Sandoz Confidential Page 33 Risk Management Plan, Version 4.2 Zoledronic acid

7.2 Part VI.2 Elements for a Public Summary

7.2.1 Part VI.2.1 Overview of disease epidemiology Osteoporosis Osteoporosis causes a decrease in the amount of calcium in the bone and the bone becomes weaker. More females have osteoporosis than males, especially after menopause. In Europe, approximately 30% of all women after menopause (cessation of a woman's ability to give rise to offspring) have osteoporosis and at least 40% of these women will sustain one or more fractures during their lifetime [Melton III LJ, 1992]. Due to worldwide ageing populations a notable increase in the frequency of osteoporosis in women after menopause is likely. The frequency of osteoporosis rises from 5% among women aged 50 years to 50% at 85 years of age. Among men, the comparable numbers are 2.4% and 20%, respectively [Woolf AD, 2003].The highest frequency of osteoporosis in Europe is seen in the Scandinavian countries, in particular Norway, where more than 100 of 10,000 people have hip fractures [Lofthus CM, 2001]. Paget’s disease: Paget's disease is caused by an abnormal breakdown of bone, followed by abnormal bone formation. The new bone is weaker and deformed. Some patients have no symptoms but others may have bone pain and broken bones. A decreasing trend in the global frequency of Paget’s disease (PD) was observed since 1980 [Tiegs RD, 2000] [Doyle T, 2002]. For the US, England and Wales increasing numbers of new cases of PD with the age of ≥ 50 years were reported [Tiegs RD, 2000]. Most cases are diagnosed in people aged ≥ 70 [Tiegs RD, 2000] [Miron- Canelo JA, 1997] [van Staa TP, 2002]. The frequency is higher in men than in women [Tiegs RD, 2000] [Doyle T, 2002].

7.2.2 Part VI.2.2 Summary of treatment benefits Osteoporosis Bisphosphonates including zoledronic acid are medications that are very effective in increasing the bone mineral density (BMD) – the amount of calcium and other types of minerals in a particular area of bone - and reducing the risk of fractures in patients with osteoporosis [Dunn RL, 2013] [Levis S, 2012]. The efficacy and safety of zoledronic acid 5 mg once a year for 3 consecutive years was shown in women after menopause with osteoporosis. Zoledronic acid notably decreases the frequency of new vertebral fractures. Studies show, that the risk of hip fractures was reduced by 41%. Treatment with zoledronic acid increased BMD by 3.2-6.7% in different bone regions, e.g. lower spine, hip, thigh bone neck, the radial bone of the forearm. Also in men, a similar notable increase in the hip BMD was observed after 24 months of treatment with zoledronic acid as compared to the effects observed in women after menopause.

Sandoz Confidential Page 34 Risk Management Plan, Version 4.2 Zoledronic acid

Paget’s disease Zoledronic acid was studied in over 30 years old men and women with mild to moderate Paget’s disease of the bone. After 6 months, one infusion of 5 mg zoledronic acid showed an effect in 96% and 89% of cases compared to 74% and 58% with daily doses of 30 mg risedronic acid for 2 months. Similarly the pain severity and impairment by pain decreased over 6 months for the two drugs. After a prolonged observation period, more patients treated with risedronic acid needed another treatment than patients treated with zoledronic acid. In patients with Paget’s disease, 6 months after treatment with 5 mg zoledronic acid a bone of normal quality with no signs of impaired bone structure and no mineralisation defects was shown with biopsies.

7.2.3 Part VI.2.3 Unknowns relating to treatment benefits There is limited data available for zoledronic acid in children and adolescents. Therefore it should not be used in these age groups. There is limited experience in Black patients.

