Sandronic

Zoledronic Acid.

Each 100 mL contains: Zoledronic Acid Monohydrate equivalent to Zoledronic Acid 4 mg.

Pharmacology: Zoledronic Acid Monohydrate belongs to the class of bisphosphonates and acts primarily on bone. It is an inhibitor of osteoclastic bone resorption.
The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone, but the precise molecular mechanism leading to the inhibition of osteoclastic activity is still unclear. Zoledronic Acid Monohydrate inhibits bone resorption without adversely affecting the formation, mineralization or mechanical properties of bone.

Prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor induced hypercalcemia) in patients with advanced malignancies involving bone.
Treatment of hypercalcemia of malignancy (HCM).

DOSAGE: SANDRONIC 4 mg/100 mL solution for infusion is a ready to use presentation and must not be further diluted or mixed with other infusion solutions except for patients with renal impairment. It should be administered as a single intravenous solution in a separate infusion line in no less than 15 minutes.
Prevention of skeletal related events in patients with advanced malignancies involving bone: In adults and elderly patients the recommended SANDRONIC dose is a single 4 mg infusion given every 3-4 weeks.
Patients should also be administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily.
Treatment of Hypercalcemia of Malignancy (HCM): In adults and elderly patients the recommended SANDRONIC dose in hypercalcemia (albumin-corrected serum calcium ≥ 12.0 mg/dl or 3.0 mmol/L) is a single 4 mg infusion. Patients must be maintained well hydrated prior to and following administration of SANDRONIC.
Treatment of patients with renal impairment: Patients with hypercalcemia of malignancy (HCM): SANDRONIC treatment in patients with hypercalcemia of malignancy (HCM) and who have severe renal impairment should be considered only after evaluating the risks and benefit of treatment. No dose adjustment is necessary in HCM patients with serum creatinine < 400 micromol/L or 4.5 mg /dL (see Precautions).
Prevention of skeletal related events in patients with advanced malignancies involving bone: When initiating treatment with SANDRONIC in patients with multiple myeloma or metastatic bone lesions from solid tumors, serum creatinine levels and creatinine clearance (CrCl) should be determined. CrCl is calculated from serum creatinine levels using the Cockcroft-Gault formula. SANDRONIC is not recommended for patients presenting with severe renal impairment prior to initiation of therapy, which is defined for this population as CrCl < 30 mL/min.
In patients with bone metastases presenting with mild to moderate renal impairment prior to initiation of therapy, which is defined for this population as CrCl 30-60 mL/min, the following SANDRONIC dose is recommended. (See Table 1.)


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Following initiation of therapy, serum creatinine should be measured prior to each dose of SANDRONIC and treatment should be withheld if renal function has deteriorated. Renal deterioration was defined as follows: For patients with normal baseline serum creatinine (< 1.4 mg/dL) an increased of ≥ 0.5 mg/dL.
For patients with an abnormal baseline serum creatinine (> 1.4 mg/dL) an increased of > 1.0 mg/dL.
SANDRONIC treatment was resumed only when the creatinine level returned to within 10% of the baseline value. SANDRONIC should be resumed at the same dose as that prior to treatment interruption.
Administration: Zoledronic Acid Monohydrate must only be administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates.
Zoledronic Acid Monohydrate must not be mixed with calcium or other divalent cation containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs in no less than 15 minutes. Patients must be maintained in a well hydrated state prior to and following administration of Zoledronic Acid Monohydrate.
Preparation of reduced SANDRONIC doses: In patients with mild to moderate renal impairment in patients with HCM, which is defined as CrCl 30 to 60 mL/min, reduced SANDRONIC dosages are recommended: See Table 2.


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Clinical experience with acute overdose of Zoledronic Acid Monohydrate is limited. Patients who have received doses higher than those recommended should be carefully monitored, since renal function impairment (including renal failure) and serum electrolyte (including calcium, phosphorus and magnesium) abnormalities have been observed. In the event of hypocalcemia, calcium gluconate infusions should be administered as clinically indicated.

Zoledronic Acid Monohydrate is contraindicated in pregnancy, breast feeding women, patients with hypersensitivity to Zoledronic Acid Monohydrate, other bisphosphonates or any of the excipients in the formulation of Zoledronic Acid.

