Leaflet RELISTOR 12mg / 0.6ml solution for injection

Relistor 12 mg/0.6 mL solution for injection

Each vial of 0.6 mL contains 12 mg of methylnaltrexone bromide.

One mL of solution contains 20 mg of methylnaltrexone bromide.

For the full list of excipients, see section 6.1.

Solution for injection.

Clear solution, colourless to pale-yellow, essentially free from visible particulates.

Relistor is indicated for the treatment of opioid-induced constipation when response to laxativetherapy has not been sufficient in adult patients, aged 18 years and older.

Opioid-induced constipation in adult patients with chronic pain (except palliative care patients withadvanced illness)

The recommended dose of methylnaltrexone bromide is 12 mg (0.6 mL of solution) subcutaneously,as needed, given as at least 4 doses weekly, up to once daily (7 doses weekly).

In these patients, the treatment with usual laxatives should be stopped when commencing treatmentwith Relistor (see section 5.1).

Opioid-induced constipation in adult patients with advanced illness (palliative care patients)

The recommended dose of methylnaltrexone bromide is 8 mg (0.4 mL of solution) (for patientsweighing 38-61 kg) or 12 mg (0.6 mL of solution) (for patients weighing 62-114 kg).

The usual administration schedule is one single dose every other day. Doses may also be given withlonger intervals, as per clinical need.

Patients may receive two consecutive doses 24 hours apart, only when there has been no response(bowel movement) to the dose on the preceding day.

Patients whose weight falls outside of the ranges should be dosed at 0.15 mg/kg. The injection volumefor these patients should be calculated as follows:

Dose (mL) = patient weight (kg) x 0.0075

In palliative care patients, Relistor is added to usual laxative treatment (see section 5.1).

No dose adjustment is recommended based on age (see section 5.2).

In patients with severe renal impairment (creatinine clearance less than 30 mL/min), the dose ofmethylnaltrexone bromide should be reduced from 12 mg to 8 mg (0.4 mL of solution) for thoseweighing 62 to 114 kg. Patients with severe renal impairment whose weight falls outside the 62 to114 kg range (see section 5.2) need to reduce their mg/kg dose by 50 %. These patients should use

Relistor vials and not the pre-filled syringe. There are no data available from patients with end-stagerenal impairment on dialysis, and methylnaltrexone bromide is not recommended in these patients (seesection 4.4).

No dose adjustment is necessary in patients with mild to moderate hepatic impairment (see section5.2).

There are no data available from patients with severe hepatic impairment (Child-Pugh Class C), andmethylnaltrexone bromide is not recommended in these patients (see section 4.4).

The safety and efficacy of methylnaltrexone bromide in children less than 18 years has not beenestablished. No data are available.

Relistor is given as a subcutaneous injection.

It is recommended to rotate injection sites. It is not recommended to inject into areas where the skin istender, bruised, red, or hard. Areas with scars or stretch marks should be avoided.

The three areas of the body recommended for injection of Relistor are upper legs, abdomen, and upperarms.

Relistor can be injected without regard to food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Use of methylnaltrexone bromide in patients with known or suspected mechanical gastrointestinalobstruction, patients at increased risk for recurrent obstruction or in patients with acute surgicalabdomen is contraindicated due to the potential for gastrointestinal perforation.

Severity and worsening symptoms

Patients should be advised to promptly report severe, persistent, and/or worsening symptoms.

If severe or persistent diarrhoea occurs during treatment, patients should be advised not to continuetherapy with methylnaltrexone bromide and consult their physician.

Constipation not related to opioid use

The activity of methylnaltrexone bromide has been studied in patients with constipation induced byopioids. Therefore, Relistor should not be used for treatment of patients with constipation not relatedto opioid use.

Rapid onset of bowel movements

Data from clinical trials suggest treatment with methylnaltrexone bromide can result in the rapid onset(within 30 to 60 minutes on average) of a bowel movement.

Opioid-induced constipation in adult patients with advanced illness

Methylnaltrexone bromide treatment has not been studied in adult patients with advanced illness inclinical trials for longer than 4 months, and should therefore only be used for a limited period (seesection 5.1).

Methylnaltrexone bromide is not recommended in patients with severe hepatic impairment or withend-stage renal impairment requiring dialysis (see section 4.2).

