Public Assessment Report Decentralised Procedure

Public Assessment Report

Decentralised Procedure

BINOSTO 70 MG EFFERVESCENT TABLETS (alendronate sodium)

UK/H/3515/001/DC UK licence no: PL 42786/0001

EFFRX PHARMA GMBH

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

LAY SUMMARY

Binosto 70 mg effervescent tablets (alendronate sodium trihydrate (alendronic acid), effervescent tablets, 70 mg)

This is a summary of the Public Assessment Report (PAR) for Binosto 70 mg effervescent tablets . It explains how Binosto 70 mg effervescent tablets was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Binosto 70 mg effervescent tablets.

For practical information about using Binosto 70 mg effervescent tablets, patients should read the package leaflet or contact their doctor or pharmacist.

What are Binosto 70 mg effervescent tablets and what are they used for? The application for Binosto 70 mg effervescent tablets was submitted as a hybrid application. This means that it is similar to a reference medicine containing the same active substance, but but it is administered as a buffered oral solution whereas the reference product is administered as a tablet. The Company has provided additional own data to demonstrate the safety and efficacy of Binosto 70 mg effervescent tablets regarding this difference from the reference medicine.

Assessment of the application concluded that the effervescent tablets are similar to the reference medicine containing the same active substance (alendronic acid) but it is administered as a buffered oral solution whereas the reference product is administered as a tablet. The Company provided data to demonstrate the safety and efficacy of Binosto 70 mg effervescent tablets.

The reference medicine for Binosto 70 mg effervescent tablets is Fosamax 70 mg Tablets (Merck Sharp & Dohme).

Binosto 70 mg effervescent tablets are used to treat osteoporosis and to reduce the risk of spine and hip fractures.

What is osteoporosis? Osteoporosis is a thinning and weakening of the bones. It is common in women after the menopause. At the menopause, the ovaries stop producing the female hormone, oestrogen, which helps to keep a woman’s skeleton healthy. As a result, bone loss occurs and bones become weaker. The earlier a woman reaches the menopause, the greater the risk of osteoporosis.

Early on, osteoporosis usually has no symptoms. If left untreated, however, it can result in broken bones. Although these usually hurt, breaks in the bones of the spine may go unnoticed until they cause height loss. Broken bones can happen during normal, everyday activity, such as lifting, or from minor injury that would not generally break normal bone. Broken bones usually occur at the hip, spine, or wrist and can lead not only to pain but also to considerable problems like stooped posture (‘dowager’s hump’) and loss of mobility.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

How do Binosto 70 mg effervescent tablets, work? The active ingredient (alendronic acid) in this medicine belongs to a group of non-hormonal medicines called bisphosphonates. Alendronic acid prevents the loss of bone that occurs in women after they have been through the menopause, and helps build bone. It reduces the risk of spine and hip fractures.

How are Binosto 70 mg effervescent tablets, used? The pharmaceutical form of Binosto 70 mg effervescent tablets is an effervescent tablet and is administered as an oral solution. Binosto 70 mg effervescent tablets must be dissolved in half a glass of plain water before taking. Do not chew or swallow the tablet whole.

Take one Binosto 70 mg effervescent tablet once a week, as an oral solution.

Please read section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment.

How long should Binosto 70 mg effervescent tablets be taken for? It is important that the patient continues to take Binosto 70 mg effervescent tablets for as long as their doctor prescribes the medicine. Binosto 70 mg effervescent tablets can treat the patient’s osteoporosis only if the patient continues to take the effervescent tablets. If the patient has any further questions on the use of this product, the patient should ask their doctor or pharmacist.

Binosto 70 mg effervescent tablets can only be obtained with a prescription.

What benefits of Binosto 70 mg effervescent tablets have been shown in studies? Because Binosto 70 mg effervescent tablets is a hybrid application referring to Fosamax 70 mg Tablets (Merck Sharp & Dohme), a clinical safety study has been provided for Binosto 70 mg effervescent tablets to evaluate the advantages and determine the differences between Binosto 70 mg effervescent tablets which is administered as a buffered oral solution and the reference product Fosamax 70 mg Tablets (Merck Sharp & Dohme) which is administered as a tablet. A bioequivalence study has also been provided which successfully demonstrates that the test product Binosto 70 mg effervescent tablets is bioequivalent to the reference medicine Fosamax 70 mg Tablets. Two medicines are bioequivalent when they produce the same levels of active substance in the body.

