Onbrez Breezhaler 150 and 300 microgram inhalation powder, hard capsules

1. Name Of The Medicinal Product

2. Qualitative And Quantitative Composition

Onbrez Breezhaler 150 microgram inhalation powder, hard capsules:

Each capsule contains indacaterol maleate equivalent to 150 microgram indacaterol.

The delivered dose leaving the mouthpiece of the Onbrez Breezhaler inhaler is indacaterol maleate equivalent to 120 microgram indacaterol.

Excipients:

Each capsule contains 24.8 mg lactose.

Onbrez Breezhaler 300 microgram inhalation powder, hard capsules:

Each capsule contains indacaterol maleate equivalent to 300 microgram indacaterol.

The delivered dose leaving the mouthpiece of the Onbrez Breezhaler inhaler is indacaterol maleate equivalent to 240 microgram indacaterol.

Excipients:

Each capsule contains 24.6 mg lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Inhalation powder, hard capsule

Onbrez Breezhaler 150 microgram inhalation powder, hard capsules:

Clear colourless capsules containing a white powder, with “IDL 150” printed in black above and company logo (

Onbrez Breezhaler 300 microgram inhalation powder, hard capsules:

Clear colourless capsules containing a white powder, with “IDL 300” printed in blue above and company logo (

4. Clinical Particulars

4.1 Therapeutic Indications

Onbrez Breezhaler is indicated for maintenance bronchodilator treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD).

4.2 Posology And Method Of Administration

Posology

The recommended dose is the inhalation of the content of one 150 microgram capsule once a day, using the Onbrez Breezhaler inhaler. The dose should only be increased on medical advice.

The inhalation of the content of one 300 microgram capsule once a day, using the Onbrez Breezhaler inhaler has been shown to provide additional clinical benefit with regard to breathlessness, particularly for patients with severe COPD. The maximum dose is 300 microgram once daily.

Onbrez Breezhaler should be administered at the same time of the day each day.

If a dose is missed the next dose should be taken at the usual time the next day.

Elderly population

Maximum plasma concentration and overall systemic exposure increase with age but no dose adjustment is required in elderly patients.

Paediatric population

There is no relevant use of Onbrez Breezhaler in the paediatric population (under 18 years).

Hepatic impairment

No dose adjustment is required for patients with mild and moderate hepatic impairment. There are no data available for use of Onbrez Breezhaler in patients with severe hepatic impairment.

Renal impairment

No dose adjustment is required for patients with renal impairment.

Method of administration

For inhalation use only.

Onbrez Breezhaler capsules must be administered only using the Onbrez Breezhaler inhaler (see section 6.6).

Onbrez Breezhaler capsules must not be swallowed.

4.3 Contraindications

Hypersensitivity to the active substance, to lactose or to any of the other excipients.

4.4 Special Warnings And Precautions For Use

Asthma

Onbrez Breezhaler should not be used in asthma due to the absence of long-term outcome data in asthma with Onbrez Breezhaler.

Paradoxical bronchospasm

As with other inhalation therapy, administration of Onbrez Breezhaler may result in paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs Onbrez Breezhaler should be discontinued immediately and alternative therapy substituted.

Deterioration of disease

Onbrez Breezhaler is not indicated for the treatment of acute episodes of bronchospasm, i.e. as rescue therapy. In the event of deterioration of COPD during treatment with Onbrez Breezhaler, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. An increase in the daily dose of Onbrez Breezhaler beyond the maximum dose of 300 microgram is not appropriate.

Systemic effects

Although no clinically relevant effect on the cardiovascular system is usually seen after the administration of Onbrez Breezhaler at the recommended doses, as with other beta₂-adrenergic agonists, indacaterol should be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to beta₂-adrenergic agonists.

Cardiovascular effects

Like other beta₂-adrenergic agonists, indacaterol may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms. In case such effects occur, treatment may need to be discontinued. In addition, beta-adrenergic agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave and ST segment depression, although the clinical significance of these observations is unknown.

Clinically relevant effects on prolongation of the QT_c-interval have not been observed in clinical studies of Onbrez Breezhaler at recommended therapeutic doses (see section 5.1).

Hypokalaemia

Beta₂-adrenergic agonists may produce significant hypokalaemia in some patients, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment (see section 4.5), which may increase the susceptibility to cardiac arrhythmias.

Hyperglycaemia

Inhalation of high doses of beta₂-adrenergic agonists may produce increases in plasma glucose. Upon initiation of treatment with Onbrez Breezhaler plasma glucose should be monitored more closely in diabetic patients.

During clinical studies, clinically notable changes in blood glucose were generally more frequent by 1-2% on Onbrez Breezhaler at the recommended doses than on placebo. Onbrez Breezhaler has not been investigated in patients with not well controlled diabetes mellitus.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Sympathomimetic agents

Concomitant administration of other sympathomimetic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Onbrez Breezhaler.

Onbrez Breezhaler should not be used in conjunction with other long-acting beta₂-adrenergic agonists or medicinal products containing long-acting beta₂-adrenergic agonists.

Hypokalaemic treatment

Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta₂-adrenergic agonists, therefore use with caution (see section 4.4).

Beta-adrenergic blockers

Beta-adrenergic blockers may weaken or antagonise the effect of beta₂-adrenergic agonists. Therefore indacaterol should not be given together with beta-adrenergic blockers (including eye drops) unless there are compelling reasons for their use. Where required, cardioselective beta-adrenergic blockers should be preferred, although they should be administered with caution.

Metabolic and transporter based interactions

Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-glycoprotein (P-gp) raises the systemic exposure of indacaterol by up to two-fold. The magnitude of exposure increases due to interactions does not raise any safety concerns given the safety experience of treatment with Onbrez Breezhaler in clinical studies of up to one year at doses up to twice the maximum recommended therapeutic dose.

Indacaterol has not been shown to cause interactions with co-medications. In vitro investigations have indicated that indacaterol has negligible potential to cause metabolic interactions with medicinal products at the systemic exposure levels achieved in clinical practice.

