IASIBON 50mg tablets medication leaflet

Iasibon 50 mg film coated tablets

Each film-coated tablet contains 50 mg of ibandronic acid (as sodium monohydrate).

Contains 0.86 mg lactose (as lactose monohydrate).

For the full list of excipients, see section 6.1.

White round biconvex tablets

Iasibon is indicated in adults for the prevention of skeletal events (pathological fractures, bonecomplications requiring radiotherapy or surgery) in patients with breast cancer and bone metastases.

Iasibon therapy should only be initiated by physicians experienced in the treatment of cancer.

The recommended dose is one 50 mg film-coated tablet daily.

No dose adjustment is required (see section 5.2).

No dose adjustment is necessary for patients with mild renal impairment (CLcr ≥ 50 and < 80 mL/min).

For patients with moderate renal impairment (CLcr ≥ 30 and < 50 mL/min) a dosage adjustment to one50 mg film-coated tablet every second day is recommended (see section 5.2).

For patients with severe renal impairment (CLcr < 30 mL/min) the recommended dose is one 50 mgfilm-coated tablet once weekly. See dosing instructions, above.

Elderly population (> 65 years)

No dose adjustment is necessary (see section 5.2).

The safety and efficacy of Iasibon in children and adolescents below the age of 18 years have not beenestablished. No data are available (see section 5.1 and 5.2).

For oral use.

Iasibon tablets should be taken after an overnight fast (at least 6 hours) and before the first food or drinkof the day. Medicinal products and supplements (including calcium) should similarly be avoided priorto taking Iasibon tablets. Fasting should be continued for at least 30 minutes after taking the tablet.

Water may be taken at any time during the course of Iasibon treatment (see section 4.5). Water with ahigh concentration of calcium should not be used. If there is concern regarding potentially high levels ofcalcium in the tap water (hard water), it is advised to use bottled water with a low mineral content.

- The tablets should be swallowed whole with a full glass of water (180 to 240 mL) while thepatient is standing or sitting in an upright position.

- Patients should not lie down for 60 minutes after taking Iasibon.

- Patients should not chew, suck or crush the tablet because of a potential for oropharyngealulceration.

- Water is the only drink that should be taken with Iasibon.

- Hypersensitivity to ibandronic acid or to any of the excipients listed in section 6.1.

- Hypocalcaemia

- Abnormalities of the oesophagus which delay oesophageal emptying such as stricture or achalasia

- Inability to stand or sit upright for at least 60 minutes

Patients with disturbances of bone and mineral metabolism

Hypocalcaemia and other disturbances of bone and mineral metabolism should be effectively treatedbefore starting Iasibon therapy. Adequate intake of calcium and vitamin D is important in all patients.

Patients should receive supplemental calcium and/or vitamin D if dietary intake is inadequate.

Gastrointestinal irritation

Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa.

Because of these possible irritant effects and a potential for worsening of the underlying disease, cautionshould be used when Iasibon is given to patients with active upper gastrointestinal problems (e.g.

known Barrett’s oesophagus, dysphagia, other oesophageal diseases, gastritis, duodenitis or ulcers).

Adverse experiences such as oesophagitis, oesophageal ulcers and oesophageal erosions, in some casessevere and requiring hospitalization, rarely with bleeding or followed by oesophageal stricture orperforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk ofsevere oesophageal adverse experiences appears to be greater in patients who do not comply with thedosing instruction and/or who continue to take oral bisphosphonates after developing symptomssuggestive of oesophageal irritation. Patients should pay particular attention and be able to comply withthe dosing instructions (see section 4.2).

Physicians should be alert to any signs or symptoms signaling a possible oesophageal reaction andpatients should be instructed to discontinue Iasibon and seek medical attention if they developdysphagia, odynophagia, retrosternal pain or new or worsening heartburn.

While no increased risk was observed in controlled clinical trials there have been post-marketing reportsof gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications.

Acetylsalicylic acid and NSAIDs

Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) andbisphosphonates are associated with gastrointestinal irritation, caution should be taken duringconcomitant administration.

Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post-marketing setting in patientsreceiving ibandronate for oncology indications (see section 4.8).

The start of treatment or of a new course of treatment should be delayed in patients with unhealed opensoft tissue lesions in the mouth.

A dental examination with preventive dentistry and an individual benefit-risk assessment isrecommended prior to treatment with ibandronate in patients with concomitant risk factors.

