1. Name Of The Medicinal Product
Disodium Pamidronate 15mg/ml Concentrate for Solution for Infusion
2. Qualitative And Quantitative Composition
1ml of concentrate contains 15mg disodium pamidronate.
One ampoule of 1ml contains 15mg of disodium pamidronate.
One ampoule of 2ml contains 30mg of disodium pamidronate.
One ampoule of 4ml contains 60mg of disodium pamidronate.
One ampoule of 6ml contains 90mg of disodium pamidronate.
3. Pharmaceutical Form
Concentrate for solution for infusion.
Colourless solution, free from particles.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of conditions associated with increased osteoclast activity:
• Tumour-induced hypercalcaemia
• Osteolytic lesions and bone pain in patients with bone metastases associated with breast cancer or multiple myeloma
• Paget's disease of bone.
4.2 Posology And Method Of Administration
Disodium pamidronate concentrate must never be given as a bolus injection (see "Warnings"). The concentrate of disodium pamidronate concentrate in ampoules should be diluted in a calcium-free infusion solution (0.9 % Sodium Chloride Intravenous Infusion B.P. is recommended) and infused slowly.
The infusion rate should never exceed 60mg/hour (1mg/min), and the concentration of disodium pamidronate concentrate in the infusion solution should not exceed 60mg/250ml. In patients with established or suspected renal impairment (e.g. those with tumour-induced hypercalcaemia or multiple myeloma) it is recommended that the infusion rate does not exceed 20mg/h (see also "Renal Impairment"). In order to minimise local reactions at the infusion site, the cannula should be inserted carefully into a relatively large vein.
Until further experience is gained, disodium pamidronate concentrate is only recommended for use in adult patients.
Tumour-induced hypercalcaemia
It is recommended that patients be rehydrated with 0.9% w/v sodium chloride solution before or during treatment.
The total dose of disodium pamidronate concentrate 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.
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The total dose of disodium pamidronate concentrate 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 repeated courses.
A significant decrease in serum calcium is generally observed 24-48 hours after administration of Disodium Pamidronate Injection, and normalisation is usually achieved within three to seven 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 disodium pamidronate concentrate may become less effective as the number of treatments increases.
Osteolytic lesions and bone pain in multiple myeloma
The recommended dose is 90mg every four weeks.
Osteolytic lesions and bone pain in bone metastases associated with breast cancer
The recommended dose is 90mg every four weeks. This dose may also be administered at three weekly intervals to coincide with chemotherapy if desired.
Paget's disease of Bone
The recommended treatment course consists of a total dose of 180mg administered in unit doses of either 30mg once a week for six consecutive weeks, or 60mg every other week over six weeks. Experience to date suggests that any mild and transient unwanted effects (see "Side-effects") tend to occur after the first dose. For this reason if unit doses of 60mg are used it is recommended that treatment be started with an initial additional dose of 30mg (i.e. total dose 210mg). Each dose of 30 or 60mg should be diluted in 125 or 250 ml 0.9% w/v Sodium Chloride Intravenous Infusion B.P. respectively, and the infusion rate should not exceed 60mg/hour (1mg/min). This regimen or increased dose levels according to disease severity, up to a maximum total dose of 360mg (in divided doses of 60mg) can be repeated every six months until remission of disease is achieved, and if relapse occurs.
Renal Impairment
Pharmacokinetic studies indicate that no dose adjustment is necessary in patients with any degree of renal impairment. However, until further experience is gained a maximum infusion rate of 20mg/h is recommended in renally impaired patients.
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 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 Pharmacokinetic properties - Hepatic impairment). Clinical data in patients with severe hepatic impairment is not available. Pamidronate should be administered to this patient population with caution.
Children
There is no clinical experience of the use of disodium pamidronate in children.
4.3 Contraindications
Known hypersensitivity to disodium pamidronate or to other bisphosphonates.
4.4 Special Warnings And Precautions For Use
Warnings
Disodium pamidronate concentrate should be given under the supervision of a physician with the facilities to monitor clinical and biochemical effects.
Disodium pamidronate concentrate should not 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").
Disodium pamidronate concentrate should not be given with other bisphosphonates because their combined effects have not been investigated.
Convulsions have been precipitated in some patients with tumour-induced hypercalcaemia due to the electrolyte changes associated with this condition and its effective treatment.
