- pamidronate disodium
POM: Prescription only medicine
This information is intended for use by health professionals
Tumour-induced hypercalcaemia:Patients must be adequately rehydrated with 0.9% w/v sodium chloride solution before or/and during administration of pamidronate disodium (see section 4.4). The total dose of pamidronate disodium to be used for a treatment course depends on the patient's initial serum calcium levels. The following guidelines are derived from clinical data on uncorrected calcium values. However, doses within the ranges given are also applicable for calcium values corrected for serum protein or albumin in rehydrated patients.
Initial plasma calcium level
Recommended total dose of pamidronate disodium
Concentration of solution for infusion
Maximum infusion rate
Osteolytic lesions in multiple myeloma:The recommended dose is 90 mg every 4 weeks.
Osteolytic lesions in bone metastases associated with breast cancer:The recommended dose is 90 mg every 4 weeks. This dose may also be administered at 3 weekly intervals to coincide with chemotherapy if desired.Treatment should be continued until there is evidence of a substantial decrease in a patient's general performance status.
|Indication||Treatment scheme||Solution for infusion (mg/ml)||Infusion rate (mg/h)|
|Bone metastases Multiple Myeloma||90 mg/2h every 4 weeks 90 mg/4h every 4 weeks||90/ 250 90/ 500||45 22.5|
Renal impairmentMedac Disodium Pamidronate 3 mg/ml should not be administered to patients with severe renal impairment (creatinine clearance < 30 ml/min) unless in case of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk (see also section 4.4 and 5.2).As with other intravenous bisphosphonates, monitoring of renal function is recommended, for instance, measurements of serum creatinine prior to each dose of pamidronate disodium. In patients receiving pamidronate disodium for bone metastases or multiple myeloma who show evidence of deterioration in renal function, treatment with pamidronate disodium should be withheld until renal function returns to within 10 % of the baseline value. This recommendation is based on a clinical study, in which renal deterioration was defined as follows:• For patients with normal baseline creatinine, increase of 0.5 mg/dl.• For patients with abnormal baseline creatinine, increase of 1.0 mg/dl.A pharmacokinetic study conducted in patients with cancer and normal or impaired renal function indicates that the dose adjustment is not necessary in mild (creatinine clearance 61 to 90 ml/min) to moderate renal impairment (creatinine clearance 30 to 60 ml/min). In such patients, the infusion rate should not exceed 90 mg/4h (approximately 20 to 22 mg/h).
Hepatic impairmentA pharmacokinetic study indicates that no dose adjustment is necessary in patients with mild to moderate abnormal hepatic function. Pamidronate disodium has not been studied in patients with severe hepatic impairment. Therefore no specific recommendations can be given for pamidronate disodium in such patients (see section 4.4).
Paediatric populationThe safety and efficacy of pamidronate disodium in children and adolescents aged < 18 years have not been established (see section 4.4).
Method of administrationMedac Disodium Pamidronate 3 mg/ml is a sterile concentrate and must therefore always be diluted in a calcium-free infusion solution (0.9 % sodium chloride or 5 % glucose) before use. The resulting solution must be infused slowly (see also section 4.4).For information concerning compatibility with infusion solutions, see section 6.6.The infusion rate should never exceed 60 mg/hour (1 mg/min), and the concentration of pamidronate disodium in the infusion solution should not exceed 90 mg/250 ml. A dose of 90 mg must usually be administered as a 2-hour infusion in a 250 ml solution for infusion. In patients with multiple myeloma and patients with tumour-induced hypercalcaemia, it is recommended that the infusion rate does not exceed 90 mg in 500 ml over 4 hours. In order to minimise local reactions at the infusion site, the cannula should be inserted carefully into a relatively large vein.Pamidronate disodium should be given under the supervision of a physician with the facilities to monitor the clinical and biochemical effects. Patients treated with Medac Disodium Pamidronate 3 mg/ml should be given the package leaflet and the patient reminder card.Use only freshly prepared and clear dilutions!
