest that glipizide may affect these abilities. Patients should be aware of the symptoms of hypoglycaemia and be careful about driving and the use of machinery, especially when optimum stabilisation has not been achieved, for example during the change-over from other medications or during irregular use.

4.8 Undesirable Effects

The majority of side effects have been dose related, transient, and have responded to dose reduction or withdrawal of the medication. However, clinical experience thus far has shown that, as with other sulphonylureas, some side effects associated with hypersensitivity may be severe and deaths have been reported in some instances.

Hypoglycaemia

See Special Warnings and Special Precautions for Use and Overdose sections.

Gastrointestinal

Gastrointestinal complaints include nausea, diarrhoea, constipation and gastralgia. They appear to be dose related and usually disappear on division or reduction of dosage.

Dermatologic

Allergic skin reactions including erythema, morbilliform or maculopapular reactions, urticaria, pruritus and eczema have been reported. They frequently disappear with continued therapy. However, if they persist, the drug should be discontinued. As with other sulphonylureas, photosensitivity reactions have been reported.

Miscellaneous

Confusion, dizziness, drowsiness, headache, tremor, and visual disturbances have each been reported in patients treated with glipizide. They are usually transient and do not require discontinuance of therapy; however, they may also be symptoms of hypoglycaemia.

Laboratory Test

The pattern of laboratory test abnormalities observed with glipizide is similar to that for other sulphonylureas. Occasional mild to moderate elevations of SGOT, LDH, alkaline phosphatase, BUN and creatinine were noted. The relationship of these abnormalities to glipizide is uncertain, and they have rarely been associated with clinical symptoms.

Hepatic disorder

Cholestatic jaundice, impaired hepatic function, and hepatitis have been reported. Discontinue treatment if cholestatic jaundice occurs.

Haematologic Reactions

Leucopenia, agranulocytosis, thrombocytopenia, haemolytic anaemia, aplastic anaemia and pancytopenia have been reported.

Metabolic Reactions

Hepatic porphyria and porphyria cutanea tarda have been reported. Disulfiram-like reactions have been reported with other sulphonylureas.

Endocrine Reactions

Hyponatraemia has been reported.

4.9 Overdose

There is no well documented experience with glipizide overdosage.

Overdosage of sulphonylureas including glipizide can produce glycaemia. Mild hypoglycaemic symptoms without loss of consciousness or neurologic findings should be treated actively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycaemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalisation. If hypoglycaemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL (5.55 mmol/L). Patients should be closely monitored for a minimum of 48 hours and depending on the status of the patient at this time the physician should decide whether further monitoring is required. Clearance of glipizide from plasma may be prolonged in persons with liver disease. Because of the extensive protein binding of glipizide, dialysis is unlikely to be of benefit.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Glipizide is an oral blood glucose lowering drug of the sulphonylurea class. The primary mode of action of glipizide is the stimulation of insulin secretion from the beta-cells of pancreatic islet tissue. Stimulation of insulin secretion by glipizide in response to a meal is of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the post-prandial insulin response continues to be enhanced after at least 6 months of treatment. The insulinotropic response to a meal occurs within 30 minutes after oral dose of glipizide in diabetic patients, but elevated insulin levels do not persist beyond the time of the meal challenge. There is also increasing evidence that extrapancreatic effects involving potentiation of insulin action form a significant component of the activity of glipizide.

Blood sugar control persists for up to 24 hours after a single dose of glipizide, even though plasma levels have declined to a small fraction of peak levels by that time (see “Pharmacokinetics” below).

5.2 Pharmacokinetic Properties

Gastrointestinal absorption of glipizide in man is uniform, rapid and essentially complete. Peak plasma concentrations occur 1-3 hours after a single oral dose. The half-life of elimination ranges from 2-4 hours in normal subjects, whether given intravenously or orally. The metabolic and excretory patterns are similar with the two routes of administration, indicating that first-pass metabolism is not significant. Glipizide does not accumulate in plasma on repeated oral administration. Total absorption and disposition of an oral dose was unaffected by food in normal volunteers, but absorption was delayed by about 40 minutes. Thus, glipizide was more effective when administered about 30 minutes before, rather than with, a test meal in diabetic patients. Protein binding was studied in serum from volunteers who received either oral or intravenous glipizide and found to be 98-99% one hour after either route of administration. The apparent volume of distribution of glipizide after intravenous administration was 11 litres, indicative of localisation within the extracellular fluid compartment. In mice, no glipizide or metabolites were detectable autoradiographically in the brain or spinal cord of males or females, nor in the foetuses of pregnant females. In another study, however, very small amounts of radioactivity were detected in the foetuses of rats given labelled drug.

The metabolism of glipizide is extensive and occurs mainly in the liver. The primary metabolites are inactive hydroxylation products and polar conjugates and are excreted mainly in the urine. Less than 10% unchanged glipizide is found in urine.

5.3 Preclinical Safety Data

Acute toxicity studies showed no specific susceptibility. The acute oral toxicity of glipizide was extremely low in all species tested (LD50 greater than 4 g/kg). Chronic toxicity tests in rats and dogs at doses up to 8.0 mg/kg did not show any evidence of toxic effects.

A 20-month study in rats and an 18-month study in mice at doses up to 75 times the maximum human dose revealed no evidence of drug related carcinogenicity. Bacterial and in vivo mutagenicity tests were uniformly negative. Studies in rats of both sexes at doses up to 75 times the human dose showed no effects on fertility.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Microcrystalline cellulose	Ph. Eur.
Starch	Ph. Eur.
Stearic acid	HSE
Lactose	Ph. Eur.

6.2 Incompatibilities

None stated.

6.3 Shelf Life

12 months.

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

Blister strips containing 28 or 60 tablets

6.6 Special Precautions For Disposal And Other Handling

None.

Administrative Data

7. Marketing Authorisation Holder

Pharmacia Limited

Ramsgate Road,

Sandwich,

Kent, CT13 9NJ

United Kingdom.

8. Marketing Authorisation Number(S)

Minodiab 5 - PL 00032/0319

9. Date Of First Authorisation/Renewal Of The Authorisation

Minodiab 5 - 5^th April 2002

10. Date Of Revision Of The Text

September 2010

Company Ref: MG 6_0

Simple Linctus Sugar Free (Thornton & Ross Ltd)

1. Name Of The Medicinal Product

Simple Linctus Sugar Free

2. Qualitative And Quantitative Composition

Citric acid monohydrate (E330) BP 125mg per 5ml.