What are the possible side effects of Binosto 70 mg effervescent tablets? The most common side effects with Binosto 70 mg effervescent tablets (which may affect more than 1 in 10 people) are bone, muscle and/or joint pain which is sometimes severe.

Common side effects with Binosto 70 mg effervescent tablets (which may affect 1 to 10 people in 100) are: • heartburn; difficulty swallowing; pain upon swallowing; ulceration of the gullet (oesophagus – the tube that connects the mouth with the stomach) which can cause chest pain, heartburn or difficulty or pain upon swallowing

• joint swelling

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

• abdominal pain; uncomfortable feeling in the stomach or belching after eating; constipation; full or bloated feeling in the stomach; diarrhoea; flatulence

• hair loss; itching

• headache; dizziness

• tiredness; swelling in the hands or legs

For the full list of all side effects reported with Binosto 70 mg effervescent tablets see section 4 of the package leaflet available on the MHRA website.

Why are Binosto 70 mg effervescent tablets, approved? The MHRA decided that the benefits of Binosto 70 mg effervescent tablets are greater than its risks and recommended that it be approved for use.

What measures are being taken to ensure the safe and effective use of Binosto 70 mg effervescent tablets? Safety information has been included in the Summary of Product Characteristics and the package leaflet for Binosto 70 mg effervescent tablets including the appropriate precautions to be followed by healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore new safety signals reported by patients/healthcare professionals will be monitored/reviewed continuously.

Other information about Binosto 70 mg effervescent tablets. Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Germany, Denmark, Estonia, Finland, France, Greece, Hungary, Iceland, Ireland, Italy, Lithuania, Latvia, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Slovak Republic, Spain, Sweden and the UK agreed to grant a Marketing Authorisation for Steovess 70mg Effervescent Tablets to Takeda GmbH (PL 31752/0027; UK/H/3515/001/DC) on 18 December 2011. A Marketing Authorisation was granted in the UK on 27 January 2012.

Subsequent to a Change of Ownership procedure, the Marketing Authorisation (PL 31752/0027) was granted to EffRx Pharma GmbH on 04 December 2013 (PL 42786/0001).

The product name of Steovess 70mg Effervescent Tablets was changed to the current product name, Binosto 70 mg effervescent tablets on 04 February 2014.

The full PAR for Binosto 70 mg effervescent tablets follows this summary.

For more information about treatment with Binosto 70 mg effervescent tablets read the package leaflet, or contact your doctor or pharmacist.

This summary was last updated in February 2015.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

TABLE OF CONTENTS

Module 1: Information about initial procedure Page 6

Module 2: Summary of Product Characteristics Page 7

Module 3: Patient Information Leaflets Page 8

Module 4: Labelling Page 9

Module 5: Scientific Discussion Page 11

1 Introduction 2 Quality aspects 3 Non-clinical aspects 4 Clinical aspects 5 Overall conclusions

Module 6 Steps taken after initial procedure Annex 1 Page 24

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Module 1

Product Name Binosto 70 mg effervescent tablets

Type of Application Hybrid application, Article 10.3

Active Substance Alendronate sodium (alendronic acid)

Form Effervescent tablets

Strength 70mg

MA Holder Nycomed GmbH, Byk-Gulden-Str. 2, 78467 Konstanz, Germany

RMS UK

CMS Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Germany, Denmark, Estonia, Finland, France, Greece, Hungary, Iceland, Ireland, Italy, Lithuania, Latvia, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Slovak Republic, Spain, Sweden

Procedure Number UK/H/3515/001/DC

Timetable Day 210 – 18 December 2011

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Module 2 Summary of Product Characteristics

The current approved version of the SmPC is available on the MHRA website.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Module 3 Patient Information Leaflet

The current approved version of the PIL is available on the MHRA website.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Module 4 Labelling

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Module 5 Scientific discussion during initial procedure

I INTRODUCTION On 18 December 2011, Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Germany, Denmark, Estonia, Finland, France, Greece, Hungary, Iceland, Ireland, Italy, Lithuania, Latvia, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Slovak Republic, Spain, Sweden and the UK agreed to grant a marketing authorisation to Nycomed GmbH for the medicinal product Steovess 70mg Effervescent Tablets (UK/H/3515/001/DC). The licence was granted via the Decentralised Procedure (DCP), with the UK as Reference Member State (RMS). After the national phase, a licence was granted in the UK on 27 January 2012 (PL 31752/0027).

