Flixotide Diskhaler 100 mcg

1. Name Of The Medicinal Product

Flixotide_TM Diskhaler_TM100 Micrograms

2. Qualitative And Quantitative Composition

Fluticasone Propionate (micronised) 100 micrograms

3. Pharmaceutical Form

Inhalation Powder.

4. Clinical Particulars

4.1 Therapeutic Indications

Fluticasone propionate given by inhalation offers preventative treatment for asthma. At recommended doses it has a potent glucocorticoid anti-inflammatory action within the lungs, with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically.

Prophylactic management in: -

Adults

Mild asthma:

Patients requiring intermittent symptomatic bronchodilator asthma medication on a regular daily basis.

Moderate asthma:

Patients with unstable or worsening asthma despite prophylactic therapy or bronchodilator alone.

Severe asthma:

Patients with severe chronic asthma and those who are dependent on systemic corticosteroids for adequate control of symptoms. On introduction of inhaled fluticasone propionate many of these patients may be able to reduce significantly, or to eliminate, their requirement for oral corticosteroids.

Children:

Any child who requires prophylactic medication, including patients not controlled on currently available prophylactic medication.

Route of administration: by inhalation.

4.2 Posology And Method Of Administration

The onset of therapeutic effect is within 4 to 7 days.

Adults and children over 16 years: 100 to 1,000 micrograms twice daily.

Patients should be given a starting dose of inhaled fluticasone propionate, which is appropriate to the severity of their disease.

Prescribers should be aware that fluticasone propionate is as effective as other inhaled steroids approximately at half the microgram daily dose. For example, a 100mcg of fluticasone propionate is approximately equivalent to 200mcg dose of beclometasone dipropionate (CFC containing) or budesonide

Due to the risk of systemic effects, doses above 500 micrograms twice daily should be prescribed only for adult patients with severe asthma where additional clinical benefit is expected, demonstrated by either an improvement in pulmonary function and/or symptom control, or by a reduction in oral corticosteroid therapy (see 4.4 Special Warnings and Precautions for Use and 4.8 Undesirable Effects).

Typical Adult Starting Doses:

For patients with mild asthma, a typical starting dose is 100 micrograms twice daily. In moderate and more severe asthma, starting doses may need to be 250 to 500 micrograms twice daily. Where additional clinical benefit is expected, doses of up to 1000 micrograms twice daily may be used. Initiation of such doses should be prescribed only by a specialist in the management of asthma (such as a consultant physician or general practitioner with appropriate experience).

The dose should be titrated down to the lowest dose at which effective control of asthma is maintained.

Typical starting doses for children over 4years of age:

50 to 100 micrograms twice daily .

Many children's asthma will be well controlled using the 50 to 100 microgram twice daily dosing regime. For those patients whose asthma is not sufficiently controlled, additional benefit may be obtained by increasing the dose up to 200 micrograms twice daily. The maximum licensed dose in children is 200 micrograms twice daily.

The starting dose should be appropriate to the severity of the disease. The dose should be titrated down to the lowest dose at which effective control of asthma is maintained.

Special patient groups:

There is no need to adjust the dose in elderly patients or those with hepatic or renal impairment.

4.3 Contraindications

Flixotide preparations are contra-indicated in patients with a history of hypersensitivity to any of their components.

4.4 Special Warnings And Precautions For Use

Flixotide Diskhalers are not designed to relieve acute symptoms for which an inhaled short acting bronchodilator is required. Patients should be advised to have such rescue medication available.

Severe asthma requires regular medical assessment, including lung-function testing, as patients are at risk of severe attacks and even death. Increasing use of short-acting inhaled β₂-agonists to relieve symptoms indicates deterioration of asthma control. If patients find that short-acting relief bronchodilator treatment becomes less effective, or they need more inhalations than usual, medical attention must be sought.

In this situation patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroids or a course of oral corticosteroids). Severe exacerbations of asthma must be treated in the normal way.

There have been very rare reports of increases in blood glucose levels, in patients with or without a history of diabetes mellitus (See 4.8 'Undesirable Effects'). This should be considered in particular when prescribing to patients with a history of diabetes mellitus.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. Flixotide Diskhaler should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important therefore that the dose of inhaled corticosteroid is reviewed regularly and reduced to the lowest dose at which effective control of asthma is maintained.

Prolonged treatment with high doses of inhaled corticosteroids may result in adrenal suppression and acute adrenal crisis. Children aged < 16 years taking higher than licensed doses of fluticasone (typically

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

When changing from a dry powder inhaler to a metered dose inhaler, administration of high doses, above 1000 mcg daily, is recommended through a spacer to reduce side effects in the mouth and throat. However, this may increase drug delivery to the lungs. As systemic absorption is largely through the lungs, there may be an increase in the risk of systemic adverse effects. A lower dose may be required.

The benefits of inhaled fluticasone propionate should minimise the need for oral steroids. However, patients transferred from oral steroids, remain at risk of impaired adrenal reserve for a considerable time after transferring to inhaled fluticasone propionate. The possibility of adverse effects may persist for some time.

These patients may require specialised advice to determine the extent of adrenal impairment before elective procedures. The possibility of residual impaired adrenal response should always be considered in emergency (medical or surgical) and elective situations likely to produce stress, and appropriate corticosteroid treatment considered.

Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled fluticasone propionate and, if necessary, by giving a systemic steroid and/or an antibiotic if there is an infection.

For the transfer of patients being treated with oral corticosteroids:

The transfer of oral steroid-dependent patients to Flixotide and their subsequent management needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.

Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression. With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.

After approximately a week, gradual withdrawal of the systemic steroid is started by reducing the daily dose by one milligram prednisolone, or its equivalent. For maintenance doses of prednisolone in excess of 10mg daily, it may be appropriate to cautiously use larger reductions in dose at weekly intervals.

Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with inhaled fluticasone propionate and to continue withdrawal of systemic steroid, unless there are objective signs of adrenal insufficiency.