Excipients: Each 5ml contains Liquid Maltitol 4.2g

For full list of excipients see section 6.1

3. Pharmaceutical Form

Oral Solution

4. Clinical Particulars

4.1 Therapeutic Indications

For relief of the symptoms of coughs.

4.2 Posology And Method Of Administration

Oral.

Recommended doses

Adults, the elderly and children over 12 years: one 5ml spoonful, repeated up to four times per day.

Children under 12 years: not recommended.

4.3 Contraindications

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

4.4 Special Warnings And Precautions For Use

This medicinal product is not recommended for the use in children below the age of 12 years due to lack of data on safety and efficacy.

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

No adverse effects are known for the product, however as with all medicines use should be avoided during pregnancy unless recommended by a doctor.

4.7 Effects On Ability To Drive And Use Machines

Simple Linctus Sugar Free has no influence on the ability to drive and use machines.

4.8 Undesirable Effects

There are no known side effects from using this medicine when used as directed, however, if you notice any side effects, stop use and consult a doctor or pharmacist.

4.9 Overdose

Overdose with this preparation is unlikely to occur due to the low concentrations of the active substance, however in the event of an overdose, treatment should be symptomatic.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic Group: Cough and Cold Preparations

ATC Code: R05

5.2 Pharmacokinetic Properties

None stated

5.3 Preclinical Safety Data

None.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Aniseed Flavour (contains propylene glycol) PHL-090803

Glycerol (E422)

Liquid Maltitol

Sodium Benzoate (E211)

Purified water

6.2 Incompatibilities

Not Applicable.

6.3 Shelf Life

12 months unopened. Discard 2 months after first opening.

6.4 Special Precautions For Storage

Do not store above 25°C

6.5 Nature And Contents Of Container

100ml:	Amber glass bottle with plastic cap and liner or white 28mm cap with tamper evident band and EPE Saranex liner
200ml:	Amber glass bottle with plastic cap and liner or white 28mm cap with tamper evident band and EPE Saranex liner
500ml:	Amber glass bottle with plastic cap and liner or white 28mm cap with tamper evident band and EPE Saranex liner.
2000ml:	Amber glass bottle with plastic cap and liner.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

L.C.M. Ltd

Linthwaite Laboratories

Huddersfield

HD7 5QH

8. Marketing Authorisation Number(S)

PL 12965/0050

9. Date Of First Authorisation/Renewal Of The Authorisation

02/07/2010

10. Date Of Revision Of The Text

25/01/2011

11 DOSIMETRY (IF APPLICABLE)

Not Applicable

12 INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF APPLICABLE)

Not Applicable

Levothyroxine 50mcg tablets

1. Name Of The Medicinal Product

Levothyroxine 50micrograms Tablets (Thyroxine 50 micrograms Tablets).

2. Qualitative And Quantitative Composition

Each tablet contains 50 micrograms Levothyroxine Sodium anhydrous also known as thyroxine sodium anhydrous.

3. Pharmaceutical Form

Tablet.

White uncoated biconvex tablets engraved on one face FW21 with a breakline on the other.

4. Clinical Particulars

4.1 Therapeutic Indications

Recommended clinical indications: Control of hypothyroidism, congenital hypothyroidism and juvenile myxoedema.

4.2 Posology And Method Of Administration

Adults:

Initially 50 to 100 micrograms daily, preferably taken before breakfast. Adjust at three to four week intervals by 50 micrograms until normal metabolism is steadily maintained: this may require doses of 100 to 200 micrograms daily.

For patients over 50 years, it is not advisable to exceed 50 micrograms daily initially and where there is cardiac disease, 25 micrograms daily or 50 micrograms on alternate days is more suitable initially. In this condition the daily dose may be increased by 25 micrograms at intervals of perhaps 4 weeks.

For patients younger than 50 years, and in the absence of heart disease, a serum Levothyroxine (T4) level of 70 to 160 nanomoles per litre, or a serum thyrotrophin level of less than 5 milli-units per litre should be targeted. For patients aged over 50 years, with or without cardiac disease, clinical response is probably a more acceptable criteria of dosage rather than serum levels.

A pre-therapy ECG is valuable because ECG changes due to hypothyroidism may be confused with ECG evidence of cardiac ischaemia. If too rapid an increase in metabolism is produced (causing diarrhoea, nervousness, rapid pulse, insomnia, tremors, and sometimes anginal pain where there is latent cardiac ischaemia), dosage must be reduced, or withheld for a day or two, and then re-started at a lower dose level.

Elderly: As for patients aged over 50 years.

Paediatric patients:

The maintenance dose is generally 100 to 150 micrograms per m² body surface area.

For neonates and infants with congenital hypothyroidism, where rapid replacement is important the initial recommended dosage is 10 to 15 micrograms per kg BW per day for the first 3 months. Thereafter, the dose should be adjusted individually according to the clinical findings and thyroid hormone and TSH values.

For children with acquired hypothyroidism, the initial recommended dosage is 12.5-50 micrograms per day. The dose should be increased gradually every 2-4 weeks according to the clinical findings and thyroid hormone and TSH values until the full replacement dose is reached. Infants should be given the total daily dose at least half an hour before the first meal of the day.

When applicable:

Tablets are to be disintegrated in some water (10 to 15 mL) and the resultant suspension, which must be prepared freshly as required, is to be administered with some more liquid (5-10 mL).

4.3 Contraindications

Thyrotoxicosis. Hypersensitivity to any components of Levothyroxine tablets.

4.4 Special Warnings And Precautions For Use

Patient with panhypopituitarism or other causes predisposing to adrenal insufficiency may react to Levothyroxine treatment, and it is advisable to start corticosteroid therapy before giving Levothyroxine to such patients.

Special care is needed for the elderly and for patients with symptoms of myocardial insufficiency, or ECG evidence of myocardial infarction. Thyroid replacement therapy may cause an increase in dosage requirements of insulin or other anti-diabetic therapy. Care is needed for patients with diabetes mellitus and diabetes insipidus.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Levothyroxine increases the effect of anticoagulants and it may be necessary to reduce the anticoagulation dosage if excessive, hypoprothrombinaemia and bleeding are to be avoided.

Acenocoumarol, pheninedione and warfarin enhances the effect of Levothyroxine.

Antiepileptics such as carbamazepine, Phenobarbital, phenytoin, and primidone accelerate metabolism of Levothyroxine (may increase requirements in hypothyroidism) and may displace them from plasma proteins.