This application was made under Article 10.3 of Directive 2001/83 EC for Binosto 70 mg effervescent tablets, containing the active substance alendronic acid. The reference medicinal product for this application is Fosamax 10mg Tablets (Merck, Sharp and Dohme Limited, UK), which has been registered in at least one European member state for over 10 years.

Alendronic acid is a bisphosphonate that acts as a potent inhibitor of osteoclast-mediated bone resorption. It is indicated in the treatment of postmenopausal osteoporosis.

The results of three studies comparing the test product versus Fosamax (Merck, Sharp and Dohme) have been submitted to support this application. The studies were conducted in accordance with Good Clinical Practice (GCP).

A formal Environmental Risk Assessment has not been performed because the product is intended for substitution. Hence, no increase in environmental risk is expected.

The pharmacovigilance system, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable European Risk Management Plan has been provided.

The RMS has been assured that acceptable standards of Good Manufacturing Practice (GMP) are in place for these product types at all sites responsible for the manufacture and assembly of this product.

For manufacturing sites outside the Community, the RMS has accepted copies of current GMP certificates of satisfactory inspection summary reports or‘close-out letters’ issued by the inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those non-Community sites.

Subsequent to a Change of Ownership procedure, the Marketing Authorisation (PL 31752/0027) was granted to EffRx Pharma GmbH on 04 December 2013 (PL 42786/0001).

The product name of Steovess 70mg Effervescent Tablets was changed to the product name Binosto 70 mg effervescent tablets on 04 February 2014.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

II. ABOUT THE PRODUCT

Name of the product in the Reference Member State Binosto 70 mg effervescent tablets

Name(s) of the active substance(s) (USAN) Alendronate sodium (alendronic acid) Pharmacotherapeutic classification Bisphosphonate (ATC code) ATC code: M05 BA04 Pharmaceutical form and strength(s) 70mg effervescent tablets Reference number for the Mutual Recognition Procedure UK/H/3515/001/DC Reference Member State United Kingdom Member States concerned Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Germany, Denmark, Estonia, Finland, France, Greece, Hungary, Iceland, Ireland, Italy, Lithuania, Latvia, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Slovak Republic, Spain, Sweden Marketing Authorisation Number(s) PL 31752/0027 Name and address of the authorisation holder Nycomed GmbH, Byk-Gulden-Str. 2, 78467 Konstanz, Germany

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS DRUG SUBSTANCE INN: Alendronate sodium Chemical Names: Sodium trihydrogen (4-amino-1-hydroxybutylidene)diphosphonate trihydrate (4-amino-1-hydroxybutylidene)bisphosphonic acid monosodium salt trihydrate. Structure:

Molecular formula: C4H12NNaO7P2, 3H2O Molecular weight: 325.1 Physical form: A white or almost white crystalline, micronised powder, soluble in water, very slightly soluble in methanol, practically insoluble in methylene chloride

Alendronate sodium is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance are covered by a European Directorate for the Quality of Medicines and Healthcare (EDQM) Certificate of Suitability.

Satisfactory specifications have been provided for all packaging used for the active substance. Confirmation has been provided that the primary packaging complies with EC Directive 2002/72/EC, concerning materials in contact with foodstuff.

A suitable retest period has been determined, based on stability data from batches of active substance stored in the proposed packaging under standard conditions.

DRUG PRODUCT Other ingredients Other ingredients consist of pharmaceutical excipients sodium dihydrogen citrate, citric acid anhydrous, sodium hydrogen carbonate, sodium carbonate anhydrous, strawberry flavour [maltodextrin (maize), arabic gum, propylene glycol (E 1520), nature-identical flavouring substances], acesulfame potassium and sucralose. With the exception of sucralose, sodium dihydrogen citrate and strawberry flavour, all excipients are controlled to their respective European Pharmacopoeia monographs. Sucralose is controlled to a suitable US National Formulary specification. Sodium dihydrogen citrate is controlled to a Deutscher Arzneimittel Codex (DAC) specification. The strawberry flavouring is controlled to a suitable in-house specification and is also in-line with current EU Directives concerning flavourings. Satisfactory certificates of analysis have been provided for all excipients.

None of the excipients are sourced from animal/human origin or from genetically modified sources.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Pharmaceutical development The objective of the pharmaceutical development programme was to produce an effervescent tablet that could be considered a hybrid medicinal product to Fosamax 10mg Tablets (Merck, Sharp and Dohme Limited, UK).

Suitable pharmaceutical development data have been provided for this application.

Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory based on process validation data and controls on the finished product. Process validation has been carried out on batches of the product. The results are satisfactory.