Patients transferred from oral steroids whose adrenocortical function is still impaired should carry a steroid warning card indicating that they need supplementary systemic steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

Replacement of systemic steroid treatment with inhaled therapy sometimes unmasks allergies such as allergic rhinitis or eczema previously controlled by the systemic drug. These allergies should be symptomatically treated with antihistamine and/or topical preparations, including topical steroids.

Treatment with Flixotide Diskhalers should not be stopped abruptly.

Special care is necessary in patients with active or quiescent pulmonary tuberculosis.

Ritonavir can greatly increase the concentration of fluticasone propionate in plasma. Therefore, concomitant use should be avoided, unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side-effects. There is also an increased risk of systemic side effects when combining fluticasone propionate with other potent CYP3A inhibitors (see 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Under normal circumstances, low plasma concentrations of fluticasone propionate are achieved after inhaled dosing, due to extensive first pass metabolism and high systemic clearance mediated by cytochrome P450 3A4 in the gut and liver. Hence, clinically significant drug interactions mediated by fluticasone propionate are unlikely.

In an interaction study in healthy subjects with intranasal fluticasone propionate, ritonavir (a highly potent cytochrome P450 3A4 inhibitor) 100 mg b.i.d. increased the fluticasone propionate plasma concentrations several hundred fold, resulting in markedly reduced serum cortisol concentrations. Information about this interaction is lacking for inhaled fluticasone propionate, but a marked increase in fluticasone propionate plasma levels is expected. Cases of Cushing's syndrome and adrenal suppression have been reported. The combination should be avoided unless the benefit outweighs the increased risk of systemic glucocorticoid side-effects.

In a small study in healthy volunteers, the slightly less potent CYP3A inhibitor ketoconazole increased the exposure of fluticasone propionate after a single inhalation by 150%. This resulted in a greater reduction of plasma cortisol as compared with fluticasone propionate alone. Co-treatment with other potent CYP3A inhibitors, such as itraconazole, is also expected to increase the systemic fluticasone propionate exposure and the risk of systemic side-effects. Caution is recommended and long-term treatment with such drugs should if possible be avoided.

4.6 Pregnancy And Lactation

There is inadequate evidence of safety of fluticasone propionate in human pregnancy. Administration of corticosteroids to pregnant animals can cause abnormalities of fetal development, including cleft palate and intra-uterine growth retardation. There may therefore be a very small risk of such effects in the human fetus. It should be noted, however, that the fetal changes in animals occur after relatively high systemic exposure. Because fluticasone propionate is delivered directly to the lungs by the inhaled route it avoids the high level of exposure that occurs when corticosteroids are given by systemic routes.

Administration of fluticasone propionate during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus.

The secretion of fluticasone propionate in human breast milk has not been investigated. Subcutaneous administration of fluticasone propionate to lactating laboratory rats produced measurable plasma levels and evidence of fluticasone propionate in the milk. However, plasma levels in humans after inhalation at recommended doses are likely to be low.

When fluticasone propionate is used in breast feeding mothers the therapeutic benefits must be weighed against the potential hazards to mother and baby.

4.7 Effects On Ability To Drive And Use Machines

Fluticasone propionate is unlikely to produce an effect.

4.8 Undesirable Effects

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

System Organ Class	Adverse Event	Frequency
Infections & Infestations	Candidiasis of the mouth and throat Pneumonia (in COPD patients)	Very Common Common
Immune System Disorders	Hypersensitivity reactions with the following manifestations: Cutaneous hypersensitivity reactions Angioedema (mainly facial and oropharyngeal oedema), Respiratory symptoms (dyspnoea and/or bronchospasm), Anaphylactic reactions	Uncommon Very Rare Very Rare Very Rare
Endocrine Disorders	Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decreased bone mineral density, cataract, glaucoma	Very Rare
Metabolism & Nutrition Disorders	Hyperglycaemia (see 4.4 'Special Warnings and Precautions for Use')	Very Rare
Gastrointestinal Disorders	Dyspepsia	Very Rare
Musculoskeletal & Connective Tissue Disorders	Arthralgia	Very Rare
Psychiatric Disorders	Anxiety, sleep disorders, behavioural changes, including hyperactivity and irritability (predominantly in children) Depression, aggression (predominantly in children)	Very Rare Not known
Respiratory, Thoracic & Mediastinal Disorders	Hoarseness/dysphonia Paradoxical bronchospasm	Common Very Rare
Skin & Subcutaneous Tissue Disorders	Contusions	Common

Hoarseness and candidiasis of the mouth and throat (thrush) occurs in some patients. Such patients may find it helpful to rinse out their mouth with water after using the Diskhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with the Flixotide Diskhaler.

Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma.(see 4.4 Special Warnings and Special Precautions for Use).

As with other inhalation therapy, paradoxical bronchospasm may occur (see 4.4 'Special Warnings and Precautions for Use'). This should be treated immediately with a fast-acting inhaled bronchodilator. Flixotide Diskhaler should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

There was an increased reporting of pneumonia in studies of patients with COPD receiving FLIXOTIDE 500 micrograms. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbation frequently overlap.

4.9 Overdose

Acute: Inhalation of the drug in doses in excess of those recommended may lead to temporary suppression of adrenal function. This does not necessitate emergency action being taken.

In these patients treatment with fluticasone propionate by inhalation should be continued at a dose sufficient to control asthma adrenal function recovers in a few days and can be verified by measuring plasma cortisol.

Chronic: refer to section 4.4: risk of adrenal suppression.

Monitoring of adrenal reserve may be indicated. Treatment with inhaled fluticasone propionate should be continued at a dose sufficient to control asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Fluticasone propionate given by inhalation at recommended doses has a potent glucocorticoid anti-inflammatory action within the lungs, with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically.

5.2 Pharmacokinetic Properties

Systemic absolute bioavailability of fluticasone propionate is estimated at 12-26% of an inhaled dose, dependent on presentation. Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the dose may be swallowed.

Absolute oral bioavailability is negligible (<1%) due to a combination of incomplete absorption from the GI tract and extensive first-pass metabolism. 87-100% of an oral dose is excreted in the faeces, up to 75% as parent compound. There is also a non-active major metabolite.

After an intravenous dose, fluticasone propionate is extensively distributed in the body. The very high clearance rate indicates extensive hepatic clearance.

