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VI.2 Elements for a Public Summary VI.2.1 Overview of disease epidemiology Pamidronate disodium belongs to a group of medicines called bisphosphonates which can help to regulate the amount of calcium in the blood. High blood calcium levels (hypercalcaemia) occur in a number of conditions, including some types of cancer. Often, hypercalcaemia is caused by the release of calcium from bones. The drug sticks to bones and helps to reduce the release of calcium into the blood. Patients with spread of disease of breast cancer to bone are dominated by osteolytic lesions and in some patients with cancer results in bone loss throughout the body associated with bone pain. Pamidronate disodium is used to treat osteolytic lesions and relieve bone pain in patients with spread of bone diseases associated with breast cancer and disease of bone marrow (multiple myeloma). Pamidronate disodium is also used to treat Paget’s disease which results in a change in bone structure. VI.2.2 Summary of treatment benefits 34 As this is an abridged application for injection, no studies were conducted only data from published sources has been provided. Hypercalcaemia can lead to depletion in the volume of extracellular fluid and a reduction in the glomerular filtration rate (GFR). By controlling hypercalcaemia, pamidronate disodium improves GFR and lowers elevated serum creatinine levels in most patients. In two clinical trials with a total of 82 cancer patients who had hypercalcaemia, Pamidronate was administered as a single 24-hour intravenous infusion. Majority of patients had decreased serum calcium levels by 24 hours after initiation of treatment. By 7 days of treatment with Pamidronate, 40% to 100% of the patients receiving different doses of Aredia, had normal-corrected serum calcium levels. Clinical trials in patients with breast cancers and predominantly lytic bone metastases or with multiple myeloma showed that pamidronate disodium prevented or delayed skeletal-related events (hypercalcaemia, fractures, radiation therapy, surgery to bone, spinal cord compression) and decreased bone pain). Paget’s disease of bone, is characterized by local areas of increased bone resorption and formation with qualitative changes in bone remodelling. Clinical and biochemical remission of the disease has been demonstrated by bone scintigraphy, decrease in urinary hydroxyproline and serum alkaline phosphatase and by symptomatic improvement. In a clinical trial, 64 patients with Paget's disease of bone, who received Pamidronate at different doses had significant decrease in serum alkaline phosphatase and urine hydroxyproline/creatinine ratios demonstrating an improvement for these patients. However no statistically significant difference was observed for the bone pain response, mobility, and global evaluation. Improvement in radiologic lesions was observed. 25 patients retreated with 90 mg of Pamidronate had a significant decrease in the laboratory parameters serum alkaline phosphatase and the urine hydroxyproline/creatinine ratio. VI.2.3 Unknowns relating to treatment benefits The test product is aqueous intravenous solution for infusion (ready to use). The reference product requires reconstitution before use. However the final concentration of both test and reference products are the same at the time of use. Therefore, the test product exhibits the same efficacy and safety as that of the reference product. The safety of pamidronate disodium has not been studied in patients with severe liver impairment, severe kidney impairment, on fertility, in pregnant and breast-feeding females and in children and adolescents. VI.2.4 Summary of safety concerns Important identified risks Risk What is Known Preventability Deterioration of renal function (nephropathy) Bisphosphonates, including pamidronate disodium, have been associated with renal toxicity established as deterioration of kidney function and potential kidney failure. Yes Patients must be assessed prior to administration of Pamidronate disodium to assure that they are appropriately hydrated. This is especially important for patients 35 Necrosis of bone of the jaw (Osteonecrosis of the jaw) Severe muscle pain (Musculoskeletal pain) Renal deterioration, progression to kidney failure and dialysis have been reported in patients after the initial dose or a single dose of pamidronate disodium. Deterioration of kidney function (including renal failure) has also been reported following long treatment with pamidronate disodium in patients with multiple myeloma. Pamidronate disodium is excreted intact primarily via kidney, thus the risk of renal adverse reactions may be greater in patients with impaired renal function. Due to risk of clinically significant deterioration in kidney function which may progress to renal failure, single doses of pamidronate disodium should not exceed 90mg and the recommended infusion time should be observed. Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with bisphosphonates, including pamidronate disodium. Many of these patients were also receiving chemotherapy and corticosteroids. 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). receiving diuretic therapy. Patients who receive intravenous infusion of pamidronate disodium should have periodic evaluation of standard laboratory and clinical parameters of kidney function. As with other i.v. bisphosphonates renal monitoring is recommended, for instance, measurement of serum creatinine to each dose of pamidronate. Patients treated with pamidronate disodium for bone metastases or multiple myeloma should have the dose withheld if kidney function has deteriorated. Severe and occasionally Yes May require either radiation Yes Patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates including pamidronate disodium. 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. Clinical judgement of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. 