Novartis Pharmaceuticals UK Ltd

Re-treatment of Paget’s disease: specific re-treatment data are not available. After a singleinitial treatment with Aclasta in Paget’s disease, an extended remission period is observed in responding patients. Re-treatment consists of an additional intravenous infusion of 5 mg Aclasta after an interval of one year or longer from initial treatment in patients who have relapsed. Limited data on re-treatment of Paget’s disease are available However, re-treatment with Aclasta may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, in patients who failed to achieve normalisation of serum alkaline phosphatase, or in patients with symptoms, as dictated by medical practice (see section 5.1).

Patients who were classified as responders at the end of the 6 month core study were eligible to enter an extended follow-up period. Of the 1543 Aclasta-treated patients and 115107 risedronate-treated patients who entered an extended observation study, after a meanmedian duration of follow-up of 3.8 years18 months from time of dosing, the proportion of patients ending the Extended Observation Period due to the need for re‑treatment (clinical judgment) was higher for risedronate (48 patients, or 41.7%) compared with zoledronic acid (11 patients, or 7.2%). The mean time of ending the Extended Observation Period due to the need for Paget’s re-treatment from the initial dose was longer for zoledronic acid (7.7 years) than for risedronate (5.1 years).141 Aclasta-treated patients maintained their therapeutic response compared to 71 risedronate-treated patients. This corresponds to a 96% reduction of risk of relapse in Aclasta versus risedronate-treated patients.

Six patients who achieved therapeutic response 6 months after treatment with Aclasta and later experienced disease relapse during the extended follow-up period were re-treated with Aclasta after a mean time of 6.5 years from initial treatment to re-treatment. Five of the 6 patients had SAP within the normal range at month 6 (Last Observation Carried Forward, LOCF).

Patients with renal impairment

Aclasta is contraindicatedshould not be used in patients with creatinine clearance < 35 ml/min (see sections 4.3 and 4.4).

 
The following contraindication has been added to Section 4.3:

Severe renal impairment with creatinine clearance < 35 ml/min (see section 4.4).


The following sentence has been added to the beginning of Section 4.4.  and reference to creatinine clearance <35ml/min has been removed.
 

The use of Aclasta in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.

Minor grammatical changes have been made to Section 4.8

Class effects:

Renal impairment

Zoledronic acid has been associated with renal impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunction or additional risk factors (e.g advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicinal products, concomitant diuretic therapy, severe dehydration), with the majority of whomthem receivinged a 4 mg dose every 3–4 weeks, but it has been observed in patients after a single administration.

The last paragraph in Section 5.2 has been amended as shown

Special populations (see section 4.2)

Renal impairment

The renal clearance of zoledronic acid was correlated with creatinine clearance, renal clearance representing 75 ± 33% of the creatinine clearance, which showed a mean of 84 ± 29 ml/min (range 22 to 143 ml/min) in the 64 patients studied. Small observed increases in AUC_(0-24hr), by about 30% to 40% in mild to moderate renal impairment, compared to a patient with normal renal function, and lack of accumulation of drug with multiple doses irrespective of renal function, suggest that dose adjustments of zoledronic acid in mild (Cl_cr = 50–80 ml/min) and moderate renal impairment down to a creatinine clearance of 35 ml/min are not necessary. The use of Aclasta in patients with severe renal impairment (creatinine clearance < 35 ml/min) is contraindicated due to an increased risk of renal failure in this population.As only limited data are available in severe renal impairment (creatinine clearance < 30 ml/min), no dosing recommendations are possible for this population.

10.     DATE OF REVISION OF THE TEXT

06.02.2012

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Aclasta on an individual patient basis, particularly after 5 or more years of use.

Atypical fractures of the femur

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.

During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.

Updates to Section 4.2, 4.4, 4.5, 4.8 and 5.2 as shown below - new text underlined:

In Section 4.2 the following paragraph was amended:

Patients with renal impairment

Use of Aclasta should not be used in patients with creatinine clearance < 35 ml/min is not recommended due to limited clinical experience in this population (see section 4.4).

The following changes have been made to the beginning of Section 4.4:

4.4     Special warnings and precautions for use

Renal impairment has been observed following the administration of Aclasta (see section 4.8), especially in patients with pre-existing renal dysfunction or other risks including advanced age, concomitant nephrotoxic medicinal products, concomitant diuretic therapy (see section 4.5), or dehydration occurring after Aclasta administration. Renal failure requiring dialysis or with a fatal outcome has rarely occurred in patients with underlying renal impairment or with any of the risk factors described above.