4.6 Pregnancy And Lactation

Pregnancy

There are no data from the use of indacaterol in pregnant women available. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant exposures (see section 5.3). Like other beta₂-adrenergic agonists, indacaterol may inhibit labour due to a relaxant effect on uterine smooth muscle. Onbrez Breezhaler should only be used during pregnancy if the expected benefits outweigh the potential risks.

Lactation

It is not known whether indacaterol/metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of indacaterol/metabolites in milk (see section 5.3). A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Onbrez Breezhaler therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

A decreased pregnancy rate has been observed in rats. Nevertheless, it is considered unlikely that indacaterol will affect reproductive or fertility performance in humans following inhalation of the maximum recommended dose (see section 5.3).

4.7 Effects On Ability To Drive And Use Machines

Onbrez Breezhaler has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable Effects

Summary of the safety profile

The most common adverse reactions at the recommended doses were nasopharyngitis (9.1%), cough (6.8%), upper respiratory tract infection (6.2%) and headache (4.8%). These were in the vast majority mild or moderate and became less frequent if treatment was continued.

At the recommended doses, the adverse reaction profile of Onbrez Breezhaler in patients with COPD shows clinically insignificant systemic effects of beta₂-adrenergic stimulation. Mean heart rate changes were less than one beat per minute, and tachycardia was infrequent and reported at a similar rate as under placebo treatment. Relevant prolongations of QT_cF were not detectable in comparison to placebo. The frequency of notable QT_cF intervals [i.e. >450 ms (males) and >470 ms (females)] and reports of hypokalaemia were similar to placebo. The mean of the maximum changes in blood glucose were similar between Onbrez Breezhaler and placebo.

Tabulated summary of adverse reactions

The Onbrez Breezhaler Phase III clinical development programme involved patients with a clinical diagnosis of moderate to severe COPD. 2,154 patients were exposed to indacaterol up to one year at doses up to twice the maximum recommended dose. Of these patients, 627 were on treatment with 150 microgram once daily and 853 on treatment with 300 microgram once daily. Approximately 40% of patients had severe COPD. The mean age of patients was 63 years, with 47% of patients aged 65 years or older, and the majority (89%) was Caucasian.

Adverse reactions in Table 1 are listed according to MedDRA system organ class in the COPD safety database. Within each system organ class, adverse reactions are ranked by frequency in descending order according to the following convention (CIOMS III): Very common (

Table 1 Adverse reactions

Adverse Reactions	Frequency category
Infections and infestations
Nasopharyngitis	Common
Upper respiratory tract infection	Common
Sinusitis	Common
Metabolism and nutrition disorders
Diabetes mellitus and hyperglycaemia	Common
Nervous system disorders
Headache	Common
Paraesthesia	Uncommon
Cardiac disorders
Ischaemic heart disease	Common
Atrial fibrillation	Uncommon
Respiratory, thoracic and mediastinal disorders
Cough	Common
Pharyngolaryngeal pain	Common
Rhinorrhoea	Common
Respiratory tract congestion	Common
Musculoskeletal and connective tissue disorders
Muscle spasm	Common
General disorders and administration site conditions
Peripheral oedema	Common
Non-cardiac chest pain	Uncommon

At twice the maximum recommended dose, the safety profile of Onbrez Breezhaler was overall similar to that of recommended doses. Additional adverse reactions were tremor (common) and anaemia (uncommon).

Description of selected adverse reactions

In Phase III clinical studies, healthcare providers observed during clinic visits that on average 17-20% of patients experienced a sporadic cough that occurred usually within 15 seconds following inhalation and typically lasted for 5 seconds (about 10 seconds in current smokers). It was observed with a higher frequency in female than in male patients and in current smokers than in ex-smokers. This cough experienced post inhalation was generally well tolerated and did not lead to any patient discontinuing from the studies at the recommended doses (cough is a symptom in COPD and only 6.8% of patients overall reported cough as an adverse event). There is no evidence that cough experienced post inhalation is associated with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy.

4.9 Overdose

In COPD patients, single doses of 10 times the maximum recommended therapeutic dose were associated with a moderate increase in pulse rate, systolic blood pressure and QT_c interval.

An overdose of indacaterol is likely to lead to exaggerated effects typical of beta₂-adrenergic stimulants, i.e. tachycardia, tremor, palpitations, headache, nausea, vomiting, drowsiness, ventricular arrhythmias, metabolic acidosis, hypokalaemia and hyperglycaemia.

Supportive and symptomatic treatment is indicated. In serious cases, patients should be hospitalised. Use of cardioselective beta blockers may be considered, but only under the supervision of a physician and with extreme caution since the use of beta-adrenergic blockers may provoke bronchospasm.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Long-acting beta₂-adrenergic agonist, ATC code: R03AC18.

Mechanism of action

The pharmacological effects of beta₂-adrenoceptor agonists are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle. In vitro studies have shown that indacaterol, a long-acting beta₂-adrenergic agonist, has more than 24-fold greater agonist activity at beta₂-receptors compared to beta₁-receptors and 20-fold greater agonist activity compared to beta₃-receptors.

When inhaled, indacaterol acts locally in the lung as a bronchodilator. Indacaterol is a partial agonist at the human beta₂-adrenergic receptor with nanomolar potency. In isolated human bronchus, indacaterol has a rapid onset of action and a long duration of action.

Although beta₂-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta₁-receptors are the predominant receptors in the human heart, there are also beta₂-adrenergic receptors in the human heart comprising 10-50% of the total adrenergic receptors. The precise function of beta₂-adrenergic receptors in the heart is not known, but their presence raises the possibility that even highly selective beta₂-adrenergic agonists may have cardiac effects.

Pharmacodynamic effects

Onbrez Breezhaler, administered once a day at doses of 150 and 300 microgram consistently provided clinically significant improvements in lung function (as measured by the forced expiratory volume in one second, FEV₁) over 24 hours across a number of clinical pharmacodynamic and efficacy studies. There was a rapid onset of action within 5 minutes after inhalation, with an increase in FEV₁ relative to baseline of 110-160 ml, comparable to the effect of the fast-acting beta₂-agonist salbutamol 200 microgram and statistically significantly faster compared to salmeterol/fluticasone 50/500 microgram. Mean peak improvements in FEV₁ relative to baseline were 250-330 ml at steady state.