Initiation or discontinuation of anti-convulsant therapy may alter Levothyroxine dosage requirements.

If co-administered with cardiac glycosides adjustment of dosage may be necessary. The effect of sympathomimetic agents are enhanced.

Blood sugar levels are raised and dosage of anti-diabetic agents may require adjustment.

Tricyclic anti-depressants response may be accelerated because Levothyroxine increases sensitivity to catecholamines.

Manufacturer of lofepramine advises to avoid Levothyroxine.

Coletyramine reduces the gastrointestinal absorption of Levothyroxine. Oral contraceptives may increase the requirement of thyroid therapy dosage. Other drugs may affect thyroid function tests and this must be considered when monitoring a patient on Levothyroxine therapy.

Rifampicin accelerates metabolism of Levothyroxine (may increase requirements in hypothyroidism).

Phenylbutazone shows false low total plasma-Levothyroxine concentration.

Amiodarone contain iodine and can cause disorders of Levothyroxine function; both hypothyroidism and hyperthyroidism may occur.

Metabolism of propranolol reduces the effect of Levothyroxine.

Sucralfate reduces absorption of Levothyroxine.

4.6 Pregnancy And Lactation

The safety of Levothyroxine treatment during pregnancy is not known, but any possible risk of foetal abnormalities should be weighed against the risk to the foetus of untreated hypothyroidism. Levothyroxine is excreted in breast milk in low concentrations, and it is contentious whether this can interfere with neonatal screening.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Side-effects are usually indicative of excessive dosage and usually disappear on reduction of dosage or withdrawal of treatment for a few days. Such effects include: anginal pain, cardiac arrhythmias, palpitations, cramps in skeletal muscles, tachycardia, diarrhoea, vomiting, tremors, restlessness, excitability, insomnia, headache, flushing, sweating, excessive loss of weight, and muscular weakness.

4.9 Overdose

Signs and symptoms may be an exaggeration of the side-effects, as well as agitation, confusion, irritability, hyperactivity, mydriasis, tachypnoea, pyrexia, increased bowel movements and convulsions. The appearance of clinical hyperthyroidism may be delayed for up to five days. Gastric lavage or emesis is required if the patient is seen within several hours of taking the dose. Treatment is symptomatic. Tachycardia may be controlled in an adult by 40mg doses of propanolol given every 6 hours. Other symptoms may be controlled by Diazepam and/or chlorpromazine as appropriate.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Levothyroxine 50 micrograms Tablets are tablets containing Levothyroxine sodium used for the treatment of hypothyroidism. Levothyroxine is deiodinated in peripheral tissues to form triiodothyronine which is thought to be the active tissue form of thyroid hormone. Triiodothyronine has a rapid action but a shorter duration of activity than Levothyroxine.

The chief action of Levothyroxine is to increase the rate of cell metabolism.

5.2 Pharmacokinetic Properties

Levothyroxine sodium is incompletely and variably absorbed from the gastrointestinal tract. It is almost completely bound to plasma proteins and has a half-life in the circulation of about a week in healthy subjects, but longer in patients with myxoedema.

A large portion of the Levothyroxine leaving the circulation is taken up by the liver.

Part of a dose of Levothyroxine is metabolised to triiodothyronine.

Levothyroxine is excreted in the urine as free drug, deiodinated metabolites and conjugates. Some Levothyroxine is excreted in the faeces. There is limited placental transfer of Levothyroxme.

5.3 Preclinical Safety Data

No further data of relevance.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Citrate

Lactose

Maize starch

Powdered Acacia

Magnesium Stearate

Purified Water

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months for polypropylene containers.

24 months for blister packs.

6.4 Special Precautions For Storage

Do not store above 25°C and store in the original container.

6.5 Nature And Contents Of Container

Polypropylene container with tamper-evident low density polyethylene lid, containing 28, 56,100, 112 or 1000 Levothyroxine 50 micrograms tablets.

Blister packaging PVC/PVdC film (heat treated foil/heat seal lacquer) containing 28,56 and 112 Levothyroxine tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Forley Generics Limited

NLA Tower

12-16 Addiscombe Road

Croydon

CR0 OXT

United Kingdom

8. Marketing Authorisation Number(S)

PL 16201/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

Aug 2004

10. Date Of Revision Of The Text

02/09/2010

One-Alpha Injection

1. Name Of The Medicinal Product

One-Alpha^® Injection

2. Qualitative And Quantitative Composition

Alfacalcidol (1α-hydroxyvitamin D₃) 2 micrograms/ml.

3. Pharmaceutical Form

Injection

4. Clinical Particulars

4.1 Therapeutic Indications

One-Alpha^® is indicated in all conditions where there is a disturbance of calcium metabolism due to impaired 1 α-hydroxylation such as when there is reduced renal function.

The main indications are:

a) Renal osteodystrophy

b) Hyperparathyroidism (with bone disease)

c) Hypoparathyroidism

d) Neonatal hypocalcaemia

e) Nutritional and malabsorptive rickets and osteomalacia

f) Pseudo - deficiency (D - dependent) rickets and osteomalacia

g) Hypophosphataemic vitamin D resistant rickets and osteomalacia

4.2 Posology And Method Of Administration

One-Alpha^® Injection should be administered intravenously as a bolus over approximately 30 seconds. Shake the ampoule for a minimum of 5 seconds before use.

The dosage of One-Alpha^® Injection is the same as for One-Alpha^® in its oral presentations.

Initial dosage for all indications is:

Adults	1 microgram/day
Dosage in the elderly	0.5 microgram/day
Neonates and premature infants	0.05 - 0.1 microgram/kg/day
Children under 20 kg bodyweight	0.05 microgram/kg/day
Children over 20 kg bodyweight	1 microgram/day

The dose of One-Alpha^® should be adjusted thereafter to avoid hypercalcaemia according to the biochemical response.

Indices of response include plasma levels of calcium (ideally corrected for protein binding), alkaline phosphatase, parathyroid hormone, as well as radiographic and histological investigations.

Maintenance doses are generally in the range of 0.25 - 1 microgram per day.

When administered as intravenous injection to patients undergoing haemodialysis the initial dosage for adults is 1 microgram per dialysis. The maximum dose recommended is 6 micrograms per dialysis and not more than 12 micrograms per week. The injection should be administered into the return line from the haemodialysis machine at the end of each dialysis.

