Disodium Pamidronate 3 Mg/Ml Concentrate For Solution For Infusion.
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Disodium Pamidronate 3 mg/ml Concentrate for Solution for Infusion.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml concentrate for solution for infusion contains 3 mg pamidronate disodium as pamidronic acid 2.527 mg.
1 vial of 5 ml contains 15 mg pamidronate disodium.
1 vial of 10 ml contains 30 mg pamidronate disodium.
1 vial of 20 ml contains 60 mg pamidronate disodium.
1 vial of 30 ml contains 90 mg pamidronate disodium.
This medicinal product contains less than 1 mmol sodium (23 mg) per single dose, i.e. essentially ‘sodium free’.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear and colourless solution, free from visible particles. pH: 7.0 - 8.0 Osmolality: 31 mOsmol/l
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of conditions associated with increased osteoclast activity:
• Tumour-induced hypercalcaemia
• Osteolytic lesions in patients with bone metastases associated with breast cancer in addition to specific therapy of the tumour
• Osteolytic lesions in multiple myeloma stage III.
4.2 Posology and method of administration
Patients treated with pamidronate disodium should be given the package leaflet and the patient reminder card.
Pamidronate disodium must never be given as a bolus injection (see section 4.4). Disodium Pamidronate 3mg/ml is a concentrate for solution for infusion and must therefore always be diluted in a calcium-free solution for infusion (0.9% w/v sodium chloride solution or 5% w/v glucose solution) before use. The resulting solution must be infused slowly (see also section 4.4).
Use only freshly prepared and clear dilutions.
For information concerning compatibility with solutions for infusion, see section 6.6.
The infusion rate should not exceed 60 mg/h (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 should normally be administered as a 2-hour infusion in a 250 ml infusion solution. However, in patients with established or suspected renal impairment (e.g. those with tumour-induced hypercalcaemia or multiple myeloma) it is recommended not to exceed 90 mg in 500 ml over 4 hours (see section 4.2).
In order to minimise local reactions at the infusion site, the cannula should be inserted carefully into a relatively large vein.
Adults and elderly
Predominantly lytic bone metastases and multiple myeloma
The recommended dose of pamidronate disodium for the treatment of predominantly lytic bone metastases and multiple myeloma is 90 mg administered as a single infusion every 4 weeks.
In patients with bone metastases who receive chemotherapy at 3-weekly intervals, pamidronate disodium 90 mg may also be given on a 3-weekly schedule.
Tumour-induced hypercalcaemia
Patients must be adequately rehydrated with 0.9% w/v sodium chloride solution, prior to and during administration of pamidronate disodium.
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.
Table 1 Recommended doses according to serum calcium levels
|
Initial serum calcium |
Recommended total | |
|
(mmol/l) |
(mg %) |
dose (mg) |
|
up to 3.0 |
up to |
15-30 |
|
12.0 | ||
|
3.0-3.5 |
12.0- |
30-60 |
|
14.0 | ||
|
3.5-4.0 |
14.0- |
60-90 |
|
16.0 | ||
|
>4.0 |
>16.0 |
90 |
The total dose of pamidronate disodium may be administered either in a single infusion or in multiple infusions over 2-4 consecutive days. The maximum dose per treatment course is 90 mg for both initial and repeat courses.
A significant decrease in serum calcium is generally observed 24-48 hours after administration of pamidronate disodium, and normalisation is usually achieved within 3 to 7 days. If normocalcaemia is not achieved within this time, a further dose may be given. The duration of the response may vary from patient to patient, and treatment can be repeated whenever hypercalcaemia recurs. Clinical experience to date suggests that pamidronate disodium may become less effective as the number of treatments increases.
Special Population
Renal impairment
Pamidronate disodium should not be administered to patients with severe renal impairment (creatinine clearance <30 ml/min) unless in cases of life-threatening tumour-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 (see sections 4.4 and 5.2).
As with other i.v. bisphosphonates, renal monitoring is recommended, for instance, measurement 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, pamidronate disodium treatment 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 61-90 ml/min) to moderate renal impairment (creatinine clearance 30-60 ml/min). In such patients, the infusion rate should not exceed 90 mg/4 h (approximately 20-22 mg/h).
Hepatic impairment
Although patients with hepatic impairment exhibited higher mean AUC and Cmax values compared to patients with normal hepatic function, this is not perceived as being clinically relevant. As pamidronate is still rapidly cleared from the plasma almost entirely into the bone and as it is administered on a monthly basis for chronic treatment, drug accumulation is not expected. Therefore no dose adjustment is necessary in patients with mild to moderate abnormal hepatic function (see section 5.2). Pamidronate disodium has not been studied in patients with severe hepatic impairment (see section 4.4). Pamidronate should be administered to this patient population with caution.
