Contents

2. Contents • 1. Introduction • 2. Product Information • 3. Key Selling Points • 4. Visit Recommendations • 5. Therapeutic Indication • Off-Label Use • Mechanism of Action • Posology & Administration • Contraindication • Adverse Drug Reaction • Special Warnings & Precautions • Interactions • Benefits and Advantages of Zoledro-Denk • Consultation with your Patient • Take Home Messages • Train the Brain – Quiz • References • Additional Information Click on thetitle toredirecttothepageswithfurtherinformation! Click toreturntothispage!

3. 18. Contents – Additional Information • I. Physiology & Pharmacology • a) Physiology • b) Bisphosphonates • Diseases and Treatment with Zoledro-Denk • Comparison with other drugs • Effects of Z.A. on Survival • II. Clinical Studies • Overview- Clinical studies • Individual Clinical studies • III. Guidelines & Recommendations • IV. Nice toKnow

4. 1. Introduction Zoledro-DENK At a glance … • … contains Zoledronic acid (zoledronate) – • a high potency bisphosphonate • … inhibits bone resorption and falls • ...various anti-tumor properties • … multiple indications • ... administration: intravenous infusion* • …visit your physician, oncologist, gynaecologist, • urologist, gerontologist, orthopaedist, clinician (onco)

5. 2. Zoledro-Denk

6. 3. KeySellingPoints • High-potency bisphosphonate! • Strong inhibitor of osteoclastic bone resorption • Significant benefit in osteoporosis as well as other conditions causing bone loss • Various anti-tumor properties • Prevention of skeletal-related events (one of two bisphosphonates currently approved by the FDA*) • Once-a-month, once a year or unique application** • => good compliance! Only ca.15min administration time! • Amelioration of pain and other symptoms • Improvement of the quality of life! • Risk reduction of mortality after recent hip fracture!***

7. 4. Visit Recommendations * e.g. Breast cancer, prostate cancer, other solid tumors ....

8. 5. Therapeutic Indications Zoledro-Denk 4 mg / 5 ml is used: • To preventskeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia) in adult patients with advanced malignancies involving bone • To treatadult patients with tumor-induced hypercalcemia (TIH) • To treat osteoporosis • in post-menopausal women, and in men at increased risk of fracture, including those with a recent low-trauma hip fracture • associated with long-term systemic glucocorticoid therapy in post-menopausal women and in men at increased risk of fracture • To treat Paget’s disease of the bone in adults

9. Train the Brain - Quiz Active ingredient(s) and indications of Zoledro-Denk. • ContainsZoledronicacid (4mg/5ml). Preventionofskeletalrelatedevents in adult patientswithadvancedmalignanciesinvolvingbone, treatmentof adult patientswith tumor-inducedhypercalcemia, treatmentofosteoporosis, treatmentofPaget’sdiseaseofthebone in adults

10. 6. ZoledronicAcid-Off Label Use • Preventionof bone loss in postmenopausal women with breast cancer receivingaromatase inhibitor therapy1 • Bone protection in adults with multiple myeloma: Patients with normal (not accelerated) bone metabolism2 • Children (symptomatic osteopenia or localized bone disease)3 • ZA-Add-on therapy to adjuvant treatment of breast cancer4-6 • Thalassemia-induced osteoporosis7 =>increasing BMD, reducing bone resorptionand pain • Early rheumatoid arthritis and clinical synovitis of the hand and wrist receiving methotrexate8 => structural benefit • Prevents and treats bone demineralization in young adult women afterallo-SCT (allogeneicstemcelltransplantation)9

11. 6. Off Label: Zoledr.acid in Pediatry Osteogenesisimperfecta (OI) • brittle bone disease: genetic bone disorder • people with OI: born with defective connective tissue, or without the ability to produce it  usually because of a deficiency of Type-I collagen Clinical trial results with Zoledronic acid : • treatment of severe OI in pediatric patients aged 1 to 17 years • compared to intravenous pamidronate • treatment effects on BMD (bone mineral density) were similar • overall incidence of fractures was comparable for the zoledronic acid and pamidronate-treated patients (43% (32/74) vs. 41% (31/76))