7.2.4 Part VI.2.4 Summary of safety concerns

Table 6-5 Important identified risks Risk What is known Preventability Symptoms after the first The majority of the side effects, A mild pain reliever such as dose of zoledronic acid 5 mg such as fever and chills, pain in the ibuprofen or paracetamol to / 100 ml muscles or joints, and headache, reduce these side effects can be (Post-dose symptoms) occur within the first three days recommend. following the dose of zoledronic acid. The symptoms are usually mild to moderate and go away within three days. The chance of experiencing these side effects decreases with subsequent doses of zoledronic acid. Impaired function of the Kidney disorders (e.g. decreased If a patient has severe kidney kidneys urine output) were observed with problems, the drug should not be (Renal dysfunction) zoledronic acid 5 mg / 100 ml as given. The doctor should be well as uncommonly (may affect informed if a patient has a kidney up to 1 in 100 people) abnormal problem, or is used to have one. kidney test results. A blood test to check the kidney functions (levels of creatinine) should be done before each dose of zoledronic acid 5 mg / 100 ml. It is important to drink at least one or two glasses of fluid (such as water), within a few hours before receiving zoledronic acid 5 mg / 100 ml. Sandoz Confidential Page 35 Risk Management Plan, Version 4.2 Zoledronic acid

Risk What is known Preventability Undesirable effects of the Redness and irritation of the eye Adherence to recommended eyes occur commonly (may affect up to posology and diligent therapy (Ocular adverse events) 1 in 10 people) with zoledronic monitoring. acid 5 mg / 100 ml, uncommonly eye infection or irritation or inflammation with pain and redness, or eye sensitivity to light, rarely (may affect up to 1 in 1,000 people) painful redness and/or swelling of the eye and inflammation of the eye (scleritis) or of the eye’s cavity with unknown frequency. Low blood calcium A decreased blood calcium was The drug should not be (Hypocalcaemia) uncommonly observed with administered if the patient has zoledronic acid 5 mg / 100 ml. In hypocalcaemia (calcium levels in patients with Paget’s disease, blood are too low). symptoms due to low blood It is important to take calcium calcium, such as muscle spasms, and vitamin D supplements (for or numbness, or a tingling example tablets) for at least the sensation especially in the area first ten days after being given around the mouth can occur. zoledronic acid 5 mg / 100 ml. The doctor should be informed if the patient is unable to take daily calcium supplements. Poor healing of sores inside Pain in the mouth, teeth and jaw, Before the treatment with the mouth swelling or sores inside the mouth, zoledronic acid 5 mg / 100 ml, (Osteonecrosis of the jaw) numbness or a feeling of the doctor should be informed if heaviness in the jaw, or loosening the patient has or has had pain, of a tooth were observed with swelling or numbness in gums, zoledronic acid 5 mg / 100 ml. jaw or both, if the jaw feels heavy, or if a tooth was lost. Before a dental treatment or dental surgery is done, the dentist should be informed that the patient is receiving treatment with zoledronic acid 5 mg / 100 ml. What should be done before initiation of therapy with zoledronic acid 5 mg / 100 ml: - Every jaw procedure which is not absolutely necessary and will require bone to heal should be avoided prior to therapy initiation. - A routine clinical dental exam to detect potential dental and periodontal infections is recommended. -Teeth with a poor prognosis or in need of extraction should be extracted and other dental Sandoz Confidential Page 36 Risk Management Plan, Version 4.2 Zoledronic acid

Risk What is known Preventability surgeries should be completed prior to the initiation of zoledronic acid therapy. To preventive dentistry besides establishing of a good condition of the teeth, also belongs establishing of a good condition of the teeth root canals. - A patient should take care of oral self-care hygiene before and during zoledronic acid therapy. Serious allergic reactions Severe allergic reactions including A patient should not take this (Anaphylaxis) dizziness and difficulty breathing, medication if he/she is allergic to swelling mainly of the face and zoledronic acid, other throat were observed with bisphosphonates or any of the zoledronic acid 5 mg / 100 ml. other ingredients of the drug product.

