Silkis 3 micrograms per g ointment

1. Name Of The Medicinal Product

Silkis 3 micrograms per g ointment

2. Qualitative And Quantitative Composition

One gram of ointment contains 3 micrograms of calcitriol (INN).

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Ointment

White, translucent ointment

4. Clinical Particulars

4.1 Therapeutic Indications

Topical treatment of mild to moderately severe plaque psoriasis (psoriasis vulgaris) with up to 35% of body surface area involvement.

4.2 Posology And Method Of Administration

Silkis Ointment should be applied to the psoriasis affected areas twice per day, once in the morning and once in the evening before retiring and after washing. It is recommended that not more than 35% of the body surface be exposed to daily treatment. Not more than 30 g of ointment should be used per day. There is limited clinical experience available for the use of this dosage regimen of more than 6 weeks.

There is no experience of the use of Silkis in children (see 4.4. Special Warnings and Precautions for Use). Patients with kidney or liver dysfunction should not use Silkis (see also 4.3. Contra-indications).

4.3 Contraindications

Patients on systemic treatment of calcium homeostasis.

Patients with kidney or liver dysfunction.

Patients with hypercalcaemia and patients known to suffer from abnormal calcium metabolism.

Silkis must not be used in patients known to be hypersensitive to the active substance or to any of the excipients.

4.4 Special Warnings And Precautions For Use

The ointment can be applied to the face with caution, as there is an increased risk of irritation in this area. Contact with the eyes should be avoided. The hands should be washed after applying the ointment in order to avoid unintentional application to non lesional areas. Not more than 35% of the body surface should be exposed to daily treatment. Not more than 30g of ointment should be used per day.

Due to potential effects on calcium metabolism, substances which stimulate absorption must not be added to the ointment, and the ointment must not be covered with an occlusive dressing.

In case of severe irritation or contact allergy, the treatment with Silkis should be discontinued and the patient should obtain medical advice. If contact allergy is demonstrated this discontinuation is definitive.

In view of the particular sensitivity of neonatal versus adult rodents to the toxic effects of calcitriol, exposure of children to calcitriol ointment should be avoided (see also 4.2. Posology and Method of administration)

Although no clinically significant hypercalcaemia was observed in clinical studies with a dosage under 30 g/day of Silkis ointment, some absorption of calcitriol through the skin does occur and excessive use of the ointment can lead to systemic side-effects, such as an increase in urine and serum calcium levels.

There is no information about the use of Silkis in other clinical forms of psoriasis (other than plaque psoriasis) i.e. Psoriasis guttata acuta, pustular psoriasis, psoriasis erythrodermica and rapid progressive plaque psoriasis.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Silkis must be used with caution in patients receiving medications known to increase the serum calcium level, such as thiazide diuretics. Caution must also be exercised in patients receiving calcium supplements or high doses of vitamin D. There is no experience of the concurrent use of calcitriol and other medications for the treatment of psoriasis.

Information of interaction of systemic medications after the use of calcitriol ointment is limited. As no relevant elevation of plasma level is seen after the use of calcitriol on the skin, interaction with systemic medication is unlikely.

Silkis Ointment has a slight irritant potential, and therefore, it is possible that concomitant use of peeling agents, astringents or irritants products may produce additive irritant effects.

4.6 Pregnancy And Lactation

Use during Pregnancy:

There are no adequate data from the use of Silkis in pregnant women. Studies in animals have shown developmental toxicity at doses which caused maternal toxicity (see section 5.3). The potential risk for humans is unknown.

Silkis should only be used during pregnancy in restricted amounts when clearly necessary. Calcium levels should be monitored.

Use during Lactation:

Calcitriol has been found in milk of lactating dams. Due to the lack of human data, it should not be used during breastfeeding.

4.7 Effects On Ability To Drive And Use Machines

No effects on ability to drive and use machines have been observed.

4.8 Undesirable Effects

Between 10% and 20% of patients can be expected to experience adverse reactions. Adverse reactions are usually localised to the application site and mild to moderate in nature.

Very common adverse reactions: Adverse reactions occurring in Common adverse reactions: Adverse reactions occurring in Uncommon adverse reactions: Adverse reactions occurring in Rare adverse reactions: Adverse reactions occurring in Very rare adverse reactions: Adverse reactions occurring in <1/10000 of patients Not known: cannot be estimated from the available data Adverse reactions reported by more than two patients in the clinical studies are included.
MedDRA System Organ Class	Frequency	Preferred term
Skin and Subcutaneous disorders	Common	Pruritus, Skin discomfort, Skin irritation, Erythema
Uncommon	Dry skin, Psoriasis (aggravated)
	Not known*	Skin oedema, Contact dermatitis

*Adverse reactions reported from post marketing surveillance

In case of severe irritation or contact allergy, the treatment with Silkis should be discontinued and the patient should obtain medical advice. If contact allergy is demonstrated this discontinuation is definitive.

4.9 Overdose

The most common symptoms which may occur after accidental administration are anorexia, nausea, vomiting, constipation, hypotonia and depression. Lethargy and coma are occasionally observed. If hypercalcaemia or hypercalciuria occurs, the use of Silkis should be discontinued until the serum or urinary calcium levels have returned to normal.

If the medication is applied excessively no more rapid or better results will be obtained and marked redness, peeling or discomfort may occur.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: D 05AX03

Calcitriol inhibits the proliferation and stimulates differentiation of keratinocytes. Calcitriol inhibits proliferation of T-cells and normalises the production of various inflammation factors.

Topical administration of Silkis Ointment to patients with plaque psoriasis results in an improvement of the skin lesions. This effect is noted from 4 weeks after the start of treatment.

5.2 Pharmacokinetic Properties

The mean absorption of calcitriol is estimated at around 10%. Following absorption, both unchanged calcitriol and metabolites have been demonstrated in plasma. The effect of the metabolites on calcium homeostasis is negligible. In most patients, circulating levels of exogenous calcitriol are below the level of detection (2pg/ml).

In clinical trials, no relevant increase in plasma calcitriol levels after treatment of large body surface areas of up to 6000 cm² (35% body surface area) was noted.

5.3 Preclinical Safety Data

Animal studies show that repeated excessive exposure to calcitriol leads to renal failure and tissue calcification due to hypervitaminosis D associated with hypercalciuria, hypercalcaemia, and hyperphosphataemia.

No indication of teratogenicity was observed in embryofoetal toxicity studies designed to assess the teratogenic potential of calcitriol. Some evidence of developmental toxicity was obtained in a cutaneous rabbit study at doses which caused maternal toxicity. No such effect was found in rats.

Local toxicity studies in animals with Calcitriol showed slight skin and eye irritation.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Liquid paraffin, white soft paraffin and alpha- tocopherol.

6.2 Incompatibilities

There are no relevant data on the compatibility of Silkis with other medicinal products. Therefore, Silkis should be used according to the posology and method of administration provided above (Section 4.2), and should not be mixed with other medicinal products.

6.3 Shelf Life

3 years

Shelf life after first opening : 8 weeks.

6.4 Special Precautions For Storage

No special precautions for storage.

6.5 Nature And Contents Of Container

The product is packaged in collapsible aluminium tubes coated internally with an epoxy - phenolic resin and fitted with a white high density polyethylene or polypropylene screw cap. Tubes contain either 15, 30 or 100g of ointment.

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

None.