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:

− Potency of the medicinal product that inhibit bone resorption (higher risk for highly potentcompounds), route of administration (higher risk for parenteral administration) and cumulativedose of bone resorption therapy− Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking− Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy tohead and neck− Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease,invasive dental procedures e.g. tooth extractions

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, andimmediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of soresor discharge during treatment with Iasibon. While on treatment, invasive dental procedures should beperformed only after careful consideration and be avoided in close proximity to Iasibon administration.

The management plan of the patients who develop ONJ should be set up in close collaboration betweenthe treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary interruption of

Iasibon treatment should be considered until the condition resolves and contributing risk factors aremitigated where possible.

Osteonecrosis of the external auditory canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly inassociation with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canalinclude steroid use and chemotherapy and/or local risk factors such as infection or trauma. Thepossibility of osteonecrosis of the external auditory canal should be considered in patients receivingbisphosphonates who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonatetherapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or shortoblique fractures can occur anywhere along the femur from just below the lesser trochanter to just abovethe supracondylar flare. These fractures occur after minimal, or no trauma and some patients experiencethigh or groin pain, often associated with imaging features of stress fractures, weeks to months beforepresenting with a completed femoral fracture. Fractures are often bilateral; therefore, the contralateralfemur should be examined in bisphosphonate-treated patients who have sustained a femoral shaftfracture. Poor healing of these fractures has also been reported.

Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fractureshould be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain andany patient presenting with such symptoms should be evaluated for an incomplete femur fracture(section 4.8).

Atypical fractures of other long bones

Atypical fractures of other long bones, such as the ulna and tibia have also been reported in patientsreceiving long-term treatment. As with atypical femoral fractures, these fractures occur after minimal,or no trauma and some patients experience prodromal pain prior to presenting with a completedfracture. In cases of ulna fracture, this may be associated with repetitive stress loading associated withthe long-term use of walking aids (see section 4.8).

Clinical studies have not shown any evidence of deterioration in renal function with long term Iasibontherapy. Nevertheless, according to clinical assessment of the individual patient, it is recommended thatrenal function, serum calcium, phosphate and magnesium should be monitored in patients treated with

Iasibon.

Rare hereditary problems

Iasibon tablets contain lactose and should not be administered to patients with rare hereditary problemsof galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Patients with known hypersensitivity to other bisphosphonates

Caution is to be taken in patients with known hypersensitivity to other bisphosphonates.

Medicinal product -Food Interactions

Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron),including milk and food, are likely to interfere with absorption of Iasibon tablets. Therefore, with suchproducts, including food, intake must be delayed at least 30 minutes following oral administration.

Bioavailability was reduced by approximately 75 % when Iasibon tablets were administered 2 hoursafter a standard meal. Therefore, it is recommended that the tablets should be taken after an overnightfast (at least 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken(see section 4.2).

Metabolic interactions are not considered likely, since ibandronic acid does not inhibit the major humanhepatic P 450 isoenzymes and has been shown not to induce the hepatic cytochrome P 450 system inrats (see section 5.2). Ibandronic acid is eliminated by renal excretion only and does not undergo anybiotransformation.

H2-antagonists or other medicinal products that increase gastric pH.

In healthy male volunteers and postmenopausal women, intravenous ranitidine caused an increase inibandronic acid bioavailability of about 20 % (which is within the normal variability of thebioavailability of ibandronic acid), probably as a result of reduced gastric acidity. However, no dosageadjustment is required when Iasibon is administered with H2-antagonists or medicinal products thatincrease gastric pH.

Acetylsalicylic acid and NSAIDs

Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (NSAIDs) andbisphosphonates are associated with gastrointestinal irritation, caution should be taken duringconcomitant administration (see section 4.4).

Aminoglycosides

Caution is advised when bisphosphonates are administered with aminoglycosides, since both substancescan lower serum calcium levels for prolonged periods. Attention should also be paid to the possibleexistence of simultaneous hypomagnesaemia.

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore,

Iasibon should not be used during pregnancy.

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats havedemonstrated the presence of low levels of ibandronic acid in the milk following intravenousadministration. Iasibon should not be used during breast-feeding.

There is no data on the effects of ibandronic acid in humans. In reproductive studies in rats by the oralroute, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic aciddecreased fertility at high daily doses (see section 5.3).

On the basis of the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it isexpected that Iasibon has no or negligible influence on the ability to drive and use machines.