12. 7. Mechanism of Action video Mayo Clinic Proceedings Volume 83, Issue 9 , Pages 1032-1045, September 2008 Video: Mechanism of action, Novartis/you tube

13. 7. Mechanism of Action osteoclast zoledronic acid • Inhibits osteoclastic activity • Induces osteoclast apoptosis • Blocks the osteoclasticresorption • Protects from loss of density and bone Pictures from Video: Mechanism of action, Novartis you tube

14. Train the Brain - Quiz Mechanism of action of Zoledronic acid? • ZA inhibits osteoclastic activity, induces osteoclast apoptosis, blocks the osteoclasticresorption => slows bone loss

15. 8. Posology Zoledro-Denk (1) Prevention of skeletal related events in patients with advanced malignancies involving bone • Adults and elderly • 4 mg every3 to 4 weeks • plus: an oral calcium supplement of 500 mg and 400 IU vitamin D daily • Patients with bone metastases • The decision for treatment should consider that the onset of treatment effect is 2 to 3 months. eg. CalciD-Denk

16. 8. Posology Zoledro-Denk (2) Treatment of TIH* • Adults and elderly • single dose of 4 mg Z.A. *tumorinducedhypercalcemia:albumin-correctedserumcalcium ≥ 12.0 mg/dl or 3.0 mmol/l

17. 8. Posology Zoledro-Denk (3) Treatment of osteoporosis • Adults and elderly • Post-menopausal osteoporosis, • osteoporosis in men and the treatment of • osteoporosis associated with long-term systemic glucocorticoid therapy: single intravenous infusion once a year • Continued treatment should be re-evaluated periodically based on the benefits and potential risks on an individual patient basis, particularly after 5 or more years of use • Patients with a recent low-trauma hip fracture • infusion two or more weeks after hip fracture repair

18. 8. Posology Zoledro-Denk (4) Treatment of Paget’s disease of the Bone • Adults and elderly • Treatment should be prescribed only by physicians with experience in the treatment of Paget's disease of the bone • Singleintravenous infusion of 4 mg Z.A. • Re-treatment of Paget's disease: additionalintravenous infusion after an interval of one year or longer from initial treatment in patients who have relapsed • Limited data on re-treatment of Paget's disease available

19. 8. Posology Zoledro-Denk (5) Patients with Paget’s disease and osteoporosis • Zoledro-Denkplus adequate calcium and vitamin D intake • Patients with Paget's disease • Adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following administration • Patients with a recent low-trauma hip fracture • Loading dose of 50,000 to 125,000 IU of vitamin D given orally or via the intramuscular route priorto the first infusion eg. CalciD-Denk

20. 8. Posology Zoledro-Denk (6) Renal impairment (1) • TIH: • Severer.i.: onlyafter evaluating the risks and benefits of treatment •  In the clinical studies, patients with serum creatinine > 400 µmol/l or > 4.5 mg/dl were excluded • No dose adjustment with serum creatinine < 400 µmol/l or < 4.5 mg/dl • Prevention of SREs (in pats. with advanced malignancies involving bone): • Serum creatinine and creatinine clearance (CLcr; calculated from serum creatinine using the Cockcroft-Gault formula) should be determined • Not recommended for patients presenting with severe renal impairment* prior to initiation of therapy  In clinical trials, patients with serum creatinine • > 265 µmol/l or > 3.0 mg/dl were excluded • Osteoporosis and Paget’s disease: • Contraindicated in patients with CLcr< 35 ml/min • No dose adjustment with CLcr > 35 ml/min *defined for this population as CLcr < 30 ml/min

