Medicinal Products

ZOLEDRONIC ACID ZENTIVA LAB 4 mg / 100 ml solution for infusion box of 1 vial of 100 ml

Generic drug from Zometa
Therapeutic class: Rheumatology
active ingredients: Zoledronic Acid
laboratory: Sanofi-Aventis France

Injection solution for IV infusion
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 ZENTIVA LAB 4 mg / 100 ml solution for infusion box of 1 vial of 100 ml

· 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.

Against indications

· Hypersensitivity to the active substance, other bisphosphonates or to any of the excipients listed under Composition

· Breastfeeding (see section on Pregnancy and breastfeeding ).

Zoledronic acid Zentiva Lab undesirable effects

Summary of the security profile

An acute phase reaction has generally been reported within three days following zoledronic acid administration with symptoms including bone pain, fever, fatigue, arthralgia, myalgia, chills, and arthritis with subsequent joint swelling; 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 phase reaction, hypocalcemia, atrial fibrillation, anaphylaxis, interstitial pneumonitis. 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 from clinical studies and reports of post-marketing adverse events, mainly after chronic administration of zoledronic acid 4 mg:

Table 2

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

Blood and lymphatic system disorders

Frequent

Anemia.

Rare

Thrombocytopenia, leucopenia.

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

Headache.

Rare

Dizziness, paresthesia, dysgeusia, hypoesthesia, hyperesthesia, tremors, drowsiness.

Very rare

Convulsions, hypoesthesia and tetany (secondarily to hypocalcemia).

Eye disorders

Frequent

Conjunctivitis.

Rare

Blurred vision, scleritis and orbital inflammation.

Rare

Uveitis.

Very rare

Episcleritis.

Heart conditions

Rare

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

Rare

Bradycardia, cardiac arrhythmia (secondarily to hypocalcemia).

Respiratory, thoracic and mediastinal disorders

Rare

Dyspnoea, cough, bronchoconstriction.

Rare

Interstitial pneumonitis.

Gastrointestinal disorders

Frequent

Nausea, vomiting, decreased appetite.

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 spasm, osteonecrosis of the jaw.

Renal and urinary disorders

Frequent

Renal damage.

Rare

Acute renal failure, hematuria, proteinuria.

General disorders and administration site conditions

Frequent

Fever, flu-like syndrome (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.

Rare

Symptoms of the acute phase reaction:

arthritis and joint swelling.

investigations

Very common

Hypophosphatemia.

Frequent

Increased serum creatinine and serum uric acid, hypocalcemia.

Rare

Hypomagnesemia, hypokalemia.

Rare

Hyperkalemia, hypernatremia.

Description of selected adverse reactions

Impairment of renal function

Alterations in renal function have 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 include dehydration, pre-existing renal impairment, repeated cycles of zoledronic acid or other bisphosphonates, concomitant use of nephrotoxic drugs, and a 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 and treated with drugs that inhibit bone resorption, such as ZOLEDONIC ACID ZENTIVA LAB. 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.

Acute phase reaction

This side effect consists of a constellation of symptoms that include fever, myalgia, headache, extremity pain, nausea, vomiting, diarrhea, arthralgia, and arthritis with consequent joint swelling. 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 reactions have been reported (rare frequency): atypical subtrochanteric and diaphyseal femoral fractures (class-related bisphosphonate side effects).

Side effects related to hypocalcemia

Hypocalcemia is a significant risk identified with zoledronic acid in its approved indications. The review of hypocalcemia cases from clinical trials and cases of hypocalcemia reported since the time of marketing provides sufficient evidence to establish the link between treatment with zoledronic acid, the occurrence of hypocalcemia and appearance of secondary cardiac arrhythmia. Similarly, there is evidence of an association between hypocalcemia and secondary neurological effects reported in these cases, including: convulsions, hypoaesthesia, and tetanus (see Warnings and Precautions section ).

Reporting of suspected adverse reactions

The reporting of suspected adverse reactions after authorization of the drug is important. It allows continuous monitoring of the benefit / risk ratio of the drug. Health professionals declare any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (Ansm) and the network of Regional Pharmacovigilance Centers - Website: www.ansm.sante.fr.

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