7. Marketing Authorisation Holder

Galderma (UK) Limited

Meridien House

69-71 Clarendon Road

Watford

Herts

WD17 1DS

UK

8. Marketing Authorisation Number(S)

PL 10590/0047

9. Date Of First Authorisation/Renewal Of The Authorisation

10.07.1995 / 09.02.2004

10. Date Of Revision Of The Text

July 2009

Slow-K Tablets 600 mg

1. Name Of The Medicinal Product

Slow-K^® Tablets 600mg

2. Qualitative And Quantitative Composition

Potassium chloride 600mg PhEur

Excipients: also includes sucrose.

For a full list of excipients see 6.1.

3. Pharmaceutical Form

Pale orange, round, biconvex, sugar-coated modified release tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

The correction and/or prevention of hypokalaemia in those patients who cannot tolerate and/or refuse to take liquid or effervescent potassium chloride, or when there is a problem of compliance with these preparations.

4.2 Posology And Method Of Administration

Slow-K is taken orally. It is important that the tablets should be swallowed whole, with fluid, during meals, whilst the patient is sitting upright.

Adults:

The dosage of Slow-K should be adapted to the cause, degree and duration of potassium depletion. 2 to 3 tablets daily are usually an adequate supplement. In states of severe potassium deficiency, a higher dose of 9 to 12 tablets daily may be needed.

If the dosage exceeds 16mmol K⁺ (2 tablets) it should be taken in divided doses. Where intermittent diuretic therapy is being used, it is advisable to give Slow-K on intervening days between administration of the diuretic. The response to treatment should preferably be monitored by repeat determination of plasma potassium and Slow-K continued until the hypokalaemia has been corrected.

Children: Not recommended.

Elderly: No special dosage regime is usually necessary, but concurrent renal insufficiency should be taken into account (See Section 4.4 “Special warnings and precautions”).

4.3 Contraindications

Hypersensitivity to potassium administration, eg hyperkalaemic periodic paralysis, congenital paramyotonia, or hypersensitivity to any of the excipients. Marked renal failure (even when not yet associated with manifest hyperkalaemia), untreated Addison's Disease, hyporeninaemic hypoaldosteronism, acute dehydration, hyperkalaemia and conditions involving extensive cell destruction (eg severe burns).

All solid forms of potassium medication are contra-indicated in the presence of obstructions in the digestive tract (eg resulting from compression of the oesophagus due to dilation of the left atrium or from stenosis of the gut).

In cases of metabolic acidosis, the hypokalaemia should be treated not with potassium chloride but with an alkaline potassium salt (eg potassium bicarbonate).

Concomitant treatment with potassium sparing diuretics (eg spironolactone, triamterene, amiloride) (see also section 4.5 Interactions with other medicaments and other forms of interaction).

4.4 Special Warnings And Precautions For Use

If a patient under treatment with Slow-K develops severe vomiting, severe abdominal pains or flatulence, or gastro-intestinal haemorrhage, the preparation should be withdrawn at once, because in the presence of an obstruction it could conceivably give rise to ulceration or perforation (see also section 4.8 Undesirable effects).

Oral potassium preparations should be prescribed with particular caution in patients with a history of peptic ulcer.

Caution should be exercised when prescribing solid oral potassium preparations, particularly in high dosage, in patients concurrently receiving anticholinergics, because of their potential to slow gastro-intestinal motility (see also section 4.5 Interactions with other medicaments and other forms of interaction).

Patients with ostomies may have altered intestinal transit times and are better treated with other forms of potassium salts.

In patients suffering from impaired renal function, special care should be exercised when prescribing potassium salts owing to the risk of their producing hyperkalaemia. Monitoring of the serum electrolytes is particularly necessary in patients with diseases of the heart or kidneys.

In some patients, diuretic-induced magnesium deficiency will prevent restoration of intracellular deficits of potassium, so that hypomagnesaemia should be corrected at the same time as hypokalaemia.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Drugs which interfere with potassium excretion may promote hyperkalaemia when given together with Slow-K.

Combined treatment with the following increase the risk of hyperkalaemia: ACE inhibitors, angiotensin-II-receptor antagonists, ciclosporin, NSAIDs, β-blockers, heparin, digoxin, potassium sparing diuretics (see Section 4.3 Contra-indications).

4.6 Pregnancy And Lactation

Pregnancy

For Slow-K no clinical data on exposed pregnancies are available.

There is no indication in animal studies of direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development, parturition or postnatal development (see also section 5.3 Preclinical safety data).

As a general rule, no drugs should be taken during the first 3 months of pregnancy, and the benefits and risks of taking drugs should be carefully considered throughout the whole of pregnancy, solid forms of oral potassium preparations should be given to pregnant women only if clearly needed.

Lactation

The excretion of potassium in milk has not been studied in animals or human.

The normal K⁺ content of human milk is about 13mmol/litre. Since oral potassium becomes part of the body's potassium pool, provided this is not excessive, Slow-K can be expected to have little or no effect on the potassium level in human milk.

Slow-K should only be given during breast-feeding when the expected benefit to the mother outweighs the potential risk to the baby.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

Side effects are rare with Slow-K, as any excess potassium is rapidly excreted in the urine.

Gastrointestinal tract: Rare: oral potassium preparations may provoke gastro-intestinal disturbances (nausea, vomiting, abdominal pains, diarrhoea) necessitating either a reduction in dosage or withdrawal of medication (see Section 4.4 “Special warnings and precautions for use”). Isolated cases: obstruction, bleeding and ulceration, with or without perforation of the upper or lower GIT, have been reported, usually associated with other factors known to predispose a patient to these effects (eg delayed GIT transit time, obstruction of GIT).

Skin: Rare: Pruritus and/or skin rash, urticaria.

Electrolytes: Hyperkalaemia may develop in patients having difficulty with either renal potassium excretion or potassium metabolism.

4.9 Overdose

Signs and symptoms: Mainly cardiovascular (hypotension, shock, ventricular arrhythmias, bundle-branch block, ventricular fibrillation leading possibly to cardiac arrest) and neuromuscular (paraesthesiae, convulsions, areflexia, flaccid paralysis of striated muscle leading possibly to respiratory paralysis). Beside elevation of serum potassium concentration, typical ECG changes are also encountered (increasing amplitude and peaking of T waves, disappearance of P wave, widening of QRS complex and S-T segment depression).

Treatment: Gastric lavage, administration of cation exchange agents, infusion of glucose and insulin, forced diuresis and possibly peritoneal dialysis or haemodialysis.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Potassium supplement

ATC code: A12 BA01

The potassium chloride in Slow-K is finely distributed in a neutral wax base, from which it is gradually released over a period of 3 to 6 hours during its passage through the digestive tract. This special form of potassium substitution therapy is designed to avoid high localised concentrations of potassium chloride which might irritate or damage the mucosa. The potassium chloride in Slow-K is completely absorbed in the intestinal tract.

5.2 Pharmacokinetic Properties

The potassium chloride in Slow-K has been shown to be completely absorbed; occasionally patients may notice “ghost” tablet cores in the faeces, these do not contain any potassium.

Following a single dose of Slow-K, potassium chloride is released over a period of approximately 4 hours. Renal excretion of potassium chloride following ingestion of Slow-K occurs 30 to 60 minutes later than when the same dose is given in the form of a solution. In the presence of a normal potassium balance, 90% of the potassium supplied by Slow-K is excreted renally within 8 hours, and more than 98% by 24 hours.