5.3 Preclinical Safety Data

No clinically relevant findings were observed in preclinical studies.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose Ph Eur

6.2 Incompatibilities

None known

6.3 Shelf Life

24 months

6.4 Special Precautions For Storage

Whilst the disks provide good protection to the blister contents from the effects of the atmosphere, they should not be exposed to extremes of temperature and should not be stored above 30^oC. A disk may be kept in the diskhaler at all times but a blister should only be pierced immediately prior to use. Failure to observe this instruction will affect the operation of the diskhaler.

6.5 Nature And Contents Of Container

A circular double-foil (PVC/Aluminium) disk with four blisters, containing a mixture of fluticasone propionate and lactose. The foil disk is inserted into the Diskhaler device.

The following packs are registered: 5, 7, 10, 14 or 15 disks with or without a diskhaler. Refill packs of 5, 7, 10, 14 or 15 disks. A starter pack consisting of diskhaler pre-loaded with one disk (with or without a peak flow meter and diary card). A starter pack plus a spare disk (with or without a peak flow meter and diary card).

The following packs are marketed: cartons containing 14 disks (14x4 blisters), together with a Diskhaler inhaler. Cartons containing 5 disks (5x4 blisters) together with a Diskhaler inhaler (250 micrograms and 500 micrograms hospital packs only). Refill packs containing 14 disks (14x4 blisters).

6.6 Special Precautions For Disposal And Other Handling

See Patient Information Leaflet for detailed instructions.

Administrative Data

7. Marketing Authorisation Holder

Glaxo Wellcome UK Ltd

trading as Allen & Hanburys

Stockley Park West

Uxbridge,

Middlesex

UB11 1BT

8. Marketing Authorisation Number(S)

PL 10949/0006

9. Date Of First Authorisation/Renewal Of The Authorisation

25 February 1993

10. Date Of Revision Of The Text

23 August 2011

11. LEGAL STATUS

POM.

Fleet Phospho-Soda

1. Name Of The Medicinal Product

Fleet Phospho-soda 24.4g / 10.8g oral solution

2. Qualitative And Quantitative Composition

	per 45ml dose	per 1ml
Disodium phosphate dodecahydrate	10.8 g	0.24 g
Sodium dihydrogen phosphate dihydrate	24.4 g	0.542 g

Each 45ml bottle contains 5.0 g sodium.

Fleet Phospho-soda contains a very small amount of ethanol, less than 100 mg per dose.

For a full list of excipients, see Section 6.1

3. Pharmaceutical Form

Oral solution. Clear colourless solution with a ginger-lemon odour, free from precipitation and turbidity.

4. Clinical Particulars

4.1 Therapeutic Indications

As a bowel cleanser in preparing the patient for colon surgery, or for preparing the colon for x-ray or for endoscopic examination.

Bowel cleansing agents are not to be considered as treatments for constipation.

4.2 Posology And Method Of Administration

Adults Only: Not to be given to children under the age of 18 years.

Elderly patients: As for Adults.

The taking of Fleet Phospho-soda should be started the day before the hospital appointment.

For hospital appointments before 12 noon the dosage instructions for morning appointments should be followed and for appointments after 12 noon the dosage instructions for an afternoon appointment should be followed.

MORNING APPOINTMENT:

Day before appointment

7am – In place of breakfast drink at least one full glass of “clear liquid” or water, more if desired.

“Clear liquids” include water, clear soup, strained fruit juices without pulp, black tea or black coffee, clear carbonated and non-carbonated soft drinks.

1^st Dose – Straight afterwards, dilute 45ml in half a glass (120ml) cold water. Drink this solution followed by one full glass (240ml) cold water, more if desired.

Drink as much extra liquids as possible to replace the fluids lost during bowel movements.

1pm lunch – In place of lunch drink at least three full glasses (720ml) of “clear liquid” or water, more if desired.

7pm supper – In place of supper drink at least one full glass of “clear liquid” or water, more if desired.

2^nd Dose – Straight afterwards, dilute 45ml in half a glass (120ml) cold water. Drink this solution followed by one full glass (240ml) cold water, more if desired.

Additional water or “clear liquids” may be taken up until midnight if necessary.

Drinking large amounts of clear liquids also helps ensure that the bowel will be clean for the procedure.

AFTERNOON APPOINTMENT:

Day before appointment

1pm lunch – A light snack may be taken. After lunch, no more solid food must be taken until after the hospital appointment.

7pm supper – In place of supper drink at least one full glass of “clear liquid” or water, more if desired.

1^st Dose – Straight afterwards, dilute 45ml in half a glass (120ml) cold water. Drink this solution followed by one full glass (240ml) cold water, more if desired.

Drink as much extra liquids as possible to replace the fluids lost during bowel movements.

During the evening, drink at least three full glasses of water or “clear liquid” before going to bed.

Day of appointment

7am breakfast – In place of breakfast drink at least one full glass of “clear liquid” or water, more if desired.

2^nd Dose – Straight afterwards, dilute 45ml in half a glass (120ml) cold water. Drink this solution followed by one full glass (240ml) cold water

Drink as much extra liquids as possible to replace the fluids lost during bowel movements. Drinking large amounts of clear liquids also helps ensure that the bowel will be clean for the procedure.

More water or “clear liquid” may be taken up until 8am.

This product normally produces a bowel movement in ½ to 6 hours.

After the procedure:

In order to replace fluid lost during the preparation for the procedure patients should be encouraged to drink plenty of fluid afterwards.

4.3 Contraindications

Do not use:

• In children under the age of 18 years.

• When nausea, vomiting or abdominal pain are present.

• There is a hypersensitivity to the active ingredients or any of excipients.

Do not use in patients with:

• Clinically significant impairment of renal function;

• Primary hyperparathyroidism associated with hypercalcaemia

• Congestive heart failure;

• Ascites;

• Known or suspected gastrointestinal obstruction;

• Megacolon (congenital or acquired);

• Perforation;

• Ileus;

• Active inflammatory bowel disease.

