Zerlinda (MRP DK/H/2265/001)

Transcription

1 Zerlinda (MRP DK/H/2265/001) VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Prevention of bone complications, e.g. fractures, in adult patients with bone metastases (spread of cancer from primary site to the bone) Metastases to bone are common in patients with advanced malignancies, particularly in patients with breast, prostate, lung, kidney, and bladder cancer. The survival for patients with breast cancer, multiple myeloma (cancer of white cells responsible for antibody production), or prostate cancer ranges from approximately 21 to 33 months after initial diagnosis of bone metastases or bone lesions. In studies, most patients non exposed to any drug experienced at least 1 on-study bone complication. Fractures occurred in 39% of patients with breast cancer, in 22% of patients with prostate cancer, and in 22% of patients with bone metastases from lung cancer or other solid tumours during 12, 15, and 21 months of follow-up, respectively. Consequently, fractures are a significant clinical concern in these patient populations, and preventing or delaying fractures is an important treatment objective, particularly in patients with advanced breast cancer. 1 Reduction of the amount of calcium in the blood in adult patients where it is too high due to the presence of a tumour The increase of the amount of calcium in the blood (hypercalcaemia) affects up to 10% to 30% of cancer patients, and cancer-related hypercalcemia is the leading cause of hypercalcemia in hospitalized patients. Patients with breast cancer, lung cancer, and myeloma (cancer of white cells responsible for antibody production) are most commonly affected, but hypercalcemia can also occur with other malignancies, including kidney, gynecologic, and head and neck cancers. Unfortunately, cancer-related hypercalcemia has a poor prognosis (predicting the outcome), as it is most often associated with disseminated (diffuse process) disease. Eighty percent of patients will die within a year, and there is a median survival of 3 to 4 months. The mainstay of treatment for cancer-related hypercalcemia is hydration with normal saline and intravenous bisphosphonates. 2 VI.2.2 Summary of treatment benefits Prevention of bone complications, e.g. fractures, in adult patients with bone metastases (spread of cancer from primary site to the bone) The efficacy of zoledronic acid in prevention of bone complication has been proved in three studies that included more than 3000 patients. These trials demonstrated that zoledronic acid (4 mg via 15-minute i.v. infusion every 3-4 weeks) effectively reduced the incidence of bone complications associated with malignant bone disease for patients with breast cancer, multiple myeloma (cancer of white cells responsible for antibody production), prostate cancer, or solid tumours other than breast or prostate cancer. The primary efficacy end point in all three trials was the proportion of patients who experienced at least one bone complications. 3 Reduction of the amount of calcium in the blood in adult patients where it is too high due to the presence of a tumour The superior efficacy of zoledronic acid (4 or 8 mg) compared with pamidronate disodium (90 mg) was established following an analysis in patients with moderate to severe increased amount of calcium in the blood due to presence of a tumour. 247 patients were included in two trials. The complete remission (disappearance of the signs and symptoms of a disease) was significantly higher for zoledronic-acid-treated patients (88.4% for 4 mg and 86.7% for 8 mg) than for pamidronate disodium-treated patients (69.7%). Furthermore, patients treated 1