Finished product specification The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used.

Container Closure System The finished product is supplied in packs holding paper/low-density polyethylene/aluminium/zinc ionomer resin blisters, containing 4, 12 or 24 tablets.

Specifications and certificates of analysis for the primary packaging material have been provided. These are satisfactory. All primary packaging is controlled to European Pharmacopoeia standards and complies with EU Directive 2005/79/EC, concerning materials in contact with food.

Stability Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing.

Based on the results, a shelf-life of 3 years has been set, with the storage conditions, ‘This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from moisture.’

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labelling The SmPC, PIL and labelling are pharmaceutically satisfactory.

The applicant has submitted results of PIL user testing. The results indicate that the PIL is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains.

MAA Form The MAA form is pharmaceutically satisfactory.

Expert Report The pharmaceutical expert report is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Conclusion It is recommended that a Marketing Authorisation is granted for this application.

III.2 NON-CLINICAL ASPECTS The pharmacological, pharmacokinetic and toxicological properties of alendronate sodium are well-known. As alendronate sodium is a well-known active substance, no further studies are required.

A non-clinical overview, based on a literature review, has been written by an appropriately qualified person and is a suitable summary of the non-clinical aspects of the dossier.

The summary of product characteristics is satisfactory from a non-clinical viewpoint.

The grant of a marketing authorisation is recommended.

III.3 CLINICAL ASPECTS Pharmacokinetics Two pharmacokinetic studies have been submitted to support this application. The first was performed with a different formulation to that proposed for marketing. This failed the bioequivalence criteria; however a second bioequivalence study was carried out with the proposed reformulated (micronized) product, which is satisfactory. These studies are described below.

Study 1 An open-label, randomised three-period, cross-over study was performed comparing a single oral dose of 70mg alendronate effervescent tablets manufactured for Nycomed GmbH (Test) with a single oral dose of Fosamax 70 mg (Merck Sharp and Dohme - Reference), in healthy female volunteers aged between 45 and 75 years of age.

Three treatments were investigated in this study, separated by a wash-out of at least 14 days: • Treatment a: a single dose of TEST, administered after at least 12 hours fasting, followed by 4 hours fasting period. • Treatment b: a single dose of TEST, administered after at least 12 hours fasting, followed by a standard breakfast 15 minutes after administration. • Treatment c: a single dose of REFERENCE, administered after at least 12 hours fasting, followed by 4 hours fasting period.

The test, Alendronate 70 mg effervescent tablet was dissolved in 120 ml of plain water (Volvic®) at room temperature. The solution was stirred regularly until the tablet has fully dissolved.

The reference (Fosamax 70 mg Tablets), was swallowed whole with 240 ml of plain water (Volvic®) at room temperature. The oral cavity was inspected and a hand check performed after administration.

Both formulations were administered with subjects in an upright position and subjects were not permitted to lie down for 4 hours.

A washout period of at least 14 days and not more than 28 days was kept between doses in each subject. Urine samples were collected pre- and up to 48 hours post dose.

The following pharmacokinetic variables were calculated for alendronate

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

• Ae0-48 (cumulative amount excreted into urine during the entire period of sample collection) [μg] • Et (rate of alendronate excretion in urine for each collection interval) [μg/h]. • Emax (maximum urinary excretion rate) [μg/h]. • t(Emax) (time of the maximum urinary excretion) [h] • ke: elimination rate constant • t1/2= ln(2)/ ke.

ANOVA was performed on all parameters except tEmax.

Bioequivalence was assumed if the 90% confidence interval of treatment ratios T/R for Ae0-48 was within 80.00-125.00%.

A summary of the results is presented below:

For the purposes of showing bioequivalence the above ratios between treatments “a” and “c” are relevant. The ratios between treatment “b” and either “a” or “c”, are relevant to show the effect of food intake immediately after the intake of alendronate.

The lower limit of the 90% confidence interval for Ae0-48 (79.54%) failed the predefined acceptance range of 80.00-125.00%.

Study 2 This further study used the new micronized formulation of the test product.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

A randomised, single-dose, two-way, four-period, crossover replicate bioavailability study was performed comparing 70mg alendronate effervescent tablets manufactured for Nycomed GmbH (Test) versus Fosamax 70mg (Merck, Sharp and Dohme – Reference) in healthy adult volunteers under fasted conditions.

Urine samples were collected for pharmacokinetic analysis pre- and up to 48 hours post dose. A washout period of at least 14 days between doses was applied.

