Download Pamidronate disodium belongs to a group of medicines called

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
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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
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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.
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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
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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-
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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
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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
-
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