The bronchodilator effect did not depend on the time of dosing, morning or evening.

Onbrez Breezhaler was shown to reduce lung hyperinflation, resulting in increased inspiratory capacity during exercise and at rest, compared to placebo.

Effects on cardiac electrophysiology

A double-blind, placebo- and active (moxifloxacin)-controlled study for 2 weeks in 404 healthy volunteers demonstrated maximum mean (90% confidence intervals) prolongations of the QT_cF interval (in milliseconds) of 2.66 (0.55, 4.77) 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) following multiple doses of 150 microgram, 300 microgram and 600 microgram, respectively. Therefore, this shows no concern for a pro-arrhythmic potential related to QT-interval prolongations at recommended therapeutic doses or at twice the maximum recommended dose. There was no evidence of a concentration-delta QT_c relationship in the range of doses evaluated.

As demonstrated in 605 patients with COPD in a 26-week, double-blind, placebo-controlled Phase III study, there was no clinically relevant difference in the development of arrhythmic events monitored over 24 hours, at baseline and up to 3 times during the 26-week treatment period, between patients receiving recommended doses of Onbrez Breezhaler treatment and those patients who received placebo or treatment with tiotropium.

Clinical efficacy and safety

The clinical development programme included one 12-week, two six-month (one of which was extended to one year to evaluate safety and tolerability) and one one-year randomised controlled studies in patients with a clinical diagnosis of COPD. These studies included measures of lung function and of health outcomes such as dyspnoea, exacerbations and health-related quality of life.

Lung function

Onbrez Breezhaler, administered once a day at doses of 150 microgram and 300 microgram, showed clinically meaningful improvements in lung function. At the 12-week primary endpoint (24-hour trough FEV₁), the 150 microgram dose resulted in a 130-180 ml increase compared to placebo (p<0.001) and a 60 ml increase compared to salmeterol 50 microgram twice a day (p<0.001). The 300 microgram dose resulted in a 170-180 ml increase compared to placebo (p<0.001) and a 100 ml increase compared to formoterol 12 microgram twice a day (p<0.001). Both doses resulted in an increase of 40-50 ml over open-label tiotropium 18 microgram once a day (150 microgram, p=0.004; 300 microgram, p=0.01). The 24-hour bronchodilator effect of Onbrez Breezhaler was maintained from the first dose throughout a one-year treatment period with no evidence of loss in efficacy (tachyphylaxis).

Symptomatic benefits

Both doses demonstrated statistically significant improvements in symptom relief over placebo for dyspnoea and health status (as evaluated by Transitional Dyspnoea Index [TDI] and St. George's Respiratory Questionnaire [SGRQ], respectively). The magnitude of response was generally greater than seen with active comparators (Table 2). In addition, patients treated with Onbrez Breezhaler required significantly less rescue medication, had more days when no rescue medication was needed compared to placebo and had a significantly improved percentage of days with no daytime symptoms.

Pooled efficacy analysis over 6 months' treatment demonstrated that the rate of COPD exacerbations was statistically significantly lower than the placebo rate. Treatment comparison compared to placebo showed a ratio of rates of 0.68 (95% CI [ 0.47, 0.98]; p-value 0.036) and 0.74 (95% CI [0.56, 0.96]; p-value 0.026) for 150 microgram and 300 microgram, respectively.

Limited treatment experience is available in individuals of African descent.

Table 2 Symptom relief at 6 months treatment duration

Treatment Dose (microgram)	Indacaterol 150 once a day	Indacaterol 300 once a day	Tiotropium 18 once a day	Salmeterol 50 twice a day	Formoterol 12 twice a day	Placebo
Percentage of patients who achieved MCID TDI†	57 a 62 b	71 b 59 c	57 b	54 a	54 c	45 a 47 b 41 c
Percentage of patients who achieved MCID SGRQ†	53 a 58 b	53 b 55 c	47 b	49 a	51 c	38 a 46 b 40 c
Reduction in puffs/day of rescue medication use vs. baseline	1.3 a 1.5 b	1.6 b	1.0 b	1.2 a	n/e	0.3 a 0.4 b
Percentage of days with no rescue medication use	60 a 57 b	58 b	46 b	55 a	n/e	42 a 42 b

Study design with ^a: indacaterol 150 microgram, salmeterol and placebo; ^b: indacaterol 150 and 300 microgram, tiotropium and placebo; ^c: indacaterol 300 microgram, formoterol and placebo

^† MCID = minimal clinically important difference (

n/e= not evaluated at six months

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Onbrez Breezhaler in all subsets of the paediatric population in chronic obstructive pulmonary disease (COPD) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic Properties

Indacaterol is a chiral molecule with R-configuration.

Pharmacokinetic data were obtained from a number of clinical studies, from healthy volunteers and COPD patients.

Absorption

The median time to reach peak serum concentrations of indacaterol was approximately 15 min after single or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose (150 microgram to 600 microgram) in a dose proportional manner. Absolute bioavailability of indacaterol after an inhaled dose was on average 43% to 45%. Systemic exposure results from a composite of pulmonary and gastrointestinal absorption; about 75% of systemic exposure was from pulmonary absorption and about 25% from gastrointestinal absorption.

Indacaterol serum concentrations increased with repeated once-daily administration. Steady state was achieved within 12 to 14 days. The mean accumulation ratio of indacaterol, i.e. AUC over the 24-h dosing interval on Day 14 compared to Day 1, was in the range of 2.9 to 3.5 for once-daily inhaled doses between 150 microgram and 600 microgram.

Distribution

After intravenous infusion the volume of distribution of indacaterol during the terminal elimination phase was 2557 litres indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.

Biotransformation

After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.

In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolised indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.

Elimination

In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.20 litres/hour. When compared with the serum clearance of indacaterol of 23.3 litres/hour, it is evident that renal clearance plays a minor role (about 2 to 5% of systemic clearance) in the elimination of systemically available indacaterol.

In a human ADME study where indacaterol was given orally, the faecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human faeces primarily as unchanged parent substance (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing ranged from 40 to 52 hours which is consistent with the observed time-to-steady state of approximately 12-14 days.

