Aclasta – Indications, Posology, Against indications, Undesirable effects

Aclasta – Indications, Posology, Against indications, Undesirable effects
Source RESIP-BCB
ACLASTA 5 Mg Solution for perfusion Box of 1 Bottle of 100 ml
Therapeutic class:   Rhumatology
Active ingredients:   Acid zoledronic
Statute:   Drug subjected to medical regulation
Rate of refunding S:   65%
Laboratory:   Novartis Europharm Ltd

Indications

- Treatment of:
. post-menopausic osteoporosis,
. male osteoporosis,
among patients at the high risk of fractures, in particular at the patients having had a fracture of secondary recent hip to a moderate traumatism.
- Treatment of the disease of Paget.

Posology

- For the treatment of the post-menopausic osteoporosis and the male osteoporosis, the amount recommended is an intravenous perfusion of 5 Mg of Aclasta, managed once per annum.
- Among patients having had a fracture of recent hip secondary to a moderated traumatism, it is recommended to carry out the administration of Aclasta 2 weeks or more after the intervention on the fracture (see heading pharmacodynamic properties).
- For the disease of Paget, Aclasta must only be prescribed by doctors experienced in the treatment of this pathology. The amount recommended is a single intravenous perfusion of 5 Mg of Aclasta. Repetition of the treatment of the disease of Paget: no specific data is available concerning a repeated treatment. It was observed one period of remission prolonged among patients responders with the treatment of the disease of Paget after a single administration of Aclasta (see heading pharmacodynamic properties).
- Aclasta (5 mg/100 ml, solution for perfusion ready with employment) is managed via a device of perfusion, with air intake and at speed of constant perfusion. The duration of the perfusion should not be lower than 15 minutes. For more information on the perfusion of Aclasta, to see heading instructions for the use, handling and elimination.
- The patients must be correctly hydrated before the administration of Aclasta. That is particularly important for the old patients and the patients who receive a treatment diuretic.
- A contribution adapted out of calcium and vitamin D is recommended simultaneously to the administration of Aclasta. Moreover, among patients reached of the disease of Paget, it is strongly advised to twice a day manage a supplementation adapted out of calcium corresponding to a contribution in calcium-element from at least 500 Mg, during at least 10 days following the administration of Aclasta (see heading warning statements and precautions for use).
- Among patients having had a fracture of recent hip secondary to a moderated traumatism, it is recommended to administrate an amount of load from 50000 to 125000 UI of vitamin D by oral or intramuscular way, before the 1st perfusion of Aclasta.
- The incidence of the undesirable effects occurring in the first three days following the administration of Aclasta can be decreased by managing paracetamol or ibuprofene after the administration of Aclasta.
- Renal insufficient Patients (see heading warning statements and precautions for use):
. The use of Aclasta is not recommended among patients whose clearance of creatinin is < 35 ml/min because of a clinical experiment limited in this population.
. No adjustment of the amount is necessary among patients whose clearance of creatinin is > = 35 ml/min.
- Hepatic insufficient Patients:
No adjustment of the amount is necessary (see heading pharmacokinetic properties).
- Old Patients (> = 65 years):
No adjustment of the amount is necessary since the biodisponibility, the distribution and elimination were similar among old patients and younger patients.
- Children and teenagers:
Aclasta should not be used at the child and the teenager in 18 year old lower part taking into account the absence of data concerning safety and the effectiveness.

Against indications

CONTRA-INDICATE:
- Over-sensitiveness with the active substance or the one of the excipients or others bisphosphonates.
- Aclasta is contra-indicated among patients having a hypocalcemy (see heading warning statements and precautions for use).
- Aclasta is contra-indicated in the expectant mother or who nurses: there do not exist sufficiently relevant data concerning the zoledronic use of the acid in the expectant mother. Studies carried out in the animal with the acid zoledronic highlighted a toxicity on the reproduction, of which malformations. The possible hazard on the human being is not known. The zoledronic excretion of the acid in the mother’s milk is not known.
- Children and teenagers: Aclasta should not be used at the child and the teenager in 18 year old lower part taking into account the absence of data concerning safety and the effectiveness.
DISADVISE:
Aclasta is not recommended among patients reached of severe impaired renal function (clearance of creatinin < 35 ml/min) because of a clinical experiment limited in this population. The creatininemy will have to be measured before the administration of Aclasta.