Table 6-6 Important potential risks Risk What is known Poor healing of broken bones: Zoledronic acid 5 mg / 100 ml and drugs that are similar, (Osteonecrosis outside the jaw: AVN, may increase the rare chance of broken bones not healing fracture non-union and/or delayed well. Osteoporosis (the condition by itself) may increase the union) chance of broken bones not healing well. Brain lesions caused by clogged or In one study with Aclasta® (Novartis’ zoledronic acid 5 mg / burst blood vessels 100 ml), the patients who received Aclasta® (Cerebrovascular adverse accident) had a small increase in the chance of vascular brain lesions (also known as strokes or cerebrovascular accidents). This increased chance was not seen in any other trial. Irregular heart beating In one Aclasta® study, patients who received Aclasta® had (Atrial fibrillation) a small increase in the chance of an irregular heart beat (called atrial fibrillation). This increased risk was not seen in any other trial. Abdominal and digestive (“stomach”) Heartburn, indigestion, stomach, ulcers and other problems digestive symptoms are more common when drugs (Gastrointestinal adverse events) similar to zoledronic acid 5 mg / 100 ml are taken by mouth (zoledronic acid 5 mg / 100 ml cannot be taken by mouth). It is unclear if patients treated with zoledronic acid 5 mg / 100 ml may have more abdominal and digestive problems. Unusual breaks in thigh bone Patients who use zoledronic acid 5 mg / 100 ml (and drugs (Atypical femur fracture) that are similar) for many years may increase the chance of an unusual type of break in the thigh bone that happens in the middle of the bone after no or only a small amount of injury. The increased chance could not be proven since osteoporosis by itself also seems to increase the chance of these types of breaks in the thigh bone. Interaction with drugs which can notably It is important for the doctor to know all the medicines the affect the kidney function patient is taking, especially if he/she is taking any (Interaction with products that can medicines known to be harmful to your kidneys (e.g. significantly affect renal function) aminoglycosides) or diuretics (“water pills”) that may cause dehydration. Sandoz Confidential Page 37 Risk Management Plan, Version 4.2 Zoledronic acid

Risk What is known Interaction with paracetamol / A transient, mild, elevation of one liver value (alanine amino acetaminophen transferase) was observed in some patients receiving zoledronic acid 5 mg / 100 ml who also received high doses of paracetamol. This generally normalises without treatment. Mix up of zoledronic acid products for Due to similar names, there is a potential for a mix up of different indications Zoledronic acid 5 mg/100 ml solution for infusion (non- (Medication error) oncology indication) and Zoledronic acid 4 mg/100 ml solution for infusion or 4 mg/5 ml concentrate for solution for infusion (oncology indication).

Sandoz Confidential Page 38 Risk Management Plan, Version 4.2 Zoledronic acid

Table 6-7 Missing information Risk What is known Use in pregnancy / lactation There is not enough information to ensure the safe use of zoledronic acid 5 mg/100 ml in pregnant women and it is not known whether zoledronic acid 5 mg/100 ml is excreted into human breast milk. Zoledronic acid 5 mg/100 ml is not approved for use during pregnancy or women who are in breastfeeding. Use in patients with severe kidney There is not enough information to ensure the safe use of problems zoledronic acid 5 mg/100 ml in patients with severe kidney (Use in patients with severe renal problems. impairment) Zoledronic acid 5 mg/100 ml is not approved for use in patients who have an estimate of kidney function below 35ml/min.

7.2.5 Part VI.2.5 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures.

This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). Full details on these conditions and the key elements of any educational material can be found in Annex 11 “Mock-up of proposed additional risk minimisation measures“; how they are implemented in each country however will depend upon agreement between the manufacturer and the national authorities. These additional risk minimisation measures are for the following risks:

Table 6-8 Summary of risk minimisation measures for Renal dysfunction Risk minimisation measure(s) Summary description of main additional risk minimisation measures: Healthcare Professional and patient education Objective and rationale: Educate HCPs and patients on avoiding contraindications and risk factors related to renal impairment. Proposed action: The elements of the educational material have been agreed with the CHMP for Aclasta®. HCP Educational Material: The HCP Educational Material contains the following key elements: The SmPC Reminder card with the following key messages: • to calculate CrCl based on actual body weight using the Cockcroft-Gault formula before each treatment with Zoledronic acid 5 mg / 100 ml, Solution for Infusion • Contraindication in patients with CrCl < 35 ml/min • Contraindication in pregnancy and in breast-feeding women due to potential teratogenicity Sandoz Confidential Page 39 Risk Management Plan, Version 4.2 Zoledronic acid