The following precautions should be taken into account to minimise the risk of renal adverse reactions:

·             Creatinine clearance should be measured before each Aclasta dose.

·             Aclasta should not be used in patients with creatinine clearance < 35 ml/min (see section 5.2).

·             Transient increase in serum creatinine may be greater in patients with underlying impaired renal function.

·             Monitoring of serum creatinine should be considered in at-risk patients.

·             Aclasta should be used with caution when concomitantly used with other medicinal products that could impact renal function (see section 4.5).

·             Patients, especially elderly patients and those receiving diuretic therapy, should be appropriately hydrated prior to administration of Aclasta.

·             A single dose of Aclasta should not exceed 5 mg and the duration of infusion should be at least 15 minutes (see section 4.2).The dose of 5 mg zoledronic acid must be administered over at least 15 minutes.

Aclasta is not recommended in patients with severe renal impairment (creatinine clearance < 35 ml/min) due to limited clinical experience in this population. Patients should have their serum creatinine level measured before receiving Aclasta.

Patients must be appropriately hydrated prior to administration of Aclasta. This is especially important in the elderly and for patients receiving diuretic therapy. Caution is indicated when Aclasta is administered in conjunction with medicinal products that can significantly impact renal function (e.g. aminoglycosides or diuretics that may cause dehydration), see section 4.5.

Pre-existing hypocalcaemia must be treated by adequate intake of calcium and vitamin D before initiating therapy with Aclasta (see section 4.3). Other disturbances of mineral metabolism must also be effectively treated (e.g. diminished parathyroid reserve, intestinal calcium malabsorption). Physicians should consider clinical monitoring for these patients.

Elevated bone turnover is a characteristic of Paget’s disease of the bone. Due to the rapid onset of effect of zoledronic acid on bone turnover, transient hypocalcaemia, sometimes symptomatic, may develop and is usually maximal within the first 10 days after infusion of Aclasta (see section 4.8).

Adequate calcium and vitamin D intake are recommended in association with Aclasta administration. In addition, in patients with Paget's disease, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured for at least 10 days following Aclasta administration (see section 4.2). Patients should be informed about symptoms of hypocalcaemia and receive adequate clinical monitoring during the period of risk. Measurement of serum calcium before infusion of Aclasta is recommended for patients with Paget´s disease.

Severe and occasionally incapacitating bone, joint and/or muscle pain have been infrequently reported in patients taking bisphosphonates, including Aclasta (see section 4.8).

Aclasta contains the same active substance found in Zometa (zoledronic acid), used for oncology indications, and a patient being treated with Zometa should not be treated with Aclasta.

Osteonecrosis of the jaw (ONJ)

Osteonecrosis of the jaw has been reported predominantly in patients with cancer receiving treatment regimens including bisphosphonates, including zoledronic acid. Many of these patients were also receiving chemotherapy and corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including osteomyelitis. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. The clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

 
In Section 4.5 this paragraph was added at the end of the section. 

In patients with renal impairment, the systemic exposure to concomitant medicinal products that are primarily excreted via the kidney may increase.

In Section 4.8 the following changes were made:

4.8     Undesirable effects

 The overall percentage of patients who experienced adverse reactions were 44.7%, 16.7% and 10.2% after the first, second and third infusion, respectively. Incidence of individual adverse reactions following the first infusion was: fever (17.1%), myalgia (7.8%), flu-like symptoms (6.7%), arthralgia (4.8%) and headache (5.1%). The incidence of these reactions decreased markedly with subsequent annual doses of Aclasta. The majority of these reactions occur within the first three days following Aclasta administration. The majority of these reactions were mild to moderate and resolved within three days of the event onset. The percentage of patients who experienced adverse reactions was lower in a smaller study (19.5%, 10.4%, 10.7% after the first, second and third infusion, respectively), where prophylaxis against adverse reactions was used as described below.

The incidence of adverse reactions occurring within the first three days after administration of Aclasta can be reduced with the administration of paracetamol or ibuprofen shortly following Aclasta administration as needed (see section 4.2).