Special populations

A population pharmacokinetic analysis showed that there is no clinically relevant effect of age (adults up to 88 years), sex, weight (32-168 kg) or race on the pharmacokinetics of indacaterol. It did not suggest any difference between ethnic subgroups in this population.

Patients with mild and moderate hepatic impairment showed no relevant changes in C_max or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.

Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.

5.3 Preclinical Safety Data

Effects on the cardiovascular system attributable to the beta₂-agonistic properties of indacaterol included tachycardia, arrhythmias and myocardial lesions in dogs. Mild irritancy of the nasal cavity and larynx were seen in rodents. All these findings occurred at exposures sufficiently in excess of those anticipated in humans.

Although indacaterol did not affect general reproductive performance in a rat fertility study, a decrease in the number of pregnant F₁ offspring was observed in the peri- and post-developmental rat study at an exposure 14-fold higher than in humans treated with Onbrez Breezhaler. Indacaterol was not embryotoxic or teratogenic in rats or rabbits.

Genotoxicity studies did not reveal any mutagenic or clastogenic potential. Carcinogenicity was assessed in a two-year rat study and a six-month transgenic mouse study. Increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in rats were consistent with similar findings reported for other beta₂-adrenergic agonists. No evidence of carcinogenicity was seen in mice. Systemic exposures (AUC) in rats and mice at the no-observed adverse effect levels in these studies were at least 7- and 49-fold higher, respectively, than in humans treated with Onbrez Breezhaler once a day at a dose of 300 microgram.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule content

Lactose monohydrate

Capsule shell

Gelatin

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Do not store above 30°C.

Onbrez Breezhaler capsules must always be stored in the blister to protect from moisture and only removed immediately before use.

6.5 Nature And Contents Of Container

Onbrez Breezhaler is a single-dose inhalation device. Inhaler body and cap are made from acrylonitrile butadiene styrene, push buttons are made from methyl methacrylate acrylonitrile butadiene styrene. Needles and springs are made from stainless steel.

PA/Alu/PVC - Alu blister packs, containing 10 hard capsules, with an inhaler made from plastic materials provided in each pack.

Carton containing 10 capsules (1x10 capsule blister strips) and one Onbrez Breezhaler inhaler.

Carton containing 30 capsules (3x10 capsule blister strips) and one Onbrez Breezhaler inhaler.

Multipack comprising 2 packs (each containing 30 capsules and 1 inhaler).

Multipack comprising 3 packs (each containing 30 capsules and 1 inhaler).

Multipack comprising 30 packs (each containing 10 capsules and 1 inhaler).

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

The Onbrez Breezhaler inhaler provided with each new prescription should be used. Dispose of each inhaler after 30 days of use.

Instructions for handling and use

	Pull off the cap.
	Open inhaler: Hold the base of the inhaler firmly and tilt the mouthpiece. This opens the inhaler.
	Prepare capsule: Immediately before use, with dry hands, remove one capsule from the blister.
	Insert capsule: Place the capsule into the capsule chamber. Never place a capsule directly into the mouthpiece.
	Close the inhaler: Close the inhaler until you hear a “click”.
	Pierce the capsule: • Hold the inhaler upright with the mouthpiece pointing up. • Pierce the capsule by firmly pressing together both side buttons at the same time. Do this only once. • You should hear a “click” as the capsule is being pierced.
	Release the side buttons fully.
	Breathe out: Before placing the mouthpiece in your mouth, breathe out fully. Do not blow into the mouthpiece.
	Inhale the medicine To breathe the medicine deeply into your airways: • Hold the inhaler as shown in the picture. The side buttons should be facing left and right. Do not press the side buttons. • Place the mouthpiece in your mouth and close your lips firmly around it. • Breathe in rapidly but steadily and as deeply as you can.
	Note: As you breathe in through the inhaler, the capsule spins around in the chamber and you should hear a whirring noise. You will experience a sweet flavour as the medicine goes into your lungs. Additional information Occasionally, very small pieces of the capsule can get past the screen and enter your mouth. If this happens, you may be able to feel these pieces on your tongue. It is not harmful if these pieces are swallowed or inhaled. The chances of the capsule shattering will be increased if the capsule is accidentally pierced more than once (step 6). If you do not hear a whirring noise: The capsule may be stuck in the capsule chamber. If this happens: • Open the inhaler and carefully loosen the capsule by tapping the base of the inhaler. Do not press the side buttons. • Inhale the medicine again by repeating steps 8 and 9.
	Hold breath: After you have inhaled the medicine: • Hold your breath for at least 5-10 seconds or as long as you comfortably can while taking the inhaler out of your mouth. • Then breathe out. • Open the inhaler to see if any powder is left in the capsule. If there is powder left in the capsule: • Close the inhaler. • Repeat steps 8, 9, 10 and 11. Most people are able to empty the capsule with one or two inhalations. Additional information Some people may occasionally cough briefly soon after inhaling the medicine. If you do, don't worry. As long as the capsule is empty, you have received enough of your medicine.
	After you have finished taking your medicine: • Open the mouthpiece again, and remove the empty capsule by tipping it out of the capsule chamber. Put the empty capsule in your household waste. • Close the inhaler and replace the cap. Do not store the capsules in the Onbrez Breezhaler inhaler.
	Mark daily dose tracker: On the inside of the pack there is a daily dose tracker. Put a mark in today's box if it helps to remind you of when your next dose is due.

7. Marketing Authorisation Holder

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

8. Marketing Authorisation Number(S)

Onbrez Breezhaler 150 microgram inhalation powder, hard capsules: EU/1/09/593/001-005

Onbrez Breezhaler 300 microgram inhalation powder, hard capsules: EU/1/09/593/006-010

9. Date Of First Authorisation/Renewal Of The Authorisation

30.11.2009

10. Date Of Revision Of The Te

Co-Amilofruse tablets 5 / 40mg

1. Name Of The Medicinal Product

Co-Amilofruse tablets 5/40mg

2. Qualitative And Quantitative Composition

Furosemide 40mg

Amiloride hydrochloride (anhydrous) 5mg as the equivalent quantity of Amiloride hydrochloride

For excipients, see section 6.1

3. Pharmaceutical Form

Tablets

Orange circular tablets engraved with Berk 4F5 with breakline.