Children and adolescents (<18 years)
There is no clinical experience with pamidronate disodium in children. Therefore until further experience is gained, pamidronate disodium is only recommended for use in adult patients.
4.3 Contraindications
Pamidronate disodium is contraindicated
• in patients with known or suspected hypersensitivity to pamidronate disodium or to other bisphosphonates, or to any of the excipients of pamidronate disodium.
4.4 Special warnings and precautions for use General
Pamidronate disodium 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 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 pamidronate disodium. Patients who have undergone thyroid surgery may be particularly susceptible to develop hypocalcaemia due to relative hypoparathyroidism.
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.
Convulsions have been precipitated in some patients with tumour-induced hypercalcaemia due to electrolyte changes associated with this condition and its effective treatment.
Patients with anaemia, leukopenia or thrombocytopenia should have regular haematology assessments.
The medicinal product contains 0.65 mmol sodium per maximum dose (90 mg). This should be taken into consideration in patients on a controlled sodium diet.
Special population
Renal impairment
Bisphosphonates, including pamidronic acid, 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 pamidronate disodium. Deterioration of renal function (including renal failure) has also been reported following long-term treatment with pamidronate disodium in patients with multiple myeloma.
Pamidronate disodium 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 pamidronate disodium 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 pamidronate disodium.
Patients receiving frequent infusions of pamidronate disodium 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 pamidronate disodium.
Patients treated with pamidronate disodium for bone metastases or multiple myeloma should have the dose withheld if renal function has deteriorated (see section 4.2).
Pamidronate disodium should not be administered to patients with severe renal impairment (creatinine clearance <30 ml/min) unless in cases of life-threatening tumour-induced hypercalcaemia where the benefit outweighs the potential risk (see section 4.2). Because there is only limited pharmacokinetic data with severe renal impairment no dose recommendations for this patient population can be made (see sections 4.2 and 5.2).
Pamidronate disodium should not be given with other bisphosphonates because their combined effects have not been investigated.
There is very little experience of the use of pamidronate disodium in patients receiving haemodialysis.
Hepatic impairment
As there are no clinical data available in patients with severe hepatic impairment, no specific recommendations can be given for this patient population (see section 4.2).
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 be given oral calcium and vitamin D supplementation, in order to minimise the risk of hypocalcaemia.
Osteonecrosis of the jaw
Osteonecrosis 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 dentures.
All 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. 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 canal
Osteonecrosis 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.
Musculosketal pain
In 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 pamidronate disodium for infusion. The time to onset of symptoms varied from one day to several months after starting the medicinal product. Most patients had relief of symptoms after stopping treatment. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
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.
4.5 Interaction with other medicinal products and other forms of interaction
Pamidronate disodium has been administered concomitantly with commonly used anticancer agents without interactions occurring.
Pamidronate disodium has been used in combination with calcitonin in patients with severe hypercalcaemia, resulting in a synergistic effect producing a more rapid fall in serum calcium.
Caution is warranted when pamidronate disodium is used with other potentially nephrotoxic medicinal products.
In multiple myeloma patients, the risk of renal dysfunction may be increased when pamidronate disodium is used in combination with thalidomide.
Since pamidronate binds to bone, it could in theory interfere with bone scintigraphy examinations.
Caution is advised when pamidronate is administered with anti-angiogenic medicinal products, as an increase in the incidence of ONJ has been observed in patients treated concomitantly with these medicinal products.
4.6 Fertility, pregnancy and lactation
Fertility
There are no data available.
Women of child-bearing potential
Women of child-bearing potential must use highly effective contraception during treatment.
Pregnancy:
There 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. Studies in animals have shown reproductive toxicity (see section 5.3). Dystocia was observed in the rats.
The potential risk for humans is unknown. Therefore, pamidronate should not be administered to pregnant women except in cases of life-threatening hypercalcaemia.
Breast-feeding:
It is not known whether Disodium Pamidronate 3 mg/ml is excreted into human milk. Very 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 breastfed infant is not likely. A study in lactating rats has shown that pamidronate will pass into the milk. However due to extremely limited experience and the potential of pamidronate to have an important impact on bone mineralisation breastfeeding during the therapy is not recommended.
4.7 Effects on ability to drive and use machines
Patients should be warned that somnolence and/or dizziness may occur following pamidronate disodium infusion, in which case they should not drive, operate potentially dangerous machinery, or engage in other activities that may be hazardous because of decreased alertness.
4.8 Undesirable effects
Adverse reactions to pamidronate disodium 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.
Adverse reactions (Table 2) are ranked under headings of frequency, the most frequent first, using the following convention: Frequency estimate: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000) including isolated reports, not known (cannot be estimated from the available data).
The following adverse drug reactions were reported from clinical studies and from postmarketing experience with pamidronate.