(a) Renal bone disease:

Patients with relatively high initial plasma calcium levels may have autonomous hyperparathyroidism, often unresponsive to One-Alpha^®. Other therapeutic measures may be indicated.

Before and during treatment with One-Alpha^®, phosphate binding agents should be considered to prevent hyperphosphataemia. It is particularly important to make frequent plasma calcium measurements in patients with chronic renal failure because prolonged hypercalcaemia may aggravate the decline of renal function.

(b) Hyperparathyroidism:

In patients with primary or tertiary hyperparathyroidism about to undergo parathyroidectomy, pre-operative treatment with One-Alpha^® for 2-3 weeks alleviates bone pain and myopathy without aggravating pre-operative hypercalcaemia. In order to decrease post-operative hypocalcaemia, One-Alpha^® should be continued until plasma alkaline phosphatase levels fall to normal or hypercalcaemia occurs.

(c) Hypoparathyroidism:

In contrast to the response to parent vitamin D, low plasma calcium levels are restored to normal relatively quickly with One-Alpha^®. Severe hypocalcaemia is corrected more rapidly with higher doses of One-Alpha^® (eg 3-5 micrograms) together with calcium supplements.

(d) Neonatal hypocalcaemia:

Although the normal starting dose of One-Alpha^® is 0.05-0.1 microgram/kg/day (followed by careful titration), in severe cases, doses of up to 2 microgram/kg/day may be required. Whilst ionised serum calcium levels may provide a guide to response, measurement of plasma alkaline phosphatase activity may be more useful. Levels of alkaline phosphatase approximately 7.5 times above the adult range indicates active disease.

(e) Nutritional and malabsorptive rickets and osteomalacia:

Nutritional rickets and osteomalacia can be cured rapidly with One-Alpha^®. Malabsorptive osteomalacia (responding to large doses of IM or IV parent vitamin D) will respond to small doses of One-Alpha^®.

(f) Pseudo-deficiency (D-dependent) rickets and osteomalacia:

Although large doses of parent vitamin D would be required, effective doses of One-Alpha^® are similar to those required to heal nutritional Vitamin D deficiency rickets and osteomalacia.

(g) Hypophosphataemic vitamin D-resistant rickets and osteomalacia:

Neither large doses of parent vitamin D nor phosphate supplements are entirely satisfactory. Treatment with One-Alpha^® at normal dosage rapidly relieves myopathy when present and increases calcium and phosphate retention. Phosphate supplements may also be required in some patients.

4.3 Contraindications

Hypercalcaemia, metastatic calcification.

Hypersensitivity to alfacalcidol or any of the other ingredients.

4.4 Special Warnings And Precautions For Use

One-Alpha^® Injection should be avoided in patients with known sensitivity to injections containing propylene glycol.

One-Alpha^® should be used with caution for:

• small premature infants

• patients being treated with cardioactive glycosides or digitalis as hypercalcaemia may lead to arrhythmia in such patients

• patients with nephrolithiasis

During treatment with One-Alpha^® serum calcium and serum phosphate should be monitored regularly especially in children, patients with renal impairment and patients receiving high doses. To maintain serum phosphate at an acceptable level in patients with renal bone disease a phosphate binding agent may be used.

Hypercalcaemia may appear in patients treated with One-Alpha^®, the early symptoms are as follows:

• polyurina

• polydipsia

• weakness, headache, nausea, constipation

• dry mouth

• muscle and bone pain

• metallic taste

Hypercalcaemia can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (in about one week). One-Alpha^® treatment may then be restarted at a reduced dose (half the previous dose).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Patients taking barbiturates or anticonvulsants may require larger doses of One-Alpha^® to produce the desired effect due to the induction of hepatic detoxification enzymes.

Use with caution in patients being treated with thiazide diuretics as they may have an increased risk of developing hypercalcaemia.

4.6 Pregnancy And Lactation

There are no adequate data from the use of alfacalcidol in pregnant women. Animal studies are insufficient with respect to effects on pregnancy. The potential risks for humans are unknown. Caution should be taken when prescribing to pregnant women as hypercalcaemia during pregnancy may produce congenital disorders in the offspring.

Although it has not been established, it is likely that increased amounts of 1,25 dihydroxyvitamin D will be found in the milk of lactating mothers treated with One-Alpha^®. This may influence calcium metabolism in the infant.

4.7 Effects On Ability To Drive And Use Machines

One-Alpha^® has no or negligible influence on the ability to drive or use machines.

4.8 Undesirable Effects

The most frequently reported undesirable effects are hypercalcaemia and various skin reactions. Hypercalcaemia can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (about 1 week). One-Alpha^® treatment may then be restarted at half the previous dose.

Based on data from post-market use the total undesirable effect 'reporting rate' is rare or very rare being approximately 1:10,000 patients treated.

•Metabolism and Nutrition Disorders

Hypercalcaemia

Hyperphosphataemia

•Skin and Subcutaneous Tissue Disorders

Pruritus

Rash

Urticaria

•Renal and Urinary Disorders

Nephrocalcinosis

Renal impairment

4.9 Overdose

Hypercalcaemia is treated by suspending the administration of One-Alpha^®.

In severe cases of hypercalcaemia general supportive measures should be undertaken. Keep the patient well hydrated by i.v. infusion of saline (force diuresis), measure electrolytes, calcium and renal function indices; assess electrocardiographic abnormalities, especially in patients on digitalis. More specifically, treatment with glucocorticosteroids, loop diuretics, bisphosphonates, calcitonin and eventually haemodialysis with low calcium content should be considered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Alfacalcidol is converted rapidly in the liver to 1,25 dihydroxyvitamin D. This is the metabolite of vitamin D which acts as a regulator of calcium and phosphate metabolism. Since this conversion is rapid, the clinical effects of One-Alpha^® and 1,25 dihydroxyvitamin D are very similar.

Impaired 1 α-hydroxylation reduces 1,25 dihydroxyvitamin D production. This contributes to the disturbances in mineral metabolism found in several disorders, including renal bone disease, hypoparathyroidism, neonatal hypocalcaemia and vitamin D dependent rickets. These disorders, which require high doses of parent vitamin D for their correction, will respond to small doses of One-Alpha^®.

The delay in response and high dosage required in treating these disorders with parent vitamin D makes dosage adjustment difficult. This can result in unpredictable hypercalcaemia which may take weeks or months to reverse. The major advantage of One-Alpha^® is the more rapid onset of response, which allows a more accurate titration of dosage. Should inadvertent hypercalcaemia occur it can be reversed within days of stopping treatment.

