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

Copaxone

Generic Name: glatiramer acetate

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

Copaxone (glatiramer acetate injection)

Indications and Usage for Copaxone

 Copaxone is indicated for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RRMS), including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.

Copaxone Dosage and Administration

Recommended Dose

Copaxone is for subcutaneous use only. Do not administer intravenously. The recommended dose of Copaxone is 20 mg/day.

Instructions for Use

Remove one blister that contains the syringe from the Copaxone prefilled syringes package. Since this product should be refrigerated, let the prefilled syringe stand at room temperature for 20 minutes to allow the solution to warm to room temperature. Inspect the Copaxone syringe visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution in the syringe should appear clear, colorless to slightly yellow. If particulate matter or discoloration is observed, discard the Copaxone syringe.

Areas for self-injection include arms, abdomen, hips, and thighs. The prefilled syringe is for single use only. Discard unused portions.

Dosage Forms and Strengths

Single-use prefilled syringe containing 1 mL solution with 20 mg of glatiramer acetate and 40 mg of mannitol.

Contraindications

Copaxone is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.

Warnings and Precautions

Immediate Post-Injection Reaction

Approximately 16% of patients exposed to Copaxone in the 5 placebo-controlled trials compared to 4% of those on placebo experienced a constellation of symptoms immediately after injection that included at least two of the following: flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. The symptoms were generally transient and self-limited and did not require treatment. In general, these symptoms have their onset several months after the initiation of treatment, although they may occur earlier, and a given patient may experience one or several episodes of these symptoms. Whether or not any of these symptoms actually represent a specific syndrome is uncertain. During the postmarketing period, there have been reports of patients with similar symptoms who received emergency medical care.

Whether an immunologic or nonimmunologic mechanism mediates these episodes, or whether several similar episodes seen in a given patient have identical mechanisms, is unknown.

Chest Pain

Approximately 13% of Copaxone patients in the 5 placebo-controlled studies compared to 6% of placebo patients experienced at least one episode of what was described as transient chest pain. While some of these episodes occurred in the context of the Immediate Post-Injection Reaction described above, many did not. The temporal relationship of this chest pain to an injection of Copaxone was not always known. The pain was transient (usually lasting only a few minutes), often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients experienced more than one such episode, and episodes usually began at least 1 month after the initiation of treatment. The pathogenesis of this symptom is unknown.

Lipoatrophy and Skin Necrosis

At injection sites, localized lipoatrophy and, rarely, injection site skin necrosis have been reported during the postmarketing experience. Lipoatrophy may occur at various times after treatment onset (sometimes after several months) and is thought to be permanent. There is no known therapy for lipoatrophy. To assist in possibly minimizing these events, the patient should be advised to follow proper injection technique and to rotate injection sites daily.

Potential Effects on Immune Response

Because Copaxone can modify immune response, it may interfere with immune functions. For example, treatment with Copaxone may interfere with the recognition of foreign antigens in a way that would undermine the body's tumor surveillance and its defenses against infection. There is no evidence that Copaxone does this, but there has not been a systematic evaluation of this risk. Because Copaxone is an antigenic material, it is possible that its use may lead to the induction of host responses that are untoward, but systematic surveillance for these effects has not been undertaken.

Although Copaxone is intended to minimize the autoimmune response to myelin, there is the possibility that continued alteration of cellular immunity due to chronic treatment with Copaxone may result in untoward effects.

Glatiramer acetate-reactive antibodies are formed in most patients exposed to daily treatment with the recommended dose. Studies in both the rat and monkey have suggested that immune complexes are deposited in the renal glomeruli. Furthermore, in a controlled trial of 125 RRMS patients given Copaxone, 20 mg, subcutaneously every day for 2 years, serum IgG levels reached at least 3 times baseline values in 80% of patients by 3 months of initiation of treatment. By 12 months of treatment, however, 30% of patients still had IgG levels at least 3 times baseline values, and 90% had levels above baseline by 12 months. The antibodies are exclusively of the lgG subtype and predominantly of the lgG-1 subtype. No lgE type antibodies could be detected in any of the 94 sera tested; nevertheless, anaphylaxis can be associated with the administration of most any foreign substance, and therefore, this risk cannot be excluded.

