Medicinal Products

ZOLEDRONIC ACID KABI 4 mg / 5 mL

Generic drug from Zometa
Therapeutic class: Rheumatology
active ingredients: Zoledronic acid
laboratory: Fresenius Kabi France

Injectable solution for infusion or IV infusion
Box of 1 bottle of 5 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 KABI 4 mg / 5 mL Injectable solution for injection or infusion IV Box of 1 vial of 5 ml

ZOLEDRONIC ACID KABI 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 500mg 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 (HIT):

Adult and elderly subject

The recommended dose for hypercalcemia (albumin corrected serum calcium ³ 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 KABI 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 ZOLEDRONIC ACID KABI therapy in patients with multiple myeloma or with metastatic bone involvement secondary to solid tumors, serum creatinine and creatinine clearance (CL cr ) should be evaluated. CL cr is calculated according to the Cockcroft-Gault formula from serum creatinine. ZOLEDRONIC ACID KABI is not recommended in patients with severe renal impairment prior to initiation of treatment, that is, CL CL 265 μmol / l or 3.0 mg / dL were excluded.

In patients with bone metastases with mild to moderate renal impairment prior to initiation of therapy, renal impairment defined by a CL cr of 30 to 60 ml / min, the recommended dose of ZOLEDRONIC ACID KABI is as follows (see also section Warnings and precautions for use ).

Clearance of creatinine initiated at (ml / min)

Re-ordered dose of ZOLEDRONIC ACID KABI *

> 60

4.0 mg of zoleic acid

50-60

3, 5 mg * of zoleic acid

40-49

3, 3 mg * of zoleic acid

30-39

3.0 mg * of zoleic acid

* Doses were calculated to achieve an AUC value of 0.66 (mg • h / l) (for CLcr = 75 ml / min). The goal 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 before each zoledronic acid administration and treatment 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 ). Treatment with ZOLEDRONIC ACID KABI should be resumed at the same dose as before treatment discontinuation.

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, but no dosage recommendation can be made.

Administration mode

Intravenous way.

ZOLEDRONIC ACID KABI 4 mg / 5 ml concentrate for solution for infusion, then diluted in 100 ml (see section Instructions for use, handling and disposal ), should be administered as a single intravenous infusion for a duration of at least 15 minutes.

In patients with mild to moderate renal impairment, reduced doses of ZOLEDRONIC ACID KABI are recommended (see section "Posology" above and Warnings and Precautions section ).

Instructions for preparing reduced doses of KABI ZOLEDRONIC ACID

Take an appropriate volume of the concentrated solution, as follows:

· 4.4 ml for a dose of 3.5 mg

· 4.1 ml for a dose of 3.3 mg

· 3.8 ml for a dose of 3.0 mg

The amount taken from the concentrated solution should then be diluted in 100 ml sterile 0.9% w / v sodium chloride solution or 5% w / v glucose solution. The dose should be administered as an intravenous infusion lasting at least 15 minutes.

ZOLEDRONIC ACID KABI should not be mixed with solutions containing calcium or other infusion solutions containing divalent cations such as lactated Ringer's solution and should be administered in a dissociated manner from other infusions via a separate line.

Patients should be properly hydrated before and after administration of ZOLEDRONIC ACID KABI.

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 Kabi

Summary of the security profile

Within three days of administration of ZOLEDRONIC ACID KABI, as indicated in the Therapeutic Indications and Dosage and Method of Administration sections, an acute reaction phase has generally been reported 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 1.

Table of adverse effects

The following adverse reactions, listed in Table 1, were collected in clinical studies and reports of post-marketing adverse events, mainly after chronic administration of zoledronic acid 4 mg:

Table 1

Adverse reactions are listed 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 / 10000, <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 *

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 reaction / 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, used as indicated in the sections Therapeutic indications and Dosage and method of administration . Individually recruited clinical trials were conducted to investigate the incidence of bone-related adverse effects of zoledronic acid. The various safety analyzes drawn from these tests show that impairments of renal function are as follows: multiple myeloma (3.2%), prostate cancer (3.1%), breast cancer (4.3%), lung tumors and solids (3.2%). Factors that may increase the risk of deterioration of renal function are dehydration, pre-existing renal impairment, repeated cycles of ZOLEDRONIC ACID KABI 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 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.

Reaction in acute phase

This side effect consists of a set 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, used as indicated in the sections Therapeutic indications and Dosage and method of administration . 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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