The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of thefemur, osteonecrosis of the jaw, gastrointestinal irritation, and ocular inflammation (see paragraph“Description of selected adverse reactions” and section 4.4).

Treatment was most frequently associated with a decrease in serum calcium to below normal range(hypocalcaemia), followed by dyspepsia.

Table 1 lists adverse reactions from 2 pivotal phase III studies (Prevention of skeletal events in patientswith breast cancer and bone metastases: 286 patients treated with ibandronic acid 50 mg administeredorally), and from post-marketing experience.

Adverse reactions are listed according to MedDRA system organ class and frequency category.

Frequency categories are defined using the following convention: 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), not known (cannot be estimated from the available data). Within each frequency grouping,adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse Drug Reactions Reported for Oral Administration of Ibandronate

System Very Common Uncommon Rare Very rare Not known

Organ Class common

Blood and Anaemialymphaticsystemdisorders

System Very Common Uncommon Rare Very rare Not known

Organ Class common

Immune Hypersensitivity Asthmasystem † exacerbationdisorders bronchospasm†,angioedema†,

Anaphylacticreaction/shock†

**

Metabolism Hypocalcaemiaand **nutritiondisorders

Nervous Paraesthesia,system dysgeusiadisorders (tasteperversion)

Eye Oculardisorders inflammation†**

Gastrointest Oesophagitis, Haemorrage,inal abdominal pain, duodenaldisorders dyspepsia, ulcer,nausea gastritis,dysphagia,dry mouth

Skin and Pruritus Stevens-Johnsonsubcutaneou Syndrome†,s tissue Erythemadisorders Multiforme†,

Dermatitis

Bullous†

Musculoskel Atypic Osteonecrosis of Atypicaletal and al jaw†**, fractures ofconnective subtro osteonecrosis of long bonestissue chante the external other thandisorders ric and auditory canal the femurdiaphy (bisphosphonateseal class adversefemor reaction)†alfractures†

Renal and Azotaemiaurinary (uraemia)disorders

System Very Common Uncommon Rare Very rare Not known

Organ Class common

General Asthenia Chest pain,disorders influenza-and like illness,administrati malaise, painon siteconditions

Investigatio Bloodns parathyroidhormoneincreased

**See further information below†Identified in post-marketing experience.

Decreased renal calcium excretion may be accompanied by a fall in serum phosphate levels notrequiring therapeutic measures. The serum calcium level may fall to hypocalcaemic values.

Osteonecrosis of jaw

Cases of osteonecrosis of the jaw have been reported, predominantly in cancer patients treated withmedicinal products that inhibit bone resorption, such as ibandronic acid (see section 4.4.) Cases of ONJhave been reported in the post-marketing setting for ibandronic acid.

Atypical subtrochanteric and diaphyseal femoral fractures

Although the pathophysiology is uncertain, evidence from epidemiological studies suggests anincreased risk of atypical subtrochanteric and diaphyseal femoral fractures with long-termbisphosphonate therapy for postmenopausal osteoporosis, particularly beyond three to five years of use.

The absolute risk of atypical subtrochanteric and diaphyseal long bone fractures (bisphosphonate classadverse reaction) remains very low.

Ocular inflammation

Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronicacid. In some cases, these events did not resolve until the ibandronic acid was discontinued.

Anaphylactic reaction/shock

Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated withintravenous ibandronic acid.

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 system listedin Appendix V.

No specific information is available on the treatment of overdosage with Iasibon. However, oraloverdosage may result in upper gastrointestinal events, such as upset stomach, heartburn, oesophagitis,gastritis or ulcer. Milk or antacids should be given to bind Iasibon. Due to the risk of oesophagealirritation, vomiting should not be induced, and the patient should remain fully upright.

Pharmaco-therapeutic group: Medicinal products for treatment of bone diseases, bisphosphonate, ATC

Code: M05BA06

Ibandronic acid belongs to the bisphosphonate group of compounds which act specifically on bone.

Their selective action on bone tissue is based on the high affinity of bisphosphonates for bone mineral.

Bisphosphonates act by inhibiting osteoclast activity, although the precise mechanism is still not clear.

In vivo, ibandronic acid prevents experimentally-induced bone destruction caused by cessation ofgonadal function, retinoids, tumours or tumour extracts. The inhibition of endogenous bone resorptionhas also been documented by45 Ca kinetic studies and by the release of radioactive tetracyclinepreviously incorporated into the skeleton.

At doses that were considerably higher than the pharmacologically effective doses, ibandronic acid didnot have any effect on bone mineralisation.

