Medicinal Products

ZOLEDRONIC ACID SANDOZ 4 mg / 100 mL

Generic drug from Zometa
Therapeutic class: Rheumatology
active ingredients: Zoledronic acid
laboratory: Sandoz

Injection solution for IV infusion
Box of 1 bottle of 100 ml
All forms

Indication

· Prevention of bone complications (pathological fractures, spinal cord compression, irradiation or bone surgery, tumor-induced hypercalcemia) in adult patients with advanced malignant disease with bone involvement.

· Treatment of tumor-induced hypercalcemia (HIT) in adult patients.

Dosage ZOLEDRONIC ACID SANDOZ 4 mg / 100 mL Solution for IV infusion Pack of 1 vial of 100 ml

Zoledronic acid Sandoz should only be prescribed and administered to patients by healthcare professionals who have experience with intravenous bisphosphonate administration.

Dosage

Prevention of bone complications in patients with advanced malignant disease with bone involvement

Adult and elderly subject

The recommended dose for the prevention of bone complications in patients with advanced malignant bone disease is 4 mg zoledronic acid every 3 to 4 weeks.

Patients should also receive an oral intake of 500 mg of calcium and 400 IU of vitamin D per day.

The decision to treat patients with bone metastases to prevent bone-related complications should be considered taking into account that the time for treatment is 2 to 3 months.

Treatment of tumor-induced hypercalcemia

Adult and elderly subject

The recommended dose for hypercalcemia (albumin-corrected serum albumin ≥12.0 mg / dl or 3.0 mmol / l) is a single dose of 4 mg zoledronic acid.

Renal failure

TIH:

Treatment with Zoledronic Acid Sandoz in patients with tumor-induced hypercalcemia and severe renal impairment should be considered only after evaluation of the risks and benefits of this treatment. In clinical studies, patients with serum creatinine> 400 μmol / l or> 4.5 mg / dl were excluded. No dose adjustment is necessary in patients with tumor-induced hypercalcemia with serum creatinine <400 μmol / l or <4.5 mg / dl (see Warnings and Precautions ).

Prevention of bone complications in patients with advanced malignant pathology with bone involvement:

Upon initiation of Sandoz Zoledronic Acid therapy in patients with multiple myeloma or with metastatic bone involvement secondary to solid tumors, serum creatinine and creatinine clearance (CLcr) should be evaluated. CLcr is calculated according to the Cockcroft-Gault formula from serum creatinine. Zoledronic acid Sandoz is not recommended in patients with severe renal impairment prior to initiation of treatment, renal impairment which is defined by CLcr 265 μmol / l or 3.0 mg / dl were excluded.

In patients with normal renal function (defined by a Clcr> 60 ml / min), zoledronic acid 4 mg / 100 ml solution for infusion can be directly administered without further preparation.

In patients with bone metastases with mild to moderate renal impairment prior to initiation of renal impairment, which is defined by a CLcr of 30 to 60 ml / min, the recommended dose of Zoledronic Acid Sandoz is as follows (see section 4.4). Warnings and precautions for use ).

Initial creatinine clearance (ml / min)

Recommended Dose of Zoledronic Acid Sandoz *

> 60

4.0 mg zoledronic acid

50-60

3.5 mg * zoledronic acid

40-49

3.3 mg * zoledronic acid

30-39

3.0 mg * zoledronic acid

* Doses were calculated to achieve an AUC value of 0.66 (mg • h / l) (for CLcr = 75 ml / min). The aim is that in patients with renal impairment, reduced doses of zoledronic acid will achieve the same AUC as observed in patients with a creatinine clearance of 75 ml / min.

After initiation of treatment, serum creatinine should be measured prior to Zoledronic Acid Sandoz administration and should be discontinued if renal function has deteriorated. In clinical studies the impairment of renal function was defined as follows:

· An increase of 0.5 mg / dl or 44 μmol / l in patients who had a baseline creatinine value (<1.4 mg / dl or <124 μmol / l).

· An increase of 1.0 mg / dL or 88 μmol / L in patients who had an abnormal baseline creatinine value (> 1.4 mg / dL or> 124 μmol / L).