The following pharmacokinetic variables were calculated • Ae (fractional amount of alendronate excreted during each collection interval) [μg] was determined by multiplying the alendronate concentration in the analysed aliquot by the urine volume for the respective period. Concentrations below the lower limit of quantification (LLOQ) were imputed as zero. • Ae0-48 (cumulative amount excreted into urine during the entire period of sample collection) [μg] was calculated as sum of all fractional amounts of alendronate excreted after administration. In addition, the cumulative amount of alendronate was provided for the preceding intervals. • Et (rate of alendronate excretion for each collection interval) [μg/h] was obtained by dividing the fractional amounts excreted through the duration of the corresponding sampling intervals. • Emax (maximum excretion rate) [μg/h]. • t(Emax) (time of the maximum urinary excretion) [h] was given as the endpoint of the respective sampling interval.

Additionally, the terminal elimination half-life (t1/2) was calculated. • t1/2=ln(2)/ λz. The terminal elimination rate constant λz was estimated by linear regression analysis from a range of logarithmic (ln) transformed Ae values in the terminal phase. The midpoint of the sampling intervals (tmid) was used for the estimation of λz. The number of data points and the corresponding time interval used for the estimation of λz was given in the listings.

A summary of the pharmacokinetic results in female subjects only is presented below:

A summary of the pharmacokinetic results for both male and female subjects is presented below:

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Based on the data from this study, the 70mg effervescent tablets can be considered equivalent to Fosamax 70mg.

Pharmacodynamics No new data have been submitted and none are required for an application of this type.

Clinical efficacy One additional study was submitted to support this application.

Study 3 The applicant has submitted the results and reports of this exploratory/ safety study, which was done to evaluate the advantages of effervescent compared to conventional tablets; and to determine differences in the gastrointestinal transit, gastric emptying and effect on gastric pH between the reference product Fosamax and two effervescent alternate formulations- the test effervescent formulation EX101 and the comparator effervescent Merck-Katdare Blend formulation.

The study was conducted as an open-label, three-way crossover study performed in 12 healthy female volunteers. The study aimed to • evaluate of dosage advantages of effervescent tablets compared with conventional tablets • determine the differences between gastrointestinal transit of the two effervescent tablets, with respect to post-dose fasting • compare of gastric emptying times for the three formulations • study the effect of the three formulations on gastric pH.

The endpoints were • scintigraphic analysis of the gastric emptying of the formulations in-vivo. • pH telemetry of all subjects from 2 hours prior to dosing through to 4 hours post-dose.

Subjects were fasted for 10 hours pre-dose. All subjects were pregnancy tested, before a naso-gastric tube was inserted on the study days. pH monitoring was conducted from 2 hours pre-dose until four hours post-dose. Synmed pH probes were inserted via the naso-gastric tube and the position checked by chest x-rays. At dosing the subjects received the appropriate treatment as per the randomisation table generated by Bio-Images Research Ltd.

Fosamax® tablets radiolabelled with 4MBq 99mTc-DTPA were administered with 240 ml Volvic water.

Both effervescent formulations were administered in 100ml Volvic water radiolabelled with 4 MBq99mTc-DTPA, with additional 20 ml Volvic water added to the empty dosing glass,

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC swirled and then swallowed.

Scintigraphy was performed immediately after dosing and then every 5 minutes until complete gastric emptying was observed.

The results are presented below: Gastric Emptying The numerical descriptors of gastric emptying, i.e., time to 50 % and 90 % gastric emptying of the radiolabel (T50 and T90 respectively) were calculated. There were 5 instances when the T90 was not achieved during the imaging time.

Mean values for T50 and T90

p values for T50 and T90

Neither of the effervescent tablets triggered a consistent or rapid emptying after ingestion, when compared to the Fosamax® tablets. There were no statistically significant differences in T50 and T90 when comparing Fosamax® to the effervescent tablets, in this respect.

Effect on gastric pH Mean values for pH parameters

P-values for pH parameters

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

pH at 30 minutes post-dose in subjects where T50>30 minutes

Generally with the Fosamax tablet, the gastric pH increased immediately after dosing. The pH rapidly decreased following this transient increase and remained between approximately 1 and 2 until completion of scintigraphic imaging (that is, until complete gastric emptying).

After dosing with EX101, the gastric pH generally increased to approximately 5 and remained at a plateau then gradually decreased.