5.2 Pharmacokinetic Properties

In patients on regular haemodialysis administration of doses between 1 - 4 micrograms of intravenous 1 α-hydroxyvitamin D₃ resulted in increased levels of 1,25 dihydroxyvitamin D. Formation of 1,25 dihydroxyvitamin D₃ occurred within 1 hour after intravenous 1 α-hydroxyvitamin D₃ and peak concentrations were reached between 2 and 5 hours. Elimination half life of the formed 1,25 dihydroxyvitamin D was between 14 and 30 hours.

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Citric acid, ethanol, sodium citrate, propylene glycol and water for injection.

6.2 Incompatibilities

None known.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store at 2-8°C.

Keep the ampoule in the outer carton in order to protect it from light.

6.5 Nature And Contents Of Container

10 x 0.5ml amber glass ampoules.

10 x 1.0ml amber glass ampoules.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

LEO Laboratories Limited

Longwick Road

Princes Risborough

Bucks

HP27 9RR

8. Marketing Authorisation Number(S)

PL 0043/0183

9. Date Of First Authorisation/Renewal Of The Authorisation

11/11/2005

10. Date Of Revision Of The Text

May 2009

Sumatriptan 6 mg / 0.5 ml Solution for Injection

1. Name Of The Medicinal Product

Sumatriptan 6 mg/0.5 ml Solution for Injection

2. Qualitative And Quantitative Composition

Each pre-filled pen contains 6 mg of sumatriptan, as sumatriptan succinate.

Excipient:

Sodium 1.3 mg

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Solution for Injection

Clear, colourless to pale yellow solution..

The pH is between 4.2 and 5.3. The osmolarity is between 260 to 340 mOsmols.

4. Clinical Particulars

4.1 Therapeutic Indications

Subcutaneous injection of Sumatriptan is indicated for the acute relief of migraine attacks, with or without aura, and for the acute treatment of cluster headache. Sumatriptan Injection should only be used where there is a clear diagnosis of migraine or cluster headache.

4.2 Posology And Method Of Administration

Sumatriptan Injection should not be used prophylactically.

Sumatriptan should be injected subcutaneously using a pre-filled pen. After removal of the needle shield, the open end of the pre-filled pen is to be placed on the injection site, straight up at a right angle (90°). By pressing the blue button a first click sound is heard. The thumb needs to be released immediately. A second click sound warns that the injection is finished. The safety needle cover of the pen will automatically extend to cover the needle. The inspection window will be blue confirming the injection is complete. Patients should be advised to observe strictly the instruction leaflet for the Sumatriptan Injection especially regarding the use of the pre-filled pen.

Adults

Migraine and cluster headache:

It is recommended to start the treatment at the first sign of a migraine headache, cluster headache or associated symptoms such as nausea, vomiting or photophobia. It is equally effective at whatever stage of the attack it is administered.

Migraine:

The recommended adult dose of Sumatriptan is a single 6 mg subcutaneous injection. Patients who do not respond to this dose should not take a second dose of Sumatriptan for the same attack. Sumatriptan may be taken for subsequent attacks. Patients who respond initially but whose migraine returns may take a further dose at any time in the next 24 hours provided that one hour has elapsed since the first dose.

The maximum dose in 24 hours is two 6 mg injections (12 mg).

Sumatriptan is recommended as monotherapy for the acute treatment of a migraine attack and should not be given concomitantly with other acute migraine therapies like ergotamine or derivatives or ergotamine (including methysergide) (see Section 4.3). If a patient fails to respond to a single dose of Sumatriptan there are no reasons, either on theoretical grounds or from limited clinical experience, to withhold products containing acetylsalicylic acid or non-steroidal anti-inflammatory drugs or paracetamol for further treatment of the attack.

Cluster headache:

The recommended adult dose is a single 6 mg subcutaneous injection for each cluster attack. The maximum dose in 24 hours is two 6 mg injections (12 mg) with a minimum interval of one hour between the two doses.

Children and Adolescents (under 18 years of age):

Sumatriptan is not recommended for use in children and adolescents as sumatriptan injection has not been studied in these age categories.

Elderly (over 65):

Experience of the use of Sumatriptan in patients aged over 65 years is limited. The pharmacokinetics do not differ significantly from a younger population but, until further clinical data are available, the use of Sumatriptan in patients aged over 65 years is not recommended.

4.3 Contraindications

Hypersensitivity to sumatriptan or to any of the excipients.

Sumatriptan should not be given to patients who have had myocardial infarction or have ischaemic heart disease, coronary vasospasm (Prinzmetal's angina), peripheral vascular disease or patients who have symptoms or signs consistent with ischaemic heart disease.

Sumatriptan should not be administered to patients with a history of cerebrovascular accident (CVA) or transient ischaemic attack (TIA).

Sumatriptan should not be administered to patients with severe hepatic impairment.

The use of sumatriptan in patients with moderate and severe hypertension and mild uncontrolled hypertension is contraindicated.

The concomitant administration of ergotamine or derivatives of ergotamine (including methysergide) or any triptan/5-hydroxytryptamine₁ (5-HT₁) receptor agonist is contraindicated (See section 4.5).

Concurrent administration of monoamine oxidase inhibitors and sumatriptan is contraindicated.

Sumatriptan must not be used within two weeks of discontinuation of therapy with monoamine oxidase inhibitors (see section 4.5).

4.4 Special Warnings And Precautions For Use

Warnings:

Sumatriptan is not indicated for use in the management of hemiplegic, basilar or ophthalmoplegic migraine.

The recommended doses of Sumatriptan should not be exceeded.

This medicinal product contains less than 1 mmol sodium (23mg) per dose, i.e. 'essential sodium free'.

Sumatriptan should not be given intravenously, because of its potential to cause vasospasm. The vasospasm may result in arrhythmias, ischaemic ECG changes or myocardial infarction.

Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should be noted that migraineurs may be at risk of certain cerebrovascular events (e.g. cerebrovascular accident, transient ischaemic attack).

Following administration, sumatriptan can be associated with transient symptoms including chest pain and tightness which may be intense and involve the throat. Where such symptoms are thought to indicate ischaemic heart disease, no further doses of sumatriptan should be given and appropriate evaluation should be carried out.

