Zoledronic acid Teva · 4.6 Fertility, pregnancy and lactation · 1

HOS-096200 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile Within three days after zoledronic acid administration, an acute phase reaction has commonly been reported, with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, rigors and arthritis with subsequent joint swelling; these symptoms usually resolve within a few days (see description of selected adverse reactions). The following are the important identified risks with zoledronic acid in the approved indications: Renal function impairment, osteonecrosis of the jaw, acute phase reaction, hypocalcaemia, atrial fibrillation, anaphylaxis, interstitial lung disease. The frequencies for each of these identified risks are shown in Table 1. Tabulated list of adverse reactions The following adverse reactions, listed in Table 1, have been accumulated from clinical studies and post-marketing reports following predominantly chronic treatment with 4 mg zoledronic acid: 7 Table 1 Adverse reactions are ranked under headings of frequency, the most frequent first, 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). Blood and lymphatic system disorders Common: Anaemia Uncommon: Thrombocytopenia, leukopenia Rare: Pancytopenia Immune system disorders Uncommon: Hypersensitivity reaction Rare: Angioneurotic oedema Psychiatric disorders Uncommon: Anxiety, sleep disturbance Rare: Confusion Nervous system disorders Common: Headache Uncommon: Dizziness, paraesthesia, dysgeusia, hypoaesthesia, hyperaesthesia, tremor, somnolence Very rare: Convulsions, hypoaesthesia and tetany (secondary to hypocalcaemia) Eye disorders

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HOS-096196 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients listed in section 6.1 • Breast-feeding (see section 4.6)

HOS-096195 · has-indication-information · PDF-Seite 2

- Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in adult patients with advanced malignancies involving bone. - Treatment of adult patients with tumour-induced hypercalcaemia (TIH).

HOS-096198 · has-interaction-information · PDF-Seite 6

In clinical studies, zoledronic acid has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro (see section 5.2), but no formal clinical interaction studies have been performed. 6 Caution is advised when bisphosphonates are administered with aminoglycosides, calcitonin or loop diuretics, since these agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required (see section 4.4). Caution is indicated when Zoledronic Acid Teva is used with other potentially nephrotoxic medicinal products. Attention should also be paid to the possibility of hypomagnesaemia developing during treatment. In multiple myeloma patients, the risk of renal dysfunction may be increased when Zoledronic Acid Teva is used in combination with thalidomide. Caution is advised when Zoledronic Acid Teva is administered with anti-angiogenic medicinal products as an increase in the incidence of ONJ has been observed in patients treated concomitantly with these medicinal products.

HOS-096199 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction studies with zoledronic acid have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Zoledronic Acid Teva should not be used during pregnancy. Women of child-bearing potential should be advised to avoid becoming pregnant. Breast-feeding It is not known whether zoledronic acid is excreted into human milk. Zoledronic Acid Teva is contraindicated in breast-feeding women (see section 4.3). Fertility Zoledronic acid was evaluated in rats for potential adverse effects on fertility of the parental and F1 generation. This resulted in exaggerated pharmacological effects considered to be related to the compound’s inhibition of skeletal calcium metabolisation, resulting in periparturient hypocalcaemia, a bisphosphonate class effect, dystocia and early termination of the study. Thus these results precluded determining a definitive effect of zoledronic acid on fertility in humans.

HOS-096197 · has-warning-information · PDF-Seite 4

General Patients must be assessed prior to administration of Zoledronic Acid Teva to ensure that they are adequately hydrated. Overhydration should be avoided in patients at risk of cardiac failure. Standard hypercalcaemia-related metabolic parameters, such as serum levels of calcium, phosphate and magnesium, should be carefully monitored after initiating Zoledronic Acid Teva therapy. If hypocalcaemia, hypophosphataemia, or hypomagnesaemia occurs, short-term supplemental therapy may be necessary. Untreated hypercalcaemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered. Other medicinal products containing zoledronic acid as active substances are available for osteoporosis indications and treatment of Paget´s disease of the bone. Patients being treated with Zoledronic acid Teva should not be treated with such medicinal products or any other bisphosphonate concomitantly, since the combined effects of these agents are unknown. Renal insufficiency Patients with TIH and evidence of deterioration in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of treatment with Zoledronic Acid Teva outweighs the possible risk. The decision to treat patients with bone metastases for the prevention of skeletal related events should consider that the onset of treatment effect is 2-3 months. Zoledronic acid has been associated with reports of renal dysfunction. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of zoledronic acid and other bisphosphonates as well as use of other nephrotoxic medicinal products. While the risk is reduced with a dose of 4 mg zoledronic acid administered over 15 minutes, deterioration in renal function may still occur. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of 4 mg zoledronic acid. Increases in serum creatinine also occur in some patients with chronic administration of zoledronic acid at recommended doses for prevention of skeletal related events, although less frequently. 4 Patients should have their serum creatinine levels assessed prior to each dose of zoledronic acid. Upon initiation of treatment in patients with bone metastases with mild to moderate renal impa

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