Undesirable effects

The total percentage of patients who presented symptoms occurring after the administration was respectively 44,7%,16,7% and 10,2% after the first, second and third perfusion respectively. The individual incidence of these symptoms after the first administration was: fever (17,1%), myalgia (7,8%), syndrome pseudogrippal (6,7%), arthralgie (4,8%) and cephalgia (5,1%). The incidence of these symptoms decreased clearly with the successive amounts of Aclasta. The majority of these symptoms occurred in the first three days following the administration of Aclasta, was of light intensity with moderated and disappeared in the three days according to their occurred. The percentage of patients presenting of the symptoms after the injection was respectively of 19,5%,10,4%,10,7% after the first, second and third perfusion, in a study moreover small size where the symptomatic treatment describes below had been used.
- The incidence of the symptoms occurring in the first three days following the administration of Aclasta can be decreased by managing paracetamol or ibuprofene shortly after the administration of Aclasta (see heading posology and mode of administration).
- In the study pivot HORIZON-PFT (post-menopausic osteoporosis) (see heading pharmacodynamic properties), the total incidence of auricular fibrillations was of 2,5% (96 of the 3862) and of 1,9% (75 of the 3852) at the patients receiving Aclasta respectively and the placebo. The auricular rate of fibrillations classified as serious undesirable events was of 1,3% (51 out of 3862) in the patients treated by Aclasta compared with 0,6% (22 out of 3852) in the patients receiving the placebo. The mechanism of the increase in this incidence of auricular fibrillations is not known. In studies HORIZON-PFT and HORIZON-RFT (study after fracture of hip), the total incidence of auricular fibrillations was comparable between the group Aclasta (2,6%) and placebo (2,1%) groups it. The total incidence of reported auricular fibrillations as undesirable event engraves was of 1,3% for the Aclasta group and 0,8% for the placebo group.
- The undesirable effects very frequent (> = 1/10), frequent (> = 1/100, < 1/10), not very frequent (> = 1/1000, < 1/100) and rare (> = 1/10000, < 1/1000) are presented in Table 1. Within each group of frequency, the undesirable effects are presented according to an decreasing order of gravity.
TABLE 1 (a).
- Investigations:
Not very frequent: Increase in the blood pressure.
- Cardiac affections:
Frequent: Auricular fibrillation.
- Affections of the nervous system:
. Frequent: Cephalgias, giddinesses.
. Not very frequent: Lethargy, paraesthesias, somnolence, tremors, syncope.
- Ocular Affections:
. Not very frequent: Conjunctivitis, ocular pain.
. Rare: Uvéite, épisclérite, iritis.
- Affections of the ear and the labyrinth:
Not very frequent: Giddinesses.
- Respiratory affections, thoracic and médiastinales:
Not very frequent: Dyspnea.
- Gastro-intestinal Affections:
. Frequent: Nauseas, vomiting.
. Not very frequent: Diarrhea, dyspepsia, abdominal pain, oral dryness.
- Affections of the kidney and the urinary tracts:
Not very frequent: Increase in the creatinemy, pollakiurie.
- Affections of the skin and subcutaneous fabric:
Not very frequent: Cutaneous eruption, sweats night, hyperhidrose, prurit, erythema.
- Musculosquelettic and systemic Affections:
. Frequent: Osseous myalgias, arthralgies, pains, rachidian pains, pains on the level of the ends.
. Not very frequent: Cervicalgies, musculosquelettic stiffness, articular swelling, pains of the shoulder, spasms muscular, musculosquelettic pains, noncardiac thoracic pains, arthritis, muscular weakness, articular stiffness.
- Disorders of the metabolism and the nutrition:
. Frequent: Hypocalcemy (b).
. Not very frequent: Anorexia, reduction in the appetite.
- Affections and infestations:
Not very frequent: Seize up.
- Vascular affections:
Not very frequent: Hypertension, puffed out vasomotrices.
- General Disorders and anomalies with the site of administration:
. Very frequent: Fever.
. Frequent: Syndrome pseudogrippal, shivers, tiredness, asthenia, pains, faintness, rigidity (b).
. Not very frequent: Peripheral edema, thirst.
- Affections of the immune system:
Unspecified frequency (c): Reactions of over-sensitiveness including of rare cases of bronchoconstriction, urticaria and angioedème and of very rare cases of anaphylactic reaction or shock.
- Psychiatric Affections:
Not very frequent: Insomnia.
(A) additional undesirable events were reported individually in the studies but were not included because of a poolée presentation of the data:
Not very frequent: dental dysgueusy, oesophagite, pains.
(B) Frequent in the event of disease of Paget only. For the hypocalcemy to see below.
(C) Based on data after marketing. These data result from a population of dubious size and can lend to confusion. It is not possible to estimate their frequency or to establish a relationship to the exposure to the drug.
EFFECTS OF CLASS:
- Anomaly of the renal function:
The acid zoledronic was associated with an anomaly of the renal function appearing in the form of a deterioration of the renal function (C. – with-D. increase in the creatininemy) and in rare cases acute impaired renal function. An impaired renal function was observed after the zoledronic administration of acid, in particular at the patients presenting a preexistent renal deterioration or additional risk factors (for example, anti-cancer chemotherapy, concomitant drugs nephrotoxic, severe dehydration, etc). The majority of these patients received an amount of 4 Mg all the 3 to 4 weeks, but an anomaly of the renal function was also observed among patients having received only one administration.
- During clinical studies in the osteoporosis, the modifications of the clearance of creatinin (measured each year before the injection) and the incidence of the impaired renal function were comparable in the two groups of treatment (Aclasta and placebo) over one three years period. A transitory increase in the creatininemy was observed over 10 days at 1,8% of the patients treated by Aclasta versus 0,8% of the patients treated by the placebo.
- Hypocalcémie:
. During clinical studies in the osteoporosis, approximately 0,2% of the patients presented a notable reduction in the calcemy (less than 1,87 mmol/L), following the administration of Aclasta. No case of symptomatic hypocalcemy was observed.
. During studies undertaken among patients reached of the disease of Paget, a symptomatic hypocalcemy was observed at approximately 1% of the patients. Among all patients, the hypocalcemy was resolvent.
. According to the evaluation of the biological parameters resulting from a vast clinical study, it was observed values, transients and asymptomatic, of calcemy lower than the normal values of reference at 2,3% of the patients treated with Aclasta compared with 21% of the patients treated with Aclasta in the studies of the disease of Paget. The frequency of hypocalcemy was much less low with the following perfusions.
. All the patients received a supplementation in vitamin D and calcium: in the study undertaken on the post-menopausic osteoporosis (study PFT), in the study on the prevention of the clinical fractures after fracture of hip (study RFT) like in the studies of the disease of Paget (see also heading posology and mode of administration). In study RFT, the majority of the patients received an amount of load in vitamin D before the administration of Aclasta although the rate of vitamin D was not measured in a systematic way (see heading posology and mode of administration).
- Local Reactions:
During a vast study, local reactions to the site of perfusion, such as a redness, a swelling and/or a pain (0,7%), were observed after the zoledronic administration of acid.
- Ostéonécrose of the jaw:
Cases of ostéonécrose (mainly of the jaw) were little frequently reported, mainly at patients reached of a cancer and treaties by bisphosphonates, of which acid zoledronic. Much of them presented signs of local infection including an osteomyelitis. The majority of the cases concerns patients reached of a cancer and having undergone a dental extraction or other dental surgeries. The ostéonécrose of the jaw presents multiple well documented risk factors including the diagnosis of a cancer, the associated treatments (for example: chemotherapy, radiotherapy, corticothérapie) and of the associated affections (for example: weakens, disorders of coagulation, infection, preexistent oral disease). Although causality cannot be established, it is advisable to avoid a dental surgery whose cure could be delayed (see heading warning statements and precautions for use). During a vast clinical study carried out in 7736 patients, a ostéonécrose of the jaw was observed in a patient treated by Aclasta and a patient treated by the placebo. In both cases, the evolution was favorable.