Fleet Phospho-soda should not be used in combination with other laxative products containing sodium phosphate.

4.4 Special Warnings And Precautions For Use

Fleet® Phospho-soda® has been rarely associated with severe and potentially fatal cases of electrolyte disorders in elderly patients. The benefit/risk ratio of Fleet® Phospho-soda® needs to be carefully considered before initiating treatment in this at-risk population. Special attention should be taken when prescribing Fleet® Phospho-soda® to any patient with regard to known contraindications and the importance of adequate hydration and, in at-risk populations (see below and sections 4.2 and 4.3.), the importance of also obtaining baseline and post-treatment electrolyte levels.

Dehydration

This product usually works within ½ to 6 hours. If there has been no bowel movement within 6 hours of taking Fleet Phospho-soda, instruct the patient to stop use and contact a doctor immediately as dehydration could occur.

Patients should be warned to expect frequent, liquid stools. Patients should be encouraged to drink as much liquid as possible to help prevent dehydration. Inadequate fluid intake when using any effective purgative may lead to excessive fluid loss possibly producing dehydration and hypovolemia. Dehydration and hypovolemia from purgation may be exacerbated by inadequate oral fluid intake, nausea, vomiting, loss of appetite, or use of diuretics, angiotensin converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBS), and non-steroidal anti-inflammatory drugs (NSAIDs) and may be associated with acute renal failure. There have been rare reports of acute renal failure with purgatives, including sodium phosphates and PEG-3350.

Patients with conditions that may predispose to dehydration or those taking medications which may decrease glomerular filtration rate, should be assessed for hydration status prior to use of purgative preparations and managed appropriately.

Nephrocalcinosis

Nephrocalcinosis associated with acute renal failure and deposits of calcium-phosphate crystals in the renal tubules has been rarely reported in patients using sodium phosphates for bowel cleansing; Nephrocalcinosis is a serious adverse event that may result in permanent renal function impairment and the requirement of long-term dialysis. The majority of these reports occurred in elderly female patients taking drugs to treat hypertension or other drug products, such as diuretics or NSAIDs, that may result in dehydration.

Care should be taken to prescribe Fleet Phospho-soda per recommendations with a particular attention to known contraindications and adequate hydration.

At risk patients

Use with caution in patients with an increased risk for underlying renal impairment, pre-existing electrolyte disturbances, increased risk for electrolyte disturbances (e.g. dehydration, gastric retention, colitis, inability to take adequate oral fluid, hypertension or other conditions in which the patients are taking products that may result in dehydration, see below), hypotension with clinical impact or associated with hypovolaemia, , heart disease, acute myocardial infarction, unstable angina, , or with debilitated or elderly patients. In these at-risk patients, consider obtaining baseline and post-treatment sodium, potassium, calcium, chloride, bicarbonate, phosphate, blood urea nitrogen and creatinine values.

Electrolyte disorders

There is a risk of elevated serum levels of sodium and phosphate and decreased levels of calcium and potassium; consequently hypernatraemia, hyperphosphataemia, hypocalcaemia, hypokalaemia, and acidosis may occur.

Slight QT interval prolongation may rarely occur as a result of electrolyte imbalances such as hypocalcaemia or hypokalaemia. These changes are clinically insignificant.

Hypomotility

Use with caution in patients with hypomotility disorders or who have had gastro-intestinal surgery or have other medical conditions predisposing them to hypomotility disorders. If the patient has had a colostomy or ileostomy, or must keep to a salt-free diet, the preparation must be used with caution, since a disturbance of electrolyte balance, dehydration or a disturbance of acid balance may arise.

Lesions

Single or multiple aphthoid-like punctiform lesions located in the rectosigmoid region have been observed by endoscopy. These were either lymphoid follicles or discrete inflammatory infiltrates or epithelial congestions/changes revealed by the colonic preparation. These abnormalities are not clinically significant and disappear spontaneously without any treatment.

Sodium content

Fleet Phospho-soda contains 5.0g sodium in each 45 ml dose. Consideration should therefore be given to the potential harm to patients requiring a low-sodium diet.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Use with caution in patients taking calcium channel blockers, diuretics, lithium treatment or other medications that might affect electrolyte levels as hyperphosphataemia, hypocalcaemia, hypokalaemia, hypernatraemic dehydration and acidosis may occur.

During the intake of Fleet Phospho-soda the absorption of drugs from the gastrointestinal tract may be delayed or even completely prevented. The efficacy of regularly taken oral drugs (e.g. oral contraceptives, antiepileptic drugs, antidiabetics, antibiotics) may be reduced or completely absent. Caution is also advised when taking medicines known to prolong the QT interval.

Use with caution in patients who are taking parathyroid hormone medications.

4.6 Pregnancy And Lactation

For Fleet Phospho-soda, no clinical data on exposed pregnancies and no data from animal studies with respect to effects on pregnancy, embryonal/fetal development, parturition and postnatal development are available. The potential risk for humans is unknown. Fleet Phospho-soda should not be used during pregnancy unless clearly necessary.

It is not known whether Fleet Phospho-soda is excreted in human milk. As sodium phosphate may pass into the breast milk, it is advised that breast milk is expressed and discarded from the first dose to 24 hours after the second dose of the bowel cleansing solution. Women should not breast-feed their infants until 24 hours after receiving the second dose of Fleet Phospho-soda.

4.7 Effects On Ability To Drive And Use Machines

Fleet^® Phospho-Soda^® may cause dizziness, probably as a result of dehydration, and this may have a mild to moderate effect on the ability to drive or use machinery.