2 with zoledronic acid had a more rapid normalization of calcium in the blood levels than those in the pamidronate disodium group. 3 VI.2.3 Unknowns relating to treatment benefits Based on the currently available data an important gap in knowledge was identified in relation to zoledronic acid efficacy in races other than Caucasians and in children aged 1 year to 17 years. VI.2.4 Summary of safety concerns Important identified risks Risk What is known Preventability Kidney failure (Renal function impairment) Bone damage in the jaw (Osteonecrosis of jaw), has been associated with reports of kidney insufficiency. Factors that may increase the potential for deterioration in kidney function include dehydration, preexisting kidney insufficiency, multiple cycles of zoledronic acid and other bisphosphonates as well as use of other medicinal products that might damage the kidneys. While the risk is reduced with a dose of 4 mg zoledronic acid administered over 15 minutes, deterioration in kidney function may still occur. Kidney deterioration, progression to dialysis (remove waste and excessive water from the blood) has been reported in patients after the initial dose or a single dose of 4 mg zoledronic acid. The kidney blood tests modification occurs in some patients with chronic administration of zoledronic acid at recommended doses for prevention of bone complications, although less frequently. Pain in the mouth, teeth and/or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth could be signs of bone damage in the jaw. Bone damage in the jaw has been reported in patients, predominantly those with cancer, receiving treatment with zoledronic acid. Many of these patients were also receiving anticancer treatment and corticosteroids (synthetic analogues of steroid hor- Treatment in patients with high amount of calcium in the blood due to presence of a tumour that also have severe kidney insufficiency should be considered only after evaluating the risks and benefits of treatment. Due to the potential impact of zoledronic acid on kidney function, and lack of clinical safety data in patients with severe kidney insufficiency, the use of zoledronic acid is not recommended in patients with severe kidney insufficiency. Patients should have their kidney specific blood tests assessed prior to each dose of zoledronic acid. Upon initiation of treatment in patients with bone metastases with mild to moderate kidney insufficiency, lower doses of zoledronic acid are recommended. In patients who show evidence of kidney deterioration during treatment, zoledronic acid should be withheld. A teeth examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors. While on treatment, these patients should avoid invasive teeth procedures if possible. For patients who develop bone damage in the jaw while on bisphosphonate therapy, teeth 2

3 Risk What is known Preventability mones). The majority of reported cases have been associated with dental procedures such as tooth extraction. Many had signs of local infection including infection of the bone. The risk factors that should be considered when evaluating an individual s risk of developing bone damage in the jaw: the amount of drug activity of the bisphosphonate, route of administration, intravenously and by injection administration, cumulative dose, cancer, anticancer treatment, radiotherapy, corticosteroids, smoking, history of teeth disease, poor oral hygiene, gum disease, invasive teeth procedures and poorly fitting dentures. Flu-like symptoms (Acute phase reaction) A constellation of symptoms that includes fever, headache, extremity pain, nausea, vomiting, diarrhoea, joint and muscle ache, joint inflammation with subsequent joint swelling. The onset time is 3 days post zoledronic acid infusion. surgery may exacerbate the condition. For patients requiring teeth procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of bone damage in the jaw. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. Reduced levels of calcium in the blood (Hypocalcaemia) Eye problems (Ocular adverse events) Irregular heart rhythm (Atrial fibrillation) Reduced levels of calcium in the blood sometimes leading to muscle cramps, dry skin, burning sensation have been reported in patients treated with zoledronic acid. Irregular heart beat (cardiac arrhythmia), seizures, numbness and tetany (secondary to hypocalcaemia) have been reported secondary to cases of severe reduced levels of calcium in the blood. Cases of severe reduced levels of calcium in the blood requiring hospitalisation have been reported. In some instances, hypocalcaemia may be lifethreatening. Tearing of the eye, eye sensitivity to light, painful redness and/or swelling of the eye have been reported. Irregular heart rhythm has been seen in patients receiving zoledronic acid for postmenopausal osteoporosis. It is currently unclear whether zoledronic acid causes this irregular heart rhythm but it should be reported to the doctor Related blood parameters such as calcium, phosphate and magnesium should be monitored after initiation of the treatment. In case they are decreased, short-term supplemental therapy may be necessary. 3