4. Clinical Particulars

4.1 Therapeutic Indications

Co-amilofruse is a potassium sparing diuretic which is indicated where a prompt diuresis is required. It is of particular value in conditions where potassium conservation is important: congestive cardiac failure, nephrosis, corticosteroid therapy, oestrogen therapy and for ascites associated with cirrhosis.

4.2 Posology And Method Of Administration

Oral administration

Adults: One to two tablets to be taken in the morning

Children: Not recommended

Elderly: The dosage should be adjusted according to the diuretic response. Serum electrolytes and urea should be carefully monitored.

4.3 Contraindications

Patients with hypovolaemia or dehydration (with or without accompanying hypotension). Patients with an impaired renal function and a creatinine clearance below 30ml/min per 1.73 m² body surface area, anuria or renal failure with anuria not responding to furosemide, renal failure as a result of poisoning by nephrotoxic or hepatotoxic agents or renal failure associated with hepatic coma, hyperkalaemia, severe hypokalaemia, severe hyponatraemia, concomitant potassium supplements or potassium sparing diuretics, precomatose states associated with cirrhosis, Addisons's disease, and breast feeding women.

Co-amilofruse is contraindicated in children and adolescents under 18 years of age as safety in this age group has not yet been established.

Hypersensitivity to furosemide, amiloride, sulphonamides or sulphonamide derivatives, or any of the excipients of the product.

4.4 Special Warnings And Precautions For Use

Co-amilofruse should be discontinued before a glucose tolerance test.

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

Urinary output must be secured. Patients with partial obstruction of urinary outflow, for example patients with prostatic hypertrophy or impairment of micturition have an increased risk of developing acute retention and require careful monitoring.

Where indicated, steps should be taken to correct hypotension or hypovolaemia before commencing therapy.

Particularly careful monitoring is necessary in:

• patients with hypotension.

• patients who are at risk from a pronounced fall in blood pressure.

• patients where latent diabetes may become manifest or the insulin requirements of diabetic patients may increase.

• patients with gout.

• patients with hepatic cirrhosis together with impaired renal function.

• patients with hypoproteinaemia, e.g. associated with nephrotic syndrome (the effect of furosemide may be weakened and its ototoxicity potentiated). Cautious dose titration is required.

Caution should be observed in patients liable to electrolyte deficiency. 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. Hypovolaemia or dehydration as well as any significant electrolyte and acid-base disturbances must be corrected. This may require temporary discontinuation of Co-amilofruse.

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 Co-amilofruse is taken in combination with certain other drugs which may lead to an increase in potassium levels.

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.

Patients with rare hereditary problems of 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 Co-amilofruse. 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 Co-amilofruse 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.

When amiloride is taken in combination with potassium salts, with drugs which reduce potassium excretion, with nonsteroidal anti-inflammatory drugs or with ACE inhibitors, an increase in serum potassium concentration and hyperkalaemia may occur.

The toxic effects of nephrotoxic drugs may be increased by concomitant administration of potent diuretics such as furosemide.

Oral Co-amilofruse 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.

In common with other diuretics, serum lithium levels may be increased when lithium is given concomitantly with Co-amilofruse, 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 Co-amilofruse and may cause acute renal failure in cases of pre-existing hypovolaemia or dehydration. Salicylic toxicity may be increased by furosemide. Co-amilofruse may sometimes attenuate the effects of other drugs (e.g. the effects of anti-diabetics and of pressor amines) and sometimes potentiate them (e.g. the effects of salicylates, theophylline and curare-type muscle relaxants).

Furosemide may potentiate the ototoxicity of aminoglycosides and other ototoxic drugs. Since this may lead to irreversible damage, these drugs must only be used with Co-amilofruse 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.

Amiloride may cause raised blood digoxin levels. Some electrolyte disturbances (e.g. hypokalaemia, hypomagnesaemia) may increase the toxicity of certain other drugs (e.g. digitalis preparations and drugs inducing QT interval prolongation syndrome).

Attenuation of the effect of Co-amilofruse may occur following concurrent administration of phenytoin.

Concomitant administration of carbamazepine or aminoglutethimide may increase the risk of hyponatraemia.

Corticosteroids administered concurrently may cause sodium retention.

Corticosteroids, carbenoxolone, liquorice, B₂ sympathomimetics in large amounts, and prolonged use of laxatives, reboxetine and amphotericin may increase the risk of developing hypokalaemia.

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

4.6 Pregnancy And Lactation

Pregnancy:

Results of animal work, in general, show no hazardous effect of furosemide in pregnancy. There is clinical evidence of safety of the drug in the third trimester of human pregnancy; however, furosemide crosses the placental barrier. It must not be given during pregnancy unless there are compelling medical reasons. Treatment during pregnancy requires monitoring of foetal growth.

The safety of Amiloride Hydrochloride has not been established and is therefore not recommended for use during pregnancy.

Lactation:

Furosemide passes into breast milk and may inhibit lactation. It is not known whether Amiloride Hydrochloride is excreted in breast milk. Breastfeeding must be avoided during treatment with Co-amilofruse.

4.7 Effects On Ability To Drive And Use Machines

None stated.

4.8 Undesirable Effects

Co-amilofruse Tablets are generally well tolerated.

Eosinophilia is rare.

Occasionally, thrombocytopenia may occur. In rare cases, leucopenia and, in isolated cases, agranulocytosis, aplastic anaemia or haemolytic anaemia may develop.

Bone marrow depression has been reported as a rare complication and necessitates withdrawal of treatment.

Rarely, paraesthesiae may occur.

Hepatic encephalopathy inpatients with hepatocellular insufficiency may occur.

Serum calcium levels may be reduced; in very rare cases tetany has been observed. Nephrocalcinosis / Nephrolithiasis has been reported in premature infants.

Serum cholesterol and triglyceride levels may rise during furosemide treatment. During long term therapy they will usually return to normal within six months.

Glucose tolerance may decrease with furosemide. In patients with diabetes mellitus this may lead to a deterioration of metabolic control; latent diabetes mellitus may become manifest.