In clinical studies, treatment with zoledronic acid was resumed only when the serum creatinine value returned to the baseline ± 10%. (See Warnings and Precautions section ). Treatment with Zoledronic Acid Sandoz should be resumed at the same dose as that given before discontinuation of therapy.

Pediatric population

The safety and efficacy of zoledronic acid in children aged 1 to 17 years has not been established. Currently available data are described under Pharmacodynamic properties and Pharmacokinetic properties, but no dosage recommendation can be given.

Administration mode

Intravenous way.

Zoledronic acid Sandoz 4 mg / 100 ml solution for infusion should be administered as a single intravenous infusion lasting at least 15 minutes.

In patients with normal renal function, function defined by a Clcr> 60 ml / min, zoledronic acid 4 mg / 100 ml solution for infusion, should not be diluted.

In patients with mild to moderate renal impairment, reduced doses of Zoledronic Acid Sandoz are recommended (see section "Posology" above and section 5.2 Pharmacokinetic properties ).

For the preparation of reduced doses for patients with an initial Clcr ≤ 60 ml / min, refer to Table 1 below. Remove the indicated volume of Zoledronic Acid Sandoz solution from the vial and replace with an equivalent volume of sterile 9 mg / ml (0.9%) sodium chloride solution for injection or a 5% glucose solution for injection.

Table 1: Preparation of reduced doses of Zoledronic Acid Sandoz 4 mg / 100 ml solution for infusion

Clearance of initial creatine (ml / min)

Remove the following volume of Zoledronic Acid Sandoz Solution for Infusion (ml) from the vial

Replace with an equivalent volume of sterile sodium chloride 9 mg / ml (0.9%) or 5% glucose solution for injection (ml)

Adequate dose (mg zoledronic acid in 100 ml)

50-60

12.0

12.0

3.5

40-49

18.0

18.0

3.3

30-39

25.0

25.0

3.0

Zoledronic Acid Sandoz 4 mg / 100 ml solution for infusion should not be mixed with other infusion solutions and should be administered separately from other infusions via a separate line.

Patients should be properly hydrated before and after administration of Zoledronic Acid Sandoz.

Against indications

· Hypersensitivity to the active substance, to other bisphosphonates or to any of the excipients listed in section Composition .

· Breastfeeding (see section on Pregnancy and breastfeeding ).

Adverse effects Zoledronic acid Sandoz

Summary of the security profile

An acute reaction phase has generally been reported within three days of zoledronic acid administration with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, and chills; these symptoms usually resolve within a few days (see description of selected side effects).

The significant risks identified with zoledronic acid in approved indications are as follows:

Impairment of renal function, osteonecrosis of the jaw, acute reaction phase, hypocalcemia, ocular adverse effects, atrial fibrillation, anaphylaxis. The frequency of each of these identified risks is presented in Table 2.

Table of adverse effects

The following adverse reactions, listed in Table 2, were collected in clinical studies and reports of post-marketing adverse events, mainly after chronic administration of zoledronic acid 4 mg:

Table 2

Adverse reactions are ranked in order of decreasing frequency using the following convention: very common (≥1 / 10), common (≥1 / 100, <1/10), infrequent (≥1 / 1000, <1 / 100), rare (≥1 / 10, 000, <1/1000), very rare (<1 / 10, 000), not known (can not be estimated based on available data).

Blood and lymphatic system disorders

Frequent

Anemia

Rare

Thrombocytopenia, leukopenia

Rare

pancytopenia

Immune system disorders

Rare

Hypersensitivity reaction

Rare

Quincke's edema (angioneurotic)

Psychiatric disorders

Rare

Anxiety, sleep disorders

Rare

Confusion

Nervous system disorders

Frequent

cephalalgia

Rare

Dizziness, paresthesia, taste disturbance, hypoesthesia, hyperesthesia, tremors, drowsiness

Eye disorders

Frequent

Conjunctivitis

Rare

Blurred vision, scleritis and orbital inflammation

Very rare

Uveitis, episcleritis

Heart conditions

Rare

Hypertension, hypotension, atrial fibrillation, hypotension may lead to syncope or circulatory collapse