21. 8. Posology Zoledro-Denk (7) Renal impairment (2) • Bone metastases: • Mild to moderate renal impairment* prior to initiation of therapy *Doses have been calculated assuming target AUC of 0.66 (mg•hr/l) (CLcr=75 ml/min). The reduced doses for patients with renal impairment are expected to achieve the same AUC as that seen in patients with creatinine clearance of 75 ml/min. • Serum creatinine should be measured prior to each dose and treatment should be withheld if renal function has deteriorated • Treatment should be resumed at the same dose as that given prior to treatment interruption *defined for this population as CLcr30-60 ml/min

22. 8. Posology Zoledro-Denk (8)

23. 8. Posology Zoledro-Denk (9) General note • Patients must be appropriately hydrated prior to administration of Zoledro-Denk • Especially important for the elderly and for patients receiving diuretic therapy • The incidence of post-dose symptoms occurring within the first three days after administration of Zoledro-Denkcan be reduced with the administration of paracetamol or ibuprofen shortly following administration of Zoledro-Denk SPC Zoledro-Denk *hypercalcemia:albumin-correctedserumcalcium ≥ 12.0 mg/dl or 3.0 mmol/l

24. Train the Brain - Quiz Posology of Zoledro-Denk in hepatic impairment and elderly patients? • Hepatic impairment: No adjustment of dosage. Elderly patients • (> 65y): No adjustment of dosage.

25. 8. Overdose • Clinical experience with acute overdose is limited*. • Patients with an overdose should be carefully monitored: • renal function impairment (including renal failure) • serum electrolyte (including calcium, phosphorus and magnesium) abnormalities have been observed** • In the event of Hypocalcemia: calcium gluconate infusions as clinically indicated

26. 8. Method of Administration (1) • Intravenous use. • To be given as a single intravenous infusion in no less than 15 minutes.** • 4 mg/5 ml concentrate for solution for infusion, further diluted in 100 ml calcium-free infusion solution.* Must not be mixed with calcium or other divalent cation-containing infusion solutions such as lactated Ringer’s solution. Patients must be maintained well hydrated prior to and following administration. SPC Zoledro-Denk *sodiumchloride 9 mg/ml (0.9 %) solutionforinjectionorglucose 50 mg/ml (5 %) solutionforinjection

27. 8. Method of Administration (2) • Preparation of reduced doses: • Withdraw an appropriate volume of the concentrate for solution for infusion (4 mg/5 ml) as needed: • 4.4 ml for 3.5 mg dose • 4.1 ml for 3.3 mg dose • 3.8 ml for 3.0 mg dose • Dilute in 100 ml calcium-free infusion solution.* • Give as a single intravenous infusion over ≥ 15minutes. SPC Zoledro-Denk *sodiumchloride 9 mg/ml (0.9 %) solutionforinjectionorglucose 50 mg/ml (5 %) solutionforinjection

28. 8. Administration / Shelf-life (3) • Shelf-life after dilution: • Chem. & physical in-use stability after dilution* has • been demonstrated for 48 h/ 20-24°C or 2-8°C • Microbiol. point of view: • Should be used immediately!! • In-use storage time and conditions prior to use are • the responsibility of the user and would normally not be • longer than 24h at 2-8°C, unless dilution has taken place • in controlled and validated aseptic conditions • Shelf-life after first opening: • Should be used immediately after first opening!! *sodiumchloride 9 mg/ml (0.9 %) solutionforinjectionorglucose 50 mg/ml (5 %) solutionforinjection

29. Train the Brain - Quiz Method of administration? • To be given as a single intravenous infusion in no less than 15 minutes. Dilution in 100 ml calcium-free infusion solution (sodium chloride 9 mg/ml (0.9 %) solution for injection or glucose 50 mg/ml (5%) solution for injection.