4.8 Undesirable Effects

The following adverse reactions were reported with frequencies corresponding to: Very common (>1/10), Common (

IMMUNE SYSTEM DISORDERS
Very rare
	Hypersensitivity
METABOLISM AND NUTRITION DISORDERS
Uncommon
	Dehydration
Very rare
	Hyperphosphataemia Hypocalcaemia Hypokalaemia Hypernatraemia Metabolic acidosis Tetany
NERVOUS SYSTEM DISORDERS
Very common
	Dizziness
Common
	Headache
Very rare
	Loss of consciousness Paraesthesia
CARDIAC DISORDERS
Very rare
	Myocardial infarction Arrhythmia
VASCULAR DISORDERS
Very rare
	Hypotension
GASTROINTESTINAL DISORDERS
Very common
	Diarrhoea Abdominal pain Abdominal distension Nausea
Common
	Vomiting Colonoscopia abnormal (Single or multiple aphthoid-like punctiform lesions located in the rectosigmoid region that are not clinically significant and disappear spontaneously without any treatment)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Very rare
	Dermatitis allergic
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Very rare
	Muscle cramp
RENAL AND URINARY DISORDERS
Rare
	Nephrocalcinosis
Very rare
	Renal failure acute Renal failure chronic
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Very common
	Chills Asthenia
Common
	Chest pain

4.9 Overdose

There have been fatal cases of hyperphosphataemia with concomitant hypocalcaemia, hypernatraemia and acidosis when Fleet Phospho-soda has been used in excessive doses, given to children or to obstructed patients.

Patients experiencing overdose have presented the following symptoms: dehydration, hypotension, tachycardia, bradycardia, tachypnoea, cardiac arrest, shock, respiratory failure, dyspnoea, convulsions, ileus paralytic, anxiety, pain. Overdoses can lead to elevated serum levels of sodium and phosphate and decreased levels of calcium and potassium. In those cases, hypernatremia, hyperphosphatemia, hypocalcemia, hypokalemia, and acidosis may occur.

There are also documented cases of complete recovery from overdoses in both children accidentally given Fleet Phospho-soda, and also in patients with obstruction, one of whom received a six-fold overdose.

Recovery from the toxic effect of excess ingestion can normally be achieved by rehydration, though the intravenous administration of 10% calcium gluconate may be necessary.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

A06AD – Osmotically acting laxative.

Fleet Phospho-soda is a saline laxative that acts by osmotic processes to increase fluid retention in the lumen of the small intestine. Fluid accumulation in the ileum produces distension and, in turn, promotes peristalsis and bowel evacuation.

5.2 Pharmacokinetic Properties

Not applicable.

5.3 Preclinical Safety Data

No animal studies on reproduction toxicity have been conducted with Fleet Phospho-soda.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Glycerol

Saccharin Sodium

Sodium Benzoate (E211)

Ginger Lemon Flavour*

Purified Water

*Ginger Lemon Flavour:

Oleoresin Ginger Alcohol Oil Lemon Partially Deterpinated Oil Lemon Citric Acid Water

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years

Once opened, use immediately. Discard any unused portion.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Fleet Phospho-soda is supplied in cartons containing 2 x 45ml or 100 x 45ml (hospital pack) polyethylene bottles with polypropylene, aluminium foil-lined screw caps.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

This product must be diluted with water before use.

7. Marketing Authorisation Holder

Laboratorios Casen-Fleet S.L.U.

Autovía de Logroño, Km. 13,300

50180 UTEBO. Zaragoza (Spain)

8. Marketing Authorisation Number(S)

PL 12695/0001

9. Date Of First Authorisation/Renewal Of The Authorisation

06 July 1995 / 30 April 2010

10. Date Of Revision Of The Text

30 April 2010

Furosemide Tablets 500mg

1. Name Of The Medicinal Product

Furosemide Tablets 500mg

2. Qualitative And Quantitative Composition

Furosemide BP 500 mg.

3. Pharmaceutical Form

Tablet.

4. Clinical Particulars

4.1 Therapeutic Indications

The management of oliguria due to acute or chronic renal failure.

4.2 Posology And Method Of Administration

In patients with chronic renal insufficiency an initial daily dose of 250mg is employed. If a satisfactory diuresis is not produced then the dose may be increased in steps of 250mg at 4 - 6 hourly intervals up to a maximum daily dose of 1,500mg in 24 hours. In exceptional cases up to 2,000mg in 24 hours may be given.

For oral administration.

4.3 Contraindications

Furosemide is contraindicated in the presence of anuria, electrolyte deficiency, precoma associated with hepatic cirrhosis, digitalis intoxication, porphyria and hypersensitivity to furosemide or sulphonamides.

4.4 Special Warnings And Precautions For Use

Furosemide should be discontinued before a glucose tolerance test.

Furosemide should be used with particular caution in elderly patients or those with potential obstruction of the urinary tract or disorders rendering electrolyte balance precarious.

Regular monitoring of fluids and electrolyte balance is recommended. Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy. This may require temporary discontinuation of Furosemide. Regular monitoring of serum sodium, potassium, creatinine and glucose is generally recommended during therapy; particularly close monitoring is required in patients at high risk of developing electrolyte imbalances or in case of significant additional fluid loss. Of note, the risk of electrolyte disturbances can be increased even in mild renal failure.

Frequent checks of the serum potassium level are necessary in patients with impaired renal function and a creatinine clearance below 60ml/min per 1.73m² body surface area as well as in cases where Furosemide is taken in combination with certain other drugs which may lead to an increase in potassium levels.

Particularly careful monitoring is necessary in the following cases :

- Latent diabetes may become manifest or the insulin requirements of diabetic patients may increase.

- Hepatic failure and alcoholic cirrhosis particularly predispose to hypokalaemia and hypomagnesaemia. (Refer to section 4.8 for details of electrolyte and metabolic abnormalities).

- Use with caution in patients with a history of gout. Furosemide may predispose the patient to the development of hyperuricaemia. (Refer to Section 4.8)

- Patients with hypoproteinaemia, e.g. associated with nephrotoxic syndrome (the effect of furosemide may be weakened and its ototoxicity potentiated). Cautious dose titrated is required.

Use with caution in patients with impaired hepatic, cardiac or renal function, diabetes mellitus or adrenal disease and elderly patients.

In patients who are at high risk for radiocontrast nephropathy, furosemide is not recommended to be used for diuresis as part of the preventative measures against radiocontrast-induced nephropathy.

Acute diuresis may cause urinary retention in patients with urinary outflow obstruction (such as prostatic hyperplasia/ hypertrophy or impairment of micturition). Urinary output must be monitored in these patients.