Sumatriptan should not be given to patients with risk factors for ischaemic heart disease, including those patients who are heavy smokers or users of nicotine substitution therapies, without prior cardiovascular evaluation (See Section 4.3). Special consideration should be given to postmenopausal women and males over 40 with these risk factors. These evaluations however, may not identify every patient who has cardiac disease and, in very rare cases, serious cardiac events have occurred in patients without underlying cardiovascular disease(see section 4.8).

• There have been rare post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. Serotonin syndrome has been reported following concomitant treatment with triptans and serotonin noradrenaline reuptake inhibitors (SNRIs).

If concomitant treatment with sumatriptan and an SSRI/SNRI is clinically warranted, appropriate observation of the patient is advised.

Sumatriptan should be administered with caution to patients with conditions which may affect significantly the absorption, metabolism or excretion of the drug e.g. impaired hepatic or renal function.

Sumatriptan should be used with caution in patients with a history of seizures or other risk factors which lower the seizure threshold, as seizures have been reported in association with sumatriptan (see section 4.8).

Patients with known hypersensitivity to sulphonamides may exhibit an allergic reaction following administration of sumatriptan. Reactions may range from cutaneous hypersensitivity to anaphylaxis.

Evidence of cross- sensitivity is limited; however, caution should be exercised before using sumatriptan in these patients.

Undesirable effects may be more common during concomitant use of triptans and herbal preparations containing St John's Wort (Hypericum perforatum).

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained and treatment should be discontinued. The diagnosis of medication overuse headache (MOH) should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

There is no evidence of interactions with propranolol, flunarizine, pizotifen or alcohol.

There are limited data on an interaction with preparations containing ergotamine or another triptan/5-HT1 receptor agonist. The increased risk of coronary vasospasm is a theoretical possibility and concomitant administration is contraindicated (see section 4.3).

The period of time that should elapse between the use of sumatriptan and ergotamine-containing preparations or another triptan/5-HT1 receptor agonist is not known. This will also depend on the doses and types of products used. The effects may be additive. It is advised to wait at least 24 hours following the use of ergotamine-containing preparations or another triptan/5-HT1 receptor agonist before administering sumatriptan. Conversely, it is advised to wait at least 6 hours following use of sumatriptan before administering an ergotamine-containing product and at least 24 hours before administering another triptan/5-HT1 receptor agonist.

An interaction may occur between sumatriptan and MAOIs and concomitant administration is contra-indicated (see Section 4.3).

There have been rare post-marketing reports describing patients with serotonin syndrome (including altered mental status, autonomic instability and neuromuscular abnormalities) following the use of SSRIs and sumatriptan. Serotonin syndrome has also been reported following concomitant treatment with triptans and SNRIs(see Section 4.4). There may also be a risk of serotonergic syndrome if sumatriptan is used concomitantly with lithium.

4.6 Pregnancy And Lactation

Post-marketing data from the use of sumatriptan during the first trimester in over 1,000 women are available. Although these data contain insufficient information to draw definitive conclusions, they do not point to an increased risk of congenital defects. Experience with the use of sumatriptan in the second and third trimester is limited.

Evaluation of experimental animal studies does not indicate direct teratogenic effects or harmful effects on peri- and postnatal development. However, embryofoetal viability might be affected in the rabbit (see section 5.3). Administration of sumatriptan should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

It has been demonstrated that following subcutaneous administration sumatriptan is excreted into breast milk. Infant exposure can be minimised by avoiding breast feeding for 12 hours after treatment, during which time any breast milk expressed should be discarded.

4.7 Effects On Ability To Drive And Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Drowsiness may occur as a result of migraine or its treatment with sumatriptan. This may influence the ability to drive and to operate machinery.

4.8 Undesirable Effects

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (

Immune System Disorders

Not known: Hypersensitivity reactions ranging from cutaneous hypersensitivity (such as urticaria) to anaphylaxis.

Psychiatric disorders

Not known: Anxiety.

Nervous System Disorders

Common: Dizziness, drowsiness, sensory disturbance including paraesthesia and hypoaesthesia.

Not known: Seizures, although some have occurred in patients with either a history of seizures or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent; Tremor, dystonia, nystagmus, scotoma.

Eye disorders

Not known: Flickering, diplopia, reduced vision. Loss of vision including reports of permanent defects.

However, visual disorders may also occur during a migraine attack itself.

Cardiac disorders

Not known: Bradycardia, tachycardia, palpitations, cardiac arrhythmias, transient ischaemic ECG changes, coronary artery vasospasm, myocardial infarction, angina (see section 4.3 and 4.4).

Vascular disorders

Common: Transient increases in blood pressure arising soon after treatment. Flushing.

Not known: Hypotension, Raynaud's phenomenon.

Respiratory, Thoracic and Mediastinal Disorders

Common : Dyspnoea

Gastrointestinal disorders

Common: Nausea and vomiting occurred in some patients but it is unclear if this is related to Sumatriptan or the underlying condition.

Not known: Ischaemic colitis.

Not known: Diarrhoea.

Skin and subcutaneous tissue disorders

Not known: Hyperhidrosis.

Musculoskeletal and Connective Tissue Disorders

Common: Sensations of heaviness (usually transient and may be intense and can affect any part of the body including the chest and throat). Myalgia.

Not known: Neck stiffness.

Not known: Arthralgia.

General Disorders and Administration Site Conditions

Common: Pain, sensations of heat or cold, pressure or tightness (these events are usually transient and may be intense and can affect any part of the body including the chest and throat).

Feelings of weakness, fatigue (both events are mostly mild to moderate in intensity and transient).

Investigations

Very rare: Minor disturbances in liver function tests have occasionally been observed.

The most common side effects associated with treatment with sumatriptan administered subcutaneously are:

General Disorders and Administration Site Conditions

Very common: Transient injection site pain. Injection site stinging/burning, swelling, erythema, bruising and bleeding have also been reported.

Although direct comparisons are not available, flushing, paraesthesia and sensations of heat, pressure, and heaviness may be more common after sumatriptan injection.

Conversely, nausea, vomiting and fatigue appear to be less frequent with subcutaneous administration of sumatriptan injection than with tablets.

4.9 Overdose

There have been some reports of overdosage with Sumatriptan .

Patients have received single injections of up to 12 mg subcutaneously without significant adverse effects.

Doses in excess of 16 mg subcutaneously were not associated with side effects other than those mentioned.

If overdosage with Sumatriptan occurs, the patient should be monitored for at least ten hours and standard supportive treatment applied as required.

It is unknown what effect haemodialysis or peritoneal dialysis has on the plasma concentrations of sumatriptan.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Analgesics; antimigraine preparations; selective serotonin (5HT1) agonists.