Rare

bradycardia

Respiratory, thoracic and mediastinal disorders

Rare

Dyspnoea, cough, bronchoconstriction

Gastrointestinal disorders

Frequent

Nausea, vomiting, anorexia

Rare

Diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth

Skin and subcutaneous tissue disorders

Rare

Pruritus, rash (including erythematous and macular eruptions), increased sweating

Musculoskeletal and systemic disorders

Frequent

Bone pain, myalgia, arthralgia, generalized pain

Rare

Muscle cramps, osteonecrosis of the jaw *

Rare

Atypical subtrochanteric and diaphyseal femoral fractures (class-related adverse effects of bisphosphonates)

Renal and urinary disorders

Frequent

Renal impairment

Rare

Acute renal failure, hematuria, proteinuria

General disorders and administration site conditions

Frequent

Fever, flu-like symptoms (including fatigue, chills, malaise and flushing)

Rare

Asthenia, peripheral edema, injection site reactions (including pain, irritation, swelling, induration), chest pain, weight gain, anaphylactic shock, urticaria

investigations

Very common

hypophosphatemia

Frequent

Increased serum creatinine and serum calcium, hypocalcemia

Rare

Hypomagnesemia, hypokalemia

Rare

Hyperkalemia, hypernatremia

* Based on clinical trials with review of possible cases of osteonecrosis of the jaw. Because these reports are confounding, it is not possible to reliably establish a causal relationship to drug exposure.

Description of selected adverse reactions

Impairment of renal function

Impaired renal function has been reported with zoledronic acid. In a pooled analysis of safety data from registration studies in patients with advanced bone marrow malignancies treated for the prevention of musculoskeletal events, the frequency of suspected renal failure to be related to zoledronic acid (adverse effects) was: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung tumors and other solid tumors (3.2%). Factors that may increase the risk of deterioration of renal function are dehydration, pre-existing renal impairment, repeated cycles of zoledronic acid or other bisphosphonates, concomitant use of nephrotoxic drugs and shorter infusion time than the recommended one. Impairment of renal function, progression of renal failure and dialysis have been reported in patients following the first dose or a single dose of 4 mg zoledronic acid (see Warnings and Precautions section). )

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly jaw) have been reported, mainly in patients with cancer treated with drugs that inhibit bone resorption, such as zoledronic acid. Many of these patients showed signs of local infection including osteomyelitis, and the majority of cases involved cancer patients who underwent tooth extraction or other dental surgeries. Osteonecrosis of the jaw has multiple documented risk factors including diagnosis of cancer, associated treatments (eg, chemotherapy, radiotherapy, corticosteroids) and associated conditions (eg, anemia, bleeding disorders, infection pre-existing oral disease). Although causality has not been established, it is recommended that dental surgery be avoided and that healing may be delayed (see Warnings and Precautions section ).

Atrial fibrillation

In a 3-year, randomized, double-blind controlled trial that evaluated the efficacy and safety of 5 mg once-yearly zoledronic acid versus placebo in the treatment of postmenopausal osteoporosis (OPM), the overall incidence of atrial fibrillation was 2.5% (96/3862) in the zoledronic acid arm and 1.9% (75/3852) in the placebo arm.

The rate of atrial fibrillations classified as serious adverse events was 1.3% (51/3862) in the zoledronic acid arm and 0.6% (22/3852) in the placebo arm. The imbalance observed in this study was not observed in other studies with zoledronic acid, including those with Zometa (zoledronic acid) 4 mg given every 3-4 weeks in patients treated oncology. The mechanism of the increase of this incidence of atrial fibrillation in this single clinical study is not known.

Acute phase reaction

This side effect consists of a constellation of symptoms that include fever, myalgia, headache, extremity pain, nausea, vomiting, diarrhea, and arthralgia. The time to onset of these symptoms is ≤ 3 days after infusion of zoledronic acid. All of these symptoms can be presented as "flu-like" or "post-dose" symptoms.

Atypical fractures of the femur

After commercialization, the following adverse effects have been reported (rare frequency): atypical subtrochanteric and diaphyseal femoral fractures (class-related bisphosphonate side effects).

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