Co-administration with nonsteriodal anti-inflammatory analgesics (NSAIDs) should be avoided wherever possible. Where this is not possible, particularly careful monitoring is required to ensure that the diuretic effect is not attenuated (Refer to section 4.5).

Use with caution in patients with hypotension, liver failure, prostate enlargement.

Hypotension may occur if ACE inhibitors are added to Furosemide therapy. The dose of Furosemide should be reduced or the drug stopped before initiating the ACE inhibitor.

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The dosage of concurrently administered cardiac glycosides, diuretics, anti-hypertensive agents, or other drugs with blood-pressure-lowering potential may require adjustment as a more pronounced fall in blood pressure must be anticipated if given concomitantly with Furosemide.

A marked fall in blood pressure and deterioration in renal function may be seen when ACE inhibitors or angiotensin II receptor antagonists are added to furosemide therapy, or their dose level increased. The dose of Furosemide should be reduced for at least three days, or the drug stopped, before initiating the ACE inhibitor or angiotensin II receptor antagonist or increasing their dose.

Increased risk of hyperkalaemia when furosemide given with: Potassium salts or supplements, potassium-sparing diuretics (such as amiloride and spironolactone), ACE inhibitors, angiotensin receptor antagonists, ciclosporin, tacrolimus, trilostane and drosperinone.

The toxic effects of nephrotoxic drugs like cephaloridine, amphotericine and the aminoglycoside antibiotics may be increased by concomitant administration with potent diuretics such as furosemide . Oral furosemide and sucralfate must not be taken within 2 hours of each other because sucralfate decreases the absorption of furosemide from the intestine and so reduces its effect.

Furosemide may reduce the elimination of lithium, resulting in increased lithium toxicity, including increased risk of cardiotoxic and neurotoxic effects of lithium. Therefore, it is recommended that lithium levels are carefully monitored and where necessary, the lithium dosage is adjusted in patients receiving this combination.

Certain non-steroidal anti-inflammatory agents (e.g. indometacin, acetylsalicylic acid) may attenuate the action of Furosemide and may cause acute renal failure in cases of pre-existing hypovolaemia or dehydration. Salicylic toxicity may be increased by furosemide. Furosemide decreases the effects of some drugs (e.g. antidiabetics and pressor amines) and may potentiate the effects of others (e.g. salicylates, theophylline and curare type muscle relaxants).

Concomitant administration of carbamazepine, aminoglutethamide or trimethoprim may increase the risk of hyponatraemia.

Concurrent administration of corticosteroids may cause sodium retention and exacerbate potassium loss.

Amiloride may cause raised blood digoxin levels. Furosemide induced electrolyte disturbances (such as hypokalaemia, hypomagnesemia) may predispose the patient to arrhythmogenic effect of other drugs (such as digoxin and drugs that prolong the QT interval).

Furosemide may enhance the toxicity of cardiac glycosides by electrolyte disturbances particularly potassium and magnesium.

Attenuation of the effect of Furosemide may occur following concurrent administration of phenytoin.

Corticosteroids, glychyrrizin (contained in liquorice), B₂ sympathomimetics in large amounts,prolonged use of laxatives, reboxetine and amphotericin may increase the risk of developing hypokalaemia. Resultant hypokalaemia may potentiate the cardiac toxicity of certain drugs such as antihistamines and antiarrhythmics.

Potassium depletion that can result from furosemide administration may potentiate digitalis toxicity.

Probenecid, methotrexate and other drugs which, like furosemide, undergo significant renal tubular secretion may reduce the effect of Furosemide.

Probenecid may reduce the renal clearance of Furosemide.

Conversely, furosemide may decrease renal elimination of these drugs. In case of high-dose treatment (in particular, of both furosemide and the other drugs), this may lead to increased serum levels and an increased risk of adverse effects due to furosemide or the concomitant medication.

Impairment of renal function may develop in patients receiving concurrent treatment with furosemide and high doses of certain cephalosporins

Concomitant use of ciclosporin and furosemide is associated with increased risk of gouty arthritis.

Furosemide may potentiate the ototoxicity of aminoglycoside and other ototoxic drugs. Since this may lead to irreversible damage, these drugs must only be used with furosemide if there are compelling medical reasons.

There is a risk of ototoxic effects if cisplatin and furosemide are given concomitantly. In addition, nephrotoxicity of cisplatin may be enhanced if furosemide is not given in low doses (e.g. 40 mg in patients with normal renal function) and with positive fluid balance when used to achieve forced diuresis during cisplatin treatment.

4.6 Pregnancy And Lactation

Furosemide has been given after the first trimester of pregnancy for oedema, hypertension and toxaemia of pregnancy without causing foetal or newborn adverse effects. However, it should only be given during pregnancy if strictly indicated and for short-term treatment. As it may inhibit lactation and passes into breast milk, furosemide should be used with caution in nursing mothers.

4.7 Effects On Ability To Drive And Use Machines

Reduced mental alertness and rarely dizziness and blurred vision have been reported. Patients so affected should not drive or operate machines.