30. 9. Contraindications • Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients • Patients with hypocalcemia • Severe renal impairment • Pregnancy • Breast-feeding

31. 10. Adverse Drug Reactions (1) Generally well tolerated • common (> 1/100 to < 1/10): • Anemia • Headache • Conjunctivitis • Nausea, vomiting, anorexia • Bone pain, myalgia, arthralgia, generalized pain • Renal impairment • Fever, flu-like syndrome (including fatigue, rigors, malaise and flushing) • Blood creatinine and blood urea increased, hypocalcemia

32. 10. Adverse Drug Reactions (2) • uncommon (> 1/1,000 to < 1/100): • Thrombocytopenia, leukopenia • Hypersensitivity reaction • Anxiety, sleep disturbance • Dizziness, paresthesia, taste disturbance, hypoesthesia, hyperesthesia, tremor, somnolence • Blurred vision, scleritis and orbital inflammation • Hypertension, hypotension, atrial fibrillation, hypotension leading to syncope or circulatory collapse • Dyspnea, cough, bronchoconstriction • Diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth • Pruritus, rash (including erythematous and macular rash), increased sweating • Muscle cramps, osteonecrosis of the jaw • Acute renal failure, hematuria, proteinuria • Asthenia, peripheral edema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight increase, anaphylactic reaction/shock, urticaria • Hypomagnesemia, hypokalemia • rare (> 1/10,000 to < 1/1,000): please see SPC information

33. 10. Adverse Drug Reactions (3) (5mg/100ml Infusion)

34. 10. Adverse Drug Reactions (4) • Renal function impairment • Deterioration in renal function (i.e. increased serum creatinine). • In rare cases acute renal failure requiring dialyses/fatal outcome • Especially in patients with pre-existing renal dysfunction or additional risk factors: • e.g. advanced age • oncology patients with chemotherapy • concomitant nephrotoxic medicinal products • concomitant diuretic therapy • severe dehydration esp. in post infusion period • multiple cycles of Z.A. and other bisphosphonates • use of other nephrotoxic medicinal products

35. 10. Adverse Drug Reactions (5) • Hypocalcemia • Osteoporosis trials: approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/l). No symptomatic cases of hypocalcemiawere observed. • In the Paget's disease trials: symptomatic hypocalcemia in approximately 1% of patients, in all of whom it resolved. • Frequency of hypocalcemia: much lower following subsequent infusions. • Important: adequate supplementation with vitamin D and calcium.

36. 10. Adverse Drug Reactions (6) • Osteonecrosis of the jaw (ONJ) • Caseshave been reported, predominantly in cancer patients. • Many of these patients: signs of local infection including osteomyelitis. • Majority of the reports: refer to cancer patients following tooth extractions or other dental surgeries Although causality has not been determined, it is recommended to avoid dental surgery as recovery may be prolonged. • Atrial fibrillation • One trial: Overall incidence of atrial fibrillation: 2.5% (96 out of 3,862) in patients receiving zoledronic acid 5 mg vs. 1.9% (75 out of 3,852) with placebo. • Rate of atrial fibrillation serious adverse events: 1.3% (51 out of 3,862; zoledronic acid) vs. 0.6% (22 out of 3,852; placebo) => hasnot been observed in other trials with zoledronic acid, including those with zoledronic acid 4 mg every 3-4 weeks in oncology patients.

37. 11. Special Warnings and Precautions (1) • General (1) • Appropriate hydration prior to administration of zoledronic acid. • Avoid overhydration in patients at risk of cardiac failure. • Monitoring of serum levels of calcium, phosphate and magnesium after initiating therapy. • Adequate calcium and vitamin D intake in association with zoledronic acid administration. • In case of hypocalcemia, hypophosphatemia, or hypomagnesemia: short-term supplemental therapy may be necessary.

38. 11. Special Warnings and Precautions (2) • General (2) • Pre-existing hypocalcemia: adequate intake of calcium and vitamin D before initiating therapy. • Paget’s disease: transient hypocalcemia(maximal within the first 10 days after infusion) may develop. • No combination with any other medicines containing zoledronic acid or any other bisphosphonate (combined effects of these agents are unknown).