5.3 Preclinical Safety Data

The acute and repeated-dose oral toxicity of potassium chloride (KCl) in animals is low. Gastrointestinal irritant effects have been observed in rhesus monkeys at high oral dosages of Slow-K. Some positive results in in-vitro genotoxicity assays were attributed to very high concentrations of KCl. Carcinogenicity studies in rats administered KCl in-feed were negative. Limited information from developmental studies in rodents indicates there is no ill effect on offspring. There is no evidence from animal experiments that KCl exerts any teratogenic effects or reproductive toxicity which would be relevant to man.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Cetostearyl alcohol

Gelatin

Magnesium stearate

Acacia

Titanium dioxide (E171)

Talc

Sucrose

Red iron oxide (E172)

Yellow iron oxide (E172)

Carnauba wax

6.2 Incompatibilities

None known.

6.3 Shelf Life

5 years.

6.4 Special Precautions For Storage

Do not store above 30°C. Keep the container tightly closed.

6.5 Nature And Contents Of Container

Polypropylene Securitainer with polyethylene cap containing 100 tablets.

6.6 Special Precautions For Disposal And Other Handling

None.

Administrative Data

7. Marketing Authorisation Holder

Alliance Pharmaceuticals Ltd

Avonbridge House

Bath Road

Chippenham

Wiltshire

SN15 2BB

8. Marketing Authorisation Number(S)

PL16853/0014

9. Date Of First Authorisation/Renewal Of The Authorisation

25 June 1998

10. Date Of Revision Of The Text

1^st February 2010

Septrin for Infusion

1. Name Of The Medicinal Product

Septrin 16 mg/80 mg per ml for Infusion

2. Qualitative And Quantitative Composition

Each 5 ml of Septrin 16 mg/80 mg per ml for Infusion contains 80 mg Trimethoprim and 400 mg Sulfamethoxazole.

Excipients:

This product contains 1.7 mmoles of sodium and 13.2 vol % ethanol (alcohol) per 5 ml.

For a full list of excipients, see Section 6.1

3. Pharmaceutical Form

Solution for Infusion

A clear liquid.

4. Clinical Particulars

4.1 Therapeutic Indications

Septrin for Infusion is indicated for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

Acute uncomplicated urinary tract infection.

It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than a combination such as Septrin for Infusion.

Treatment and prevention of Pneumocystis jiroveci pneumonitis (previously known as Pneumocystis carinii pneumonia or “PCP”)

Treatment and prophylaxis of toxoplasmosis.

Treatment of nocardiosis.

In general, the indications for the use of Septrin for Infusion are the same as those for oral presentations.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology And Method Of Administration

Method of Administration: Septrin for Infusion is for administration only by the intravenous route and must be diluted before administration.

It is intended that Septrin for Infusion should be used only during such a period as the patient is unable to accept oral therapy, where initiation of treatment is particularly urgent or for convenience if the patient is already receiving intravenous fluids. Although Septrin for Infusion is useful in critically ill patients, there may be no therapeutic advantage over the oral preparation.

For instructions on dilution of the product before administration, see section 6.6.

Standard dosage recommendations for acute infections

Adults and children over 12 years:

2 ampoules (10 ml) every 12 hours.

Children aged 12 years and under:

The recommended dosage is approximately 6 mg trimethoprim and 30 mg sulfamethoxazole per kg bodyweight per 24 hours, given in two equally divided doses. As a guide the following schedules may be used diluted as described above.

6 weeks to 5 months:	1.25 ml every 12 hours
6 months to 5 years:	2.5 ml every 12 hours
6 to 12 years:	5.0 ml every 12 hours

For severe infections in all age groups, dosage may be increased by 50%.

Treatment should be continued until the patient has been symptom free for two days; the majority will require treatment for at least 5 days.

The elderly:

See Special Warnings and Precautions for Use.

Impaired hepatic function:

No data are available relating to dosage in patients with impaired hepatic function.

Special Dosage Recommendations

(Standard dosage applies unless otherwise specified)

Impaired renal function:

Adults and children over 12 years (no information is available for children under 12 years of age):

Creatinine Clearance (ml/min)	Recommended Dosage
More than 30	STANDARD DOSAGE
15-30	Half the STANDARD DOSAGE
Less than 15	Not recommended

Measurements of plasma concentrations of sulfamethoxazole at intervals of 2 to 3 days are recommended in samples obtained 12 hours after administration of Septrin 16 mg/80 mg per ml for Infusion. If the concentration of total sulfamethoxazole exceeds 150 micrograms/ml then treatment should be interrupted until the value falls below 120 micrograms/ml.

Pneumocystis jiroveci (P. carinii) pneumonitis:

Treatment

20 mg trimethoprim and 100 mg sulfamethoxazole per kg of bodyweight per day in two or more divided doses. Therapy should be changed to the oral route as soon as possible and continued for a total treatment period of two weeks. The aim is to obtain peak plasma or serum levels of trimethoprim of greater than or equal to 5 microgram/ml (verified in patients receiving 1-hour infusions of intravenous Septrin). (See 4.8 Undesirable Effects)

Prevention

Standard dosage for the duration of the period at risk.

Nocardiosis: There is no consensus on the most appropriate dosage. Adult doses of 6 to 8 tablets daily for up to 3 months have been used (one tablet contains 400 mg sulfamethoxazole and 80 mg trimethoprim).

Toxoplasmosis: There is no consensus on the most appropriate dosage for the treatment or prophylaxis of this condition. The decision should be based on clinical experience. For prophylaxis, however, the dosages suggested for prevention of Pneumocystis jiroveci pneumonitis may be appropriate.

4.3 Contraindications

Septrin 16 mg/80 mg per ml for Infusion should not be given to patients with a history of hypersensitivity to sulphonamides, trimethoprim, co-trimoxazole or any excipients of Septrin.

Septrin 16 mg/80 mg per ml for Infusion is contra-indicated in patients showing marked liver parenchymal damage.

Septrin 16 mg/80 mg per ml for Infusion is contra-indicated in severe renal insufficiency where repeated measurements of the plasma concentration cannot be performed.

Septrin 16 mg/80 mg per ml for Infusion should not be given to premature babies nor to full-term infants during the first six weeks of life except for the treatment/prophylaxis of PCP in infants 4 weeks of age or greater.

4.4 Special Warnings And Precautions For Use

Fatalities, although very rare, have occurred due to severe reactions including Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), fulminant hepatic necrosis, agranulocytosis, aplastic anaemia, other blood dyscrasias and hypersensitivity of the respiratory tract.

Septrin 16 mg/80 mg per ml for Infusion should be discontinued at the first appearance of a skin rash (see 4.8 Undesirable Effects).

Fluid overload is possible, especially when very high doses are being administered to patients with underlying cardiopulmonary disease.

An adequate urinary output should be maintained at all times. Evidence of crystalluria in vivo is rare, although sulphonamide crystals have been noted in cooled urine from treated patients. In patients suffering from malnutrition the risk may be increased.

For patients with known renal impairment special measures should be adopted (See 4.2 Posology and Method of Administration).

Regular monthly blood counts are advisable when Septrin is given for long periods, or to folate deficient patients or to the elderly since there exists a possibility of asymptomatic changes in haematological laboratory indices due to lack of available folate. These changes may be reversed by administration of folinic acid (5 to 10 mg/day) without interfering with the antibacterial activity.

Particular care is always advisable when treating elderly patients because, as a group, they are more susceptible to adverse reactions and more likely to suffer serious side effects as a result, particularly when complicating conditions exist, e.g. impaired kidney and/or liver function and/or concomitant drugs.

In glucose-6-phosphate dehydrogenase-deficient (G-6-PD) patients, haemolysis may occur.

Septrin should be given with caution to patients with severe allergy or bronchial asthma.

Septrin should not be used in the treatment of streptococcal pharyngitis due to Group A beta-haemolytic streptococci. Eradication of these organisms from the oropharynx is less effective than with penicillin.

Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

The administration of Septrin to patients known or suspected to be at risk of acute porphyria should be avoided. Both trimethoprim and sulphonamides (although not specifically sulfamethoxazole) have been associated with clinical exacerbation of porphyria.

Close monitoring of serum potassium and sodium is warranted in patients at risk of hyperkalaemia and hyponatraemia.

This medicinal product contains 13.2 vol% ethanol (alcohol), i.e. up to 521 mg per dose. This is equivalent to 2.64 ml of beer, or 1.1 ml of wine. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

This medicinal product contains sodium metabisulphite, which may rarely cause severe hypersensitivity reaction and bronchospasm.

This medicinal product contains 1.7 mmoles (or 38.87 mg) of sodium. To be taken into consideration by patients on a sodium controlled diet.

Except under careful supervision Septrin for Infusion should not be given to patients with serious haematological disorders (see 4.8 Undesirable Effects). Septrin has been given to patients receiving cytotoxic therapy with little or no additional effect on the bone marrow or peripheral blood.

The combination of the antibiotics in Septrin for Infusion should only be used where, in the judgement of the physician, the benefits of treatment outweigh any possible risks; consideration should be given to the use of a single effective antibacterial agent.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Trimethoprim may interfere with the estimation of serum/plasma creatinine when the alkaline picrate reaction is used. This may result in overestimation of serum/plasma creatinine of the order of 10%. The creatinine clearance is reduced: the renal tubular secretion of creatinine is decreased from 23% to 9% whilst the glomerular filtration remains unchanged.

In some situations, concomitant treatment with zidovudine may increase the risk of haematological adverse reactions to co-trimoxazole. If concomitant treatment is necessary, consideration should be given to monitoring of haematological parameters.

Reversible deterioration in renal function has been observed in patients treated with co-trimoxazole and ciclosporin following renal transplantation.

Concurrent use of rifampicin and Septrin results in a shortening of the plasma half-life of trimethoprim after a period of about one week. This is not thought to be of clinical significance.

When trimethoprim is administered simultaneously with drugs that form cations at physiological pH, and are also partly excreted by active renal secretion (e.g. procainamide, amantadine), there is the possibility of competitive inhibition of this process which may lead to an increase in plasma concentration of one or both of the drugs.

In elderly patients concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.

Occasional reports suggest that patients receiving pyrimethamine as malarial prophylaxis at doses in excess of 25 mg weekly may develop megaloblastic anaemia should co-trimoxazole be prescribed concurrently.

Co-trimoxazole has been shown to potentiate the anticoagulant activity of warfarin via stereo-selective inhibition of its metabolism. Sulfamethoxazole may displace warfarin from plasma-albumin protein-binding sites in vitro. Careful control of the anticoagulant therapy during treatment with Septrin is advisable.

Co-trimoxazole prolongs the half-life of phenytoin and if co-administered the prescriber should be alert for excessive phenytoin effect. Close monitoring of the patient's condition and serum phenytoin levels is advisable.

Concomitant use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in a proportion of elderly patients.

Co-trimoxazole may increase the free plasma levels of methotrexate.

Trimethoprim interferes with assays for serum methotrexate when dihydrofolate reductase from Lactobacillus casei is used in the assay. No interference occurs if methotrexate is measured by radioimmuno assay.

Administration of trimethoprim/sulfamethoxazole 160mg/800mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulfamethoxazole.

Interaction with sulphonylurea hypoglycaemic agents is uncommon but potentiation has been reported.

Caution should be exercised in patients taking any other drugs that can cause hyperkalaemia.

If Septrin is considered appropriate therapy in patients receiving other anti-folate drugs such as methotrexate, a folate supplement should be considered.

4.6 Pregnancy And Lactation

Pregnancy

There are not any adequate data from the use of Septrin for Infusion in pregnant women. Case-control studies have shown that there may be an association between exposure to folate antagonists and birth defects in humans.

Trimethoprim is a folate antagonist and, in animal studies, both agents have been shown to cause foetal abnormalities (see 5.3 Preclinical Safety Data).

Septrin for Infusion should not be used in pregnancy, particularly in the first trimester, unless clearly necessary. Folate supplementation should be considered if Septrin for Infusion is used in pregnancy.

Sulfamethoxazole competes with bilirubin for binding to plasma albumin. As significantly maternally derived drug levels persist for several days in the newborn, there may be a risk of precipitating or exacerbating neonatal hyperbilirubinaemia, with an associated theoretical risk of kernicterus, when Septrin for Infusion is administered to the mother near the time of delivery. This theoretical risk is particularly relevant in infants at increased risk of hyperbilirubinaemia, such as those who are preterm and those with glucose-6-phosphate dehydrogenase deficiency.

Lactation

The components of Septrin for Infusion (trimethoprim and sulfamethoxazole) are excreted in breast milk. Administration of Septrin for Infusion should be avoided in late pregnancy and in lactating mothers where the mother or infant has, or is at particular risk of developing, hyperbilirubinaemia. Additionally, administration of Septrin for Infusion should be avoided in infants younger than eight weeks in view of the predisposition of young infants to hyperbilirubinaemia.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

As co-trimoxazole contains trimethoprim and a sulphonamide the type and frequency of adverse reactions associated with such compounds are expected to be consistent with extensive historical experience.

Data from large published clinical trials were used to determine the frequency of very common to rare adverse events. Very rare adverse events were primarily determined from post-marketing experience data and therefore refer to reporting rate rather than a "true" frequency. In addition, adverse events may vary in their incidence depending on the indication.

The following convention has been used for the classification of adverse events in terms of frequency:- Very common

Infections and Infestations

Common: Monilial overgrowth

Blood and lymphatic system disorders

Very rare: Leucopenia, neutropenia, thrombocytopenia, agranulocytosis, megaloblastic anaemia, aplastic anaemia, haemolytic anaemia, methaemoglobinaemia, eosinophilia, purpura, haemolysis in certain susceptible G-6-PD deficient patients

Immune system disorders

Very rare: Serum sickness, anaphylaxis, allergic myocarditis, angioedema, drug fever, allergic vasculitis resembling Henoch-Schoenlein purpura, periarteritis nodosa, systemic lupus erythematosus

Metabolism and nutrition disorders

Very common: Hyperkalaemia

Very rare: Hypoglycaemia, hyponatraemia, anorexia

Psychiatric disorders

Very rare: Depression, hallucinations

Nervous system disorders

Common: Headache

Very rare: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, dizziness

Aseptic meningitis was rapidly reversible on withdrawal of the drug, but recurred in a number of cases on re-exposure to either co-trimoxazole or to trimethoprim alone.

Respiratory, thoracic and mediastinal disorders

Very rare: Cough, shortness of breath, pulmonary infiltrates

Cough, shortness of breath and pulmonary infiltrates may be early indicators of respiratory hypersensitivity which, while very rare, has been fatal.

Gastrointestinal disorders

Common: Nausea, diarrhoea

Uncommon: Vomiting

Very rare: Glossitis, stomatitis, pseudomembranous colitis, pancreatitis

Eye Disorders

Very rare: Uveitis

Hepatobiliary disorders

Very rare: Elevation of serum transaminases, elevation of bilirubin levels, cholestatic jaundice, hepatic necrosis

Cholestatic jaundice and hepatic necrosis may be fatal.

Skin and subcutaneous tissue disorders

Common: Skin rashes

Very rare: Photosensitivity, exfoliative dermatitis, fixed drug eruption, erythema multiforme, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis)

Lyell's syndrome carries a high mortality.