4.8 Undesirable Effects

Blood and lymphatic system disorders	Occassionally:	thrombocytopenia
Rare	bone marrow depression, (necessitates withdrawal of treatment). leucopenia, eosinophilia.
Very Rare:	agranulocytosis, aplastic anaemia, haemolytic anaemia.
Cardiac disorders	Uncommon	Cardiac arrhythmias
Congenital, familial and genetic disorders	Rare or very rare	Patent ductus arteriosus
Ear and labyrinth disorders	Rare or very rare	Tinnitus, reversible or irreversible loss of hearing (although usually transitory, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephritic syndrome) and/or when intravenous furosemide has been given too rapidly).
Eye disorders	Uncommon	visual disturbance
Gastrointestinal disorders	Uncommon	dry mouth, thirst, nausea, bowel motility disturbances, vomiting, diarrhea, constipation.
Rare or very rare	Acute Pancreatitis
General disorders and administration site conditions	Uncommon	Fatigue
Rare or very rare	Malaise, Fever
Hepato-biliary disorders	Rare or very rare	Pure Intrahepatic Cholestasis, Hepatic function abnormal.
Investigations	Common	creatinine increased, blood urea increased.
Rare or very rare	Transaminases increased, blood
Metabolism and nutrition disorders	Very common or common	dehydration, hyponatraemia, hypochloremic metabolic alkalosis, hypokalaemia, hypocalcaemia, hypomagnesemia (incidences of the last three are reduced by triamterene)
Uncommon	impaired glucose tolerance (by hypokalaemia), hyperuricaemia, gout, reduction of serum HDL-cholesterol, elevation of serum LDL-cholesterol, elevation of serum triglycerides
Very rare	tetany
Musculoskeletal, connective tissue and bone disorders	Uncommon	muscle cramps, muscle weakness
Nervous system disorders	Rare	Paraesthesia, confusion
Psychiatric disorder	Rare	Psychiatric disorder NOC,
Renal and urinary disorders	Uncommon	Reduced diuresis, urinary incontinence, urinary obstruction (in patients with hyperplasia of the prostate, bladder inability to empty, urethral stricture unspecified).
Rare or very rare	nephrocalcinosis (in pre-term infants treated with Furosemide), interstitial nephritis, acute renal failure.
Skin and subcutaneous tissue disorders	Rare or very rare	Rash, photosensitivity.
Ocassionally	Urticaria, purpura, erythema multiforme , exfoliative dermatitis, itching, bullous lesions.
Vascular disorders	Very common or common	decreased blood pressure, (which, if pronounced may cause signs and symptoms such as impairment of concentration and reactions, light-headedness, sensations of pressure in the head, headache, dizziness, drowsiness, weakness, disorders of vision, dry mouth, orthostatic intolerance).
Uncommon	Hypotension, hypovolaemia
Rare or very rare	Vasculitis, Thrombosis, shock

4.9 Overdose

In cases of overdosage there is a danger of dehydration and electrolyte depletion due to excessive diuresis. Treatment should be aimed at correction of electrolyte imbalance. Gastric lavage may be useful if ingestion is recent.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: CO3C A01

The evidence from many experimental studies suggests that furosemide acts along the entire nephron with the exception of the distal exchange site. The main effect is on the ascending limb of the loop of Henley with a complex effect on renal circulation. Blood-flow is diverted from the juxta-medullary region to the outer cortex.

The principle renal action of furosemide is to inhibit active chloride transport in the thick ascending limb. Re-absorption of sodium chloride from the nephron is reduced and a hypotonic or isotonic urine produced.

It has been established that prostaglandin (PG) biosynthesis and the renin-angiotensin system are affected by furosemide administration and that furosemide alters the renal permeability of the glomerulus to serum proteins.

5.2 Pharmacokinetic Properties

Furosemide is a weak carboxylic acid which exists mainly in the dissociated form in the gastrointestinal tract. Furosemide is rapidly but incompletely absorbed (60-70%) on oral administration and its effect is largely over within 4 hours. The optimal absorption site is the upper duodenum at pH 5.0. Regardless of route of administration 69-97% of activity from a radio-labelled dose is excreted in the first 4 hours after the drug is given. Furosemide is bound to plasma albumin and little biotransformation takes place. Furosemide is mainly eliminated via the kidneys (80-90%); a small fraction of the dose undergoes biliary elimination and 10-15% of the activity can be recovered from the faeces.

In renal/ hepatic impairment

Where liver disease is present, biliary elimination is reduced up to 50%. Renal impairment has little effect on the elimination rate of furosemide, but less than 20% residual renal function increases the elimination time.

The elderly

The elimination of furosemide is delayed in the elderly where a certain degree of renal impairment is present.

New born

A sustained diuretic effect is seen in the newborn, possibly due to immature tubular function.

5.3 Preclinical Safety Data

Not applicable.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose, starch, magnesium stearate, sodium starch glycollate, colloidal anhydrous silica and ultralake tartrazine 18127 (El 02).

6.2 Incompatibilities

None known.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store in a cool dry place protected from light below 25°C.

6.5 Nature And Contents Of Container

Securitainers and/or Tampertainers containing 100, 250, 500 or 1000 tablets.

PVC/Al Blister containing 28 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

Forley Generics Ltd

NLA Tower

12-16 Addiscombe Road

Croydon

CR0 OXT

United Kingdom

8. Marketing Authorisation Number(S)

PL 16201/0014

9. Date Of First Authorisation/Renewal Of The Authorisation

22 July 1999

10. Date Of Revision Of The Text

09/08/2010

Fybogel Orange

1. Name Of The Medicinal Product

Fybogel Orange.

2. Qualitative And Quantitative Composition

A unit dose (one sachet or two level 5 ml spoonfuls) contains 3.5 g ispaghula husk BP.

3. Pharmaceutical Form

Effervescent granules.

4. Clinical Particulars

4.1 Therapeutic Indications

The treatment of patients requiring a high fibre regime: for example, for the relief of constipation, including constipation in pregnancy and the maintenance of regularity; for the management of bowel function in patients with colostomy, ileostomy, haemorrhoids, anal fissure, chronic diarrhoea associated with diverticular disease, irritable bowel syndrome and ulcerative colitis.

4.2 Posology And Method Of Administration

Fybogel Orange is intended for oral use as a suspension in a drink of water. The granules should be stirred into a glass of water and taken as soon as the effervescence subsides, preferably after meals.

Adults and children over 12 years:	One sachet or two level 5ml spoonfuls morning and evening.
Elderly:	There is no indication that dosage needs to be modified for the elderly.
Children aged 6 to 12 years:	Half to one level 5 ml spoonful, depending on age and size, morning and evening.
Children under 6 years:	To be taken only when prescribed by a doctor, half to one level 5 ml spoonful depending on age and size, morning and evening.

4.3 Contraindications

Fybogel Orange is contraindicated in cases of intestinal obstruction, faecal impaction and colonic atony such as senile megacolon.

4.4 Special Warnings And Precautions For Use

Due to its aspartame content Fybogel Orange should not be given to patients with phenylketonuria.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Fybogel Orange may be used during pregnancy and lactation since the ispaghula husk is not absorbed from the gastrointestinal tract.