Hearing disorders and tinnitus, although usually transitory, may occur in rare cases, particularly in patients with renal failure, hypoproteinaemia (e.g. in nephritic syndrome) and/or when intravenous furosemide has been given too rapidly

Furosemide may cause a reduction in 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.

In isolated cases, intrahepatic cholestasis, an increase in liver transaminases or acute pancreatitis may develop.

The incidence of allergic reactions, such as skin rashes, photosensitivity, vasculitis, fever, interstitial nephritis, or shock is very low, but when these occur treatment should be withdrawn. Skin and mucous membrane reactions may occasionally occur, e.g. itching, urticaria, other rashes or bullous lesions, erythema multiforme, bullous pemphigoid, exfoliative dermatitis, purpura.

As with other diuretics, electrolytes and water balance may be disturbed as a result of diuresis after prolonged therapy. Furosemide leads to increased excretion of sodium and chloride and consequently water. In addition excretion of other electrolytes (in particular potassium, calcium and magnesium) is increased. However, as treatment is continued, the serum potassium concentration may increase due to the later onset of action of amiloride, especially in patients with impaired renal function. Symptomatic electrolyte disturbances and metabolic alkalosis may develop in the form of a gradually increasing electrolyte deficit or, e.g. where higher furosemide doses are administered to patients with normal renal function, acute severe electrolyte losses, although amiloride may contribute to the development or aggravation of metabolic acidosis. Warning signs of electrolyte disturbances include increased thirst, headache, hypotension, confusion, muscle cramps, tetany, muscle weakness, disorders of cardiac rhythm and gastrointestinal symptoms. Disturbances of electrolyte balance, particularly if pronounced, must be corrected. Pre-existing metabolic alkalosis (e.g. in decompensated cirrhosis of the liver) may be aggravated by furosemide treatment.

Rare complications may include minor psychiatric disturbances.

The diuretic action of furosemide may lead to or contribute to hypovolaemia and dehydration, especially in elderly patients. Severe fluid depletion may lead to haemoconcentration with a tendency for thromboses to develop.

Increased production of urine may provoke or aggravate complaints in patients with an obstruction of urinary outflow. Thus, acute retention of urine with possible secondary complications may occur. for example, in patients with bladder-emptying disorders, prostatic hyperplasia or narrowing of the urethra.

If furosemide is administered to premature infants during the first weeks of life, it may increase the risk of persistence of patent ductus arteriosus.

Severe anaphylactic or anaphylactoid reactions (e.g. with shock) occur rarely.

Side-effects of a minor nature such as nausea, malaise or gastric upset (vomiting or diarrhoea) and constipation may occur but are not usually severe enough to necessitate withdrawal of treatment.

As with other diuretics, treatment with furosemide may lead to transitory increases in blood creatinine and urea levels. Serum levels of uric acid may increase and attacks of gout may occur.

4.9 Overdose

Treatment of overdosage should be aimed at reversing dehydration and correcting electrolyte imbalance, particularly hyperkalaemia. Emesis should be induced or gastric lavage performed. Treatment should be symptomatic and supportive. If hyperkalaemia is seen, appropriate measures to reduce serum potassium must be instituted.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: CO3C A01

Furosemide - Furosemide is a loop diuretic which acts primarily to inhibit electrolyte reabsorption in the thick ascending Loop of Henle. Excretion of sodium, potassium and chloride ions is increased and water excretion enhanced.

Amiloride - Amiloride is a mild diuretic which moderately increases the excretion of sodium and chloride and reduces potassium excretion and appears to act mainly on the distal renal tubules. It does not appear to act by inhibition of aldosterone and does not inhibit carbonic anhydrase. Amiloride adds to the natiuretic but diminishes the kaliuretic effect of other diuretics.

A combination of furosemide and amiloride is a diuretic which reduces the potassium loss of furosemide alone while avoiding the possible gastro-intestinal disturbances of potassium supplements.

5.2 Pharmacokinetic Properties

Furosemide - approximately 65% of the dose is absorbed after oral administration. The plasma half life is biphasic with a terminal elimination phase of about 1 ½ hours. Furosemide is up to 99% bound to plasma proteins and is mainly excreted in the urine, largely unchanged, but also as the glucuronide and free amine metabolites. Variable amounts are also excreted in the bile, non-renal elimination being considerably increased in renal failure. Furosemide crosses the placental barrier and is excreted in the milk.

Amiloride - approximately 50% of the dose is absorbed after oral administration and peak serum concentrations are achieved by about 3-4 hours. The serum half life is estimated to be about 6 hours. Amiloride is not bound to plasma proteins. Amiloride is not metabolised and is excreted unchanged in the urine.

Pharmacokinetic studies have been completed

Furosemide

Cp max = 1.14ug/ml (SD = 0.67)

Tmax = 3.0 hr

AUC = 3.17ug/ml/hr (SD + 1.25)

Amiloride

Cp max = 13.42ng/ml (SD = 5.74)

Tmax = 4.0 hr

AUC = 154 ng/ml/hr (SD = 65.2)

5.3 Preclinical Safety Data

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose

Starch (white maize)

Microcrystalline cellulose

Sodium starch glycollate

Sunset yellow (E110)

Talc

Colloidal silicon dioxide

Magnesium stearate

6.2 Incompatibilities

None stated.

6.3 Shelf Life

36 months.

6.4 Special Precautions For Storage

Store in a cool dry place and protect from light.

6.5 Nature And Contents Of Container

Grey polypropylene securitainers with white polyethylene lid or HDPE containers with LDPE lids or snap-secure containers with polyethylene lid containing 500 or 100 tablets.

Blister strips with white PVC blister film containing 4, 7, 28, 56 or 1400 tablets.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

May & Baker Limited

trading as

May & Baker or Rhône-Poulenc Rorer or Rorer Pharmaceuticals or Pharmuka or

Theraplix or APS or Berk Pharmaceuticals

RPR House

50 Kings Hill Avenue

Kings Hill

West Malling

Kent ME19 4AH

or trading as

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8. Marketing Authorisation Number(S)

PL 00012/0300

9. Date Of First Authorisation/Renewal Of The Authorisation

03 June 1996

10. Date Of Revision Of The Text

16 June 2008

11. LEGAL CLASSIFICATION

POM

Calpol Six Plus Fast Melts (Packsize 12)

1. Name Of The Medicinal Product

Calpol Six Plus Fastmelts (250 mg Orodispersible Tablets)

2. Qualitative And Quantitative Composition

Paracetamol 250 mg

For excipients, see 6.1.