ATC Code: N02CC01.

Sumatriptan has been demonstrated to be a specific and selective 5-hydroxytryptamine (5-HT1D) receptor agonist with no effect on other 5-HT receptor (5-HT2-5-HT7) subtypes. The vascular 5-HT1D receptor is found predominantly in cranial blood vessels and mediates vasoconstriction. In animals, sumatriptan selectively constricts the carotid arterial circulation but does not alter cerebral blood flow. The carotid arterial circulation supplies blood to the extracranial and intracranial tissues, such as the meninges and dilatation and/or oedema formation in these vessels is thought to be the underlying mechanism of migraine in man. In addition, experimental evidence from animal studies suggests that sumatriptan inhibits trigeminal nerve activity. Both these actions (cranial vasoconstriction and inhibition of trigeminal nerve activity) may contribute to the anti-migraine action of sumatriptan in humans.

Sumatriptan remains effective in treating menstrual migraine i.e. migraine without aura that occurs between 3 days prior and up to 5 days post onset of menstruation. Sumatriptan should be taken as soon as possible in an attack.

Clinical response begins 10 to 15 minutes following a 6 mg subcutaneous injection.

Because of its route of administration Sumatriptan Injection may be particularly suitable for patients who suffer with nausea and vomiting during an attack.

5.2 Pharmacokinetic Properties

Following subcutaneous injection, sumatriptan has a high mean bioavailability (96%) with peak serum concentrations occurring in 25 minutes. Average peak serum concentration after a 6 mg subcutaneous dose is 72 ng/ml. The elimination phase half life is approximately two hours.

Plasma protein binding is low (14 to 21%), mean volume of distribution is 170 litres. Mean total plasma clearance is approximately 1160 ml/min and the mean renal plasma clearance is approximately 260 ml/min.

Non-renal clearance accounts for about 80% of the total clearance. Sumatriptan is eliminated primarily by oxidative metabolism mediated by monoamine oxidase A.

The major metabolite, the indole acetic acid analogue of sumatriptan, is mainly excreted in the urine where it is present as a free acid and the glucuronide conjugate. It has no known 5-HT1 or 5-HT2 activity. Minor metabolites have not been identified.

In a pilot study no significant differences were found in the pharmacokinetic parameters between the elderly and young healthy volunteers.

5.3 Preclinical Safety Data

Sumatriptan was devoid of genotoxic and carcinogenic activity in in-vitro systems and animal studies.

In a rat fertility study a reduction of insemination was seen at exposures sufficiently in excess of the maximum human exposure.

In rabbits embryolethality, without marked teratogenic defects, was seen. The relevance for humans of these findings is unknown.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Sodium Chloride

Water for Injection

6.2 Incompatibilities

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

6.3 Shelf Life

2 years

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Prefilled pen, composed of 1 ml type I (Ph.Eur) glass barrel with attached 27 gauge needle & ½ inch length, black chlorobutyl plunger stopper.

Package size: 1 or 2 pre-filled pens.

Not all package sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8. Marketing Authorisation Number(S)

PL 31750/0012

9. Date Of First Authorisation/Renewal Of The Authorisation

22/01/2010

10. Date Of Revision Of The Text

May 2010

Vivaglobin 160mg / ml solution for injection (subcutaneous use)

CSL Behring

Vivaglobin,

160mg/ml solution for injection

(for subcutaneous use)

Human Normal Immunoglobulin

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

In this leaflet:

• 1. What Vivaglobin is and what it is used for


• 2. Before you use Vivaglobin


• 3. How to use Vivaglobin


• 4. Possible side effects


• 5. How to store Vivaglobin


• 6. Further information

What Vivaglobin Is And What It Is Used For

What is Vivaglobin?

Vivaglobin is a solution for injection under the skin (subcutaneous use). The solution contains human normal immunoglobulin.

Immunoglobulins are important components of the body’s immune response system. They are produced from cells in the blood and act as inhibitors (antibodies) to foreign substances.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) having a broad spectrum of antibodies against various infectious agents. Vivaglobin contains the immunoglobulin G antibodies present in the healthy population. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

What is Vivaglobin used for?

Vivaglobin is used for:

• Replacement of antibodies in adults and children suffering from congenital (primary) immunodeficiency syndromes such as:
  
  
  • congenital absence of antibodies (agammaglobulinaemia) or antibody deficiency (hypogammaglobulinaemia)
  • common variable immunodeficiency
  • severe combined immunodeficiency
  • IgG subclass deficiencies with recurrent infections


• Replacement of antibodies in:
  
  
  • cancer of bone marrow (myeloma) or
  • malignant illness of white blood cells (chronic lymphatic leukaemia). This disease leads to severe antibody deficiency (secondary hypogammaglobulinaemia) and recurrent infections.

Before You Use Vivaglobin

The following sections contain information that you and your doctor should consider before using Vivaglobin.

Do NOT infuse Vivaglobin

• if you are allergic (hypersensitive) to any of the components of the product (see section 6). Please inform your doctor if you are allergic to any medicine or food.


• into a blood vessel


• into a muscle if you suffer of a severe deficiency of blood platelets (thrombocytopenia) or other disorders of blood clotting

Take special care with Vivaglobin

• if Vivaglobin is accidentally administered into a blood vessel. You could develop a severe allergic reaction (anaphylactic shock). This reaction is seen as a fall in blood pressure and shortness of breath


• if you receive human normal immunoglobulin for the first time


• if you have received another product for treatment of the same symptoms in the past


• when treatment has been interrupted for more than eight weeks

True allergic reactions are rare. They can occur in the very rare cases of IgA deficiency with anti-IgA antibodies. In this case your doctor will treat you with caution.

Rarely, Vivaglobin can induce a fall in blood pressure with anaphylactic (allergic) reaction. This reaction may also occur if you had tolerated previous treatment with normal human immunoglobulin.

Potential complications can often be avoided by ensuring

• that you are not sensitive to human normal immunoglobulin. The product should initially be injected slowly. The recommended infusion rate should be adhered to (see 3. 'How to use Vivaglobin')


• that you are carefully monitored for any symptoms throughout the infusion period especially if:
  
  
  • you receive human normal immunoglobulin for the first time
  • you switched from an alternative product or
  • there has been a long interval since the previous infusion.

In these cases you should be monitored during the first infusion and for the first hour thereafter. All other patients should be observed for at least 20 minutes after administration.