General: Patients must be assessed prior to administration of Zoledronic Acid Monohydrate to ensure that they are adequately hydrated.
Overhydration should be avoided in patients at risk of cardiac failure.
Standard hypercalcemia-related metabolic parameters, such as serum albumin-corrected levels of calcium, phosphate and magnesium as well as serum creatinine should be carefully monitored after initiating Zoledronic Acid Monohydrate therapy. If hypocalcemia, hypophosphatemia, or hypomagnesaemia occur, short-term supplemental therapy may be necessary. Untreated hypercalcemia patients generally have some degree of renal function impairment, therefore careful renal function monitoring should be considered.
Zoledronic Acid Monohydrate should also not be given together with other bisphosphonates since the combined effects of these agents are unknown.
The safety and efficacy of Zoledronic Acid Monohydrate in paediatric patients have not been established. There have been reports of bronchoconstriction in acetylsalicylic acid sensitive asthmatic patients receiving bisphosphonates.
Renal impairment: Adult patients with HCM and evidence of impairment in renal function should be appropriately evaluated with consideration given as to whether the potential benefit of continued treatment with Zoledronic Acid Monohydrate 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 to 3 months.
Bisphosphonates have been associated with reports of renal function deterioration. Factors that may increase the potential for deterioration in renal function include dehydration, pre-existing renal impairment, multiple cycles of Zoledronic Acid Monohydrate or other bisphosphonates as well as use of nephrotoxic drugs or using a shorter infusion time than currently recommended. While the risk is reduced with a dose of Zoledronic Acid Monohydrate 4 mg administered over no less than 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 Zoledronic Acid Monohydrate. Increases in serum creatinine also occur in some patients with chronic administration of Zoledronic Acid Monohydrate at recommended doses for prevention of skeletal related events, although less frequently.
Serum creatinine levels should be measured before each Zoledronic Acid Monohydrate dose. In patients with mild to moderate renal impairment at the initiation of Zoledronic Acid Monohydrate treatment, lower doses are recommended in adult patients with bone metastases. In patients who show evidence of renal deterioration during treatment, Zoledronic Acid Monohydrate should only be resumed when creatinine level returns to within 10% of baseline value (see Dosage & Administration). The use of Zoledronic Acid Monohydrate is not recommended in patients with severe renal impairment, there is a risk of renal function deterioration in patients treated with bisphosphonates, including Zoledronic Acid Monohydrate.
The use of Zoledronic Acid Monohydrate is not recommended in patients with severe renal impairment, because there are limited clinical safety and pharmacokinetic data in population and there is a risk of renal function deterioration in patients treated with bisphosphonates, including Zoledronic Acid Monohydrate.
Renal function deterioration is defined as follows: Serum creatinine ≥ 400 micromol/L or ≥ 4.5 mg/mL for patients with HCM.
Serum creatinine ≥ 265 micromol/L or ≥ 3.0 mg/mL for patients with cancer and bone metastases respectively.
In pharmacokinetics studies, patients with severe renal impairment were defined as those with baseline creatinine clearance < 30 mL/minute.
Atypical fractures of the femur: Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving 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. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in Zoledronic Acid Monohydrate-treated patients, who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of Zoledronic Acid Monohydrate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. Reports of atypical femoral fracture have been received in patients treated with Zoledronic Acid Monohydrate, however causality with Zoledronic Acid Monohydrate therapy has not been established. During Zoledronic Acid Monohydrate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Hepatic impairment: As only limited data are available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.
Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) has been reported predominantly in adult cancer patients treated with bisphosphonate, including Zoledronic Acid Monohydrate. Many of these patients were also receiving chemotherapy and corticosteroids. Many had signs of local infection including osteomyelitis.
Post marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures).
Patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonate.
While on treatment with bisphosphonate, patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. Clinical judgment of the treating physician should guide the management plan of each patient based of individual benefit/risk assessment.
Osteonecrosis of other anatomical sites: Cases of osteonecrosis of other anatomical sites including the hip, femur and external auditory canal have been reported predominantly in adult cancer patients treated with bisphosphonates, including Zoledronic Acid Monohydrate.
Musculoskeletal pain: Severe and occasionally incapacitating bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates, including Zoledronic Acid Monohydrate. However, such reports have been infrequent. This category includes Zoledronic Acid Monohydrate. The time to onset of symptoms varied from one day to several months after starting treatment. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when re-challenged with the same drug or another bisphosphonate.
Hypocalcemia: Hypocalcemia has been reported in patients treated with Zoledronic Acid Monohydrate. Cardiac arrhythmias and neurologic adverse events (seizures, tetany and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, the hypocalcemia may be life-threatening. Caution is advised when Zoledronic Acid Monohydrate is administrated with other hypocalcemia causing drugs, as they may have synergistic effect resulting in severe hypocalcemia. Serum calcium should be measured and hypocalcemia must be corrected before initiating Zoledronic Acid Monohydrate therapy. Patients should be adequately supplemented with calcium and vitamin D.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.
Women of Child-bearing potential: Women of Child-bearing potential should be advised to avoid becoming pregnant and advised of the potential hazard to the fetus while receiving Zoledronic Acid Monohydrate. There may be risk of fetal harm (e.g. skeletal and other abnormalities) if a woman becomes pregnant while receiving bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration on this risk has not been established.
Fertility: The Fertility was decreased in rats dosed subcutaneously with 0.1 mg/kg/day of Zoledronic Acid Monohydrate. There are no data available in humans.
Use in Pregnancy: Studies in rats have shown reproductive toxicological effects. The potential risk in humans is unknown Zoledronic Acid Monohydrate should not be used during pregnancy (see Contraindications).
Use in Lactation: It is not known whether Zoledronic Acid Monohydrate is excreted into human milk. Zoledronic Acid Monohydrate should not be used by breast-feeding women (see Contraindications).