Gastrointestinal (GI) conditions and GI perforation

Methylnaltrexone bromide should be used with caution in patients with known or suspected lesions ofthe GI tract.

Use of methylnaltrexone bromide in patients with colostomy, peritoneal catheter, active diverticulardisease or fecal impaction has not been studied. Therefore, Relistor should only be administered withcaution in these patients.

Cases of GI perforation have been reported in the postauthorisation period after use ofmethylnaltrexone bromide in patients with conditions that may be associated with localized or diffusereduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease,pseudo obstruction (Ogilvie’s syndrome), diverticular disease, infiltrative gastrointestinal tractmalignancies or peritoneal metastases). The overall risk-benefit profile should be taken into accountwhen using methylnaltrexone bromide in patients with these conditions or other conditions whichmight result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Patientsshould be monitored for severe, persistent, or worsening abdominal pain; methylnaltrexone bromideshould be discontinued if this symptom occurs.

Opioid withdrawal

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, vomiting, abdominalpain, palpitations, and blushing have occurred in patients treated with methylnaltrexone bromide.

Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawaland/or reduced analgesia. This should be taken into account when prescribing methylnaltrexonebromide for such patients.

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

Methylnaltrexone bromide does not affect the pharmacokinetics of medicinal products metabolised bycytochrome P450 (CYP) isozymes. Methylnaltrexone bromide is minimally metabolised by CYPisozymes. In vitro metabolism studies suggest that methylnaltrexone bromide does not inhibit theactivity of CYP1A2, CYP2E1, CYP2B6, CYP2A6, CYP2C9, CYP2C19 or CYP3A4, while it is aweak inhibitor of the metabolism of a model CYP2D6 substrate. In a clinical drug interaction study inhealthy adult male subjects, a subcutaneous dose of 0.3 mg/kg of methylnaltrexone bromide did notsignificantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

The organic cation transporter (OCT)-related drug-drug interaction potential betweenmethylnaltrexone bromide and an OCT inhibitor was studied in 18 healthy subjects by comparing thesingle-dose pharmacokinetic profiles of methylnaltrexone bromide before and after multiple 400 mgdoses of cimetidine. The renal clearance of methylnaltrexone bromide was reduced followingmultiple-dose administration of cimetidine (from 31 L/h to 18 L/h). However, this resulted in a smallreduction in total clearance (from 107 L/h to 95 L/h). Consequently, no meaningful change in AUC ofmethylnaltrexone bromide, in addition to Cmax, was observed before and after multiple-doseadministration of cimetidine.

There are no adequate data with the use of methylnaltrexone bromide in pregnant women. Studies inanimals have shown reproductive toxicity at high doses (see section 5.3). The potential risk forhumans is unknown. Methylnaltrexone bromide should not be used during pregnancy unless clearlynecessary.

It is unknown whether methylnaltrexone bromide is excreted in human breast milk. Animal studieshave shown excretion of methylnaltrexone bromide in breast milk. A decision on whether tocontinue/discontinue breast-feeding or to continue/discontinue therapy with methylnaltrexone bromideshould be made, taking into account the benefit of breast-feeding to the child and the benefit ofmethylnaltrexone bromide therapy to the woman.

Subcutaneous injections of Relistor at 150 mg/kg/day decreased fertility in rats. Doses up to25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) did notaffect fertility or general reproductive performance.

Methylnaltrexone bromide has minor influence on the ability to drive and use machines. Dizzinessmay occur and this may have an effect on the ability to drive and use machines (see section 4.8).

The most common adverse reactions in all patients exposed to methylnaltrexone bromide during allphases of placebo-controlled studies were abdominal pain, nausea, diarrhoea and flatulence.

Generally, these reactions were mild or moderate.

The adverse reactions are classified as: very common (≥1/10); common (≥1/100 to <1/10); uncommon(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.

Common: Dizziness

Common: opioid-withdrawal-like symptoms (like chills, tremor, rhinorrhea, piloerection, hot flush,palpitation, hyperhidrosis, vomiting, abdominal pain)

Not known: Gastrointestinal perforation (see section 4.4),

Common: Vomiting

Very common: Abdominal pain, nausea, diarrhoea, flatulence

Common: Injection site reactions (e.g. stinging, burning, pain , redness, oedema)

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

A study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kgadministered as an intravenous bolus.