GeneralMedac Disodium Pamidronate 3 mg/ml must never be given as a bolus injection, but should always be diluted and given as a slow intravenous infusion (see section 4.2). Patients must be assessed prior to administration of Medac Disodium Pamidronate 3 mg/ml to assure that they are appropriately hydrated. This is especially important for patients receiving diuretic therapy.Standard hypercalcaemia-related metabolic parameters including serum calcium and phosphate should be monitored following initiation of therapy with Medac Disodium Pamidronate 3 mg/ml. Patients who have undergone thyroid surgery may be particularly susceptible to develop hypocalcaemia due to relative hypoparathyroidism.Convulsions have been occurred in some patients with tumour-induced hypercalcaemia due to electrolyte changes associated with this condition and its effective treatment.In patients with cardiac disease, especially in the elderly, additional saline overload may precipitate cardiac failure (left ventricular failure or congestive heart failure). Fever (influenza-like symptoms) may also contribute to this deterioration.Patients with anaemia, leukopenia or thrombocytopenia should have regular haematology assessments.The safety and efficacy of pamidronate disodium in children and adolescents (< 18 years) has not been established. The medicinal product contains 0.65 mmol sodium per maximum dose (90 mg). To be taken into consideration by patients on a controlled sodium diet.
Renal insufficiencyBisphosphonates, including Medac Disodium Pamidronate 3 mg/ml, 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 Medac Disodium Pamidronate 3 mg/ml. Deterioration of renal function (including renal failure) has also been reported following long-term treatment with Medac Disodium Pamidronate 3 mg/ml in patients with multiple myeloma.Medac Disodium Pamidronate 3 mg/ml is excreted intact primarily via the kidney (see section 5.2), thus the risk of renal adverse reactions may be greater in patients with impaired renal function.Due to the risk of clinically significant deterioration in renal function which may progress to renal failure, single doses of Medac Disodium Pamidronate 3 mg/ml should not exceed 90 mg, and the recommended infusion time should be observed (see section 4.2). As with other i.v. bisphosphonates renal monitoring is recommended, for instance, measurement of serum creatinine prior to each dose of Medac Disodium Pamidronate 3 mg/ml. Patients receiving frequent infusions of Medac Disodium Pamidronate 3 mg/ml over a prolonged period of time, especially those with pre-existing renal disease or a predisposition to renal impairment (e.g. patients with multiple myeloma and/or tumour-induced hypercalcaemia), should have evaluations of standard laboratory and clinical parameters of renal function prior to each dose of Medac Disodium Pamidronate 3 mg/ml.Patients treated with Medac Disodium Pamidronate 3 mg/ml for bone metastases or multiple myeloma should have the dose withheld if renal function has deteriorated (see section 4.2).Medac Disodium Pamidronate 3 mg/ml should not be given with other bisphosphonates because their combined effects have not been investigated.
Hepatic insufficiencyAs there are no clinical data available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population (see section 4.2).
Calcium and vitamin D supplementationIn the absence of hypercalcaemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or vitamin D deficiency, and patients with Paget's disease of the bone, should be given oral calcium and vitamin D supplementation, in order to minimise the risk of hypocalcaemia.
Osteonecrosis of the jawOsteonecrosis of the jaw (ONJ) has been reported in clinical trials and in the post-marketing setting in patients receiving pamidronate.The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth except in medical emergency situations.A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment with bisphosphonates in patients with concomitant risk factors.The following risk factors should be considered when evaluating an individual's risk of developing ONJ:• Potency of the bisphosphonate (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bisphosphonate• Cancer, co-morbid conditions (e.g. anaemia, coagulopathies, infection), smoking• Concomitant therapies: chemotherapy, angiogenesis inhibitors (see section 4.5), radiotherapy to neck and head, corticosteroids• History of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures (e.g. tooth extractions) and poorly fitting denturesAll patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Medac Disodium Pamidronate 3 mg/ml. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to pamidronate administration.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 management plan for the patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ.Temporary interruption of pamidronate treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.
Osteonecrosis of the external auditory canalOsteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
Atypical fractures of the femurAtypical 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.
Musculoskeletal painIn post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates. However, such reports have been infrequent. This category of medicinal products includes Medac Disodium Pamidronate 3 mg/ml (pamidronate disodium for infusion).The time to onset of symptoms varied from one day to several months after starting treatment with the medicinal product. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same medicinal product or another bisphosphonate.
Excipients with known effect
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.
Women of child-bearing potentialWomen of child-bearing potential must use highly effective contraception during treatment.
PregnancyThere are no adequate data from the use of pamidronate in pregnant women. There is no unequivocal evidence for teratogenicity in animal studies. Pamidronate may pose a risk to the foetus/newborn child through its pharmacological action on calcium homeostasis. When administered during the entire period of gestation in animals, pamidronate can cause bone mineralisation defects, especially in long bones, resulting in angular distortion.The potential risk for humans is unknown. Therefore, pamidronate should not be administered to pregnant women except in cases of life-threatening hypercalcaemia.