On suspicion of an allergic or anaphylactic reaction the administration has to be discontinued immediately. In case of shock the current medical standards for shock treatment have to be applied.

Information on safety with respect to infections

When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include:

• careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded


• the testing of each donation and pools of plasma for signs of virus/infections.

Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses or other types of infections.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV, the AIDS virus), hepatitis B virus and hepatitis C virus (liver inflammation), and for the non-enveloped hepatitis A virus and parvovirus B19 (Sticker's disease).

Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly because the antibodies against these infections, which are contained in the product, are protective.

Every time you take Vivaglobin you should record the following data in your treatment diary:

• the date of administration


• the batch number of the product


• the injected volume

Taking other medicines

• Please ask your doctor or pharmacist for advice before taking any other medicines including vaccines or medicines obtained without a prescription.


• You must not mix this medicinal product with other medicinal products, solvents or diluents.


• Results of some blood tests may be affected by Vivaglobin. If you are due to receive blood tests of any sort, make sure the doctor treating you knows you are receiving Vivaglobin.

Pregnancy and lactation

• Ask your doctor or pharmacist for advice before taking any medicine if you are pregnant or breast feeding your baby.


• The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials.


• Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.


• Your doctor will decide if it is suitable for you to receive Vivaglobin if you are pregnant or breast feeding your baby.

Driving and using machines

Vivaglobin does not affect your ability to drive and use machines.

Important information about some of the ingredients of Vivaglobin

Vivaglobin contains up to 110 mg (4.8 mmol) sodium per dose (75 kg body weight) if the maximum daily dose is given (11.25 g = 70.3 ml). This should be taken into consideration if you are on a controlled sodium diet.

How To Use Vivaglobin

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

Your doctor will calculate the correct dose for you taking into account your weight and response to treatment.

A loading dose of at least 1.3 to 3.1 millilitres per kilogram divided over several days may be required. Following this, maintenance doses may be given, usually weekly, to reach a cumulative monthly dose of about 2.5 to 5 millilitres per kilogram of body weight

Method of administration

• Home treatment should be initiated and monitored by a physician experienced in the treatment of immunodeficiency and in the guidance of patients for home treatment. You will be instructed in:
  
  
  • the use of a syringe driver
  • infusion techniques
  • the keeping of a treatment diary and
  • measures to be taken in case of severe adverse events.


• Vivaglobin is a ready-for-use solution. (see section 5. 'How to store Vivaglobin' and 6. subsection 'What Vivaglobin looks like and content of the pack').


• Do not use solutions that are cloudy or have deposits.


• The solution should be administered at body temperature.


• Vivaglobin should be administered via the subcutaneous route.


• The recommended infusion rate is 22 ml/hour (millilitres per hour).

Vivaglobin should preferentially be administered into the fleshy part of the abdominal wall, thigh and/or buttocks. No more than 15 ml should be injected into a single site. Doses over 15 ml should be divided and injected into 2 or more sites.

Your doctor will instruct you how to dispose of unused product or waste material.

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

Overdose/missed doses

If you think you have had too much Vivaglobin or have missed a dose, speak to your doctor.

Possible Side Effects

Like all medicines Vivaglobin can have side effects, although not everybody gets them.

Please contact your doctor immediately, or go to the Emergency Department at your nearest hospital immediately, if you notice the following:

Very rarely (less than 1 in 10,000 treated persons)

• 
  Allergic reactions including difficulty breathing, skin reactions, swelling of the throat and lips and a fall in blood pressure. These reactions may be severe (anaphylaxis). This may happen even if you have had no reaction to previous treatment with Vivaglobin or a similar product.


• 
  Fainting e.g. dizziness, dimming of vision and ringing in the ears


• 
  Cardiovascular reactions e.g. a fall in blood pressure, particularly if the product has been inadvertently injected into a blood vessel (see also section 2 subheading 'Take special care with Vivaglobin')

Please contact your doctor if any of the following side effects occur, or if you notice any effects not listed in this leaflet

• 
  Generalised reactions e.g. chills, fever, headache (possibly caused by increased blood pressure), generally feeling unwell, feeling/being sick, rash, dizziness, joint pain or moderate back pain


• 
  Nervous system disorders e.g. migraine

Very common side effects (more than 1 in 10 treated persons)

• 
  Local reactions at the injection site e.g. swelling, soreness, redness, hardening of the skin, local heat, itching, bruising or rash
  
  The frequency of these local reactions declines rapidly within the first ten infusions, when patients became used to this form of treatment.

How To Store Vivaglobin

• Store in a refrigerator (+2 °C to +8 °C) and keep the container in the outer carton in order to protect from light. Do not freeze!


• Keep out of the reach and sight of children.


• Do not use Vivaglobin after the expiry date, which is stated on the label and carton.


• The product must be inspected visually prior to administration and should not be used if there is any variation of physical appearance (see also section 3 subheading 'Method of administration' and section 6 subheading 'What Vivaglobin looks like and contents of the pack').


• The product may be stored at room temperature (up to 25 °C) for a limited period of three months or until the expiry date (whichever date comes first) without being refrigerated again during this period. The new expiry date at room temperature should be noted on the carton. At the end of this period the product has to be used or discarded.


• Once an ampoule or injection vial has been opened the solution should be used immediately


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

Further Information

What Vivaglobin contains

• 
  The active substance is: human normal immunoglobulin, 160 mg/ml solution for injection, 480 mg/3 ml vial or 800 mg/5 ml ampoule or 1600 mg/10 ml vial or 3200 mg/20 ml vial.


• 
  Other ingredients are: glycine, sodium chloride, hydrochloric acid or sodium hydroxide (for pH adjustment), water for injections

What Vivaglobin looks like and contents of the pack

Vivaglobin is a clear solution for subcutaneous injection.

The colour can vary from colourless to pale-yellow up to light-brown during its shelf-life.

Pack sizes

3 ml of solution in a vial - pack of 1 or 10 vials

5 ml of solution in an ampoule - pack of 1 ampoule (UK only)

10 ml of solution in a vial - pack of 1, 10 or 20 vials

20 ml of solution in a vial - pack of 1 vial

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

CSL Behring GmbH

Emil-von-Behring-Strasse 76

35041 Marburg

Germany

This leaflet was last approved in: October 2009

For further information contact

CSL Behring UK Limited

Hayworth House

Market Place

Haywards Heath

West Sussex

RH16 1DB

UK

Telephone number: 01444 447 405