Novartis Pharmaceuticals UK Ltd

Adverse reactions to Aredia are usually mild and transient. The most common adverse reactions are asymptomatic hypocalcaemia and fever (an increase in body temperature of 1-2°C), typically occurring within the first 48 hours of infusion. Fever usually resolves spontaneously and does not require treatment.

Frequency estimate:  very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000) including isolated reports, not known (cannot be estimated from the available data).

When the effects of zoledronic acid (4 mg) and pamidronate (90 mg) were compared in one clinical trial, the number of atrial fibrillation adverse events was higher in the pamidronate group (12/556, 2.2%) than in the zoledronic acid group (3/563, 0.5%).  Previously, it has been observed in a clinical trial, investigating patients with postmenopausal osteoporosis, that zoledronic acid treated patients (5 mg) had an increased risk of atrial fibrillation serious adverse events compared to placebo (1.3% compared to 0.6%).  The mechanism behind the increased incidence of atrial fibrillation in association with zoledronic acid and pamidronate treatment is unknown.

Postmarketing experience:  

The following adverse reactions have been reported during post-approval use of Aredia. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cases of osteonecrosis (primarily of the jaw) have been reported  predominantly in cancer patients treated with bisphosphonates including Aredia (uncommon).  Many of these patients had signs of local infection including osteomyelitis andthe 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 oral disease).  Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see section 4.4 Special warnings and precautions for use).  Data suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma).

During post-marketing experience the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).

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.

During post-marketing experience the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).

Osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients  treated  with bisphosphonates, including Aredia.  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.

Post-marketing experience and the literature suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures).

Changes to Section 4.8 "Undesirable effects" as follows:

When the effects of zoledronic acid (4 mg) and pamidronate (90 mg) were compared in one clinical trial, the number of atrial fibrillation adverse events was higher in the pamidronate group (12/556, 2.2%) than in the zoledronic acid group (3/563, 0.5%).  Previously, it has been observed in a clinical trial, investigating patients with postmenopausal osteoporosis, that zoledronic acid treated patients (5 mg) had an increased risk of atrial fibrillation serious adverse events compared to placebo (1.3% compared to 0.6%).  The mechanism behind the increased incidence of atrial fibrillation in association with zoledronic acid and pamidronate treatment is unknown.

Postmarketing experience:

The following adverse reactions have been reported during post-approval use of Aredia. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  Uncommonly, c Cases of osteonecrosis (primarily of the jaw) have been reported  predominantly in cancer patients treated with bisphosphonates including Aredia (uncommon).  Many of these patients had signs of local infection including osteomyelitis andthe 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 oral disease).  Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see section 4.4 Special warnings and special precautions for use).  Data suggest a greater frequency of reports of ONJ based on tumour type (advanced breast cancer, multiple myeloma).

Please find below details of the key changes to the Aredia Summary of Product Characteristics:

Section 4.3: Addition of contraindications for use:

·         in pregnancy

·         in breast feeding women

Section 4.4:

• Addition of:

• Patients must be assessed prior to administration of Aredia to assure that they are appropriately hydrated. This is especially important for patients receiving diuretic therapy.
• Bisphosphonates, including Aredia, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. Renal deterioration, progression to renal failure and dialysis have been reported in patients after the initial dose or a single dose of Aredia. Deterioration of renal function (including renal failure) has also been reported following long-term treatment with Aredia in patients with multiple myeloma.
• Musculoskeletal Pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. category of drugs includes Aredia (pamidronate disodium for infusion). The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.

• The following text has been reworded:

• Aredia must never be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion (see  Section 4.2 Posology and method of administration).
• Calcium and Vitamin D Supplementation: In the absence of hypercalcaemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or Vitamin D deficiency (e.g. through malabsorption or lack of exposure to sunlight) and patients with Paget’s disease of the bone should take oral calcium and vitamin D supplementation in order to minimise the potential risk of hypocalcaemia.
• Osteonecrosis of the jaw: Osteonecrosis of the jaw has been reported predominantly in cancer patients with bisphosphonates, including Aredia. 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.

Section 4.6: Section has been reworded.

Section 4.8: Post marketing experience section has been reworded. NB: Important changes to this section appear in italics and underlined:

·         Postmarketing experience: Uncommonly, cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates including Aredia.  Many of these patients had signs of local infection including osteomyelitis andthe 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 oral disease).  Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged (see section 4.4 Special warnings and special precautions for use).

Section 5.3: The following text has been reworded:

·         Studies in rats and rabbits determined that pamidronate disodium produces maternal toxicity and embryo/foetal effects when administered at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. The effects include protracted parturition leading to dystocia, and shortened long bones in the foetus. .Animal data suggest that uptake of bisphosphonates into foetal bone is greater than into maternal bone.