In the HORIZON – Pivotal Fracture Trial [PFT] (see section 5.1), the overall incidence of atrial fibrillation was 2.5% (96 out of 3,862) and 1.9% (75 out of 3,852) in patients receiving Aclasta and placebo, respectively. The rate of atrial fibrillation serious adverse events was increased in patients receiving Aclasta (1.3%) (51 out of 3,862) compared with patients receiving placebo (0.6%) (22 out of 3,852). The mechanism behind the increased incidence of atrial fibrillation is unknown. In the osteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable between Aclasta (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled incidences were 1.3% for Aclasta and 0.8% for placebo.

Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1

Class effects:

Renal dysfunctionimpairment

Zoledronic acid has been associated with renal dysfunction impairment manifested as deterioration in renal function (i.e. increased serum creatinine) and in rare cases acute renal failure. Renal dysfunction impairment has been observed following the administration of zoledronic acid, especially in patients with pre-existing renal dysfunctioncompromise or additional risk factors (e.g advanced age, oncology patients with chemotherapy, concomitant nephrotoxic medicationsmedicinal products, concomitant diuretic therapy, severe dehydration), the majority of whom received a 4 mg dose every 3–4 weeks, but it has been observed in patients after a single administration.

In clinical trials in osteoporosis, the change in creatinine clearance (measured annually prior to dosing) and the incidence of renal failure and impairment was comparable for both the Aclasta and placebo treatment groups over three years. There was a transient increase in serum creatinine observed within 10 days in 1.8% of Aclasta-treated patients versus 0.8% of placebo-treated patients.

Hypocalcaemia

In clinical trials in osteoporosis, approximately 0.2% of patients had notable declines of serum calcium levels (less than 1.87 mmol/l) following Aclasta administration. No symptomatic cases of hypocalcaemia were observed.

In the Paget’s disease trials, symptomatic hypocalcaemia was observed in approximately 1% of patients, in all of whom it resolved.

Based on laboratory assessment, transient asymptomatic calcium levels below the normal reference range (less than 2.10 mmol/l) occurred in 2.3% of Aclasta-treated patients in a large clinical trial compared to 21% of Aclasta-treated patients in the Paget’s disease trials. The frequency of hypocalcaemia was much lower following subsequent infusions.

All patients received adequate supplementation with vitamin D and calcium in the post-menopausal osteoporosis trial, the prevention of clinical fractures after hip fracture trial, and the Paget’s disease trials (see also section 4.2). In the trial for the prevention of clinical fractures following a recent hip fracture, vitamin D levels were not routinely measured but the majority of patients received a loading dose of vitamin D prior to Aclasta administration (see section 4.2).

Local reactions

In a large clinical trial, local reactions at the infusion site, such as redness, swelling and/or pain, were reported (0.7%) following the administration of zoledronic acid.

Osteonecrosis of the jaw

Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported, predominantly in cancer patients treated with bisphosphonates, including zoledronic acid. Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well documented risk factors including a diagnosis of cancer, concomitant therapies (e.g. chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (e.g. anaemia, coagulopathies, infection, pre-existing dental disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see section 4.4). In a large clinical trial in 7,736 patients, osteonecrosis of the jaw has been reported in one patient treated with Aclasta and one patient treated with placebo. Both cases resolved.

 
In Section 5.2 the fourth paragraph was amended as follows:

Zoledronic acid is not metabolised and is excreted unchanged via the kidney. Over the first 24 hours, 39 ± 16% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue. This uptake into bone is common for all bisphosphonates and is presumably a consequence of the structural analogy to pyrophosphate. As with other bisphosphonates, the retention time of zoledronic acid in bones is very long. From the bone tissue it is released very slowly back into the systemic circulation and eliminated via the kidney. The total body clearance is 5.04 ± 2.5 l/h, independent of dose, and unaffected by gender, age, race or body weight. The inter- and intra-subject variation for plasma clearance of zoledronic acid was shown to be 36% and 34%, respectively. Increasing the infusion time from 5 to 15 minutes caused a 30% decrease in zoledronic acid concentration at the end of the infusion, but had no effect on the area under the plasma concentration versus time curve.

Aclasta has a new indication, for the treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in post-menopausal women and in men at increased risk of fracture.

The following additional information has been included in the Aclasta Summary of Product Characteristics (SmPC):

Section 4.6 -

“Aclasta is not recommended in women of childbearing potential.”