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Incidence in Controlled Clinical Trials

Among 563 patients treated with Copaxone in blinded placebo controlled trials, approximately 5% of the subjects discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: injection site reactions, dyspnea, urticaria, vasodilatation, and hypersensitivity. The most common adverse reactions were: injection site reactions, vasodilatation, rash, dyspnea, and chest pain.

Table 1 lists treatment-emergent signs and symptoms that occurred in at least 2% of patients treated with Copaxone in the placebo-controlled trials. These signs and symptoms were numerically more common in patients treated with Copaxone than in patients treated with placebo. Adverse reactions were usually mild in intensity.

Table 1: Adverse reactions in controlled clinical trials with an incidence ≥2% of patients and more frequent with Copaxone than with placebo

		GA 20 mg (N=563)	Placebo (N=564)
* Injection site atrophy comprises terms relating to localized lipoatrophy at injection site
Blood And Lymphatic System Disorders	Lymphadenopathy	7%	3%
Cardiac Disorders	Palpitations	9%	4%
	Tachycardia	5%	2%
Eye Disorders	Eye Disorder	3%	1%
	Diplopia	3%	2%
Gastrointestinal Disorders	Nausea	15%	11%
	Vomiting	7%	4%
	Dysphagia	2%	1%
General Disorders And Administration Site Conditions	Injection Site Erythema	43%	10%
	Injection Site Pain	40%	20%
	Injection Site Pruritus	27%	4%
	Injection Site Mass	26%	6%
	Asthenia	22%	21%
	Pain	20%	17%
	Injection Site Edema	19%	4%
	Chest Pain	13%	6%
	Injection Site Inflammation	9%	1%
	Edema	8%	2%
	Injection Site Reaction	8%	1%
	Pyrexia	6%	5%
	Injection Site Hypersensitivity	4%	0%
	Local Reaction	3%	1%
	Chills	3%	1%
	Face Edema	3%	1%
	Edema Peripheral	3%	2%
	Injection Site Fibrosis	2%	1%
	Injection Site Atrophy*	2%	0%
Immune System Disorders	Hypersensitivity	3%	2%
Infections And Infestations	Infection	30%	28%
	Influenza	14%	13%
	Rhinitis	7%	5%
	Bronchitis	6%	5%
	Gastroenteritis	6%	4%
	Vaginal Candidiasis	4%	2%
Metabolism And Nutrition Disorders	Weight Increased	3%	1%
Musculoskeletal And Connective Tissue Disorders	Back Pain	12%	10%
Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps)	Benign Neoplasm of Skin	2%	1%
Nervous System Disorders	Tremor	4%	2%
	Migraine	4%	2%
	Syncope	3%	2%
	Speech Disorder	2%	1%
Psychiatric Disorders	Anxiety	13%	10%
	Nervousness	2%	1%
Renal And Urinary Disorders	Micturition Urgency	5%	4%
Respiratory, Thoracic And Mediastinal Disorders	Dyspnea	14%	4%
	Cough	6%	5%
	Laryngospasm	2%	1%
Skin And Subcutaneous Tissue Disorders	Rash	19%	11%
	Hyperhidrosis	7%	5%
	Pruritus	5%	4%
	Urticaria	3%	1%
	Skin Disorder	3%	1%
Vascular Disorders	Vasodilatation	20%	5%

Adverse reactions which occurred only in 4-5 more subjects in the Copaxone group than in the placebo group (less than 1% difference), but for which a relationship to Copaxone could not be excluded, were arthralgia and herpes simplex.

Laboratory analyses were performed on all patients participating in the clinical program for Copaxone. Clinically significant laboratory values for hematology, chemistry, and urinalysis were similar for both Copaxone and placebo groups in blinded clinical trials. In controlled trials one patient discontinued treatment due to thrombocytopenia (16 x109/L), which resolved after discontinuation of treatment.

Data on adverse reactions occurring in the controlled clinical trials were analyzed to evaluate differences based on sex. No clinically significant differences were identified. Ninety-six percent of patients in these clinical trials were Caucasian. The majority of patients treated with Copaxone were between the ages of 18 and 45. Consequently, data are inadequate to perform an analysis of the adverse reaction incidence related to clinically relevant age subgroups.