Risk minimisation measure(s) • Need to ensure appropriate hydration of the patient especially those at an advanced age and those receiving diuretic therapy • Need to infuse Zoledronic acid 5 mg / 100 ml, Solution for Infusion slowly over a period of not less than 15 minutes • One-yearly dosing regime • Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid 5 mg / 100 ml, Solution for Infusion administration • Need for appropriate physical activity, non-smoking and healthy diet Patient information pack: The patient information pack should be provided and contain the following key messages: • Package leaflet • Contraindication in patients with severe kidney problems • Contraindication in pregnancy and in breast-feeding women • Need for adequate calcium and vitamin D supplementation, appropriate physical activity, non- smoking and healthy diet • Key signs and symptoms of serious adverse events (SAEs) • When to seek attention from the health care provider

Table 6-9 Summary of risk minimisation measures for Osteonecrosis of the jaw Risk minimisation measure(s) Summary description of main additional risk minimisation measures: Patient education Objective and rationale: to alert patients on risk of Osteonecrosis of the jaw Proposed action: The patient reminder card contains the following key messages:  Need to inform the doctor/nurse about any problems with the mouth or teeth, prior to starting the treatment with zoledronic acid  Need to go for a dental examination if the patients were previously treated with bisphosphonates, are taking medicines called corticosteroids, are smokers, have cancer, or have not had a dental check-up for a long time. While being treated,  Need to maintain good oral hygiene and receive routine dental check-ups  Need to inform doctor in case of planning to have dental surgeries as well as inform dentist about being treated with zoledronic acid 5 mg

Sandoz Confidential Page 40 Risk Management Plan, Version 4.2 Zoledronic acid

Table 6-10 Summary of risk minimisation measures for Use in patients with severe renal impairment Risk minimisation measure(s) Summary description of main additional risk minimisation measures: Healthcare Professional and patient education Objective and rationale: Educate HCPs and patients on avoiding contraindications and risk factors related to renal impairment. Proposed action: The elements of the educational material have been agreed with the CHMP for Aclasta®. HCP Educational Material: The HCP Educational Material contains the following key elements: The SmPC Reminder card with the following key messages: • to calculate CrCl based on actual body weight using the Cockcroft-Gault formula before each treatment with Zoledronic acid 5 mg / 100 ml, Solution for Infusion • Contraindication in patients with CrCl < 35 ml/min • Contraindication in pregnancy and in breast-feeding women due to potential teratogenicity • Need to ensure appropriate hydration of the patient especially those at an advanced age and those receiving diuretic therapy • Need to infuse Zoledronic acid 5 mg / 100 ml, Solution for Infusion slowly over a period of not less than 15 minutes • One-yearly dosing regime • Adequate calcium and vitamin D intake are recommended in association with Zoledronic acid 5 mg / 100 ml, Solution for Infusion administration • Need for appropriate physical activity, non-smoking and healthy diet Patient information pack: The patient information pack should be provided and contain the following key messages: • Package leaflet • Contraindication in patients with severe kidney problems • Contraindication in pregnancy and in breast-feeding women • Need for adequate calcium and vitamin D supplementation, appropriate physical activity, non- smoking and healthy diet • Key signs and symptoms of serious adverse events (SAEs) • When to seek attention from the health care provider