4.7 Effects On Ability To Drive And Use Machines

None.

4.8 Undesirable Effects

A small amount of abdominal distension and flatulence may sometimes occur.

4.9 Overdose

In the event of overdosage conservative measures should be taken. The patient may notice abdominal discomfort and flatulence, and attention should be paid to maintaining an adequate fluid intake, particularly if the granules have been taken without water contrary to administration instructions.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ispaghula husk is capable of absorbing up to 40 times its own weight in water in vitro, and part of its activity can be attributed to its action as a simple bulking agent. In addition, colonic bacteria are believed to use the hydrated material as a metabolic substrate. This results in an increase in the bacterial cell mass with consequent softening of the faeces.

5.2 Pharmacokinetic Properties

The mode of action of Fybogel Orange is physical and does not depend on absorption into the systemic circulation.

5.3 Preclinical Safety Data

No preclinical findings relevant to the prescriber have been reported.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Potassium bicarbonate	USP
Sodium bicarbonate	Ph Eur
Citric acid	Ph Eur
Riboflavin sodium phosphate	Ph Eur
Beta-carotene 10% (E160a)	HSE
Aspartame	Ph Eur
Orange flavour	HSE
Saccharin sodium	Ph Eur
Polysorbate 80	Ph Eur
Silica, colloidal anhydrous	Ph Eur

6.2 Incompatibilities

None known.

6.3 Shelf Life

Three years.

6.4 Special Precautions For Storage

Store below 30°C in a dry place.

6.5 Nature And Contents Of Container

Sachets, one, seven, ten or thirty sachets enclosed in a carton. Tub containing 100-300 g Fybogel Orange.

6.6 Special Precautions For Disposal And Other Handling

Fybogel Orange granules are to be dispersed in water forming a drink.

7. Marketing Authorisation Holder

Reckitt Benckiser Healthcare (UK) Limited,

Dansom Lane,

Hull,

HU8 7DS.

8. Marketing Authorisation Number(S)

PL 00063/0026

9. Date Of First Authorisation/Renewal Of The Authorisation

24^th April 1995 / 26^th June 1997.

10. Date Of Revision Of The Text

19/01/2007

Freederm Treatment 4% w / w Gel

1. Name Of The Medicinal Product

FREEDERM^® TREATMENT 4% w/w GEL

2. Qualitative And Quantitative Composition

Nicotinamide 4% w/w.

For a full list of excipients, see List of excipient(s).

3. Pharmaceutical Form

Topical gel.

4. Clinical Particulars

4.1 Therapeutic Indications

For the topical treatment of mild to moderate inflammatory acne vulgaris.

4.2 Posology And Method Of Administration

Apply to the affected area twice daily after the skin has been thoroughly washed with warm water and soap. Enough gel should be used to cover the affected area.

No difference in dose or dose schedule is recommended for adults, children or the elderly.

For topical administration only.

4.3 Contraindications

Contraindicated in persons who have shown hypersensitivity to any of its components.

4.4 Special Warnings And Precautions For Use

For external use only and to be kept away from the eyes and mucous membranes, including those of the nose and mouth. If excessive dryness, irritation or peeling occurs reduce the dosage to one application per day or every other day.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

None known.

4.6 Pregnancy And Lactation

Vitamin B derivative requirements such as nicotinamide, are increased during pregnancy and infancy. Nicotinamide is excreted in breast milk. As with all medicines, care should be exercised during the first trimester of pregnancy.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

The most frequently encountered adverse effect reported is dryness of the skin. Other less frequent adverse effects include pruritus, erythema, burning sensation and irritation.

4.9 Overdose

Not applicable.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Niacin (nicotinic acid) is an essential B complex Vitamin (B₃), whose deficiency results in the clinical syndrome known as pellagra. Nicotinic acid is converted in the body to nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP), which function as coenzymes for a wide variety of vital oxidation-reduction reactions. Nicotinamide (niacinamide), the active ingredient, is the physiologically active form of niacin and is the chemical form of Vitamin B₃ found in virtually all multivitamin products. Though nicotinic acid and nicotinamide are so closely related chemically, they differ somewhat in pharmacological properties. Nicotinic acid products exhibit moderately intense cutaneous vasodilation, resulting frequently in mild headaches and flushing or tingling of the skin, but such reactions have not been observed with nicotinamide. Nicotinic acid has also been used for its effect to lower plasma cholesterol, again a property not shared by nicotinamide.

Nicotinamide has demonstrated beneficial effects on inflammatory acne. It is considered that these effects are related to its significant anti-inflammatory activity.

5.2 Pharmacokinetic Properties

Following oral administration, nicotinamide is readily absorbed from the gastro- intestinal tract and widely distributed in the body tissues. The main route of metabolism is the conversion to N -methylnicotinamide and the 2-pyridone and 4-pyridone derivatives; nicotinuric acid is also formed. Small amounts of nicotinamide are excreted unchanged in the urine; this amount increases with larger doses.

5.3 Preclinical Safety Data

Nicotinic acid amide (nicotinamide) has been recognised since 1937 as an essential B complex vitamin whose deficiency results in the clinical syndrome known as pellagra. It is widely available, in tablets and in sterile solution in water for intravenous administration, for the prophylaxis and treatment of pellagra and nutritional deficiency.

In the United States, nicotinamide is included in the Food and Drug Administration's listing of nutritional agents which are Generally Recognised As Safe (GRAS).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Aluminium Magnesium Silicate; Hypromellose; Citric Acid Anhydrous; Macrogol Lauryl Ether; Ethanol Anhydrous; Purified Water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

24 months.

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Low density polyethylene or co-extruded low density polyethylene laminate 25 g tube with white polypropylene cap.

6.6 Special Precautions For Disposal And Other Handling

None stated.

7. Marketing Authorisation Holder

Diomed Developments Limited

Tatmore Place, Gosmore

Hitchin, Herts SG4 7QR, UK.

8. Marketing Authorisation Number(S)

00173/0398.

9. Date Of First Authorisation/Renewal Of The Authorisation

15 January 2009.

10. Date Of Revision Of The Text

January 2009.