Other Adverse Reactions

In the paragraphs that follow, the frequencies of less commonly reported adverse clinical reactions are presented. Because the reports include reactions observed in open and uncontrolled premarketing studies (n= 979), the role of Copaxone in their causation cannot be reliably determined. Furthermore, variability associated with adverse reaction reporting, the terminology used to describe adverse reactions, etc., limit the value of the quantitative frequency estimates provided. Reaction frequencies are calculated as the number of patients who used Copaxone and reported a reaction divided by the total number of patients exposed to Copaxone. All reported reactions are included except those already listed in the previous table, those too general to be informative, and those not reasonably associated with the use of the drug. Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Frequent adverse reactions are defined as those occurring in at least 1/100 patients and infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients.

Body as a Whole:

 

Frequent: Abscess

 

Infrequent: Injection site hematoma, injection site fibrosis, moon face, cellulitis, generalized edema, hernia, injection site abscess, serum sickness, suicide attempt, injection site hypertrophy, injection site melanosis, lipoma, and photosensitivity reaction.

Cardiovascular:

 

Frequent: Hypertension.

 

Infrequent: Hypotension, midsystolic click, systolic murmur, atrial fibrillation, bradycardia, fourth heart sound, postural hypotension, and varicose veins.

Digestive:

 

Infrequent: Dry mouth, stomatitis, burning sensation on tongue, cholecystitis, colitis, esophageal ulcer, esophagitis, gastrointestinal carcinoma, gum hemorrhage, hepatomegaly, increased appetite, melena, mouth ulceration, pancreas disorder, pancreatitis, rectal hemorrhage, tenesmus, tongue discoloration, and duodenal ulcer.

Endocrine:

 

Infrequent: Goiter, hyperthyroidism, and hypothyroidism.

Gastrointestinal:

 

Frequent: Bowel urgency, oral moniliasis, salivary gland enlargement, tooth caries, and ulcerative stomatitis.

Hemic and Lymphatic:

 

Infrequent: Leukopenia, anemia, cyanosis, eosinophilia, hematemesis, lymphedema, pancytopenia, and splenomegaly.

Metabolic and Nutritional:

 

Infrequent: Weight loss, alcohol intolerance, Cushing's syndrome, gout, abnormal healing, and xanthoma.

Musculoskeletal:

 

Infrequent: Arthritis, muscle atrophy, bone pain, bursitis, kidney pain, muscle disorder, myopathy, osteomyelitis, tendon pain, and tenosynovitis.

Nervous:

 

Frequent: Abnormal dreams, emotional lability, and stupor.

 

Infrequent: Aphasia, ataxia, convulsion, circumoral paresthesia, depersonalization, hallucinations, hostility, hypokinesia, coma, concentration disorder, facial paralysis, decreased libido, manic reaction, memory impairment, myoclonus, neuralgia, paranoid reaction, paraplegia, psychotic depression, and transient stupor.

Respiratory:

 

Frequent: Hyperventilation and hay fever.

 

Infrequent: Asthma, pneumonia, epistaxis, hypoventilation, and voice alteration.

Skin and Appendages:

 

Frequent: Eczema, herpes zoster, pustular rash, skin atrophy, and warts.

 

Infrequent: Dry skin, skin hypertrophy, dermatitis, furunculosis, psoriasis, angioedema, contact dermatitis, erythema nodosum, fungal dermatitis, maculopapular rash, pigmentation, benign skin neoplasm, skin carcinoma, skin striae, and vesiculobullous rash.

Special Senses:

 

Frequent: Visual field defect.

 

Infrequent: Dry eyes, otitis externa, ptosis, cataract, corneal ulcer, mydriasis, optic neuritis, photophobia, and taste loss.

Urogenital:

 

Frequent: Amenorrhea, hematuria, impotence, menorrhagia, suspicious papanicolaou smear, urinary frequency, and vaginal hemorrhage.

 

Infrequent: Vaginitis, flank pain (kidney), abortion, breast engorgement, breast enlargement, carcinoma in situ cervix, fibrocystic breast, kidney calculus, nocturia, ovarian cyst, priapism, pyelonephritis, abnormal sexual function, and urethritis.