Section 4.7 -

“Side effects, such as dizziness, may affect the ability to drive or use machines, though no studies on this effect with Aclasta have been performed.”

Section 4.8 - additional undesirable effects have been added with a frequency as follows:

Uncommon (≥1/1,000 to <1/100)

Nasopharyngitis, anaemia, dysgeusia, palpitations, cough, abdominal pain upper, gastrooesophageal reflux disorder, constipation, oesophagitis, toothache, gastritis, night sweats, proteinuria, acute phase reaction.

Common (≥1/100 to <1/10)

C- reactive protein increased, ocular hyperaemia, diarrhea, infusion site reaction.

The following undesirable effect has been removed:

Rigors.

Section 4.9 -

“Clinical experience with acute overdose is limited.”

Section 5.1 – addition of pharmacodynamic data and clinical data supporting the new indication:

“The selective action of bisphosphonates on bone is based on their high affinity for mineralised bone.

The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The long duration of action of zoledronic acid is attributable to its high binding affinity for the active site of farnesyl pyrophosphate (FPP) synthase and its strong binding affinity to bone mineral.”

“Clinical efficacy in osteoporosis associated with long-term systemic glucocorticoid therapy

The efficacy and safety of Aclasta in the treatment and prevention of osteoporosis associated with long-term systemic glucocorticoid therapy were assessed in a randomised, multicentre, double-blind, stratified, active-controlled study of 833 men and women aged 18‑85 years (mean age for men 56.4 years; for women 53.5 years) treated with > 7.5 mg/day oral prednisone (or equivalent). Patients were stratified with respect to duration of glucocorticoid use prior to randomisation (< 3 months versus ≥ 3 months). The duration of the trial was one year. Patients were randomised to either Aclasta 5 mg single infusion or to oral risedronate 5 mg daily for one year. All participants received 1,000 mg elemental calcium plus 400 to 1,000 IU vitamin D supplementation per day. Efficacy was demonstrated if non-inferiority to risedronate was shown sequentially with respect to the percentage change in lumbar spine BMD at 12 months relative to baseline in the treatment and prevention subpopulations, respectively. The majority of patients continued to receive glucocorticoids for the one year duration of the trial.

Effect on bone mineral density (BMD)

The increases in BMD were significantly greater in the Aclasta-treated group at the lumbar spine and femoral neck at 12 months compared to risedronate (all p<0.03). In the subpopulation of patients receiving glucocorticoids for more than 3 months prior to randomisation, Aclasta increased lumbar spine BMD by 4.06% versus 2.71% for risedronate (mean difference: 1.36% ; p<0.001). In the subpopulation of patients that had received glucocorticoids for less than 3 months prior to randomisation, Aclasta increased lumbar spine BMD by 2.60% versus 0.64% for risedronate (mean difference: 1.96% ; p<0.001). The study was not powered to show a reduction in clinical fractures compared to risedronate. The incidence of fractures was 8 for Aclasta-treated patients versus 7 for risedronate-treated patients (p=0.8055).”

• New indication - male osteoporosis in men at increased risk of fracture, including those with a recent low-trauma hip fracture

• Updated to include recommendations for the new indication and timing of infusion following hip fracture.
• Recommendations with regards to use in patients with renal impairment changed from creatinine clearance < 40 ml/min to < 35 ml/min

• Recommendations with regards to use in patients with renal impairment changed from creatinine clearance < 40 ml/min to < 35 ml/min.

• Updated to include information relating to the new indication.
• The following information has also been added:

 In the osteoporosis trials (PFT, HORIZON - Recurrent Fracture Trial [RFT]) the pooled atrial fibrillation incidences were comparable between Aclasta (2.6%) and placebo (2.1%). For atrial fibrillation serious adverse events the pooled incidences were 1.3% for Aclasta and 0.8% for placebo.

• Updated to include data on the new indication (The HORIZON-RFT study)

• Shelf life increased from 30 to 36 months

• Hypersensitivity to the active substance or to any of the excipients reworded to read "Hypersensitivity to the active substance or to any of the excipients or to any bisphosphonate"

• Paragraph on local reactions added
• Paragraph on unveitis, iritis, episcleritis and conjunctivitis reworded
• Paragraph on osteonecrosis of the jaw reworded and additional information added