7.2.6 Part VI.2.6 Planned post authorisation development plan N/A

Sandoz Confidential Page 41 Risk Management Plan, Version 4.2 Zoledronic acid

7.2.7 Part VI.2.7 Summary of changes to the Risk Management Plan over time

Table 6-11 Major Changes to the Risk Management Plan over time Version Date Safety Concerns Comment 2.0 15 May 2012 Important identified risks: Initial RMP Post-dose symptoms Renal dysfunction Ocular adverse events Hypocalcaemia Osteonecrosis of the jaw Anaphylaxis Important potential risks: Osteonecrosis outside of the jaw: AVN, fracture non-union and/or delayed union Cerebrovascular adverse events Atrial fibrillation Gastrointestinal adverse events Atypical femur fracture Medication error Potential interactions: Products that can significantly affect renal function Paracetamol/ acetaminophen Missing information: Use in pregnancy/lactation Use in patients with severe renal impairment 3.0 27 May 2014 All risks Update of the whole RMP according to the update of the originator (Novartis) EU RMP for Aclasta® (version 9.1 and 10.0) including PhV-plan and risk minimisation measures All risks Review of the RMP according to the update of the Sandoz’ Global Core Datasheet Zoledronic acid - parenteral (osteoporosis) Apr 2014 (version 2) Sandoz Confidential Page 42 Risk Management Plan, Version 4.2 Zoledronic acid

Version Date Safety Concerns Comment All risks Transfer of the whole RMP to the currently valid EU RMP-template with filling of all sections applicable for a generic product. Cerebrovascular adverse events according to the changed to Cerebrovascular Novartis RMP accidents Renal dysfunction and Use in patients In accordance with the with severe renal impairment Novartis-EU RMP for Aclasta version 9.1: HCP Educational material updated to reflect update of section 4.4 of the Aclasta® SPC and with Sandoz’ Global Core Datasheet update Zoledronic acid -parenteral (osteoporosis) Apr 2014 (version 2) to include the following information: -calculation of creatinine clearance using the Cockcroft- Gault formula prior to each dose. 3.1 19 Dec 2014 N/A In procedure AT/H/0414-0415- 0416/001, addressing the assessor’s Day 55 questions, - the issues of missing information were added in Part II Module VIII Table 3-1, - mock ups of the packaging were included in annex 11, - in annex 11, data regarding adequate calcium and vitamin D supplementation, appropriate physical activity, non-smoking and healthy diet were added in the Patient´s information. Osteonecrosis of the jaw In Part VI.2 Elements for a Public Summary, information on the Sandoz Confidential Page 43 Risk Management Plan, Version 4.2 Zoledronic acid

Version Date Safety Concerns Comment advice to perform all necessary dental procedures before treatment initiation was added. 4.0 18 Jun 2015 Osteonecrosis of the jaw According to the PRAC and CHMP recommendation regarding the risk of osteonecrosis of the jaw related to Aclasta (zoledronic acid) (see EMA/206916/2015), a Patient reminder card has been added as an additional risk minimisation measure. Additionally: SmPC, PIL and marketing experience have been updated. 4.1 03 Dec 2015 N/A Based on RMS Comments on RMP for Zoledronsäure 5 mg, osteoporosis indication DE/H/5090/IB/006/G and DE/H/5091/IB/007/G the following changes were made: Part I Table 1-1 “Indication(s) in the EEA” and “Posology and route of administration” were updated according to the updated SPC. Renal dysfunction In Part V.1, Part V.3. and Part VI.1.4 the reference to section 4.5 of the SPC was included. Osteonecrosis of the jaw In Part V.1 and Part VI.2.5 and Annex 10 details on the patient reminder card were updated. Medication error Additional risk minimization measure (packaging details) was deleted from Part V.1, Part V.3, Part VI.1.4, Part VI.2.5, Annex 10 and 11. Sandoz Confidential Page 44 Risk Management Plan, Version 4.2 Zoledronic acid

Version Date Safety Concerns Comment N/A Part VI.2 was shortened, the referencing modified and a lay term explained, and Annex 12 was updated accordingly. N/A Annex 2 was updated with the applicable SPC.

4.2 05 Jul 2016 N/A Based on the CMS comment in the Annex 7 checklist targeted follow-up for the risk ONJ the question “received a patient reminder card prior to the ONJ event” was added. Additionally the worldwide marketing status by country and the sales data in part II module SV have been updated.