Women of Child-bearing potential: Women of Child-bearing potential should be advised to avoid becoming pregnant and advised of the potential hazard to the fetus while receiving Zoledronic Acid Monohydrate. There may be risk of fetal harm (e.g. skeletal and other abnormalities) if a woman becomes pregnant while receiving bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration on this risk has not been established.
Pregnancy: Studies in rats have shown reproductive toxicological effects. The potential risk in humans is unknown Zoledronic Acid Monohydrate should not be used during pregnancy (see Contraindications).
Breast-feeding: It is not known whether Zoledronic Acid Monohydrate is excreted into human milk. Zoledronic Acid Monohydrate should not be used by breast-feeding women (see Contraindications).
Fertility: The Fertility was decreased in rats dosed subcutaneously with 0.1 mg/kg/day of Zoledronic Acid Monohydrate. There are no data available in humans.

The most serious adverse drug reactions in patients receiving Zoledronic Acid Monohydrate indication are anaphylactic reaction, ocular adverse events, osteonecrosis of the jaw, atypical femoral fracture, atrial fibrillation, renal function impairment, acute phase reaction and hypocalcemia.
Adverse reactions to Zoledronic Acid Monohydrate are usually mild and transient and similar to those reported for other bisphosphonate. Those reactions can be expected to occur in approximately one third of patients treated with Zoledronic Acid Monohydrate. Within three days after Zoledronic Acid Monohydrate administration, an acute phase reaction has commonly been reported, with symptoms including pyrexia, fatigue, bone pain, chills, influenza-like illness, arthritis with subsequent joint swelling; these symptoms usually resolve within few days. Case of arthralgia and myalgia have commonly been reported.
Very commonly, the reduction in renal calcium excretion is accompanied by a fall in serum phosphate levels, which is asymptomatic not requiring treatment. Commonly, the serum calcium may fall to asymptomatic hypocalcemic levels. Gastrointestinal reactions, such as nausea and vomiting have been commonly reported following intravenous infusion of Zoledronic Acid Monohydrate. Uncommonly local reactions at the infusion site such as redness or swelling and/or pain were also observed.
Anorexia was commonly reported in patients treated with Zoledronic Acid Monohydrate 4 mg.
Rash or pruritus have been uncommonly observed. As with other bisphosphonates, cases of conjunctivitis have been commonly reported. Severe anemia (Hb < 8.0 g/dL) was commonly reported in patients receiving Zoledronic Acid Monohydrate 4 mg. (See Table 3.)


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Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse reactions have been reported during post marketing experience with Zoledronic Acid Monohydrate via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency (which is therefore categorized as not known) or established a causal relationship to drug exposure.
Immune system disorders: Anaphylactic reaction/shock.
Nervous system disorders: Somnolence.
Eye disorders: Episcleritis, scleritis and orbital inflammation.
Cardiac disorders: Atrial fibrillation.
Vascular disorders: Hypotension leading to syncope or circulatory collapse, primarily in patients with underlying risk factors.
Respiratory, thoracic and mediastinal disorders: Bronchospasm.
Skin and subcutaneous tissue disorders: Urticaria.
Musculoskeletal and connective tissue disorders: Severe and occasionally incapacitating bone, joint and/or muscle pain, atypical subtrochanteric and diaphyseal femoral fractures (adverse reaction, including Zoledronic Acid Monohydrate).

Anticipated interaction to be considered: Caution is advised when bisphosphonates like Zoledronic Acid Monohydrate are administered with aminoglycosides and loop diuretics, since both agents may have an additive effect, resulting in a lower serum of calcium level for longer periods than required (see Precautions).
Caution is indicated when Zoledronic Acid Monohydrate is used with other potentially nephrotoxic drugs (see Adverse Reactions).
Observed interactions to be considered: Caution is advised when Zoledronic Acid Monohydrate is administered with anti-angiogenic drugs as an increase in incidence of ONJ have been observed in patients treated concomitantly with these drugs.
Absence of interactions: Zoledronic Acid Monohydrate has been administered concomitantly with commonly used anticancer agents, diuretics (except for loop diuretics, see Anticipated interaction to be considered as previously mentioned), antibiotics and analgesics without clinically apparent interactions occurring. No dose adjustment for Zoledronic Acid Monohydrate 4 mg is needed when co-administered with Thalidomide.
Zoledronic Acid Monohydrate 4 mg given as a 15 minutes infusion was administrated either alone or with Thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of Thalidomide with Zoledronic Acid Monohydrate did not significantly change the pharmacokinetics of Zoledronic Acid Monohydrate or creatinine clearance.

Store below 30°C.

Agents Affecting Bone Metabolism

M05BA08 - zoledronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.

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