Osteonecrosis of the jaw has been reported in patients with cancer receiving treatment regimens involving bisphosphonates (including disodium pamidronate). 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. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene). 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.
Precautions
Serum electrolytes, calcium and phosphate should be monitored following initiation of therapy with disodium pamidronate concentrate. Patients who have undergone thyroid surgery may be particularly susceptible to developing hypocalcaemia due to relative hypoparathyroidism.
Patients receiving frequent infusions of disodium pamidronate concentrate 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 periodic evaluations of standard laboratory and clinical parameters of renal function, as deterioration of renal function (including renal failure) has been reported following long-term treatment with disodium pamidronate concentrate in patients with multiple myeloma. However, underlying disease progression and/or concomitant complications were also present and therefore a causal relationship with disodium pamidronate concentrate is unproven.
As there are no clinical data available in patients with severe hepatic insufficiency, no specific recommendations can be given for this patient population.
There is very little experience of the use of disodium pamidronate concentrate in patients receiving haemodialysis.
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.
Pagetic patients at risk of calcium or Vitamin D deficiency (e.g. through malabsorption or lack of exposure to sunlight) should take oral supplements of both during disodium pamidronate concentrate therapy to minimise the potential risk of hypocalcaemia.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Disodium pamidronate concentrate has been administered concomitantly with commonly used anticancer agents without interactions occurring.
Disodium pamidronate concentrate 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.
Since pamidronate binds to bone, it could in theory interfere with bone scintigraphy examinations.
4.6 Pregnancy And Lactation
In animal experiments, pamidronate showed no teratogenic potential and did not affect general reproductive performance or fertility. 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 has been shown to cross the placental barrier and accumulate in fetal bone in a manner similar to that observed in adult animals.
There is insufficient clinical experience to support the use of disodium pamidronate concentrate in pregnant women. Therefore, disodium pamidronate concentrate should not be administered during pregnancy except in cases of life-threatening hypercalcaemia.
A study in lactating rats has shown that pamidronate will pass into the milk. Mothers treated with disodium pamidronate concentrate should therefore not breast-feed their infants.
4.7 Effects On Ability To Drive And Use Machines
Patients should be warned that in rare cases somnolence and/or dizziness may occur following disodium pamidronate 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 disodium pamidronate concentrate 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. Symptomatic hypocalcaemia is rare.
Frequency estimate: Very common (>1/10); common (>1/100, <1/10), uncommon (>1/1000, <1/100); very rare including isolated cases (<1/1000).
Body as a whole
Very common: fever and influenza-like symptoms sometimes accompanied by malaise, rigor, fatigue, and flushes
Local reactions
Common: reactions at the infusion site: pain, redness, swelling, induration, phlebitis, thrombophlebitis
Musculoskeletal system
Common: transient bone pain, arthralgia, myalgia, generalised pain
Uncommon: muscle cramps
Gastrointestinal tract
Common: nausea, vomiting
Uncommon: anorexia, abdominal pain, diarrhoea, constipation, dyspepsia
Very rare: gastritis
Central nervous system
Common: headache
Uncommon: symptomatic hypocalcaemia (paraesthesia, tetany), agitation, confusion, dizziness, insomnia, somnolence, lethargy
Very rare: seizures, visual hallucinations
Blood
Common: lymphocytopenia
Uncommon: anaemia, leukopenia
Very rare: thrombocytopenia
Cardiovascular system
Uncommon: hypotension, hypertension.
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 pamindronate 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 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.
Renal system
Very rare: haematuria, acute renal failure, deterioration of pre-existing renal disease
Skin
Uncommon: rash, pruritus
Special senses
Uncommon: conjunctivitis, uveitis (iritis, iridocyclitis), scleritis, episcleritis, xanthopsia
Others
Very rare: reactivation of herpes simplex and herpes zoster
Uncommon: allergic reactions including anaphylactoid reactions, bronchospasm/dyspnoea, Quincke's (angioneurotic) oedema
Very rare: anaphylactic shock
Biochemical changes
Very common: hypocalcaemia, hypophosphataemia
Common: hypomagnesaemia
Uncommon: hyperkalaemia, hypokalaemia, hypernatraemia
Very rare: abnormal liver function tests, increase in serum creatinine and urea.