Breast-feedingVery limited experience indicates maternal milk levels of pamidronate under the limit of detection. Moreover the oral bioavailability is poor so the total absorption of pamidronate by a breast fed infant is not likely. However due to extremely limited experience and the potential of pamidronate to have an important impact on bone mineralisation breast feeding during the therapy is not recommended.
FertilityThere are no data available.
Osteonecrosis of the jaw:Cases of osteonecrosis (of the jaw) have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as Medac Disodium Pamidronate 3 mg/ml (see section 4.4). Many of these patients were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries.
Atrial fibrillation:When the effects of zoledronate (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 zoledronate 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 rate 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.
Musculoskeletal and connective tissue disorders:During post-marketing experience the following reactions have been reported (frequency rare): Atypical subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction).Adverse reactions (Table 2) are ranked under headings of frequency, the most frequent first, 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).
|Infections and infestations|
|Very rare:||Reactivation of Herpes simplex, reactivation of Herpes zoster|
|Blood and lymphatic system disorders|
|Common:||Anaemia, thrombocytopenia, lymphocytopenia|
|Immune system disorders|
|Uncommon:||Allergic reactions including anaphylactoid reactions, bronchospasm/dyspnoea, Quincke's (angioneurotic) oedema|
|Very rare:||Anaphylactic shock|
|Metabolism and nutrition disorders|
|Very common:||Hypocalcaemia, hypophosphataemia|
|Very rare:||Hyperkalaemia, hypernatraemia|
|Nervous system disorders|
|Common:||Symptomatic hypocalcaemia (paraesthesia, tetany), headache, insomnia, somnolence|
|Uncommon:||Seizures, agitation, dizziness, lethargy|
|Very rare:||Confusion, visual hallucinations|
|Uncommon:||Uveitis (iritis, iridocyclitis)|
|Very rare:||Scleritis, episcleritis, xanthopsia|
|Not known:||Orbital inflammation|
|Very rare:||Left ventricular failure (dyspnoea, pulmonary oedema), congestive heart failure (oedema) due to fluid overload|
|Not known:||Atrial fibrillation|
|Respiratory, thoracic and mediastinal disorders|
|Very rare:||Acute respiratory distress syndrome, interstitial lung disease|
|Common:||Nausea, vomiting, anorexia, abdominal pain, diarrhoea, constipation, gastritis|
|Skin and subcutaneous disorders|
|Musculoskeletal and connective tissue disorders|
|Common:||Transient bone pain, arthralgia, myalgia|
|Rare:||Atypical subtrochanteric and diaphyseal femoral fractures|
|Very rare:||Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction)|
|Not known:||Osteonecrosis of the jaw|
|Renal and urinary disorders|
|Uncommon:||Acute renal failure|
|Rare:||Focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome|
|Very rare:||Deterioration of pre-existing renal disease, haematuria, renal tubular disorder, tubulointerstitial nephritis, glomerulonephropathy|
|General disorders and administration site conditions|
|Very common:||Fever and influenza-like symptoms sometimes accompanied by malaise, rigors, fatigue, and flushes|
|Common:||Reactions at the infusion site (pain, redness, swelling, induration, phlebitis, thrombophlebitis), general body pain|
|Common:||Increase in serum creatinine|
|Uncommon:||Abnormal liver function tests, increase in serum urea|
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. or search for MHRA Yellow Card in the Google Play or Apple App Store.