Bone resorption due to malignant disease is characterized by excessive bone resorption that is notbalanced with appropriate bone formation. Ibandronic acid selectively inhibits osteoclast activity,reducing bone resorption and thereby reducing skeletal complications of the malignant disease.

Clinical studies in patients with breast cancer and bone metastases have shown that there is a dosedependent inhibitory effect on bone osteolysis, expressed by markers of bone resorption, and a dosedependent effect on skeletal events.

Prevention of skeletal events in patients with breast cancer and bone metastases with Ibandronate 50 mgtablets was assessed in two randomized placebo controlled phase III trials with a duration of 96 weeks.

Female patients with breast cancer and radiologically confirmed bone metastases were randomised toreceive placebo (277 patients) or 50 mg Ibandronate (287 patients). The results from these trials aresummarised below.

Primary efficacy endpoints

The primary endpoint of the trials was the skeletal morbidity period rate (SMPR). This was a compositeendpoint which had the following skeletal related events (SREs) as sub-components:

- radiotherapy to bone for treatment of fractures/impending fractures

- surgery to bone for treatment of fractures

- vertebral fractures

- non-vertebral fractures

The analysis of the SMPR was time-adjusted and considered that one or more events occurring in asingle 12 week period could be potentially related. Multiple events were therefore, counted only once inany given 12 week period for the purposes of the analysis. Pooled data from these studies demonstrateda significant advantage for Ibandronate 50 mg p.o. over placebo in the reduction in SREs measured bythe SMPR (p = 0.041). There was also a 38 % reduction in the risk of developing an SRE for

Ibandronate treated patients when compared with placebo (relative risk 0.62, p = 0.003). Efficacy resultsare summarised in Table 2.

Table 2 Efficacy Results (Breast Cancer Patients with Metastatic Bone Disease)

All Skeletal Related Events (SREs)

Placebo Ibandronate 50 mg p-valuen = 277 n = 287

SMPR (per patient 1.15 0.99 p = 0.041year)

SRE relative risk - 0.62 p = 0.003

Secondary efficacy endpoints

A statistically significant improvement in bone pain score was shown for Ibandronate 50 mg comparedto placebo. The pain reduction was consistently below baseline throughout the entire study andaccompanied by a significantly reduced use of analgesics compared to placebo. The deterioration in

Quality of Life and WHO performance status was significantly less in Ibandronate treated patientscompared with placebo. Urinary concentrations of the bone resorption marker CTx (C-terminaltelopeptide released from Type I collagen) were significantly reduced in the Ibandronate groupcompared to placebo. This reduction in urinary CTx levels was significantly correlated with the primaryefficacy endpoint SMPR (Kendall-tau-b (p < 0.001)). A tabular summary of the secondary efficacyresults is presented in Table 3.

Table 3 Secondary Efficacy Results (Breast Cancer Patients with Metastatic Bone

Disease)

Placebo n = 277 Ibandronate 50 mg p-valuen = 287

Bone pain * 0.20 -0.10 p = 0.001

Analgesic use * 0.85 0.60 p = 0.019

Quality of Life * -26.8 -8.3 p = 0.032

WHO performance 0.54 0.33 p = 0.008score *

Urinary CTx ** 10.95 -77.32 p = 0.001

* Mean change from baseline to last assessment.

** Median change from baseline to last assessment

Paediatric population (see section 4.2 and section 5.2)

The safety and efficacy of Iasibon in children and adolescents below the age of 18 years have not beenestablished. No data is available.

The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration.

Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in thefasted state and absolute bioavailability was about 0.6 %. The extent of absorption is impaired whentaken together with food or beverages (other than water). Bioavailability is reduced by about 90 % whenibandronic acid is administered with a standard breakfast in comparison with bioavailability seen infasted subjects. When taken 30 minutes before a meal, the reduction in bioavailability is approximately30 %. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutesbefore a meal.

Bioavailability was reduced by approximately 75 % when Iasibon tablets were administered 2 hoursafter a standard meal. Therefore, it is recommended that the tablets should be taken after an overnightfast (minimum 6 hours) and fasting should continue for at least 30 minutes after the dose has been taken(see section 4.2).

After initial systemic exposure, ibandronic acid rapidly binds to bone or is excreted into urine. Inhumans, the apparent terminal volume of distribution is at least 90 l and the amount of dose reaching thebone is estimated to be 40-50 % of the circulating dose. Protein binding in human plasma isapproximately 87 % at therapeutic concentrations, and thus interaction with other medicinal products,due to displacement is unlikely.

