ZOLEDRONIC ACID ALTAN

Posology Patients must be appropriately hydrated prior to administration of Zoledronic Acid Altan. This is especially important for the elderly (≥65 years)and for patients receiving diuretic therapy. Adequate calcium and vitamin D intake are recommended in association with Zoledronic Acid Altan administration.

Osteoporosis For the treatment of post-menopausal osteoporosis, osteoporosis in men and the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy, the recommended dose is a single intravenous infusion of 5 mg Zoledronic Acid Altan administered once a year.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Zoledronic Acid Altan on an individual patient basis, particularly after 5 or more years of use.

1). In patients with a recent low-trauma hip fracture, a loading dose of 50 000 to 125 000 IU of vitamin D given orally or via the intramuscular route is recommended prior to the first Zoledronic Acid Altan infusion. Paget’s disease For the treatment of Paget’s disease, Zoledronic Acid Altan should be prescribed only by physicians with experience in the treatment of Paget’s disease of the bone.

4).

Re-treatment of Paget’s disease:

After initial treatment with Zoledronic Acid Altan in Paget´s disease, an extended remission period is observed in responding patients. Re-treatment consists of an additional intravenous infusion of 5 mg Zoledronic Acid Altan after an interval of one year or longer from initial treatment in patients who have relapsed.

1). 4). No dose adjustment is necessary in patients with creatinine clearance ≥ 35 ml/min. 2). Elderly (≥ 65 years) No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and younger subjects.

Paediatric population Zoledronic Acid Altan should not be used in children and adolescents below 18 years of age. There are no data available for children under 5 years of age. 1. Method of administration Intravenous use. Zoledronic Acid Altan is administered via a vented infusion line and given slowly at a constant infusion rate.

The infusion time must not be less than 15 minutes. 6. Patients treated with Zoledronic Acid Altan should be given the package leaflet and the patient reminder card.

2% after the first, second and third infusion, respectively. 1%), see “acute phase reactions” below. Tabulated list of adverse reactions Adverse reactions in Table 1 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 Infections and infestations Uncommon Influenza, nasopharyngitis Blood and lymphatic system disorders Uncommon Anaemia Immune system disorders Not known** Hypersensitivity reactions including rare cases of bronchospasm, urticaria and angioedema, and very rare cases of anaphylactic reaction/shock Metabolism and nutrition disorders Common Hypocalcaemia* Uncommon Decreased appetite Rare Hypophosphataemia Psychiatric disorders Uncommon Insomnia Nervous system disorders Common Headache, dizziness Uncommon Lethargy, paraesthesia, somnolence, tremor, syncope, dysgeusia Eye disorders Common Ocular hyperaemia Uncommon Conjunctivitis, eye pain Rare Uveitis, episcleritis, iritis Not known** Scleritis and parophthalmia Ear and labyrinth disorders Uncommon Vertigo Cardiac disorders Common Atrial fibrillation Uncommon Palpitations Vascular disorders Uncommon Hypertension, flushing Not known** Hypotension (some of the patients had underlying risk factors) Respiratory, thoracic and mediastinal Uncommon Cough, dyspnoea disorders Gastrointestinal disorders Common Nausea, vomiting, diarrhoea Uncommon Dyspepsia, abdominal pain upper, abdominal pain, gastro-oesophageal reflux disease, constipation, dry mouth, oesophagitis, toothache, Skin and subcutaneous tissue disorders Uncommon Rash, hyperhidrosis, Musculoskeletal and connective tissue Common Myalgia, arthralgia, bone pain, back disorders pain, pain in extremity Uncommon Neck pain, musculoskeletal stiffness, joint swelling, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscular weakness Rare Atypical subtrochanteric and diaphyseal femoral fractures† (bisphosphonate class adverse reaction) Very rare Osteonecrosis of the external auditory canal (bisphosphonate Renal and urinary disorders Uncommon Blood creatinine increased, pollakiuria, proteinuria Not known** Renal impairment.

8 Class effects)General disorders and administration Very common Pyrexia site conditions Common Influenza-like illness, chills, fatigue, asthenia, pain, malaise, infusion site reaction Uncommon Peripheral oedema, thirst, acute phase reaction, non-cardiac chest pain Not known** Dehydration secondary to to acute phase reactions (post-dose symptomsInvestigations Common C-reactive protein increased Uncommon Blood calcium decreased # Observed in patients taking concomitant glucocorticosteroids.

* Common in Paget’s disease only. ** Based on post-marketing reports. Frequency cannot be estimated from available data. † Identified in post-marketing experience. 9% (75 out of 3,852) in patients receiving Zoledronic Acid Altan and placebo, respectively.

6%) (22 out of 3,852). The mechanism behind the increased incidence of atrial fibrillation is unknown. 1%). 8% for placebo. e. increased serum creatinine) and in rare cases acute renal failure. g advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe dehydration), with the majority of them receiving a 4 mg dose every 3–4 weeks, but it has been observed in patients after a single administration.

In clinical trials in osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Zoledronic Acid Altan and placebo treatment groups over three years.

8% of placebo-treated patients. 87 mmol/l) following Zoledronic Acid Altan administration. No symptomatic cases of hypocalcaemia […]

Renal function The use of Zoledronic Acid Altan in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population. 5), or dehydration occurring after Zoledronic Acid Altan administration.

. Renal impairment has been observed in patients after a single administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.

The following precautions should be taken into account to minimise the risk of renal adverse reactions: • Creatinine clearance should be calculated based on actual body weight using the Cockcroft- Gault formula before each Zoledronic Acid Altan dose.

• Transient increase in serum creatinine may be greater in patients with underlying impaired renal function. • Monitoring of serum creatinine should be considered in at-risk patients. 5). • Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of Zoledronic Acid Altan.

2). 3). g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients. Elevated bone turnover is a characteristic of Paget’s disease of the bone. 8). Adequate calcium and vitamin D intake are recommended in association with Zoledronic Acid Altan administration.

2). Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring during the period of risk. Measurement of serum calcium before infusion of Zoledronic Acid Altan is recommended for patients with Paget´s disease.

8). 8). The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with Zoledronic Acid Altan in patients with concomitant risk factors.

The following should be considered when evaluating a patient’s risk of developing ONJ: - Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.

g. anaemia, coagulopathies, infection), smoking. - Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck. g. tooth extractions. All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, non-healing of sores or discharge during treatment with zoledronic acid.

While on treatment, invasive dental procedures should be performed with caution and avoided in close proximity to zoledronic acid treatment. The management plan for patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ.

Temporary interruption of zoledronic acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible. Osteonecrosis of the external auditory canal Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy.

Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.

Atypical fractures of the femur Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare.

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