Mechanism of actionPamidronate disodium, active substance of Medac Disodium Pamidronate 3 mg/ml, is a potent inhibitor of osteoclastic bone resorption. It binds strongly to hydroxyapatite crystals and inhibits the formation and dissolution of these crystals in vitro. Inhibition of osteoclastic bone resorption in vivo may be at least partly due to binding of the medicinal product to the bone mineral.Pamidronate suppresses the accession of osteoclast precursors onto the bone and the so induced transformation to mature absorbing osteoclasts. However, the local and direct antiresorptive effect of bone-bound biphosphonate appears to be the predominant mode of action in vitro and in vivo.Experimental studies have demonstrated that pamidronate inhibits tumour-induced osteolysis when given prior to or at the time of inoculation or transplantation with tumour cells. Biochemical changes reflecting the inhibitory effect of pamidronate disodium on tumour-induced hypercalcaemia, are characterised by a decrease in serum calcium and phosphate and secondarily by decreases in urinary excretion of calcium, phosphate and hydroxyproline. A dose of 90 mg achieves normocalcaemia in more than 90% of patients.The normalisation of the plasma-calcium-level can also normalise the plasma-parathyroid-hormon-level in adequately rehydrated patients.Serum levels of parathyroid hormone-related protein (PTHrP) inversely correlate with response to pamidronate. Medicinal products that inhibit tubular reabsorption of calcium or PTHrP secretion may help in patients who do not respond to pamidronate.Hypercalcaemia can lead to a 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.When used in addition to systemic antineoplastic therapy pamidronate reduces skeletal complications of non-vertebral fracture, radiotherapy / surgery for bone complications and increases the time to first skeletal event.Pamidronate may also reduce bone pain in about 50% women with advanced breast cancer and clinically evident bone metastases. In women with abnormal bone scans but normal plain radiographs pain should be the primary guide to treatment.Pamidronate has been shown to reduce pain, decrease the number of pathological fractures and the need for radiotherapy, correct hypercalcaemia and improve Quality of Life in patients with advanced multiple myeloma.A meta-analysis of bisphosphonates in >1,100 patients with multiple myeloma showed the NNT (number of patients needed to treat) to prevent one vertebral fracture was 10 and NNT to prevent one patient experiencing pain was 11 with best effects seen with pamidronate and clodronate.
AbsorptionPamidronate disodium is given by intravenous infusion. By definition, absorption is complete at the end of the infusion.
DistributionPlasma concentrations of pamidronate rise rapidly after the start of an infusion and fall rapidly when the infusion is stopped. The apparent distribution half-life in plasma is about 0.8 hours. Apparent steady-state concentrations are therefore achieved with infusions of more than about 2 3 hours duration. Peak plasma pamidronate concentrations of about 10 nmol/ml are achieved after an intravenous infusion of 60 mg given over 1 hour.A similar percentage (approximately 50 %) of the dose is retained in the body after administration of different doses (30 90 mg) of pamidronate disodium independent of infusion time (4 or 24 hours) Thus the accumulation of pamidronate in bone is not capacity-limited, and is dependent solely on the total cumulative dose administered. The percentage of circulating pamidronate bound to plasma proteins is relatively low (less than 50 %) and increases when calcium concentrations are pathologically elevated.
EliminationPamidronate does not appear to be eliminated by biotransformation. After an intravenous infusion, about 20-55 % of the dose is recovered in the urine within 72 hours as unchanged pamidronate. Within the time-frame of experimental studies the remaining fraction of the dose is retained in the body. From the urinary elimination of pamidronate, two decay phases with apparent half-lives of about 1.6 and 27 hours can be observed. The total plasma and renal clearance has been reported to be 88 254 ml/min and 38 60 ml/min, respectively. The apparent plasma clearance is about 180 ml/min. The apparent renal clearance is about 54 ml/min, and there is a tendency for the renal clearance to correlate with creatinine clearance.
Characteristics in patientsHepatic and metabolic clearance of pamidronate are insignificant. Impairment of liver function is therefore not expected to influence the pharmacokinetics of pamidronate disodium, although as there are no clinical data available in patients with severe liver impairment, no specific recommendations can be given for this patient population. Medac Disodium Pamidronate 3 mg/ml displays little potential for interaction with other medicinal products both at the metabolic level and at the level of protein binding (see section 5.2 above).A pharmacokinetic study conducted in patients with cancer showed no differences in plasma AUC of pamidronate between patients with normal renal function and patients with mild to moderate renal impairment. In patients with severe renal impairment (creatinine clearance < 30 ml/min), the AUC of pamidronate was approximately 3 times higher than in patients with normal renal function (creatinine clearance > 90 ml/min).
Colourless 5 ml/10 ml/20 ml/30 ml glass vials (Ph. Eur., Type 1) and bromobutylrubber stoppers (Ph. Eur., Type 1).
1, 4 or 10 vials containing 5 ml sterile concentrate. Also available as multipacks of 4 packs each containing 1 vial.
1, 4 or 10 vials containing 10 ml sterile concentrate. Also available as multipacks of 4 packs each containing 1 vial.
1, 4 or 10 vials containing 20 ml sterile concentrate. Also available as multipacks of 4 packs each containing 1 vial.
1, 4 or 10 vials containing 30 ml sterile concentrate. Also available as multipacks of 4 packs each containing 1 vial.
Not all pack sizes may be marketed.
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