39. 11. Special Warnings and Precautions (3) • Renal insufficiency • Assess creatinineclearance priorto each dose of zoledronicacid. • Transient increase in serum creatininemay be greater in patients with underlying impaired renal function. • Monitoring of serum creatininein at-risk patients. • Cautionwhen concomitantly used with other medicinal products that could impact renal function! • Appropriate hydration (especially elderly patients and those receiving diuretic therapy) prior to administration of zoledronic acid. • A single dose should not exceed 4 mg and the duration of infusion should be at least 15 minutes.

40. 11. Special Warnings and Precautions (4) • Osteonecrosis of the jaw (ONJ) • Dental examination: priorto treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene). • While on treatment: avoidinvasive dental procedures. • Atypical fractures of the femur • During bisphosphonate treatment: • Patients should be advised to report any thigh, hip or groin pain • Any patient presenting with such symptoms should be evaluated for an incomplete femur fracture

41. 11. Special Warnings and Precautions (5) • Important identified risks within the approved indications: • Acute phase reaction (common) • Renal function impairment (common) • Hypocalcemia(common) • Ocular adverse events (common: conjunctivitis) • Atrial fibrillation (uncommon/rare) • Osteonecrosis of the jaw (uncommon) • Anaphylaxis (uncommon) Within three days after administration, an acute phase reaction has commonly been reported, with symptoms including => bone pain, fever, headache, nausea, vomiting, diarrhea, fatigue, arthralgia, myalgia and rigors; these symptoms usually resolve within a few days*

42. 12. Interactions … with other medicinal products and other forms of interaction • Combination with aminoglycosides: additive effect possible  lower serum calcium level for longer periods than required • Combination with other potentially nephrotoxic medicinal products  increased nephrotoxicity and possibility of hypomagnesemiadeveloping during treatment • Combination with thalidomide in multiple myeloma patients: increased risk of renal dysfunctionpossible • In patients with renal impairment: systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase • Combination with anti-angiogenic medicinal products: osteonecrosis of the jaw (ONJ) possible

43. 13. Benefits and Advantages of Zoledro-Denk eg. Zoledro-Denk Benefits and Advantages: • Newer, more potent form of bisphosphonates • Higher response rate than pamidronate* • More rapid rate of infusion in comparison to pamidronate (15 min vs. 2-4 h)* • Especially adapted to (post-menopausal) patients who are unable to tolerate oral bisphosphonates due to inability to swallow or to remain in an upright position for the required length of time • Established role in prophylaxis of drug-induced osteopenia in prostate cancer patients (US Pharmacopeial Convention USPDI, 2005)

44. 14. Consultation with your Patient* Tutorial: Lifestyle changes and exercise Calcium rich diet Avoidance of falls • Avoidance of falls • -exercises in balancing (e.g. standing pose on one foot, balancing on a line) • - Strength training • - Train the reaction and reaction time • - check the sight of your patient (cataract? Right strength of glasses?) • - Avoid underweight (BMI > 20kg/m² ) • Stop smoking, avoid alcohol • Prescribe Ca- and Vit D- supplements for elderly with high risk of • falls/fractures eg. Zoledro-Denk eg. CalciD-Denk For printouts for your doctors and pharmacists

45. 14. Consultation with Your Patient* • What your patient can do additionally for personal safety: • Check your domestic environment, e.g. • - sufficient electric lighting, especially at night • comfortable shoes (without high heels, prefer rubber sole • instead of slippery leather sole, etc…) • - fix handles in bathroom, stairs • - uncaged pets? • - fixed furniture, knobs • - tripping hazards? Cables fixed and safe on the floors? • carpets? fixed? • stairs? Doorsill? eg. Zoledro-Denk eg. CalciD-Denk For printouts for your doctors and pharmacists