3. Pharmaceutical Form

Orodispersible tablet

Round, white, bi-convex tablets with central concave depression.

4. Clinical Particulars

4.1 Therapeutic Indications

Calpol Six Plus Fastmelts is indicated for the treatment of mild to moderate pain and as an antipyretic. It can be used in many conditions including headache, toothache, earache, sore throat, colds and influenza, aches and pains and post-immunisation fever.

4.2 Posology And Method Of Administration

Oral:

Tablets should be placed in the mouth where they melt on the tongue. The tablet will rapidly disperse to a pleasant tasting paste that can be easily ingested. Alternatively the tablet can be dispersed in a teaspoonful of water or milk.

Adults and children

Child's Age	How Much	How often (in 24 hours)
Under 6 years	Not recommended	N/A
6 - 9 years	1 tablet	4 times
9 - 12 years	2 tablets	4 times
12 – 16 years	2 to 3 tablets	4 times
Adults and children over 16 years	2 to 4 tablets	4 times
• Do not give more than 4 doses in any 24 hour period • Leave at least 4 hours between doses • Do not give this medicine to your child for more than 3 days without speaking to your doctor or pharmacist

Use in the Elderly

Normal adult dosage is appropriate. However, a reduction in dosing may be necessary in frail, elderly subjects (see Section 5.2).

4.3 Contraindications

Calpol Six Plus Fastmelts are contraindicated in patients with known hypersensitivity to paracetamol or any other ingredient and in subjects with phenylketonuria.

4.4 Special Warnings And Precautions For Use

Care is advised in the administration of paracetamol to patients with severe hepatic or severe renal impairment.

The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

Calpol Six Plus Fastmelts contain aspartame which is a source of phenylalanine equivalent to 0.04 mg/250 mg tablet. The phenylalanine in the tablets may be harmful to people with phenylketonuria.

Calpol Six Plus Fastmelts contain mannitol which may have a mild laxative effect.

The label should contain the following statements:

Contains paracetamol.

Do not give this medicine with any other paracetamol containing products.

For oral use only

Never give more medicine than shown in the table.

Do not give more than 4 doses in any 24 hour period.

Leave at least 4 hours between doses.

Do not give this medicine to your child for more than 3 days without speaking to your doctor or pharmacist

As with all medicines, if your child is currently taking any other medicine consult your doctor or pharmacist before using this product.

Keep out of the reach and sight of children.

Do not exceed the stated dose.

If symptoms persist consult your doctor.

Immediate medical advice should be sought in the event of an overdose, even if the child seems well. (label)

Immediate medical advice should be sought in the event of an overdose, even if the child seems well, because of the risk of delayed, serious liver damage (leaflet).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

Chronic alcohol intake can increase the hepatotoxicity of paracetamol overdose and may have contributed to the acute pancreatitis reported in one patient who had taken an overdose of paracetamol. Acute alcohol intake may diminish an individual's ability to metabolise large doses of paracetamol, the plasma half-life of which can be prolonged.

The use of drugs that induce hepatic microsomal enzymes, such as anticonvulsants and oral contraceptives, may increase the extent of metabolism of paracetamol, resulting in reduced plasma concentrations of the drug and a faster elimination rate.

4.6 Pregnancy And Lactation

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

None known

4.8 Undesirable Effects

Adverse effects of paracetamol are rare. Very rarelyhypersensitivity and anaphylactic reactions including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Most reports of adverse reactions to paracetamol relate to overdose with the drug.

Nephrotoxicity following therapeutic doses of paracetamol is uncommon, but papillary necrosis has been reported after prolonged administration.

4.9 Overdose

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below)

Risk Factors:

If the patient

a) Is on long term treatment with carbamazepine, phenobarbitol, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes

OR

b) Regularly consumes ethanol in excess of recommended amounts

OR

c) Is likely to be glutathione deplete e.g, eating disorders, cystic fibrosis, HIV infection, starvation, cachexia

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of the overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentrations should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patient who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Paracetamol has analgesic and antipyretic effects similar to those of aspirin and is useful in the treatment of mild to moderate pain

5.2 Pharmacokinetic Properties

Paracetamol is rapidly and almost completely absorbed from the gastro-intestinal tract. Peak plasma concentrations are reached 30-90 minutes post dose.

Paracetamol is distributed rapidly throughout all tissues. Protein binding is low.

The plasma half-life is in the range of 1 to 4 hours after therapeutic doses.

Following therapeutic doses 90-100% of the drug is recovered in the urine within 24 hours almost entirely following hepatic conjugation with glucuronic acid (about 60%), sulphuric acid (about 35%) or cysteine (about 3%). Small amounts of hydroxylated and deacetylated metabolites have also been detected. Children have less capacity for glucuronidation of the drug than do adults. In overdose there is increased N-hydroxylation followed by glutathione conjugation. When the latter is exhausted reaction with hepatic proteins is increased leading to necrosis.

In the elderly, the rate and extent of paracetamol absorption is normal but plasma half-life is longer and paracetamol clearance is lower than in young adults.

5.3 Preclinical Safety Data

There are no preclinical data of relevance to the prescriber which are additional to those already included in other sections of the SPC.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Mannitol (E421)

Crospovidone

Aspartame

Strawberry flavouring E. 9620941

Magnesium stearate

Polymethacrylate (Eudragit E 100)

Polyacrylate dispersion 30%

Colloidal Anhydrous Silica

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

36 months

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

Strip containing 12 tablets.