Musculoskeletal and connective tissue disorders

Very rare: Arthralgia, myalgia

Renal and urinary disorders

Very rare: Impaired renal function (sometimes reported as renal failure),

interstitial nephritis

Effects associated with Pneumocystis jiroveci (P.carinii) Pneumonitis (PCP) management

Very rare: Severe hypersensitivity reactions, rash, fever, neutropenia, thrombocytopenia, raised liver enzymes, hyperkalaemia, hyponatraemia, rhabdomyolysis.

At the high dosages used for PCP management severe hypersensitivity reactions have been reported, necessitating cessation of therapy. If signs of bone marrow depression occur, the patient should be given calcium folinate supplementation (5-10 mg/day). Severe hypersensitivity reactions have been reported in PCP patients on re-exposure to co-trimoxazole, sometimes after a dosage interval of a few days. Rhabdomyolysis has been reported in HIV positive patients receiving co-trimoxazole for prophylaxis or treatment of PCP.

4.9 Overdose

The maximum tolerated dose in humans is unknown.

Nausea, vomiting, dizziness and confusion are likely symptoms of overdosage. Bone marrow depression has been reported in acute trimethoprim overdosage.

In cases of known, suspected or accidental overdosage, stop therapy.

Dependent on the status of renal function, administration of fluids is recommended if urine output is low.

Both trimethoprim and active sulfamethoxazole are dialysable by renal dialysis. Peritoneal dialysis is not effective.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Combinations of sulfonamides and trimethoprim, incl. derivatives; ATC code: J01EE01

Mode of Action

Septrin is an antibacterial drug composed of two active principles, sulfamethoxazole and trimethoprim. Sulfamethoxazole is a competitive inhibitor of dihydropteroate synthetase enzyme. Sulfamethoxazole competitively inhibits the utilisation of para-aminobenzoic acid (PABA) in the synthesis of dihydrofolate by the bacterial cell resulting in bacteriostasis. Trimethoprim binds to and reversibly inhibits bacterial dihydrofolate reductase (DHFR) and blocks the production of tetrahydrofolate. Depending on the conditions the effect may be bactericidal. Thus trimethoprim and sulfamethoxazole block two consecutive steps in the biosynthesis of purines and therefore nucleic acids essential to many bacteria. This action produces marked potentiation of activity in vitro between the two agents.

Mechanism of resistance

In vitro studies have shown that bacterial resistance can develop more slowly with both sulfamethoxazole and trimethoprim in combination that with either sulfamethoxazole or trimethoprim alone.

Resistance to sulfamethoxazole may occur by different mechanisms. Bacterial mutations cause an increase the concentration of PABA and thereby out-compete with sulfamethoxazole resulting in a reduction of the inhibitory effect on dihydropteroate synthetase enzyme. Another resistance mechanism is plasmid-mediated and results from production of an altered dihydropteroate synthetase enzyme, with reduced affinity for sulfamethoxazole compared to the wild-type enzyme.

Resistance to trimethoprim occurs through a plasmid-mediated mutation which results in production of an altered dihydrofolate reductase enzyme having a reduced affinity for trimethoprim compared to the wild-type enzyme.

Trimethoprim binds to plasmodial DHFR but less tightly than to bacterial enzyme. Its affinity for mammalian DHFR is some 50,000 times less than for the corresponding bacterial enzyme.

Many common pathogenic bacteria are susceptible in vitro to trimethoprim and sulfamethoxazole at concentrations well below those reached in blood, tissue fluids and urine after the administration of recommended doses. In common with other antibiotics, however, in vitro activity does not necessarily imply that clinical efficacy has been demonstrated and it must be noted that satisfactory susceptibility testing is achieved only with recommended media free from inhibitory substances, especially thymidine and thymine.

Breakpoints

EUCAST

Enterobacteriaceae: S

S. maltophilia: S

Acinetobacter: S

Staphylococcus: S

Enterococcus: S

Streptococcus ABCG: S

Streptococcus pneumoniae: S

Hemophilus influenza: S

Moraxella catarrhalis: S

Psuedomonas aeruginosa and other non-enterobacteriaceae: S

S = susceptible, R = resistant. *These are CLSI breakpoints since no EUCAST breakpoints are currently available for these organisms.

Trimethoprim: sulfamethoxazole in the ratio 1:19. Breakpoints are expressed as trimethoprim concentration.

Antibacterial Spectrum

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. This information gives only an approximate guidance on probabilities whether microorganisms will be susceptible to trimethoprim/sulfamethoxazole or not.

Trimethoprim/sulfamethoxazole susceptibility against a number of bacteria are shown in the table below:

Commonly susceptible species:

Gram-positive aerobes: Staphylococcus aureus Staphylococcus saprophyticus Streptococcus pyogenes

Gram-negative aerobes: Enterobacter cloacae Haemophilus influenzae Klebsiella oxytoca Moraxella catarrhalis Salmonella spp. Stenotrophomonas maltophilia Yersinia spp.

Species for which acquired resistance may be a problem:

Gram-positive aerobes: Enterococcus faecalis Enterococcus faecium Nocardia spp. Staphylococcus epidermidis Streptococcus pneumoniae

Gram-negative aerobes: Citrobacter spp. Enterobacter aerogenes Escherichia coli Klebsiella pneumoniae Klebsiella pneumonia Proteus mirabilis Proteus vulgaris Providencia spp. Serratia marcesans

Inherently resistant organisms:

Gram-negative aerobes: Pseudomonas aeruginosa Shigella spp. Vibrio cholera

5.2 Pharmacokinetic Properties

Peak plasma levels of trimethoprim and sulfamethoxazole are higher and achieved more rapidly after one hour of intravenous infusion of Septrin 16 mg/80 mg per ml for Infusion than after oral administration of an equivalent dose of a Septrin oral presentation. Plasma concentrations, elimination half-life and urinary excretion rates show no significant differences following either the oral or intravenous route of administration.

Trimethoprim is a weak base with a pKa of 7.3. It is lipophilic. Tissue levels of trimethoprim are generally higher than corresponding plasma levels, the lungs and kidneys showing especially high concentrations. Trimethoprim concentrations exceed those in plasma in the case of bile, prostatic fluid and tissue, sputum, and vaginal secretions. Levels in the aqueous humor, breast milk, cerebrospinal fluid, middle ear fluid, synovial fluid and tissue (interstitial) fluid are adequate for antibacterial activity. Trimethoprim passes into amniotic fluid and fetal tissues reaching concentrations approximating those of maternal serum.

Approximately 50% of trimethoprim in the plasma is protein bound. The half-life in man is in the range 8.6 to 17 hours in the presence of normal renal function. It is increased by a factor of 1.5 to 3.0 when the creatinine clearance is less than 10 ml/minute. There appears to be no significant difference in the elderly compared with young patients.

The principal route of excretion of trimethoprim is renal and approximately 50% of the dose is excreted in the urine within 24 hours as unchanged drug. Several metabolites have been identified in the urine. Urinary concentrations of trimethoprim vary widely.

Sulfamethoxazole is a weak acid with a pKa of 6.0. The concentration of active sulfamethoxazole in amniotic fluid, aqueous humor, bile, cerebrospinal fluid, middle ear fluid, sputum, synovial fluid and tissue (interstitial) fluid is of the order of 20 to 50% of the plasma concentration. Approximately 66% of sulfamethoxazole in the plasma is protein bound. The half-life in man is approximately 9 to 11 hours in the presence of normal renal function. There is no change in the half-life of active sulfamethoxazole with a reduction in renal function but there is prolongation of the half-life of the major, acetylated metabolite when the creatinine clearance is below 25 ml/minute.