4 Risk What is known Preventability if such symptoms occur after receiving zoledronic acid. Severe allergic reaction (Anaphylaxis) Severe allergic reaction: shortness of breath, swelling mainly of the face and throat. It is contraindicated in patients allergic to zoledronic acid or another bisphosphonates. Inflammation of the tissue around the air sacks of the lungs (Interstitial lung disease) Interaction with anti-angiogenic drugs Inflammation of the tissue around the air sacks of the lungs has been reported. The concomitant administration of anti-angiogenic medicines (used to treat cancer) has been associated with an increased risk of bone damage of the jaw. Caution is recommended in case these drugs are administered together with zoledronic acid. Important potential risks Risk Unusual fracture of the thigh bone (Atypical femoral fracture) Irregular heart beat (Cardiac arrhythmias) Side effects affecting the brain and the circulatory system (Cerebrovascular AEs) Focal Segmental Glomerulosclerosis Fracture healing impairment Off-label use in Osteogenesis imperfecta Medication errors Potential interaction with products that can significantly What is known (Including reason why it is considered a potential risk) Unusual fracture of the thigh bone particularly in patients on long-term treatment for osteoporosis may occur rarely. These fractures occur after minimal or no trauma. The doctor should be contacted in case of pain, weakness or discomfort in your thigh, hip or groin as this may be an early indication of a possible fracture of the thigh bone. As a consequence of low calcium values, irregular heart beat (cardiac arrhythmia) may occur. Rarely, slow heart beat has been reported. Actavis has no data related to this important potential risk. Actavis has no data related to this important potential risk. Actavis has no data related to this important potential risk. Studies showed that for the treatment of severe osteogenesis imperfecta in paediatric patients aged 1 to 17 years there is no clear evidence of efficacy on incidence of fracture or on pain. The types of adverse reactions observed in this population were similar to those previously seen in adults with advanced malignancies involving the bone. The potential for medication errors exists if doses are not administered by taking into account of patient s renal function, the correct method of administration (no less than 15 minutes). must only be prescribed and administered to patients by healthcare professionals experienced in the administration of intravenous bisphosphonates. The concomitant use of drugs that may affect kidney function can lead to further deterioration of their functioning. 4

5 Risk affect kidney function Missing information Risk Races other than Caucasian Fertility, Pregnancy and Lactation Patients with severe kidney insufficiency (Patients with severe renal impairment) Patients with liver insufficiency What is known (Including reason why it is considered a potential risk) What is known Actavis has no data related to this missing information. There are no adequate data on the use of zoledronic acid in pregnant women. Animal reproduction studies with zoledronic acid have shown reproductive toxicity. The potential risk for humans is unknown. should not be used during pregnancy. It is not known whether zoledronic acid is eliminated into human milk. is contraindicated in breast-feeding women. was evaluated in rats for potential adverse effects on fertility and the results precluded determining a definitive effect of zoledronic acid on fertility in humans. Treatment in patients with high amount of calcium in the blood due to presence of a tumour that also have severe kidney insufficiency should be considered only after evaluating the risks and benefits of treatment. Due to the potential impact of zoledronic acid on kidney function, and lack of clinical safety data in patients with severe kidney insufficiency, the use of zoledronic acid is not recommended in patients with severe kidney insufficiency. Only limited clinical data are available in patients with severe liver insufficiency, therefore no specific recommendations can be given for this patient population. VI.2.5 Summary of risk minimisation measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimisation measures. This medicine has no additional risk minimisation measures. VI.2.6 Planned post authorisation development plan No post-authorisation safety or efficacy studies are ongoing or are planned to be conducted for zoledronic acid. VI.2.7 Summary of changes to the Risk Management Plan over time Major changes to the Risk Management Plan over time Version Date Safety Concerns Comment Identified risk -Renal function impairment -Osteonecrosis of Jaw First approved version 5

6 Version Date Safety Concerns Comment -Acute phase reaction -Hypocalcaemia -Ocular adverse events -Atrial fibrillation -Anaphylaxis Potential risks -Atypical femoral fracture -Cardiac arrhythmias -Cerebrovascular AEs -Focal Segmental Glomerulosclerosis -Fracture healing impairment -Off-label use in Osteogenesis imperfecta -Medication errors -Potential interaction with products that can significantly affect renal function Missing information -Races other than Caucasian -Fertility, Pregnancy and Lactation -Patients with severe renal impairment -Patients with hepatic insufficiency Interstitial lung disease moved from potential risks to identified risks -Interaction with anti-angiogenic drugs added as identified risk -Off-label use in Osteogenesis imperfect added as a potential risk -Medication errors added as a potential risk Update in accordance with originator s RMP No changes to the important risks. The SPC texts from sections 5.1 and 5.2 concerning the risk of osteogensis imperfecta were included in the relevant tables from the RMP (tables V.1, V.3 and VI.1.4) as requested Mutual Recognition Procedure Preliminary Variation Assessment Report RMP on zoledronic acid dated