Many of these undesirable effects may have been related to the underlying disease.
Postmarking: Rare cases of osteonecrosis (primarily of the jaws) have been reported in patients treated with disodium pamidronate or other bisphosphonates. Many had signs of local infection including osteomyelitis. The majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaws 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 cannot be determined, it is prudent to avoid dental surgery, as recovery may be prolonged (see section 4.4, “special warnings and special precautions for use).
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
Pamidronate disodium, the active substance of disodium pamidronate concentrate, 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 drug to the bone mineral.
Pamidronate 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 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 disodium pamidronate concentrate 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, disodium pamidronate concentrate 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 disodium pamidronate concentrate 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, which is characterised by local areas of increased bone resorption and formation with qualitative changes in bone remodelling, responds well to treatment with disodium pamidronate concentrate. Clinical and biochemical remission of the disease has been demonstrated by bone scintigraphy, decreases in urinary hydroxyproline and serum alkaline phosphatase, and by symptomatic improvement.
5.2 Pharmacokinetic Properties
General characteristics
Pamidronate has a strong affinity for calcified tissues, and total elimination of pamidronate from the body is not observed within the time-frame of experimental studies. Calcified tissues are therefore regarded as sites 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 rise rapidly after the start of an infusion and fall rapidly when the infusion is stopped. The apparent 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, and the apparent plasma clearance is about 180 ml/min.
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 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 (about 54 %), and increases when calcium concentrations are pathologically elevated.
Elimination
Pamidronate 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. 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, two decay phases, with apparent half-lives of about 1.6 and 27 hours, can be observed. 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 patients
Hepatic and metabolic clearance of pamidronate are insignificant. Disodium pamidronate concentrate thus displays little potential for drug-drug interactions both at the metabolic level and at the level of protein binding (see above).
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 90mg dose of disodium pamidronate concentrate 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 disodium pamidronate concentrate is administered on a monthly basis, drug accumulation is not expected. No changes in disodium pamidronate concentrate dosing regimen are recommended for patients with mild to moderate abnormal hepatic function (see Posology and method of administration).
Renal impairment
The mean plasma AUC was approximately doubled in cancer patients at risk for bone metastases with severe renal impairment (creatinine clearance <30ml/min, n=4). Urinary excretion rate decreased with decreasing creatinine clearance, although the total amount excreted in the urine was not greatly influenced by renal function. Body retention of pamidronate was therefore similar in cancer patients with and without impaired renal function, and dose adjustment is not necessary in these patients when using the recommended dose schedule (see Posology and method of administration).
5.3 Preclinical Safety Data
The toxicity of pamidronate is characterised by direct (cytotoxic) effects on organs with a copious blood supply, particularly the kidneys following i.v. exposure. The compound is not mutagenic and does not appear to have carcinogenic potential.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride
Sodium hydroxide
Hydrochloric acid
Water for Injections
6.2 Incompatibilities
Pamidronate will form complexes with divalent cations and should not be added to calcium-containing intravenous solutions.
6.3 Shelf Life
36 months.
Reconstituted solutions that have been further diluted with one of the recommended diluents for intravenous infusion should be used immediately. Discard the unused portion.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
Chemical and physical in-use stability has been demonstrated for 48 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.
6.5 Nature And Contents Of Container
1ml polyethylene ampoules in packs of 1, 2 or 4 ampoules.
2ml polyethylene ampoules in packs of 1, 2 or 4 ampoules.
4ml polyethylene ampoules in packs of 1, 2 or 4 ampoules.
6ml polyethylene ampoules in packs of 1, 2 or 4 ampoules.
6.6 Special Precautions For Disposal And Other Handling
The concentrate should be diluted with a calcium-free infusion solution (0.9% w/v Sodium Chloride Intravenous Infusion BP is recommended) before administration.
7. Marketing Authorisation Holder
Wockhardt UK Ltd
Ash Road North
Wrexham
LL13 9UF
U.K.
8. Marketing Authorisation Number(S)
15mg in 1 ml - PL 29831/0071
30mg in 2ml - PL 29831/0072
60mg in 4ml - PL 29831/0073
90mg in 6ml - PL 29831/0074
9. Date Of First Authorisation/Renewal Of The Authorisation
2nd April 2008
10. Date Of Revision Of The Text
January 2009.
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