The principal route of excretion of sulfamethoxazole is renal; between 15% and 30% of the dose recovered in the urine is in the active form. In elderly patients there is a reduced renal clearance of sulfamethoxazole.

5.3 Preclinical Safety Data

Reproductive toxicology: At doses in excess of recommended human therapeutic dose, trimethoprim and sulfamethoxazole have been reported to cause cleft palate and other foetal abnormalities in rats, findings typical of a folate antagonist. Effects with trimethoprim were preventable by administration of dietary folate. In rabbits, foetal loss was seen at doses of trimethoprim in excess of human therapeutic doses.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Propylene Glycol (E1520)

Tromethamine

Sodium Hydroxide (E524)

Sodium Metabisulphite (E223)

Ethanol

Water for Injections

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

Store below 30°C. Protect from light.

6.5 Nature And Contents Of Container

Neutral glass ampoules (5ml nominal fill volume)

Pack size: 10 x 5ml ampoules

6.6 Special Precautions For Disposal And Other Handling

Septrin for Infusion must be diluted before administration.

Dilution should be carried out immediately before use. After adding Septrin 16 mg/80 mg per ml for Infusion to the infusion solution, shake thoroughly to ensure complete mixing. If visible turbidity or crystallisation appears at any time before or during an infusion, the mixture should be discarded.

It is recommended that Septrin16 mg/80 mg per ml for Infusion is diluted according to the following schedules:

One ampoule (5 ml) to 125 ml infusion solution.

Two ampoules (10 ml) to 250 ml infusion solution.

Three ampoules (15 ml) to 500 ml infusion solution.

Septrin 16 mg/80 mg per ml for Infusion is known to be compatible, when diluted as recommended above, with the following fluids:

Glucose Intravenous Infusion BP (5% w/v and 10% w/v).

Sodium Chloride Intravenous Infusion BP (0.9% w/v).

Sodium Chloride (0.18% w/v) and Glucose (4% w/v) Intravenous Infusion BP.

Dextran 70 Injection BP (6% w/v) in glucose (5% w/v) or normal saline.

Dextran 40 Injection BP (10% w/v) in glucose (5% w/v) or normal saline.

Ringer's Solution for Injection BPC 1959.

No other substance should be mixed with the infusion.

The duration of the infusion should be approximately one to one and a half hours, but this should be balanced against the fluid requirements of the patient.

When fluid restriction is necessary, Septrin 16 mg/80 mg per ml for Infusion may be administered at a higher concentration, 5 ml diluted with 75 ml of glucose 5% w/v in water. The resultant solution, whilst being clear to the naked eye, may on occasion exceed the BP limits set for particulate matter in large volume parenterals. The solution should be infused over a period not exceeding one hour. Discard any unused solution.

7. Marketing Authorisation Holder

The Wellcome Foundation Ltd.,

Glaxo Wellcome House,

Berkeley Avenue,

Greenford,

Middlesex

Trading as

GlaxoSmithKline UK

Stockley Park West

Uxbridge

Middlesex UB11 1BT

8. Marketing Authorisation Number(S)

PL 00003/0095R

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 18 March 1974

Date of last of renewal: 17 October 2006

10. Date Of Revision Of The Text

21 July 2009

Singulair 10mg Tablets

SINGULAIR 10 mg film-coated tablets

montelukast

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, please 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 SINGULAIR is and what it is used for


2. Before you take SINGULAIR


3. How to take SINGULAIR


4. Possible side effects


5. How to store SINGULAIR


6. Further information

What SINGULAIR is and what it is used for

SINGULAIR is a leukotriene receptor antagonist that blocks substances called leukotrienes.

Leukotrienes cause narrowing and swelling of airways in the lungs and also cause allergy symptoms.

By blocking leukotrienes, SINGULAIR improves asthma symptoms, helps control asthma and improves seasonal allergy symptoms (also known as hay fever or seasonal allergic rhinitis).

Your doctor has prescribed SINGULAIR to treat asthma, preventing your asthma symptoms during the day and night.

• SINGULAIR is used for the treatment of patients who are not adequately controlled on their medication and need additional therapy.



• SINGULAIR also helps prevent the narrowing of airways triggered by exercise.



• In those asthmatic patients in whom SINGULAIR is indicated in asthma, SINGULAIR can also provide symptomatic relief of seasonal allergic rhinitis.

Your doctor will determine how SINGULAIR should be used depending on the symptoms and severity of your asthma.

What is asthma?

Asthma is a long-term disease.

Asthma includes:

• difficulty breathing because of narrowed airways. This narrowing of airways worsens and improves in response to various conditions.



• sensitive airways that react to many things, such as cigarette smoke, pollen, cold air, or exercise.



• swelling (inflammation) in the lining of the airways.

Symptoms of asthma include: Coughing, wheezing, and chest tightness.

What are seasonal allergies?

Seasonal allergies (also known as hay fever or seasonal allergic rhinitis) are an allergic response often caused by airborne pollens from trees, grasses and weeds. The symptoms of seasonal allergies typically may include: stuffy, runny, itchy nose; sneezing; watery, swollen, red, itchy eyes.

Before you take SINGULAIR

Tell your doctor about any medical problems or allergies you have now or have had.

Do not take SINGULAIR if you

• are allergic (hypersensitive) to montelukast or any of the other ingredients of SINGULAIR (see 6. Further information).

Take special care with SINGULAIR

• If your asthma or breathing gets worse, tell your doctor immediately.



• Oral SINGULAIR is not meant to treat acute asthma attacks. If an attack occurs, follow the instructions your doctor has given you. Always have your inhaled rescue medicine for asthma attacks with you.



• It is important that you or your child take all asthma medications prescribed by your doctor. SINGULAIR should not be substituted for other asthma medications your doctor has prescribed for you.



• Any patient on anti-asthma medicines should be aware that if you develop a combination of symptoms such as a flu-like illness, pins and needles or numbness of arms or legs, worsening of pulmonary symptoms, and/or rash, you should consult your doctor.



• You should not take acetyl-salicylic acid (aspirin) or anti-inflammatory medicines (also known as non-steroidal anti-inflammatory drugs or NSAIDs) if they make your asthma worse.

Use in children

For children 2 to 5 years old, SINGULAIR Paediatric 4 mg chewable tablets and SINGULAIR Paediatric 4 mg granules are available.

For children 6 to 14 years old, SINGULAIR Paediatric 5 mg chewable tablets are available.

Taking other medicines

Some medicines may affect how SINGULAIR works, or SINGULAIR may affect how other medicines work.

Please tell your doctor or pharmacist if you are taking or have recently taken other medicines, including those obtained without a prescription.

Tell your doctor if you are taking the following medicines before starting SINGULAIR:

• phenobarbital (used for treatment of epilepsy)



• phenytoin (used for treatment of epilepsy)



• rifampicin (used to treat tuberculosis and some other infections)

Taking SINGULAIR with food and drink

SINGULAIR 10 mg may be taken with or without food.

Pregnancy and breast-feeding

Use in pregnancy

Women who are pregnant or intend to become pregnant should consult their doctor before taking SINGULAIR. Your doctor will assess whether you can take SINGULAIR during this time.

Use in breast-feeding

It is not known if SINGULAIR appears in breast milk. You should consult your doctor before taking SINGULAIR if you are breast-feeding or intend to breast-feed.

Driving and using machines

SINGULAIR is not expected to affect your ability to drive a car or operate machinery. However, individual responses to medication may vary. Certain side effects (such as dizziness and drowsiness) that have been reported very rarely with SINGULAIR may affect some patients’ ability to drive or operate machinery.