Because the post marketing reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency (which is therefore categorised as not known) or establish a causal relationship to drug exposure.
Table 2 Adverse drug reactions
Infections and
Very rare: Reactivation of Herpes simplex,
|
infestations |
reactivation of Herpes zoster. |
|
Blood and lymphatic system disorders |
Common: Anaemia, thrombocytopenia, lymphocytopenia. Leukopenia. |
|
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. Common: Hypokalaemia, hypomagnesaemia. 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. |
|
Eye disorders |
Common: Conjunctivitis. Uncommon: Uveitis (iritis, iridocyclitis). Very rare: Scleritis, episcleritis, xanthopsia. Not known: Orbital inflammation. |
|
Cardiac disorders |
Common: Atrial fibrillation. Very rare: Left ventricular failure (dyspnoea, pulmonary oedema), congestive heart failure (oedema) due to fluid overload. |
|
Vascular disorders |
Common: Hypertension. Uncommon: Hypotension. |
|
Respiratory, thoracic and mediastinal disorders |
Very rare: Acute respiratory distress syndrome, interstitial lung disease. |
|
Gastrointestinal disorders |
Common: Nausea, vomiting, anorexia, abdominal pain, diarrhoea, constipation, gastritis. Uncommon: Dyspepsia. |
|
Skin and subcutaneous tissue disorders |
Common: Rash. Uncommon: Pruritus. |
|
Musculoskeletal and connective tissue disorders |
Common: Transient bone pain, arthralgia, myalgia, generalised pain. Uncommon: Muscle cramps. Very rare: osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction) Not known: severe and occasionally incapacitating bone, joint, and/or muscle pain, osteonecrosis of the jaw*, atypical subtrochanteric and diaphyseal femoral fractures*. |
|
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. Not known: tubulointerstitial nephritis, glomeruloephropathy. | |
|
General disorders and administration site conditions |
Very common: Fever and influenza-like symptoms sometimes accompanied by malaise, rigor, fatigue and flushes. Common: Reactions at the infusion site (pain, redness, swelling, induration, phlebitis, thrombophlebitis). |
|
Investigations |
Common: Increase in serum creatinine. Uncommon:: Abnormal liver function tests, increase in serum urea. |
|
*See subsection “Description of selected adverse reactions” below. | |
Description of selected Adverse Drug Reactions (class label):
Atrial fibrillation:
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%). Isolated instances of higher incidence of atrial fibrillation have also been reported in a few studies with other bisphosphonates. The mechanism of this increased incidence of atrial fibrillation in isolated studies with some bisphosphonates, including pamidronate, is unknown.
Osteonecrosis of jaw:
Cases of osteonecrosis (of the jaw) have been reported, predominantly in cancer patients treated with medicinal products that inhibit bone resorption, such as pamidronate (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.
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).
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
4.9 Overdose
Patients who have received doses higher than those recommended should be carefully monitored. In the event of clinically significant hypocalcaemia with paraesthesia, tetany and hypotension, reversal may be achieved with an infusion of calcium gluconate.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicinal products affecting bone structure and mineralisation, Bisphosphonates ATC: M05 BA 03
Pamidronate disodium 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 disodium suppresses the accession of osteoclast precursors onto the bone. However, the local and direct antiresorptive effect of bone-bound bisphosphonate appears to be the predominant mode of action in vitro and in vivo.
Experimental studies have demonstrated that pamidronate disodium 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.
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.
Clinical trials in patients with breast cancer and predominantly lytic bone metastases or with multiple myeloma showed that pamidornate prevented or delayed skeletal-related events (hypercalcaemia, fractures, radiation therapy, surgery to bone, spinal cord compression) and decreased bone pain.
Clinical trials in patients with breast cancer and predominantly lytic bone matastases or with multiple myeloma showed that pamidronate prevented or delayed skeletal-related events (hypercalcaemia, fractures, radiation therapy, surgery to bone, spinal cord compression) and decreased bone pain.
5.2 Pharmacokinetic properties
Pharmacokinetic properties
General characteristics:
Pamidronate disodium has a strong affinity for calcified tissues, and total elimination of pamidronate disodium from the body is not observed within the time-frame of experimental studies. Calcified tissues are therefore regarded as site of "apparent elimination".
Absorption:
Pamidronate disodium is given by intravenous infusion. By definition, absorption is complete at the end of the infusion.
Distribution:
Plasma concentrations of pamidronate disodium rise rapidly after the start of an infusion and fall rapidly when the infusion is stopped. The apparent distribution halflife 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 disodium concentrations of about 10 nmol/ml are achieved after an intravenous infusion of 60 mg given over 1 hour.
In animals and in man, a similar percentage of the dose is retained in the body after each dose of pamidronate disodium. Thus the accumulation of pamidronate disodium in bone is not capacity-limited, and is dependent solely on the total cumulative dose administered.