Postmarketing Experience

Reports of adverse events occurring under treatment with Copaxone not mentioned above that have been received since market introduction and may or may not have causal relationship to Copaxone are listed below. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: sepsis; SLE syndrome; hydrocephalus; enlarged abdomen; injection site hypersensitivity; allergic reaction; anaphylactoid reaction

Cardiovascular System: thrombosis; peripheral vascular disease; pericardial effusion; myocardial infarct; deep thrombophlebitis; coronary occlusion; congestive heart failure; cardiomyopathy; cardiomegaly; arrhythmia; angina pectoris

Digestive System: tongue edema; stomach ulcer; hemorrhage; liver function abnormality; liver damage; hepatitis; eructation; cirrhosis of the liver; cholelithiasis

Hemic and Lymphatic System: thrombocytopenia; lymphoma-like reaction; acute leukemia

Metabolic and Nutritional Disorders: hypercholesterolemia

Musculoskeletal System: rheumatoid arthritis; generalized spasm

Nervous System: myelitis; meningitis; CNS neoplasm; cerebrovascular accident; brain edema; abnormal dreams; aphasia; convulsion; neuralgia

Respiratory System: pulmonary embolus; pleural effusion; carcinoma of lung; hay fever

Special Senses: glaucoma; blindness; visual field defect

Urogenital System: urogenital neoplasm; urine abnormality; ovarian carcinoma; nephrosis; kidney failure; breast carcinoma; bladder carcinoma; urinary frequency

Drug Interactions

Interactions between Copaxone and other drugs have not been fully evaluated. Results from existing clinical trials do not suggest any significant interactions of Copaxone with therapies commonly used in MS patients, including the concurrent use of corticosteroids for up to 28 days. Copaxone has not been formally evaluated in combination with interferon beta.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B.

Administration of glatiramer acetate by subcutaneous injection to pregnant rats and rabbits resulted in no adverse effects on offspring development. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Copaxone should be used during pregnancy only if clearly needed.

In rats or rabbits receiving glatiramer acetate by subcutaneous injection during the period of organogenesis, no adverse effects on embryo-fetal development were observed at doses up to 37.5 mg/kg/day (18 and 36 times, respectively, the therapeutic human dose of 20 mg/day on a mg/m2 basis). In rats receiving subcutaneous glatiramer acetate at doses of up to 36 mg/kg from day 15 of pregnancy throughout lactation, no significant effects on delivery or on offspring growth and development were observed.

Labor and Delivery

The effects of Copaxone on labor and delivery in pregnant women are unknown.

Nursing Mothers

It is not known if glatiramer acetate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Copaxone is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Copaxone have not been established in patients under 18 years of age.

Geriatric Use

Copaxone has not been studied in elderly patients.

Use in Patients with Impaired Renal Function

The pharmacokinetics of glatiramer acetate in patients with impaired renal function have not been determined.

Copaxone Description

Copaxone is the brand name for glatiramer acetate (formerly known as copolymer-1). Glatiramer acetate, the active ingredient of Copaxone, consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is 5,000 – 9,000 daltons. Glatiramer acetate is identified by specific antibodies.

Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is:

(Glu, Ala, Lys, Tyr)x•xCH3COOH

(C5H9NO4•C3H7NO2•C6H14N2O2•C9H11NO3)x•xC2H4O2

CAS - 147245-92-9

Copaxone is a clear, colorless to slightly yellow, sterile, nonpyrogenic solution for subcutaneous injection. Each 1 mL of solution contains 20 mg of glatiramer acetate and 40 mg of mannitol. The pH range of the solution is approximately 5.5 to 7.0. The biological activity of Copaxone is determined by its ability to block the induction of experimental autoimmune encephalomyelitis (EAE) in mice.

Copaxone - Clinical Pharmacology

Mechanism of Action

The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS are not fully understood. However, glatiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS. This hypothesis is supported by findings of studies that have been carried out to explore the pathogenesis of experimental autoimmune encephalomyelitis, a condition induced in animals through immunization against central nervous system derived material containing myelin and often used as an experimental animal model of MS. Studies in animals and in vitro systems suggest that upon its administration, glatiramer acetate-specific suppressor T-cells are induced and activated in the periphery.

Because glatiramer acetate can modify immune functions, concerns exist about its potential to alter naturally occurring immune responses. There is no evidence that glatiramer acetate does this, but this has not been systematically evaluated [see Warnings and Precautions (5.4)].