Important information about some of the ingredients of SINGULAIR

SINGULAIR 10 mg film-coated tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

How to take SINGULAIR

• You should take only one tablet of SINGULAIR once a day as prescribed by your doctor.



• It should be taken even when you have no symptoms or have an acute asthma attack.



• Always take SINGULAIR as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.



• To be taken by mouth

For adults 15 years of age and older:

One 10 mg tablet to be taken daily in the evening. SINGULAIR 10 mg may be taken with or without food.

If you are taking SINGULAIR, be sure that you do not take any other products that contain the same active ingredient, montelukast.

If you take more SINGULAIR than you should

Contact your doctor immediately for advice.

There were no side effects reported in the majority of overdose reports. The most frequently occurring symptoms reported with overdose in adults and children included abdominal pain, sleepiness, thirst, headache, vomiting, and hyperactivity.

If you forget to take SINGULAIR

Try to take SINGULAIR as prescribed. However, if you miss a dose, just resume the usual schedule of one tablet once daily.

Do not take a double dose to make up for a forgotten dose.

If you stop taking SINGULAIR

SINGULAIR can treat your asthma only if you continue to take it.

It is important to continue taking SINGULAIR for as long as your doctor prescribes. It will help control your asthma.

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

Possible side effects

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

In clinical studies with SINGULAIR 10 mg film-coated tablets, the most commonly reported side effects (occurring in at least 1 of 100 patients and less than 1 of 10 patients treated) thought to be related to SINGULAIR were:

• abdominal pain



• headache

These were usually mild and occurred at a greater frequency in patients treated with SINGULAIR than placebo (a pill containing no medication).

Additionally, while the medicine has been on the market, the following have been reported:

• upper respiratory infection



• increased bleeding tendency



• allergic reactions including rash, swelling of the face, lips, tongue, and/or throat which may cause difficulty in breathing or swallowing



• behaviour and mood related changes [dream abnormalities, including nightmares, hallucinations, irritability, feeling anxious, restlessness, agitation including aggressive behaviour or hostility, tremor, depression, trouble sleeping, sleep walking, suicidal thoughts and actions (in very rare cases)]



• dizziness, drowsiness, pins and needles/numbness, seizure



• palpitations



• nosebleed



• diarrhoea, dry mouth, indigestion, nausea, vomiting



• hepatitis (inflammation of the liver)



• bruising, itching, hives, tender red lumps under the skin most commonly on your shins (erythema nodosum),



• joint or muscle pain, muscle cramps



• tiredness, feeling unwell, swelling, fever

In asthmatic patients treated with montelukast, very rare cases of a combination of symptoms such as flu-like illness, pins and needles or numbness of arms and legs, worsening of pulmonary symptoms and/or rash (Churg-Strauss syndrome) have been reported. You must tell your doctor right away if you get one or more of these symptoms.

Ask your doctor or pharmacist for more information about side effects. 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.

How to store SINGULAIR

• Keep out of the reach and sight of children.



• Do not use this medicine after the date shown by the six numbers following EXP on the blister. The first two numbers indicate the month; the last four numbers indicate the year. This medicine expires at the end of the month shown.



• Store in the original package in order to protect from light and moisture.



• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further information

What SINGULAIR contains

• The active substance is: montelukast. Each tablet contains montelukast sodium which corresponds to 10 mg of montelukast.



• The other ingredients are:

Microcrystalline cellulose, lactose monohydrate (89.3 mg), croscarmellose sodium, hyprolose (E463), and magnesium stearate.

Film coating: hypromellose, hyprolose (E463), titanium dioxide (E 171), red and yellow ferric oxide (E 172), and carnauba wax.

What SINGULAIR looks like and contents of the pack

10 mg SINGULAIR tablets are beige, rounded square, film-coated with SINGULAIR engraved on one side, MSD 117 on the other.

Blisters in packages of: 7, 10, 14, 20, 28, 30, 50, 56, 84, 90, 98, 100, 140, 200 tablets.

Blisters (unit doses), in packages of: 49, 50 and 56 tablets.

Not all pack sizes may be marketed

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation Holder is

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

UK

SINGULAIR 10 mg tablets are manufactured by

Merck Sharp & Dohme Limited

Shotton Lane

Cramlington

Northumberland

NE23 3JU

UK

Information is given by:

In UK:

Asthma UK

Providence House

Providence Place

London N1 ONT

Alternatively phone the Asthma UK Adviceline on 08457 010203, Monday to Friday 9 am to 5 pm, calls charged at local rate.

In Ireland:

The Asthma Society of Ireland

Eden House

15-17 Eden Quay

Dublin 1

Alternatively phone The Asthma Live Line on 01 8788122, Monday, Wednesday, Thursday 10am to 1pm, or 01 8788511 9am to 5pm, or The Asthma Line on callsave 1850 44 5464.

(The Asthma UK and The Asthma Society of Ireland are independent charities working to conquer asthma and are not associated with Merck Sharp & Dohme Limited.)

This medicinal product is authorised in the Member States of the EEA under the following names:

Austria, Belgium, Denmark, Finland, France, Greece, Spain, Sweden, Germany, Ireland, UK, Italy, Luxemburg, Netherlands, Portugal

SINGULAIR

This package leaflet was last approved in June 2010

denotes registered trademark of

Merck Sharp & Dohme Corp.

a subsidiary of Merck & Co., Inc.

Whitehouse Station

NJ

USA

© Merck Sharp & Dohme Limited 2010. All rights reserved.

PIL.SGA-10mg.09.UK.3066.II-051

Simvastatin 10mg, 20mg, 40mg Tablets

SIMVASTATIN 10 MG TABLETS

SIMVASTATIN 20 MG TABLETS

SIMVASTATIN 40 MG TABLETS

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 further questions, please ask your doctor or your pharmacist.


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

In this leaflet:

• 1. What SIMVASTATIN TABLETS are and what they are used for.


• 2. Before you take SIMVASTATIN TABLETS.


• 3. How to take SIMVASTATIN TABLETS.


• 4. Possible side effects.


• 5. Storing SIMVASTATIN TABLETS

Simvastatin 10, 20 & 40 mg Film-coated Tablets contain the active substance simvastatin 10mg, 20mg or 40mg. The other ingredients are: lactose monohydrate, pregelatinised maize starch, ascorbic acid (E300), citric acid monohydrate (E330), microcrystalline cellulose (E460(i)), butylhydroxyanisole (E320), croscarmellose sodium, magnesium stearate (E572). The film coating materials contain hydroxypropylcellulose (E463), hypromellose 15cP (E464), titanium dioxide (E171), talc (E553(b)), iron oxide yellow (E172), iron oxide red (E172) and iron oxide black (E172).

Marketing Authorization Holder/Manufacturer:

Dexcel-Pharma Limited

1 Cottesbrooke Park

Heartlands Business Park

Daventry

Northamptonshire

NN11 8YL

England

What Simvastatin Tablets are and what they are used for?

Simvastatin Film-coated Tablets belong to the group of medicines called LIPID-LOWERING medicines. These medicines are also known as "statins". They work by lowering lipids (fats) such as cholesterol and triglycerides in your blood when non-medicinal measures, such as a low-fat diet, exercise and lifestyle changes, alone have failed.

There are three tablet strengths available:

Simvastatin 10 mg Tablets are peach coloured, film coated, oval shaped tablets.

Simvastatin 20 mg Tablets are tan coloured, film coated, oval shaped tablets.

Simvastatin 40 mg Tablets are salmon-pink coloured, film coated, oval shaped tablets.