The gastric pH following dosing with the Merck-Katdare Blend formulation increased immediately after dosing and remained high (between approximately 6 and 8) for a length of time before a sharp drop to between 1 and 2.

Conclusions: • There were no statistically significant differences in the gastric emptying time between Fosamax® and the two effervescent tablets. • The time taken for the gastric pH to drop below 3, after the ingestion of the medications was statistically significantly higher with the effervescent tablets, in comparison to the Fosamax® tablet.

Clinical safety With the exception of the safety data collected for the three submitted studies, no new safety data were submitted with this application. The incidence of adverse events was no different between treatment arms for either Study 2 or Study 3. However, a higher incidence of gastrointestinal adverse events was observed in the effervescent (Test) formulation in Study 1.

However, oesophageal toxicity associated with alendronate treatment is a multifactorial effect that seems predominantly mediated by local irritations of the oesophageal mucosa

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC through crystalline matter, which is also known as ‘pill oesophagitis’. Gastroesophageal acid reflux might be a concomitant factor, as acid blockage is one of the main treatments once alendronate-associated oesophagitis occurs.

Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and labelling The SmPC, PIL and labelling are clinically satisfactory and consistent with those for the reference product.

Clinical Expert Report The clinical expert report is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier.

MAA Form The MAA Form is satisfactory from a clinical perspective.

Clinical Conclusion The grant of a marketing authorisation is recommended.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Binosto 70 mg effervescent tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk ratio.

NON-CLINICAL The non-clinical data submitted have not revealed any evidence of potential risks to human health from treatment with Binosto 70 mg effervescent tablets beyond those already described.

EFFICACY Alendronic acid has proven benefit in the proposed indication for the treatment of post menopausal osteoporosis. The proposed product is an effervescent tablet, which is dissolved in water prior to administration as an oral solution. This differs from the reference product, which is a conventional, immediate-release tablet. Hence, an oral solution formulation, being easier to swallow, is of potential benefit to those patients with difficulties in swallowing tablets.

The exploratory study submitted in this application demonstrated that following ingestion of an effervescent tablet similar to the proposed formulation, the time taken for the gastric pH to drop below 3 was statistically significantly higher, in comparison to the reference Fosamax® tablet. There was no difference in the gastric emptying time and it has not been shown that these factors translate into a reduction in upper gastrointestinal adverse events.

The safety data submitted with the studies shows no difference in safety between the micronized formulation of Binosto 70 mg effervescent tablets and Fosamax tablets.

The SPC, PIL and labelling are satisfactory.

BENEFIT-RISK ASSESSMENT The quality of the product is acceptable, and no new non-clinical or clinical safety concerns have been identified. The data supplied support the claim that the applicant’s product and the innovator product are bioequivalent. Extensive clinical experience with alendronic acid is considered to have demonstrated the therapeutic value of the compound. The benefit-risk ratio is, therefore, considered to be positive.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

Module 6

Steps Taken After Initial Procedure - Summary

Scope Procedure Product Date of Date of end Approval/ Assessment number information start of the of non report affected procedure procedure approval attached Y/N (version) To update sections UK/H/351 SmPC 18/12/2014 17/01/2015 Approved Yes-see 3, 4.2, 4.4, 4.5, 5.1 5/001/IB/0 Annex 1 and 5.2 of the 04/G Summary of Product Characteristics (SmPC) to improve the wording of the SmPC and to emphase the method of administration, that the product is a solution and tailored to those patients with difficulties in swallowing tablets.

PAR Binosto 70 mg effervescent tablets UK/H/3515/001/DC

ANNEX 1

Our Reference: PL 42786/0001-0006

Product: Binosto 70 mg effervescent tablets

Marketing Authorisation Holder: EffRx Pharma GmbH Active Ingredient(s): Alendronate sodium trihydrate

Type of Procedure: Mutual Recognition Submission Type: Variation Submission Category: Type IB Submission Complexity: Standard EU Procedure Number (if applicable): UK/H/3515/001/IB/004/G

Reason: To update sections 3, 4.2, 4.4, 4.5, 5.1 and 5.2 of the Summary of Product Characteristics (SmPC) to improve the wording of the SmPC and to emphasise the method of administration, that the product is a solution and tailored to those patients with difficulties in swallowing tablets.

Supporting Evidence Revised SmPC fragments.

Evaluation The proposed changes to the SmPC are acceptable and the updated SmPC fragments have been incorporated into the Marketing Authorisation.

Conclusion The proposed changes to the SmPC are acceptable.

Decision - Approved on 17 January 2015.