Pharmacokinetics

Results obtained in pharmacokinetic studies performed in humans (healthy volunteers) and animals support that a substantial fraction of the therapeutic dose delivered to patients subcutaneously is hydrolyzed locally. Larger fragments of glatiramer acetate can be recognized by glatiramer acetate-reactive antibodies. Some fraction of the injected material, either intact or partially hydrolyzed, is presumed to enter the lymphatic circulation, enabling it to reach regional lymph nodes, and some may enter the systemic circulation intact.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year carcinogenicity study, mice were administered up to 60 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose of 20 mg/day on a mg/m2 basis). No increase in systemic neoplasms was observed. In males receiving the 60-mg/kg/day dose, there was an increased incidence of fibrosarcomas at the injection sites. These sarcomas were associated with skin damage precipitated by repetitive injections of an irritant over a limited skin area.

In a 2-year carcinogenicity study, rats were administered up to 30 mg/kg/day glatiramer acetate by subcutaneous injection (up to 15 times the human therapeutic dose on a mg/m2 basis). No increase in neoplasms was observed.

Glatiramer acetate was not mutagenic in in vitro (Ames test, mouse lymphoma tk) assays. Glatiramer acetate was clastogenic in two separate in vitro chromosomal aberration assays in cultured human lymphocytes but not clastogenic in an in vivo mouse bone marrow micronucleus assay.

When glatiramer acetate was administered by subcutaneous injection prior to and during mating (males and females) and throughout gestation and lactation (females) at doses up to 36 mg/kg/day (18 times the human therapeutic dose on a mg/m2 basis) no adverse effects were observed on reproductive or developmental parameters.

Clinical Studies

Relapsing-Remitting Multiple Sclerosis (RRMS)

Evidence supporting the effectiveness of Copaxone in decreasing the frequency of relapses derives from 3 placebo-controlled trials, all of which used a Copaxone dose of 20 mg/day.

Study 1 was performed at a single center. Fifty patients were enrolled and randomized to receive daily doses of either Copaxone, 20 mg subcutaneously, or placebo (Copaxone: n=25; placebo: n=25). Patients were diagnosed with RRMS by standard criteria, and had had at least 2 exacerbations during the 2 years immediately preceding enrollment. Patients were ambulatory, as evidenced by a score of no more than 6 on the Kurtzke Disability Scale Score (DSS), a standard scale ranging from 0–Normal to 10–Death due to MS. A score of 6 is defined as one at which a patient is still ambulatory with assistance; a score of 7 means the patient must use a wheelchair.

Patients were examined every 3 months for 2 years, as well as within several days of a presumed exacerbation. To confirm an exacerbation, a blinded neurologist had to document objective neurologic signs, as well as document the existence of other criteria (e.g., the persistence of the neurological signs for at least 48 hours).

The protocol-specified primary outcome measure was the proportion of patients in each treatment group who remained exacerbation free for the 2 years of the trial, but two other important outcomes were also specified as endpoints: the frequency of attacks during the trial, and the change in the number of attacks compared with the number which occurred during the previous 2 years.

Table 2 presents the values of the three outcomes described above, as well as several protocol specified secondary measures. These values are based on the intent-to-treat population (i.e., all patients who received at least 1 dose of treatment and who had at least 1 on-treatment assessment):

Table 2: Study 1 Efficacy Results

	Copaxone (N=25)	Placebo (N=25)	P-Value
* Progression was defined as an increase of at least 1 point on the DSS, persisting for at least 3 consecutive months.
% Relapse-Free Patients	14/25 (56%)	7/25 (28%)	0.085
Mean Relapse Frequency	0.6/2 years	2.4/2 years	0.005
Reduction in Relapse Rate Compared to Prestudy	3.2	1.6	0.025
Median Time to First Relapse (days)	>700	150	0.03
% of Progression-Free* Patients	20/25 (80%)	13/25 (52%)	0.07

Study 2 was a multicenter trial of similar design which was performed in 11 US centers. A total of 251 patients (Copaxone: n=125; placebo: n=126) were enrolled. The primary outcome measure was the Mean 2-Year Relapse Rate. Table 3 presents the values of this outcome for the intent-to-treat population, as well as several secondary measures:

Table 3: Study 2 Efficacy Results

	Copaxone (N=125)	Placebo (N=126)	P-Value
Mean No. of Relapses	1.19/2 years	1.68 /2 years	0.055
% Relapse-Free Patients	42/125 (34%)	34/126 (27%)	0.25
Median Time to First Relapse (days)	287	198	0.23
% of Progression-Free Patients	98/125 (78%)	95/126 (75%)	0.48
Mean Change in DSS	-0.05	+0.21	0.023

In both studies, Copaxone exhibited a clear beneficial effect on relapse rate, and it is based on this evidence that Copaxone is considered effective.