The blister consists of a blister complex (Polyamide/PVC/Aluminium) and either:

an aluminium sealing sheet

or

a paper/aluminium child resistant sealing sheet.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

Administrative Data

7. Marketing Authorisation Holder

McNeil Products Limited

Foundation Park

Roxborough Way

Maidenhead

Berkshire

SL6 3UG

United Kingdom

8. Marketing Authorisation Number(S)

PL 15513/0121

9. Date Of First Authorisation/Renewal Of The Authorisation

13^th July 2005/ 11 March 2009

10. Date Of Revision Of The Text

6^th June 2011

Velosef Capsules 250mg &amp; 500mg

The wording of leaflets is regularly updated. This electronic text is the most up-to-date version and may differ from the leaflet in your pack. If you have any questions about the information provided, please ask your doctor or pharmacist.

VELOSEF
CAPSULES 250MG & 500MG

Cefradine

Your doctor has prescribed Velosef Capsules for you. Please read this before you take your medicine. This leaflet gives a summary of information about your medicine. If you want to know more, or are not sure about anything, ask your doctor or pharmacist.

REMEMBER:

This medicine is for YOU. Only a doctor can prescribe it. NEVER give it to anyone else. It may harm them even if they have the same symptoms as you.

What Is In Velosef Capsules?

The active ingredient in Velosef is cefradine. Cefradine is an antibiotic and a member of the family of medicines called cephalosporins. Velosef capsules are available in two strengths: 250mg and 500mg and are supplied in blister packs of 20 or 100 capsules.

The other ingredients are:

Orange/blue Capsules 250mg: Gelatin capsules, erythrosine, indigo carmine, iron oxide, lactose, magnesium stearate, titanium dioxide.

Blue Capsules 500mg: Gelatin capsules, indigo carmine, lactose, magnesium stearate, titanium dioxide

Who Supplies Velosef?

Product Licence Holder:

E.R. Squibb & Sons Limited

Uxbridge

Middlesex

UB8 1DH

Tel.:0800-7311-736

Product Authorisation Holder:

Bristol-Myers Squibb Pharmaceuticals Limited

Dublin

Ireland

Tel.:1-800-749-749

Manufacturer:

Bristol-Myers Squibb Srl

Via Del Murillo

Sermoneta

Latina

Italy

What Is This Medicine For?

Velosef is for the treatment of a wide range of infections caused by certain bacteria.

Before Taking Your Medicine:

Should I be taking Velosef?

DO NOT take this medicine if you have had an allergic reaction to similar medicines or any of the ingredients in Velosef Capsules. Tell your doctor if you are allergic to penicillin before you start Velosef.

What if I am pregnant or breast feeding?

If you are pregnant, or plan to become pregnant or you are breast feeding whilst taking Velosef, you must tell your doctor as soon as possible.

Do you have any trouble with your kidneys?

Tell your doctor if you have any trouble with your kidneys as the dosage might have to be adjusted.

Can I take any other medicine?

It is usually all right to take Velosef with other medicines. Always tell your doctor about all other medicines you are using, especially furosemide ('water tablets') or probenecid, and including those you have bought at a pharmacy or other places, e.g. supermarket.

Is it all right to drive?

Velosef preparations do not usually affect your ability to drive, but, if you experience any dizziness, make sure you are fit to drive before attempting to do so.

Is it all right to drink alcohol?

There is no interaction between Velosef and moderate amounts of alcohol. However, you should check with your doctor whether drinking is advisable for you.

What if I am diabetic?

If you use chemical tests to check for sugar in the urine, Velosef may cause a false positive reaction, this does not occur with dipstick type tests.

Taking Your Medicine:

How should I take Velosef Capsules?

Because people respond to medicines in different ways, your doctor will have prescribed the dose he considers best suited to you. Therefore, you should only take the dose shown on the label. The dose of Velosef is usually in the range of 1-2 capsules given 2-4 times a day. The capsules should be swallowed whole with a glass of water.

It is best to take the doses at evenly spaced times throughout the day and night. If you are unsure or confused, ask your doctor or pharmacist.

KEEP TAKING THIS MEDICINE UNTIL IT IS FINISHED. DON'T STOP JUST BECAUSE YOU FEEL BETTER. THIS WILL HELP CLEAR UP YOUR INFECTION COMPLETELY.

Can I take Velosef before or after meals?

It does not matter. If this medicine upsets your stomach it may help to take it with food.

How long should I take Velosef for?

A complete course will have been prescribed for your present infection. Continue taking the prescribed doses until the course is finished.

What if I miss or forget to take a dose?

If you miss a dose of this medicine take it as soon as possible. This will help to keep a constant amount of medicine in your body. However, if it is almost time for your next dose and you are taking the medicine FOUR TIMES A DAY - space the missed dose and the next dose 2-4 hours apart or double your next dose. Then go back to the prescribed dosing instructions. If you are taking this medicine TWICE A DAY - space the missed dose and the next dose 5-6 hours apart. Then go back to your prescribed dosing instructions.

What if I take too many capsules, or a child accidentally swallows some?

As with any other medicine if an overdose is taken go to your nearest hospital Casualty Department or tell your doctor immediately. If you are going to the hospital, take the empty container and any remaining medicine with you.

Undesirable Effects

Are there any unwanted effects of Velosef?

Any medicine may cause some unwanted or 'side-effects' in a few patients.

If you have sudden difficulty in breathing or if you develop spots, itchiness, a rash or any other skin trouble, you may be allergic to Velosef - STOP TAKING THE MEDICINE AND TELL YOUR DOCTOR AS SOON AS POSSIBLE AS A CHANGE OF MEDICINE MAY BE NEEDED.

Sometimes Velosef causes headache, dizziness, diarrhoea or loose bowel movements, thrush, feeling sick or vomiting, fever or painful joints. Very rarely, tests have shown temporary changes in liver function or kidney function. There have also been very rare reports of more serious allergic reactions including anaphylaxis and Stevens Johnson syndrome.

If you notice any of these or any other unwanted effects, tell your doctor or pharmacist.

Looking After Your Medicine:

You will see an "Expiry Date" on the outer packaging of Velosef Capsules. Do not use after this date. Keep Velosef Capsules below 25°C. The medicine should not get too hot or damp; so do not leave it near a radiator, on a window sill or in the bathroom.

If your doctor decides to stop the medicine, ask your pharmacist to tell you what to do with any you have left.

DATE OF LAST REVISION June 2005