In the event of an overdose, signs and symptoms of orthostatic hypotension should be monitored andreported to a physician. Treatment should be initiated as appropriate.

Pharmacotherapeutic group: Laxatives, Peripheral opioid receptor antagonists, ATC code: A06AH01

Methylnaltrexone bromide is a selective antagonist of opioid binding at the mu-receptor. In vitrostudies have shown methylnaltrexone bromide to be a mu-opioid receptor antagonist (inhibitionconstant [Ki] = 28 nM), with 8-fold less potency for kappa opioid receptors (Ki = 230 nM) and muchreduced affinity for delta opioid receptors.

As a quaternary amine, the ability of methylnaltrexone bromide to cross the blood-brain barrier isrestricted. This allows methylnaltrexone bromide to function as a peripherally acting mu-opioidantagonist in tissues such as the gastrointestinal tract, without impacting opioid-mediated analgesiceffects on the central nervous system.

Opioid-induced constipation in adult patients with chronic non-cancer pain

The efficacy and safety of methylnaltrexone bromide in the treatment of opioid-induced constipationin patients with chronic non-cancer pain were demonstrated in a randomized, double-blind,placebo-controlled study (Study 3356). In this study, the median patient age was 49 years(range 23-83); 60% were females. The majority of patients had a primary diagnosis of back pain.

Study 3356 compared 4-week treatment regimens of methylnaltrexone bromide 12 mg once daily andmethylnaltrexone bromide 12 mg every other day with placebo. The 4-week, double-blind period wasfollowed by an 8-week, open-label period during which methylnaltrexone bromide was to be used asneeded, but no more frequently than once daily. A total of 460 patients (methylnaltrexone bromide12 mg once daily, n=150, methylnaltrexone bromide 12 mg every other day, n=148, placebo, n=162)were treated in the double-blind period. Patients had a history of chronic non-cancer pain and weretaking opioids with stable doses of at least 50 mg of oral morphine equivalents per day. Patients hadopioid-induced constipation (< 3 rescue medication-free bowel movements per week during thescreening period). Patients were required to discontinue all previous laxative therapy.

The first co=primary endpoint was the proportion of patients having a rescue free bowel movements(RFBMs) within 4 hours of the first dose administration and the second the percentage of activeinjections resulting in any RFBM within 4 hours during the double-blind phase. A RFBM was definedas a bowel movement that occurred without laxative use during the previous 24 hours.

The proportion of patients having an RFBM within 4 hours of the first dose was 34.2% in thecombined methylnaltrexone bromide group versus 9.9% in the placebo group (p<0.001). The meanpercentage of methylnaltrexone bromide resulting in any RFBM within 4 hours were 28.9% and30.2% respectively for the once daily and every other day dose groups compared with 9.4% and9.3% respectively for the corresponding placebo regimen (p < 0.001).

The key secondary endpoint of adjusted mean change from baseline in weekly RFBMs was 3.1 in themethylnaltrexone bromide 12 mg once daily treatment group, 2.1 in the methylnaltrexone bromide12 mg every other day treatment group, and 1.5 in the placebo treatment group during the 4-weekdouble-blind period. The difference between methylnaltrexone bromide 12 mg once daily and placeboof 1.6 RFBMs per week is statistically significant (p < 0.001) and clinically meaningful.

Another secondary endpoint evaluated the proportion of patients with ≥3 RFBMs per week during the4-week double-blind phase. This was achieved in 59% of the patients in the group receiving dailymethylnaltrexone 12 mg (p<0.001 vs. placebo), in 61% of those receiving it every other day (p<0.001vs. placebo), and in 38% of the placebo treated patients. A supplementary analysis evaluated thepercentage of patients achieving ≥3 complete RFBMs per week and an increase of ≥1 complete

RFBMs per week in at least 3 of the 4 treatment weeks. This was achieved in 28.7% of the patients inthe group receiving daily methylnaltrexone 12 mg (p<0.001 vs. placebo), in 14.9% of those receivingit every other day (p=0.012 vs. placebo), and in 6.2% of the placebo treated patients.

There was no evidence of a differential effect of gender on safety or efficacy. The effect on race couldnot be analysed because the study population was predominantly Caucasian (90 %). Median dailyopioid dose did not vary meaningfully from baseline in either methylnaltrexone bromide-treatedpatients or in placebo-treated patients.