36 incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates including pamidronate disodium. Irregular heart rhythm (Atrial fibrillation) Pamidronate disodium can lead to irregular heart rhythm. Hypocalcaemia Pamidronate disodium may lead to decrease in level of calcium in the blood and could cause tingling in hands, feet and muscle spasms (symptoms of low level of calcium). Pamidronate disodium when used in combination with calcitonin in patients with severe hypercalcaemia, results in a greater effect than the sum of the individual effects (synergistic) producing a more rapid fall in serum calcium. Patients who have undergone thyroid surgery may be particularly susceptible to developing hypocalcaemia due to relative hypoparathyroidism and this may in turn increase the risk of fracture. Pamidronate disodium when used in combination with calcitonin in patients with severe hypercalcaemia, resulting in a greater effect than the sum of the individual effects (synergistic ) producing a more rapid fall in serum calcium. Interaction with calcitonin Interaction with nephrotoxic medicinal product As pamidronate disodium has nephrotoxic effect, caution is warranted when pamidronate disodium for Injection is used with other potentially nephrotoxic drugs. therapy or narcotic analgesics (or both) for symptomatic relief based on individual benefit/risk assessment. Patients treated with pamidronate disodium should stop treatment if similar symptoms experienced. Yes Inform the doctor if any previous history of rhythm disturbance with use of bisphosphonates. Patients treated with pamidronate disodium should stop treatment if similar symptoms experienced. Yes In the absence of hypercalcaemia, patient should take oral calcium and vitamin D supplementation in order to minimise the potential risk of hypocalcaemia. Patients treated with pamidronate disodium should stop treatment if similar symptoms experienced. Yes Considering individual benefit risk assessment therapy needs to be initiated. Patients treated with pamidronate disodium for high blood calcium levels should stop treatment if symptoms of low blood calcium levels experienced. Yes Need to restrict other drug substances causing poisonous effect to kidney considering individual benefit risk assessment. Patients treated 37 Interaction with thalidomide In multiple myeloma patients, the risk of kidney dysfunction may be increased when Pamidronate disodium for Injection is used in combination with thalidomide. with pamidronate disodium should stop treatment if symptoms of deterioration of kidney function (e.g. unexpected change in the amount of urine produced and/or its appearance) experienced. Yes Need to restrict thalidomide considering individual benefit risk assessment. Patients treated with pamidronate disodium for multiple myeloma should stop treatment if symptoms of deterioration of kidney function (e.g. unexpected change in the amount of urine produced and/or its appearance) experienced. Important potential risks Risk Atypical femur or thigh fractures Deterioration of cardiac disease Convulsions What is known (Including reason why it is considered a potential risk) Atypical fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. 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 bisphosphonatetreated 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. In patients with heart disease, especially in the elderly, additional saline overload may precipitate heart failure (Left ventricular failure or congestive heart failure). Fever (influenza-like symptoms) may also contribute to this deterioration. Convulsions have been precipitated in some patients with tumor- 38 induced hypercalcaemia due to electrolyte changes associated with this condition and its effective treatment. Deterioration of anaemia, leukopenia or thromocytopenia Patients with anemia, leukopenia or thrombocytopenia should have regular hematology assessments. Missing information Risk What is known Severe hepatic impairment Although patients with hepatic impairment exhibited higher mean rate of extent and maximum plasma concentration values compared to patients with normal hepatic function, this is not perceived being clinically relevant. As pamidronate is still rapidly cleared from the plasma almost entirely into the bone and as is administered on a monthly basis for chronic treatment, active substance accumulation is not expected. Therefore no dose adjustment is necessary in patients with mild to moderate abnormal hepatic function. Clinical data in patients with severe hepatic impairment is not available. Pamidronate should be administered to this patient population with caution. Severe renal impairment Pamidronate Disodium Agila should not be administered to patients with severe renal impairment (creatinine clearance < 30 mL/min) unless in cases of life-threatening tumor-induced hypercalcaemia where the benefit outweighs the potential risk. Because there is only limited clinical experience in patients with severe renal impairment no dose recommendations for this patient population can be made. Fertility Studies in animals have shown reproductive toxicity. Dystocia was observed in the rats. In rats prolonged parturition and reduced survival rate of pups were probably caused by a decrease in maternal serum calcium levels. In pregnant rats, pamidronate disodium has been shown to cross the placental barrier and accumulate in foetal bone in a manner similar to that observed in adult animals. Pregnancy There is insufficient clinical experience to support the use of pamidronate disodium in pregnant women. Therefore, pamidronate disodium should not be administered during pregnancy except in cases of life-threatening hypercalcaemia. Breast-feeding It is not known whether pamidronate disodium is excreted in human milk. A study in lactating rats has shown that pamidronate disodium will pass into the milk. Mothers treated with pamidronate disodium 39 should therefore not breast-feed their infants. There is no clinical experience with pamidronate disodium in children and adolescents. Therefore until further experience is gained, Pamidronate Disodium Agila is only recommended for use in adult patients. Children and Adolescents 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 minimizing them. An abbreviated version of this lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk minimization measures. The Summary of Product information and the package leaflet for Pamidronate Disodium Agila 3mg/ml concentrate for solution for infusion are included in Annex 2. Pamidronate Disodium Agila 3mg/ml concentrate for solution for infusion has no additional risk minimization measures. VI.2.6 Planned post authorisation development plan Not Applicable VI.2.7 Summary of changes to the Risk Management Plan over time Version Date 5.0 28 March 2014 Safety Concerns • Comments The important identified risk Part VI.2.3 Unknowns relating to of ‘Hypocalcaemia in patients who treatment benefits has been updated have undergone thyroid surgery’ was replaced with ‘Hypocalcaemia’. 4.0 06 Nov 2013 Safety Concerns were not amended in RMP version 4.0 - 3.0 23 Oct 2013 Safety Concerns were not amended in RMP version 3.0 - 2.0 17 Sep 2013 Safety Concerns were not amended in RMP version 2.0 - 40