In Study 3, 481 patients who had recently (within 90 days) experienced an isolated demyelinating event and who had lesions typical of multiple sclerosis on brain MRI were randomized to receive either Copaxone 20 mg/day (n=243) or placebo (n=238). The primary outcome measure was time to development of a second exacerbation. Patients were followed for up to three years or until they reached the primary endpoint. Secondary outcomes were brain MRI measures, including number of new T2 lesions and T2 lesion volume.

Time to development of a second exacerbation was significantly delayed in patients treated with Copaxone compared to placebo (Hazard Ratio = 0.55; 95% confidence interval 0.40 to 0.77; Figure 1). The Kaplan-Meier estimates of the percentage of patients developing a relapse within 36 months were 42.9% in the placebo group and 24.7% in the Copaxone group.

Figure 1: Time to Second Exacerbation

Patients treated with Copaxone demonstrated fewer new T2 lesions at the last observation (rate ratio 0.41; confidence interval 0.28 to 0.59; p < 0.0001). Additionally, baseline-adjusted T2 lesion volume at the last observation was lower for patients treated with Copaxone (ratio of 0.89; confidence interval 0.84 to 0.94; p = 0.0001).

Study 4 was a multinational study in which MRI parameters were used both as primary and secondary endpoints. A total of 239 patients with RRMS (Copaxone: n=119; and placebo: n=120) were randomized. Inclusion criteria were similar to those in the second study with the additional criterion that patients had to have at least one Gd-enhancing lesion on the screening MRI. The patients were treated in a double-blind manner for nine months, during which they underwent monthly MRI scanning. The primary endpoint for the double-blind phase was the total cumulative number of T1 Gd-enhancing lesions over the nine months. Table 4 summarizes the results for the primary outcome measure monitored during the trial for the intent-to-treat cohort.

Table 4: Study 4 MRI Results

	Copaxone (N=119)	Placebo (N=120)	P-Value
Medians of the Cumulative Number of T1 Gd-Enhancing Lesions	11	17	0.0030

Figure 2 displays the results of the primary outcome on a monthly basis.

Figure 2: Median Cumulative Number of Gd-Enhancing Lesions

How Supplied/Storage and Handling

Copaxone is supplied as a single-use prefilled syringe containing 1 mL of a clear, colorless to slightly yellow, sterile, nonpyrogenic solution containing 20 mg of glatiramer acetate and 40 mg of mannitol in cartons of 30 single-use prefilled syringes with 33 alcohol preps (NDC 68546-317-30).

The recommended storage condition for the Copaxone is refrigeration (2°C to 8°C / 36°F to 46°F). However, excursions from recommended storage conditions (15°C to 30°C / 59°F to 86°F) for up to one month have been shown to have no adverse impact on the product. Exposure to higher temperatures or intense light should be avoided. Copaxone should not be frozen. If a Copaxone syringe freezes, it should be discarded.

Copaxone contains no preservative. Do not use if the solution contains any particulate matter.

Patient Counseling Information

[See FDA-Approved Patient Labeling (17.7)]

Pregnancy

Instruct patients that if they are pregnant or plan to become pregnant while taking Copaxone they should inform their physician.

Immediate Post-Injection Reaction

Advise patients that Copaxone may cause various symptoms after injection, include flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria. These symptoms are generally transient and self-limited and do not require specific treatment. Inform patients that these symptoms may occur early or may have their onset several months after the initiation of treatment. A patient may experience one or several episodes of these symptoms.

Chest Pain

Advise patients that they may experience transient chest pain either as part of the Immediate Post-Injection Reaction or in isolation. Inform patients that the pain should be transient (usually only lasting a few minutes). Some patients may experience more than one such episode, usually beginning at least one month after the initiation of treatment. Patient should be advised to seek medical attention if they experience chest pain of unusual duration or intensity.