There were no clinically relevant changes from baseline in pain scores in either the methylnaltrexonebromide or placebo-treated patients.

The use of methylnaltrexone bromide for treating opioid-induced constipation beyond 48 weeks hasnot been evaluated in clinical trials.

Opioid-induced constipation in adult patients with advanced illness

The efficacy and safety of methylnaltrexone bromide in the treatment of opioid-induced constipationin patients receiving palliative care was demonstrated in two randomised, double-blind, placebo-controlled studies. In these studies, the median age was 68 years (range 21-100); 51 % were females.

In both studies, patients had advanced terminal illness and limited life expectancy, with the majorityhaving a primary diagnosis of incurable cancer; other primary diagnoses included end-stage

COPD/emphysema, cardiovascular disease/heart failure, Alzheimer’s disease/dementia, HIV/AIDS, orother advanced illnesses. Prior to screening, patients had opioid-induced constipation defined as either<3 bowel movements in the preceding week or no bowel movement for >2 days.

Study 301 compared methylnaltrexone bromide given as a single, double-blind, subcutaneous dose of0.15 mg/kg, or 0.3 mg/kg versus placebo. The double-blind dose was followed by an open-label,4-week dosing period, where methylnaltrexone bromide could be used as needed, no more frequentlythan 1 dose in a 24-hour period. Throughout both study periods, patients maintained their usuallaxative regimen. A total of 154 patients (methylnaltrexone bromide 0.15 mg/kg, n = 47;methylnaltrexone bromide 0.3 mg/kg, n = 55, placebo, n = 52) were treated in the double-blind period.

The primary endpoint was the proportion of patients with a rescue-free laxation within 4 hours of thedouble-blind dose of study medicinal product. Methylnaltrexone bromide-treated patients had asignificantly higher rate of laxation within 4 hours of the double-blind dose (62 % for 0.15 mg/kg and58 % for 0.3 mg/kg) than placebo-treated patients (14 %); p<0.0001 for each dose versus placebo.

Study 302 compared double-blind, subcutaneous doses of methylnaltrexone bromide given every otherday for 2 weeks versus placebo. During the first week (days 1, 3, 5, 7), patients received eithermethylnaltrexone bromide 0.15 mg/kg or placebo. In the second week, a patient’s assigned dose couldbe increased to 0.30 mg/kg if the patient had 2 or fewer rescue-free laxations up to day 8. At any time,the patient’s assigned dose could be reduced based on tolerability. Data from 133 (62methylnaltrexone bromide, 71 placebo) patients were analysed. There were 2 primary endpoints:proportion of patients with a rescue-free laxation within 4 hours of the first dose of study medicinalproduct and proportion of patients with a rescue-free laxation within 4 hours after at least 2 of the first4 doses of medicinal product. Methylnaltrexone bromide-treated patients had a higher rate of laxationwithin 4 hours of the first dose (48 %) than placebo-treated patients (16 %); p<0.0001.

Methylnaltrexone bromide-treated patients also had significantly higher rates of laxation within4 hours after at least 2 of the first 4 doses (52 %) than did placebo-treated patients (9 %); p<0.0001.

Stool consistency was not meaningfully improved in patients who had soft stool at baseline.

In both studies, there was no evidence to suggest differential effects of age or gender on safety orefficacy. The effect on race could not be analysed because the study population was predominantly

Caucasian (88 %).

Durability of response was demonstrated in Study 302, in which the laxation response rate wasconsistent from dose 1 through dose 7 over the course of the 2-week, double-blind period.

The efficacy and safety of methylnaltrexone bromide were also demonstrated in open-label treatmentadministered from Day 2 through Week 4 in Study 301, and in two open-label extension studies(301EXT and 302EXT) in which methylnaltrexone bromide was given as needed for up to 4 months(only 8 patients up to this point). A total of 136, 21, and 82 patients received at least one open-labeldose in studies 301, 301EXT, and 302EXT, respectively. Relistor was administered every 3.2 days(median dosing interval, with a range of 1-39 days).

The rate of laxation response was maintained throughout the extension studies for those patients whocontinued treatment.