There is no evidence that ibandronic acid is metabolized in animals or humans.

The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption (estimatedto be 40 - 50 %) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction ofibandronic acid is eliminated unchanged in the faeces.

The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but theapparent terminal half-life is generally in the range of 10 - 60 hours. However, early plasma levels fallquickly, reaching 10 % of peak values within 3 and 8 hours after intravenous or oral administrationrespectively.

Total clearance of ibandronic acid is low with average values in the range 84-160 mL/min. Renalclearance (about 60 mL/min in healthy postmenopausal females) accounts for 50-60 % of totalclearance and is related to creatinine clearance. The difference between the apparent total and renalclearances is considered to reflect the uptake by bone.

The secretory pathway of renal elimination does not appear to include known acidic or basic transportsystems involved in the excretion of other active substances. In addition, ibandronic acid does notinhibit the major human hepatic P 450 isoenzymes and does not induce the hepatic cytochrome P 450system in rats.

Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.

There is no evidence for clinically relevant interethnic differences between Asians and Caucasians inibandronic acid disposition. There are only very few data available on patients with African origin.

Exposure to ibandronic acid in patients with various degree of renal impairment is related to creatinineclearance (CLcr). Subjects with severe renal impairment (CLcr ≤ 30 mL/min) receiving oraladministration of 10 mg ibandronic acid daily for 21 days, had 2-3 fold higher plasma concentrationsthan subjects with normal renal function (CLcr ≥ 80 mL/min). Total clearance of ibandronic acid wasreduced to 44 ml/min in the subjects with severe renal impairment compared with 129 mL/min insubjects with normal renal function. No dosage adjustment is necessary for patients with mild renalimpairment (CLcr ≥ 50 and < 80 mL/min). For patients with moderate renal impairment (CLcr ≥ 30 and< 50 mL/min) or severe renal impairment (CLcr < 30 mL/min) an adjustment in the dose isrecommended (see section 4.2).

Patients with hepatic impairment (see section 4.2)

There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. Theliver has no significant role in the clearance of ibandronic acid since it is not metabolized but is clearedby renal excretion and by uptake into bone. Therefore, dosage adjustment is not necessary in patientswith hepatic impairment. Further, as protein binding of ibandronic acid is approximately 87 % attherapeutic concentrations, hypoproteinaemia in severe liver disease is unlikely to lead to clinicallysignificant increases in free plasma concentration.

Elderly (see section 4.2)

In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokineticparameters studied. As renal function decreases with age, this is the only factor to take intoconsideration (see renal impairment section).

Paediatric population (see section 4.2 and section 5.1)

There are no data on the use of Iasibon in patients less than 18 years old.

Effects in non-clinical studies were observed only at exposures sufficiently in excess of the maximumhuman exposure indicating little relevance to clinical use. As with other bisphosphonates, the kidneywas identified to be the primary target organ of systemic toxicity.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence ofgenetic activity for ibandronic acid.

No evidence of direct foetal toxicity or teratogenic effects was observed for ibandronic acid inintravenously or orally treated rats and rabbits. In reproductive studies in rats by the oral route effects onfertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. Inreproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day.

Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those expected for thisclass of medicinal products (bisphosphonates). They include a decreased number of implantation sites,interference with natural delivery (dystocia), an increase in visceral variations (renal pelvis uretersyndrome) and teeth abnormalities in F1 offspring in rats.

Povidone

Cellulose, microcrystalline

Crospovidone

Maize starch pregelatinised

Glycerol dibehenate

Silica, anhydrous colloidal

Lactose monohydrate

Macrogol 4 000

Hypromellose (E 464)

Titanium dioxide E 171

Not applicable.

5 years.

Store in the original package in order to protect from moisture.

Iasibon 50 mg film coated tablets are supplied in Polyamide/Al/PVC - Aluminum foil blister with 3, 6,9, 28 or 84 tablets, packaged in a cardboard box.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. The release of pharmaceuticals in the environment should be minimized.

Pharmathen S.A.

Dervenakion 615351 Pallini, Attiki

Greece

EU/1/10/659/001

EU/1/10/659/002

EU/1/10/659/008

EU/1/10/659/009

EU/1/10/659/0010

Date of first authorisation: 21 January 2011

Date of latest renewal: 30 September 2015

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

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