Medicinal Products

ZOLEDRONIC ACID BIOGARAN 5 mg / 100 mL

Generic drug from Aclasta
Therapeutic class: Rheumatology
active ingredients: Zoledronic acid
laboratory: Biogaran

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

Indication

Treatment of

· Postmenopausal osteoporosis

· Male osteoporosis

in patients at high risk of fracture, especially in patients who have had a recent hip fracture secondary to moderate trauma.

Treatment of osteoporosis associated with long-term systemic corticosteroid therapy

· In postmenopausal women

· at men's

at high risk of fractures.

Treatment of Paget's disease in adults.

Dosage ZOLEDRONIC ACID BIOGARAN 5 mg / 100 mL Solution for IV infusion Pack of 1 vial of 100 ml

Dosage

For the treatment of postmenopausal osteoporosis, male osteoporosis and the treatment of osteoporosis associated with long-term systemic corticosteroid therapy, the recommended dose is an intravenous infusion of 5 mg BIOGARAN ZOLEDRONIC ACID, administered once a year.

The optimal duration of bisphosphonate therapy for osteoporosis has not been established. The need for further treatment should be re-evaluated periodically on a case-by-case basis depending on the benefits and potential risks of BIOGARAN ZOLEDRONIC ACID, particularly after 5 or more years of treatment.

In patients with recent hip fracture secondary to moderate trauma, administration of BIOGARAN ZOLEDRONIC ACID is recommended 2 weeks or more after the fracture procedure (see section 5.1 ).

For Paget's disease, ZOLEDRONIC ACID BIOGARAN should only be prescribed by physicians experienced in the treatment of this condition. The recommended dose is a single intravenous infusion of 5 mg BIOGARAN ZOLEDRONIC ACID.

Repetition of Paget's Disease Treatment: Patients responding to the treatment of Paget's disease after the initial administration of BIOGARAN ZOLEDRONIC ACID were observed to have a prolonged period of remission. Repeated treatment consists of an additional intravenous infusion of 5 mg BIOGARAN ZOLEDRONIC ACID at intervals of one year or more from initial administration in patients for whom relapse has been observed. There is limited data available for repeated treatment of Paget's disease (see section 5.1 ).

Patients should be properly hydrated prior to administration of BIOGARAN ZOLEDRONIC ACID. This is particularly important for elderly patients and patients receiving diuretic therapy.

A suitable intake of calcium and vitamin D is recommended simultaneously with the administration of ZOLEDRONIC ACID BIOGARAN. In addition, in patients with Paget's disease, it is strongly advised to administer adequate calcium supplementation corresponding to a calcium-element intake of at least 500 mg twice daily for at least 10 days. following administration of BIOGARAN ZOLEDRONIC ACID (see Warnings and Precautions ) section.

In patients who have had a recent hip fracture secondary to moderate trauma, it is recommended that a loading dose of 50, 000 to 125, 000 IU of vitamin D be administered orally or intramuscularly before the first ZOLEDRONIC ACID infusion. BIOGARAN.

The incidence of adverse reactions occurring within the first three days after administration of BIOGARAN ZOLEDRONIC ACID may be decreased by administration of paracetamol or ibuprofen following administration of BIOGARAN ZOLEDRONIC ACID.

Patients with renal insufficiency

ZOLEDRONIC ACID BIOGARAN is contraindicated in patients with creatinine clearance <35 ml / min (see sections 4.3 and 4.4 ).

No dose adjustment is required in patients with creatinine clearance ≥ 35 ml / min.

Hepatic insufficiency patients

No dose adjustment is required (see section 5.2 ).

Elderly patients (≥ 65 years old)

No dose adjustment is necessary since bioavailability, distribution and elimination were similar in elderly patients and in younger patients.

Pediatric population

The safety and efficacy of BIOGARAN ZOLEDRONIC ACID in children and adolescents under 18 years of age have not been established.

Administration mode

Intravenous way.

ZOLEDRONIC ACID BIOGARAN (5 mg in 100 ml of ready-to-use solution) is administered by infusion and given at a constant infusion rate. The infusion time should not be less than 15 minutes. For information on infusion of ZOLEDRONIC ACID BIOGARAN, see section Instructions for use, handling and disposal .

Against indications

· Hypersensitivity to the active substance, other bisphosphonates or to any of the excipients.

· Patients with hypocalcemia (see Warnings and Precautions section ).

· Severe renal insufficiency with creatinine clearance <35 ml / min (see Warnings and Precautions ) section.

· Pregnancy or breast-feeding (see section Pregnancy and breast-feeding ).

Side effects Zoledronic acid Biogaran

The overall percentage of patients who experienced adverse events after administration was 44.7%, 16.7% and 10.2% after the first, second and third infusions, respectively. The individual incidence of these adverse events after the first administration was: fever (17.1%), myalgia (7.8%), flu-like symptoms (6.7%), arthralgia (4.8%) and headache (5.1%). The incidence of these effects decreased significantly with the annual sucrose doses of zoledronic acid. The majority of these effects occurred within the first three days after zoledronic acid administration, were mild to moderate and disappeared within three days of their onset. The percentage of patients with adverse events was 19.5%, 10.4%, 10.7% after the first, second and third infusions, respectively, in a smaller study where the symptomatic treatment described below was been used.

The incidence of adverse reactions occurring within the first three days after zoledronic acid administration may be decreased by administering paracetamol or ibuprofen soon after zoledronic acid if necessary (see section 4.2). administration ).

In the HORIZON-PFT pivotal study (postmenopausal osteoporosis) (see section 5.1 ), the overall incidence of atrial fibrillation was 2.5% (96 of 3 862) and 1.9% (75%). 3, 852) in patients receiving zoledronic acid and placebo, respectively. The rate of atrial fibrillation classified as serious adverse events was 1.3% (51/3862) in patients treated with zoledronic acid compared to 0.6% (22/3852) in patients receiving placebo. The mechanism of increase of this incidence of atrial fibrillation is not known. In the HORIZON-PFT and HORIZON-RFT studies (hip fracture study), the overall incidence of atrial fibrillation was comparable between the zoledronic acid group (2.6%) and the placebo group (2.1)%. The overall incidence of atrial fibrillation reported as a serious adverse event was 1.3% for the zoledronic acid group and 0.8% for the placebo group.

Adverse effects in Table 1 are listed according to the MedDRA system organ class classification and by frequency category. Frequency categories are defined using the following convention: very common (≥ 1/10); frequent (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10 000, <1/1000); very rare (<1 / 10, 000); indeterminate frequency (can not be estimated based on available data). Within each group frequency, adverse effects are presented in descending order of severity.

Table 1

Infections and infestations

Rare

Flu, nasopharyngitis

Blood and lymphatic system disorders

Rare

Anemia

Immune system disorders

Not known frequency **

Hypersensitivity Reactions Including Rare Cases of Bronchoconstriction, Urticaria and Angioedema and Very Rare Cases of Anaphylactic Reaction or Shock

Metabolism and nutrition disorders

Frequent

Rare

hypocalcemia *

Anorexia, decreased appetite

Psychiatric disorders

Rare

Insomnia

Nervous system disorders

Frequent

Rare

Headache, vertigo

Lethargy, paresthesia, drowsiness, tremors, syncope, dysgeusia

Eye disorders

Frequent

Rare

Rare

Not known frequency **

Ocular hyperemia

Conjunctivitis, eye pain

Uveitis, episcleritis, iritis

Scleritis and Ocular Inflammation

Affections of the ear and labyrinth

Rare

Dizziness

Heart conditions

Frequent

Rare

Atrial fibrillation

palpitations

Vascular disorders

Rare

Not known frequency **

Hypertension, flushing

Hypotension (in patients with underlying risk factors)

Respiratory, thoracic and mediastinal disorders

Rare

Cough dyspnea

Gastrointestinal disorders

Frequent

Rare

Nausea, vomiting, diarrhea

Dyspepsia, high abdominal pain, abdominal pain, gastroesophageal reflux, constipation, dry mouth, esophagitis, dental pain, gastritis #

Skin and subcutaneous tissue disorders

Rare

Rash, hyperhydrosis, pruritus, erythema

Musculoskeletal and systemic disorders

Frequent

Rare

Rare

Not known frequency **

Myalgia, arthralgia, bone pain, spinal pain, extremity pain

Cervicalgia, musculoskeletal stiffness, joint swelling, muscle spasms, shoulder pain, musculoskeletal chest pain, musculoskeletal pain, joint stiffness, arthritis, muscle weakness

Atypical Subtrochanteric and Diaphyseal Femoral Fractures † (Class Adverse Effects of Bisphosphonates)

Osteonecrosis of the jaw (see sections Warnings and precautions for use and side effects class effects)

Renal and urinary disorders

Rare

Not known frequency **

Increased creatinine, pollakiuria, proteinuria

Alteration of renal function. Cases of kidney function impairment requiring dialysis and rare cases with fatal outcome have been reported in patients with pre-existing renal impairment or other risk factors such as concomitant use of nephrotoxic drugs, diuretic or dehydration therapy following infusion (see Warnings and Precautions and Adverse Reactions Class Effects)

General disorders and administration site conditions

Very common

Frequent

Rare

Not known frequency **

Fever

Flu-like syndrome, chills, fatigue, asthenia, pain, malaise, infusion site reaction

Peripheral edema, thirst, acute inflammatory reaction, non-cardiac chest pain

Dehydration secondary to post-administration symptoms such as fever, vomiting and diarrhea

investigations

Frequent

Rare

Increased C-reactive protein

hypocalcemia

# Observed in patients taking concomitant corticosteroid therapy.

* Frequent in case of Paget's disease only. For hypocalcemia see below.

** Based on post-marketing data. The frequency can not be estimated from the available data.

† Identified since commercialization.

Class effects:

Alteration of renal function

Zoledronic acid has been associated with impaired renal function manifesting as deterioration of renal function (ie increased serum creatinine) and in rare cases acute renal failure. Impairment of renal function has been observed after zoledronic acid administration, particularly in patients with pre-existing renal impairment or additional risk factors (eg, elderly patients, chemotherapy for cancer, concomitant nephrotoxic drugs, diuretic therapy concomitant, severe dehydration, etc.). The majority of these patients received a dose of 4 mg every 3 to 4 weeks, but renal dysfunction was also observed in patients receiving a single administration.

In clinical studies in osteoporosis, changes in creatinine clearance (measured each year prior to injection) and the incidence of renal impairment were comparable in both treatment groups (zoledronic acid and placebo) over a period of three years. A transient increase in serum creatinine was observed in 10 days in 1.8% of patients treated with zoledronic acid versus 0.8% of patients treated with placebo.

hypocalcemia

In clinical studies in osteoporosis, approximately 0.2% of patients experienced a significant decrease in serum calcium (less than 1.87 mmol / l) following administration of zoledronic acid. No cases of symptomatic hypocalcemia were observed.

In patients with Paget's disease, symptomatic hypocalcemia was observed in approximately 1% of patients. In all patients, hypocalcemia was resolving.

Based on the evaluation of biological parameters from a large clinical study, transient and asymptomatic serum calcium values ​​below baseline (less than 2.10 mmol / l) were observed in 2.3 % of patients treated with zoledronic acid compared to 21% of patients treated with zoledronic acid in Paget's disease studies. The frequency of hypocalcemia was much lower with subsequent infusions.

All patients received vitamin D and calcium supplementation: in the postmenopausal osteoporosis study (PFT study), in the study on the prevention of clinical fractures after hip fracture (RFT study), and in Paget's disease studies (see also section Dosage and method of administration ). In the RFT study, the majority of patients received a vitamin D loading dose prior to zoledronic acid administration, although vitamin D levels were not routinely measured (see section 4.2). administration ).

Local reactions

In a large study, local reactions at the perfusion site, such as redness, swelling, and / or pain (0.7%), were observed after administration of zoledronic acid.

Osteonecrosis of the jaw

Cases of osteonecrosis (mainly jaw) have been reported infrequently, mainly in cancer patients treated with bisphosphonates, including zoledronic acid. Many of them showed signs of local infection including osteomyelitis. The majority of cases involve cancer patients who have undergone tooth extraction or other dental surgeries. Osteonecrosis of the jaw has many well-documented risk factors including the diagnosis of cancer, associated treatments (eg chemotherapy, radiotherapy, corticosteroids) and associated conditions (eg, anemia, bleeding disorders, infection, pre-existing oral disease). Although causality can not be established, it is prudent to avoid dental surgery, the healing of which may be delayed (see Warnings and Precautions section ). In a large clinical study in 7, 736 patients, osteonecrosis of the jaw was observed in one patient treated with zoledronic acid and one patient treated with placebo. In both cases, the evolution was favorable.

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. Healthcare 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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