There was no significant relationship between baseline opioid dose and laxation response inmethylnaltrexone bromide-treated patients in these studies. In addition, median daily opioid dose didnot vary meaningfully from baseline in either methylnaltrexone bromide-treated patients or in placebo-treated patients. There were no clinically relevant changes in pain scores from baseline in either themethylnaltrexone bromide or placebo-treated patients.

Effect on cardiac repolarisation

In a double-blind, randomised, parallel-group ECG study of single, subcutaneous doses ofmethylnaltrexone bromide (0.15, 0.30 and 0.50 mg/kg), in 207 healthy volunteers, no signal of

QT/QTc prolongation or any evidence of an effect on secondary ECG parameters or waveformmorphology was detected as compared to placebo and a positive control (orally administered 400 mgmoxifloxacin).

Methylnaltrexone bromide is absorbed rapidly, with peak concentrations (Cmax) achieved atapproximately 0.5 hours following subcutaneous administration. The Cmax and area under the plasmaconcentration-time curve (AUC) increase with dose increase from 0.15 mg/kg to 0.5 mg/kg in a dose-proportional manner. Absolute bioavailability of a 0.30 mg/kg subcutaneous dose versus a 0.30 mg/kgintravenous dose is 82 %.

Methylnaltrexone bromide undergoes moderate tissue distribution. The steady-state volume ofdistribution (Vss) is approximately 1.1 L/kg. Methylnaltrexone bromide is minimally bound to humanplasma proteins (11.0 % to 15.3 %) as determined by equilibrium dialysis.

Methylnaltrexone bromide is metabolised to a modest extent in humans based on the amount ofmethylnaltrexone bromide metabolites recovered from excreta. Conversion to methyl-6-naltrexolisomers and methylnaltrexone sulphate appears to be the primary pathway to metabolism. Each of themethyl-6-naltrexol isomers has somewhat less antagonist activity than parent compound, and a lowexposure in plasma of approximately 8 % of the drug-related materials. Methylnaltrexone sulphate isan inactive metabolite and present in plasma at a level of approximately 25 % of drug relatedmaterials. N-demethylation of methylnaltrexone bromide to produce naltrexone is not significant,accounting for 0.06 % of the administered dose.

Methylnaltrexone bromide is eliminated primarily as the unchanged active substance. Approximatelyhalf of the dose is excreted in the urine and somewhat less in faeces. The terminal disposition half-life(t1/2) is approximately 8 hours.

The effect of mild and moderate hepatic impairment on the systemic exposure to methylnaltrexonebromide has been studied in 8 subjects each, with Child-Pugh Class A and B, compared to healthysubjects. Results showed no meaningful effect of hepatic impairment on the AUC or Cmax ofmethylnaltrexone bromide. The effect of severe hepatic impairment on the pharmacokinetics ofmethylnaltrexone bromide has not been studied.

In a study of volunteers with varying degrees of renal impairment receiving a single dose of0.30 mg/kg methylnaltrexone bromide, renal impairment had a marked effect on the renal excretion ofmethylnaltrexone bromide. The renal clearance of methylnaltrexone bromide decreased withincreasing severity of renal impairment. Severe renal impairment decreased the renal clearance ofmethylnaltrexone bromide by 8- to 9-fold; however, this resulted in only a 2-fold increase in totalmethylnaltrexone bromide exposure (AUC). Cmax was not significantly changed. No studies wereperformed in patients with end-stage renal impairment requiring dialysis.

No studies have been performed in the paediatric population (see section 4.2).

In a study comparing single and multiple-dose pharmacokinetic profiles of intravenousmethylnaltrexone bromide at a dose of 24 mg between healthy, young (18 to 45 years of age n = 10)and elderly (65 years of age and over n = 10) subjects, the effect of age on exposure tomethylnaltrexone bromide was found to be minor. The mean steady-state Cmax and AUC for theelderly were 545 ng/mL and 412 ng*h/mL, approximately 8.1 % and 20 %, respectively, greater thanthose for young subjects. Therefore, no dose adjustment is recommended based on age.

No meaningful gender differences have been observed.