Lipoatrophy and Skin Necrosis at Injection Site

Advise patients that localized lipoatrophy, and rarely, injection site necrosis may occur at injections sites. Instruct patients to follow proper injection technique and to rotate injection areas and sites on a daily basis.

Instructions for Use

Instruct patients to read the Copaxone Patient Information leaflet carefully. Caution patients to use aseptic technique. The first injection should be performed under the supervision of a health care professional. Instruct patients to rotate injection areas and sites on a daily basis. Caution patients against the reuse of needles or syringes. Instruct patients in safe disposal procedures.

Storage Conditions

Advise patients that the recommended storage condition for Copaxone is refrigeration (36-46°F /2-8°C), although Copaxone can be stored at room temperature (59-86°F /15-30°C) for up to one month. Copaxone should not be exposed to higher temperatures or intense light.

FDA-Approved Patient Labeling

Read this information carefully before you use Copaxone. Read the information you get when you refill your Copaxone prescriptions because there may be new information. This information does not take the place of your doctor's advice. Ask your doctor or pharmacist if you do not understand some of this information or if you want to know more about this medicine.

What is Copaxone?

Copaxone (co-PAX-own) is a medicine you inject to treat Relapsing-Remitting Multiple Sclerosis. Although Copaxone is not a cure; patients treated with Copaxone have fewer relapses.

Who should not use Copaxone?

• Do not use Copaxone if you are allergic to glatiramer acetate or mannitol.

What are the possible side effects of Copaxone?

• Call your doctor right away if you develop any of the following symptoms: hives, skin rash with irritation, dizziness, sweating, chest pain, trouble breathing, or severe pain at the injection site. Do not give yourself any more injections until your doctor tells you to begin again.


• The most common side effects of Copaxone are redness, pain, swelling, itching, or a lump at the injection site. These reactions are usually mild and seldom require medical care.


• Some patients report a short-term reaction right after injecting Copaxone. This reaction can involve flushing (feeling of warmth and/or redness), chest tightness or pain with heart palpitations, anxiety, and trouble breathing. These symptoms generally appear within minutes after an injection, last a few minutes, and then go away by themselves without further problems.


• A permanent depression under the skin at the injection site may occur, due to a local destruction of fat tissue.


• If symptoms become severe, call the emergency phone number in your area. Do not give yourself any more injections until your doctor tells you to begin again.

These are not all the possible side effects of Copaxone. For a complete list, ask your doctor or pharmacist. Tell your doctor about any side effects you have while taking Copaxone.

Information for pregnant and nursing women

• Copaxone has not been studied in pregnant women. Talk to your doctor about the risks and benefits of Copaxone if you are pregnant or planning a pregnancy.


• It is not known if Copaxone passes into breastmilk. Talk to your baby's doctor about the risks and benefits of breastfeeding while using Copaxone.

How should I use Copaxone?

• The recommended dose of Copaxone for the treatment of Relapsing-Remitting Multiple Sclerosis is 20 mg once a day injected subcutaneously (in the fatty layer under the skin).


• Look at the medicine in the prefilled syringe. If the medicine is cloudy or has particles in it, do not use it. Instead, call Shared Solutions® at 1-800-887-8100 for assistance.


• Have a friend or relative with you if you need help, especially when you first start giving yourself injections.


• Each prefilled syringe should be used for only one injection. Do not reuse the prefilled syringe. After use, throw it away properly.


• Do not change the dose or dosing schedule or stop taking the medicine without talking with your doctor.

How do I inject Copaxone?

There are 3 basic steps for injecting Copaxone prefilled syringes:

1. Gather the materials.


2. Choose the injection site.


3. Give yourself the injection.

Step 1: Gather the materials

1. First, place each of the items you will need on a clean, flat surface in a well-lit area:
   
   • 1 blister pack with Copaxone Prefilled Syringe
     
     Remove only 1 blister pack from the Copaxone Prefilled Syringe carton. Keep all unused syringes in the Prefilled Syringe carton and store them in the refrigerator.
   
   
   • Alcohol prep (wipe)
   
   
   • Dry cotton ball (not supplied)
   
   


2. Let the blister pack with the syringe inside w