Simvastatin Tablets are available in calendar packs, as blister strips of 28 tablets in a carton.

Simvastatin Tablets are recommended for patients with high cholesterol and triglyceride levels, and for patients with
cardiovascular diseases (heart and blood vessels diseases) and/or diabetes mellitus with either high or normal cholesterol levels.

If you have any of these conditions, this medicine along with dietary control can help prolong your life and reduce the risk of cardiovascular diseases.

Before you take Simvastatin Tablets

Do not take Simvastatin Tablets:

• If you are allergic to simvastatin, to similar medicines or to any of the other ingredients of Simvastatin Tablets;


• If you have liver problems;


• If you are pregnant, plan to become pregnant or are breastfeeding;


• If you are taking any of the following medicines: nefazodone (an antidepressant); certain anti-HIV medicines called protease inhibitors (indinavir, ritonavir, saquinavir, nelfinavir); antifungal agents (e.g. itraconazole, ketoconazole); erythromycin, clarithromycin or telithromycin (antibiotics called "macrolides").

If you think any of these apply to you, do not take the tablets, go and talk to your doctor first and follow the advice given.

Take special care with Simvastatin Tablets:

These tablets can cause muscle problems. The risk of muscle problems is greater at higher doses of Simvastatin Tablets and in certain groups of patients. Tell your doctor:

• About all your medical conditions including allergies;


• If you have severe respiratory failure (severe breathing problems).


• If you have kidney problems;


• If you have or ever had muscle pain, cramps, tenderness or weakness; if you or close family member have a hereditary muscle disorder or a previous history of muscle problems with other cholesterol lowering drugs (e.g. "statins" or fibrates);


• If you consume substantial quantities of alcohol or if you have a past history of liver disease;


• If you have thyroid problems;


• If you are over 70 years of age;


• If you are awaiting surgery or when any medical or surgical condition is unexpectedly required.

Tell your doctor immediately if you experience unexplained muscle pain, tenderness or weakness. This is because on rare occasions, there is a risk of muscle problems which may be serious, including muscle breakdown which can result in kidney damage. The doctor may perform a blood test to check the condition of your muscles before and after starting treatment.

Taking Simvastatin Tablets with food and drink: You should avoid drinking grapefruit juice during treatment with Simvastatin since it could increase your risk of muscle damage.

Alcohol can affect the action of simvastatin and your doctor should have advised you to always keep your alcohol intake to a minimum while you are on these tablets. If you are concerned about how much alcohol you may drink while taking simvastatin, discuss this with your doctor.

Pregnancy: Do not use Simvastatin Tablets if you are pregnant, trying to become pregnant or suspect you may be pregnant. If you become pregnant while taking Simvastatin Tablets, stop taking them immediately and contact your doctor.

Breastfeeding: Do not use Simvastatin Tablets if you are breastfeeding. Consult your doctor before taking the tablets if you are breastfeeding, or planning to breastfeed.

Use in children: Simvastatin Tablets are not recommended for use in children.

Driving and using machines: Simvastatin Tablets are not expected to affect your ability to drive a car or to operate machinery. However, when driving vehicles or operating machinery, it should be taken into account that dizziness has rarely been reported.

Important information about some of the ingredients of Simvastatin Tablets: This medicine contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

Taking other medicines: Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those not prescribed. The risk of muscle problems can be greater if Simvastatin Tablets are taken with certain medicines – see below and tell your doctor if you are taking any of these: (some of these medicines have already been listed in the above section “Do not take Simvastatin Tablets”): Antifungal agents (such as itraconazole or ketoconazole); the antibiotics erythromycin, clarithromycin or telithromycin; Nefazodone, an antidepressant; HIV protease inhibitors (such as indinavir, nelfinavir, ritonavir); Ciclosporin (a drug used to suppress the immune system); Fibrates (other lipid-lowering medicines such as gemfibrozil, and bezafibrate); Amiodarone, a medicine used for irregular heart beat; Verapamil or diltiazem (drugs used to treat high blood pressure, chest pain associated with heart disease, or other heart conditions); Nicotinic acid (lipid-lowering medicine) in large doses (i.e. greater than or equal to 1 g per day).

It is also important to tell your doctor if you are taking anticoagulants (drugs that prevent blood clots, such as warfarin) or fenofibrate.

How to take Simvastatin Tablets

Always take Simvastatin Tablets exactly as your doctor has instructed you. You should check with your doctor or pharmacist if you are unsure.

The usual starting dose is 20 or 40 mg a day, given as a single dose in the evening. It is recommended that Simvastatin Tablets are taken in the evening, or at night, so that they will be working when the body is producing the most cholesterol. Your doctor may adjust your dose to a maximum of 80 mg per day, given as a single dose in the evening. The 80 mg dose is only recommended in patients with severe hypercholesterolaemia and high risk cardiovascular complications. Your doctor may prescribe lower doses, particularly if you are taking certain medications listed above or have certain kidney conditions. Your doctor may need to change this dose in order to have the best effect. Do not take more or less than your doctor has prescribed. Keep taking your tablets for as long as your doctor has asked you to. If you stop taking Simvastatin Tablets, your cholesterol may rise again.

If you take more Simvastatin Tablets than you should: Do not take more medicine than prescribed by your doctor.

If you ever take too much, go to the nearest hospital casualty department or tell your doctor immediately.

If you forget to take Simvastatin Tablets: If you miss a dose, just carry on with the next one as normal. Do not take an extra one to make up. Do not take two doses at the same time.

Possible side effects

Like all medicines, Simvastatin Tablets may occasionally cause side effects in some patients. For the most part side effects have been mild and short-lived.

The following side effects were reported rarely (between 1 in 1000 and 1 in 10,000 people are likely to be affected):

• Blood system disorders: anaemia,


• Nervous system disorders: headache, dizziness, numbness or loss of sensation in the arms and legs,


• Gastrointestinal disorders: stomach upsets (such as sickness, constipation, diarrhoea, flatulence, indigestion and abdominal pain), pancreatitis,


• Hepato-biliary disorders: liver disease (possibly presenting as yellowing of the eyes and/or skin, itchiness of the skin, dark colored urine, pale colored stools),


• Skin and subcutaneous tissue disorders: hair loss, rash, itchiness,


• Musculoskeletal, connective tissue and bone disorders: muscle damage (see below),


• General disorders: weakness,


• Allergic reaction to Simvastatin Tablets. The allergic reaction may include some of the following: swelling of the face, tongue or throat (in which case you should contact your doctor immediately), joint pains, joint and blood vessel inflammation, unusual bruising, skin eruptions, swelling, hives, skin sensitivity to the sun, a high temperature, flushing, difficulty in breathing, or tiredness.

Contact your doctor immediately if you experience muscle aches and pains, tenderness, weakness, or cramps. This is because on rare occasions, muscle damage can be serious. (See section headed “Before you take Simvastatin Tablets”).

In addition the following side effects may occur:

• Sleep disturbances, including insomnia (difficuly sleeping) and nightmares


• Memory loss


• Sexual difficulties


• Depression


• Breathing problems including persistent cough and/or shortness of breath or fever

If any of these happen, or you have any other unusual symptoms or feelings, stop taking the tablets and contact your doctor immediately.

Your doctor may want to do simple blood tests to check if your liver is working properly before and during your treatment with Simvastatin Tablets.

Storing Simvastatin Tablets

Do not use after the expiry date stated on the label.

Do not store above 25°C. Store in the original package.

If your doctor tells you to stop taking the tablets, please take them back to the pharmacist.

Keep your medicine out of the reach and sight of children.

This leaflet was last approved in November 2009.

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