The percentage of circulating pamidronate disodium bound to plasma proteins is relatively low (about 54%), and increases when calcium concentrations are pathologically elevated.
Elimination:
Pamidronate disodium does not appear to be eliminated by biotransformation and it is almost exclusively eliminated by renal excretion. After an intravenous infusion, about 20-55% of the dose is recovered in the urine within 72 hours as unchanged pamidronate disodium. Within the time-frame of experimental studies the remaining fraction of the dose is retained in the body. The percentage of the dose retained in the body is independent of both the dose (range 15-180 mg) and the infusion rate (range 1.25-60 mg/h). From the urinary elimination of pamidronate disodium, two decay phases, with apparent half-lives of about 1.6 and 27 hours, can be observed. The apparent total plasma clearance is about 180 ml/min and the apparent renal clearance is about 54 ml/min. There is a tendency for the renal clearance to correlate with creatinine clearance.
Characteristics in patients:
Hepatic and metabolic clearance of pamidronate disodium are insignificant. Disodium Pamidronate 3 mg/ml thus displays little potential for drug-drug interactions both at the metabolic level and at the level of protein binding (see section
5.2 above).
Special Populations
Hepatic impairment
The pharmacokinetics of pamidronate were studied in male cancer patients at risk for bone metastases with normal hepatic function (n=6) and mild to moderate hepatic dysfunction (n=9). Each patient received a single 90 mg dose of pamidronate infused over 4 hours. There was a statistically significant difference in the pharmacokinetics between patients with normal and impaired hepatic function. Patients with hepatic impairment exhibited higher mean AUC (39.7%) and Cmax (28.6%) values. The difference was not considered clinically relevant. The mean ratio based on log transformed parameters of impaired versus normal patients was 1.38 (90% C.I. 1.12 -1.70, P=0.02) for AUC and 1.23 (90% C.I. 0.89 - 1.70, P=0.27) for Cmax. Nevertheless, pamidronate was still rapidly cleared from the plasma. Drug levels were not detectable in patients by 12-36 hours after drug infusion. Because pamidronate is administered on a monthly basis, drug accumulation is not expected. No changes in pamidronate dosing regimen are recommended for patients with mild to moderate abnormal hepatic function (see section 4.2).
Renal impairment
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 disodium was approximately 3 times higher than in patients with normal renal function (creatinine clearance >90 ml/min).Because there is only limited pharmacokinetic data with severe renal impairment no dose recommendations for this patient population can be made (see sections 4.2 and 4.4).
5.3 Preclinical safety data
Acute toxicity
The toxicity of pamidronate disodium is characterised by direct (cytotoxic) effects on organs with a copious blood supply, particullarly the kidneys following i.v. exposure.
Reproduction toxicity
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 fetus. Animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone.
A study in lactating rats has shown that pamidronate will pass into the milk. Mutagenicity and carcinogenic potential
The compound is not mutagenic and does not appear to have carcinogenic potential.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium hydroxide (for pH adjustment) Hydrochloric acid 4% solution (for pH adjustment)
Water for Injections
6.2 Incompatibilities
Disodium pamidronate will form complexes with divalent cations and should not be added to calcium-containing intravenous solutions.
The medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Solutions of disodium pamidronate are not soluble in lipophilic nutrition solutions, e.g. soya-bean oil.
6.3 Shelf life
Unopened vial: 3 years
Shelf life after dilution in 5% glucose solution or in 0.9% sodium chloride solution: chemical and physical in-use stability has been demonstrated for 96 hours at 25 °C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions. For storage of the diluted solution, see section 6.3.
6.5 Nature and contents of container
Colourless 5 ml/10 ml/20 ml/30 ml glass vials (Ph. Eur., Type 1) and bromobutylrubber stoppers (Ph. Eur., Type 1).
Pack sizes:
1, 4 or 10 vials containing 5 ml concentrate for solution for infusion.
1, 4 or 10 vials containing 10 ml concentrate for solution for infusion.
1, 4 or 10 vials containing 20 ml concentrate for solution for infusion. 1, 4 or 10 vials containing 30 ml concentrate for solution for infusion.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Must be diluted with 5% glucose solution or 0.9% sodium chloride intravenous infusion prior to administration.
The concentration of disodium pamidronate in the infusion solution should not exceed 90 mg/ 250 ml.
Do not use solution if particles are present.
Any portion of the contents remaining after use should be discarded.
Disodium pamidronate 3 mg/ml concentrate for solution for infusion is for single use only.
The diluted solution for infusion should be visually inspected and only clear solutions practically free from particles should be used.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited Eastbourne, BN22 9AG United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/0854
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 17/02/2010
10 DATE OF REVISION OF THE TEXT
21/06/2016