Weight

An integrated analysis of pharmacokinetic data from healthy subjects indicated that methylnaltrexonebromide mg/kg dose-adjusted exposure increased as body weight increased. The meanmethylnaltrexone bromide exposure at 0.15 mg/kg over a weight range of 38 to 114 kg was 179 (range= 139-240) ng*h/mL. This exposure for the 0.15 mg/kg dose can be achieved with a weight-band-based dose adjustment using an 8 mg dose for body weight 38 to less than 62 kg and a 12 mg dose forbody weight 62 to 114 kg, yielding a mean exposure of 187 (range = 148-220) ng*h/mL. In addition,the analysis showed that 8 mg dose for body weight 38 to less than 62 kg and a 12 mg dose for bodyweight 62 to 114 kg correspond to mean doses of 0.16 (range = 0.21-0.13) mg/kg and 0.16 (range =0.19-0.11) mg/kg, respectively, based on the body weight distribution of patients participating instudies 301 and 302.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Cardiac effects wereobserved in some non-clinical studies in canines (prolongation of action potentials in Purkinje fibers orprolongation of the QTc interval). The mechanism of this effect is unknown; however, the humancardiac potassium ion channel (hERG) appears not to be involved.

Subcutaneous injections of Relistor at 150 mg/kg/day decreased fertility in rats. Doses up to25 mg/kg/day (18 times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) did notaffect fertility or general reproductive performance.

There was no evidence of teratogenicity in rats or rabbits. Subcutaneous injections of Relistor at150/100 mg/kg/day to rats resulted in decreased offspring weights; doses up to 25 mg/kg/day (18times the exposure [AUC] in humans at a subcutaneous dose of 0.3 mg/kg) had no effect on labour,delivery, or offspring survival and growth.

Methylnaltrexone bromide is excreted via the milk of lactating rats.

Studies have been conducted in juvenile rats and dogs. Following intravenous injection ofmethylnaltrexone bromide, juvenile rats were found to be more sensitive than adult rats tomethylnaltrexone-related toxicity. In juvenile rats administered intravenous methylnaltrexone bromidefor 13 weeks, adverse clinical signs (incidences of convulsions and labored breathing) occurred atdosages (≥ 3 mg/kg/day) and exposures (5.4 times the exposure {AUC} in adult humans at asubcutaneous dose of 0.15 mg/kg) that were lower than those that caused similar toxicity in adult rats(20 mg/kg/day). No adverse effects occurred in juvenile rats at 1 mg/kg/day or in adult rats at5 mg/kg/day (1.6 times and 7.8 times, respectively, the exposure {AUC} in adult humans at asubcutaneous dose of 0.15 mg/kg).

Following intravenous injection of methylnaltrexone bromide for 13 weeks, similar methylnaltrexonerelated toxicity was observed in both juvenile and adult dogs. In adult and juvenile dogs givenmethylnaltrexone bromide at 20 mg/kg/day, clinical signs indicative of CNS toxicity and prolongationof QTc interval were observed. No adverse effects occurred in either juvenile or adult dogs at a doseof 5 mg/kg/day (44 times the exposure {AUC} in adult humans at a subcutaneous dose of0.15 mg/kg).

Sodium chloride

Sodium calcium edetate

Glycine hydrochloride

Water for injections

Hydrochloric acid (to adjust pH)

Sodium hydroxide (to adjust pH)

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

4 years

After withdrawal in the injection syringe:

Due to light sensitivity, the solution for injection should be used within 24 hours.

This medicinal product does not require any special temperature storage conditions.

Keep the vial in the outer carton in order to protect from light.

For storage conditions of the medicinal product in the syringe, see section 6.3.

Clear, Type I, flint glass, single-use vial, grey butyl rubber stopper, and aluminium overseal with flip-off-cap.

Each vial contains 0.6 mL of solution for injection.

Pack sizes of 1 vial; or2 vials with 2 sterile 1 mL injection syringes with retractable injection needle and 4 alcohol swabs; or7 vials with 7 sterile 1 mL injection syringes with retractable injection needle and 14 alcohol swabs; or2 vials with 2 sterile 1 mL injection syringes with safeguard injection needle and 4 alcohol swabs; or7 vials with 7 sterile 1 mL injection syringes with safeguard injection needle and 14 alcohol swabs.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bausch Health Ireland Limited3013 Lake Drive

Citywest Business Campus

Dublin 24, D24PPT3

Ireland

EU/1/08/463/001

EU/1/08/463/002

EU/1/08/463/003

EU/1/08/463/012

EU/1/08/463/013

Date of first authorisation: 02 July 2008

Date of latest renewal: 27 May 2013

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu