Medicinal Products

ACLASTA 5 mg

Generic drug of the therapeutic class: Rheumatology
active ingredients: Zoledronic acid
laboratory: Novartis Europharm Ltd

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

● in men at high risk of fractures.

Treatment of Paget's disease in adults.

Dosage ACLASTA 5 mg Solution for injection for infusion IV Box of 1 vial of 100 ml

Dosage

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

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

In patients who have had a recent hip fracture secondary to moderate trauma, it is recommended that Aclasta be administered 2 weeks or more after surgery on the fracture (see section 5.1 ).

For Paget's disease, Aclasta should only be prescribed by doctors experienced in the treatment of this pathology. The recommended dose is a single intravenous infusion of 5 mg Aclasta.

Repetition of Paget's Disease Treatment: Patients responding to treatment of Paget's disease after the initial administration of Aclasta experienced a prolonged period of remission. Repeated treatment consists of an additional intravenous infusion of 5 mg Aclasta at an interval of one year or more from initial administration in patients for whom it has been relapsed. 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 Aclasta. 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 Aclasta. 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 Aclasta (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 Aclasta infusion. .

The incidence of adverse reactions occurring within the first three days after Aclasta administration may be decreased by administering paracetamol or ibuprofen after Aclasta administration.

Patients with renal insufficiency

Aclasta is contraindicated in patients with creatinine clearance <35 ml / min (see sections Contraindications and Warnings and Precautions ).

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 effectiveness of Aclasta in children and adolescents under 18 years of age have not been established

Administration mode

Intravenous way

Aclasta (5 mg in 100 ml of ready-to-use solution) is administered infusion route and given a constant infusion rate. The infusion time should not be less than 15 minutes. For information on infusion of Aclasta, 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 section Warnings and precautions for use ).

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

- Pregnancy or breastfeeding (see section Pregnancy and lactation ).

Aclasta side effects

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 annual Aclasta sucrose doses. The majority of these effects occurred within the first three days after administration of Aclasta, 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 Aclasta administration may be decreased by administering paracetamol or ibuprofen shortly after administration of Aclasta if necessary (see section 4.2). ).

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 Aclasta and placebo, respectively. The rate of atrial fibrillation classified as serious adverse events was 1.3% (51/3862) in Aclasta-treated patients compared to 0.6% (22/3852) in placebo-treated patients. 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 Aclasta 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 Aclasta 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 / 1, 000, <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 Uncommon

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, upper 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

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

Rare

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

Rare

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

Not known frequency **

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

Fever

Frequent

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

Rare

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

Not known frequency **

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 (Aclasta and placebo) on a period of three years. A transient increase in serum creatinine was observed in 10 days in 1.8% of patients treated with Aclasta 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 Aclasta. 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 Aclasta compared to 21% of patients treated with Aclasta 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 Aclasta 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 Aclasta and one patient treated with placebo. In both cases, the evolution was favorable.

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