46. 15. Take Home Messages • Zoledro Denk (4 mg/5 ml concentrate for solution) contains bisphosphonate Zoledronic acid (zoledronate) • Inhibitor of osteoclastic bone resorption • Zoledro Denk prevents skeletal fractures in patients with cancers, and treats tumor-induced hypercalcemia, osteoporosis and Paget’s disease of the bone • Administration: single intravenous infusion, to be given in no less than 15 minutes; patients must be maintained well hydrated prior to and following administration • Highest relative potency • Generally safe and effective

47. 16. Train the Brain – Quiz! Active ingredient(s) and indications of Zoledro-Denk. Posology of Zoledro-Denk in hepatic impairment and elderly patients? Method of administration? Contraindications? What to do in case of overdose? Mechanism of action and role in clinical practice of Zoledronic acid?

48. 16. Train the Brain – Quiz! • Contains Zoledronic acid (4mg/5ml). Prevention of skeletal related events in adult patients with advanced malignancies involving bone, treatment of adult patients with tumor-induced hypercalcemia, treatment of osteoporosis, treatment of Paget’s disease of the bone in adults • Hepatic impairment: No adjustment of dosage. Elderly patients (> 65y): No adjustment of dosage. • To be given as a single intravenous infusion in no less than 15 minutes. Dilution in 100 ml calcium-free infusion solution (sodium chloride 9 mg/ml (0.9 %) solution for injection or glucose 50 mg/ml (5 %) solution for injection. • CI: Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients; hypocalcemia; severe renal impairment; pregnancy; breast-feeding. • Clinical experience with acute overdose is limited. Patients with an overdose should be carefully monitored in regard of renal function impairment (including renal failure), and serum electrolyte (including calcium, phosphorus and magnesium) abnormalities: In case of hypocalcemia: calcium gluconate infusions as clinically indicated.

49. 16. Train the Brain – Quiz! • ZA inhibits osteoclastic activity, induces osteoclast apoptosis, blocks the osteoclastic resorption=> slows bone loss (reduces pain score and combined with this the analgesic score)

50. 17. References • Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N Engl J Med. 2007;357:1799–1809. doi: 10.1056/NEJMoa074941. • Colón-Emeric CS, Mesenbrink P, Lyles KW, et al. Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res. 2010;25:91–97. doi: 10.1359/jbmr.090704. • J ClinEndocrinolMetab. 2010 Mar;95(3):1174-81. doi: 10.1210/jc.2009-0852. Epub 2010 Jan. • Effect of osteoporosis treatment on mortality: a meta-analysis.Bolland MJ, Grey AB, Gamble GD, Reid IR. • Greenspan, SL, et al. Bisphosphonates: Safety and efficacy in the treatment and prevention of osteoporosis. American Family Physician, Vol. 61, No. 9, May 1, 2000, pp. 2731-36. • The role of bisphosphonates in breast cancer: Development of bisphosphonates, Herbert Fleisch, Breast Cancer Res. 2002; 4(1): 30–34. Published online 2001 November 30. doi:  10.1186/bcr414. • http://www.ahfsdruginformation.com/off_label/tables/Zoledronic_Acid.pdf. • https://ash.confex.com/ash/2012/webprogram/Paper54432.html. • NoopurRaje et al. Bone Marker-Directed Dosing of Zoledronic Acid for the Prevention of Skeletal Complications in Patients with Multiple Myeloma: Final Results of the Z-MARK Study. Oral and Poster Abstracts, Session: 653. Myeloma - Therapy, excluding Transplantation: Poster III, 54th ASH Annual Meeting, Atlanta, Dec 8-11, 2012. • Impact of Bone metastases on skeleton (from Amgen, you tube). • Kennedy K, Patel H. Update on the Pharmacological Prevention of Skeletal-related Events in Cancer Patients. Orthopedics. December 2011 - Volume 34 · Issue 12: 982-985; DOI: 10.3928/01477447-20111021-21. • Clines GA, Guise TA. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone. EndocrRelat Cancer 2005; 12:549.