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pamidronate
Pamidronate belongs to a class of bisphosphonates which inhibits osteoclast activity in bone. Pamidronate binds to hydroxyapatite and inhibits osteoclast migration and maturation. In cancer patients with bone metastases and multiple myeloma, lytic bone metastases are caused by increased osteoclast activity. Metastatic tumor cells secrete paracrine factors, which stimulate neighboring osteoclasts to resorb bone. By inhibiting osteoclast function, bisphosphonates interrupt the cascade of events that lead to tumor-induced osteolysis. Pamidronate normalizes serum calcium levels even in tumour induced hypercalcemia without detectable metastases. Pamidronate has been shown to reverse hypercalcemia, prevent or delay skeletal-related events and decrease bone pain.
Pamidronate has a high affinity for calcified tissues, i.e. bone.
| Cross blood brain barrier? | No information found |
| PPB | 54 % |
Pamidronate does not appear to be metabolized.
| Active metabolites | no |
| Inactive metabolites | no |
Pamidronate is excreted intact renally (biphasic elimination). Renal clearance tends to correlate with creatinine clearance. Percentage of dose retained is independent of the dose and infusion rate; accumulation is not capacity limited and is dependent solely on the cumulative dose.
| Urine | 20 - 55 % unchanged in 72 h |
| Half-life |
α phase: 1.6 h; β phase: 27 h |
- Tumour-induced hypercalcemia following adequate saline rehydration.
- Conditions associated with increased osteoclast activity: predominantly lytic bone metastases and multiple myeloma.
(Refer to the product monograph for other non-oncology indications.)
Emetogenic Potential:
Extravasation Potential: None
The following table contains adverse effects reported mainly in oncology randomized trials where incidence > placebo.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Atrial fibrillation (2%) | I E | |||
| Cardiotoxicity (rare - due to fluid overload) | D | ||||
| Hypertension (<10%) | I | ||||
| Hypotension (rare) | I | ||||
| Dermatological | Rash (<10%) | E | |||
| Gastrointestinal | Abdominal pain (17%) | E | |||
| Anorexia (21%) | E | ||||
| Dyspepsia (14%) | E | ||||
| Nausea, vomiting (48%) | I | ||||
| General | Flu-like symptoms (36%) | I | |||
| Hematological | Anemia (<10%) | E D | |||
| Myelosuppression (up to 10%) | E | ||||
| Hepatobiliary | ↑ LFTs (rare) | E | |||
| Hypersensitivity | Hypersensitivity (rare) | I | |||
| Infection | Viral (reactivation - rare) | E | |||
| Injection site | Injection site reaction (<10%) | I | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (>10%) (including ↓Ca, PO4, K, or Mg) | E | |||
| Musculoskeletal | Fracture (atypical) | D | |||
| Musculoskeletal pain (23%) (may be severe) | E | ||||
| Osteonecrosis of external ear canal (rare) | L | ||||
| Osteonecrosis of jaw (rare) | L | ||||
| Nervous System | Cognitive disturbance (rare) | E | |||
| Dizziness (rare) | E | ||||
| Headache (24%) | E | ||||
| Seizure (rare) | E | ||||
| Ophthalmic | Conjunctivitis (<10%) | E | |||
| Uveitis , scleritis or xanthopsia - rare | E | ||||
| Renal | Nephrotoxicity (rare) | D | |||
| Respiratory | Cough, dyspnea (23%) | E | |||
| Pneumonitis / ARDS (rare) | D | ||||
| Urinary | Urinary tract infection (15%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
Adverse reactions with pamidronate are usually mild and transient. The most common adverse reactions are influenza-like symptoms and mild fever. Acute “influenza-like” reactions may last up to 48 hours and usually occur only with the first pamidronate infusion. Severe musculoskeletal pain has been reported.
Deterioration of renal function has been noted with bisphosphonates, although in some cases patients may have had pre-existing renal dysfunction or be dehydrated.
Hypocalcemia has been reported, and is usually asymptomatic, but may be more common in patients with prior thyroid surgery.
Osteonecrosis of the jaw has been reported with an increased risk in patients who smoke, have comorbid or dental diseases, poorly fitting dentures, have had invasive dental procedures, are receiving steroids, radiotherapy, chemotherapy, or parenteral bisphosphonate formulations. Patients should be advised to have dental examinations prior to starting therapy and to avoid invasive dental procedures on treatment. The start of treatment or a new course of treatment should be delayed in patients with unhealed, open soft tissue lesions in the mouth. In multiple myeloma patients, consider discontinuing treatment after 2 years for stable responding patients, or decreasing the frequency to every 3 months.
Osteonecrosis of external auditory canal has been observed in patients on long-term bisphosphonate therapy. Possible risk factors include steroid use, chemotherapy, and/or local infection or trauma. Consider the possibility of osteonecrosis of external auditory canal in patients who present with otic symptoms such as chronic ear infections.
Atypical fractures of the femur (subtrochanteric or diaphyseal) have been reported with bisphosphonate use, primarily in patients receiving long-term treatment. These fractures are often bilateral, occur with minimal or no trauma, with symptoms including thigh or groin pain. Imaging features of stress fractures may be seen weeks to months before presentation with a completed femoral fracture. Poor healing of these fractures has also been reported
Refer to protocol by which patient is being treated.
Patients (especially those with hypercalcemia) must be adequately hydrated before and during treatment, but overhydration should be avoided especially in patients with cardiac disease.
Delay treatment in patients with unhealed soft tissue mouth lesions.
Do not administer doses over 90 mg or exceed the recommended infusion rate.
Calcium and vitamin D supplements should be given to patients at risk of low serum calcium and who have no history of hypercalcemia.
Tumor-induced hypercalcemia (TIH):
- Rehydration with normal saline before treatment is mandatory.
|
Initial Serum Calcium*(mmol/L)
|
Total dose over 3-4 weeks (mg)
|
Maximum IV Infusion rate
|
|
Up to 3
|
30
|
22.5 mg/h
|
|
> 3 - 3.5
|
30 or 60
|
22.5 mg/h
|
|
> 3.5 - 4
|
60 or 90
|
22.5 mg/h
(i.e. 90 mg/4 h) |
|
> 4
|
90
|
22.5 mg/h
(i.e. 90 mg/4 h)
|
*use corrected calcium levels, calculated using the following formula:
Corrected Calcium (mmol/L) = Measured Calcium (mmol/L) + (0.02X[40-Measured Albumin (g/L)])
Bone metastases:
Intravenous: 90 mg over 2 hours every 4 weeks
(or Q 3 week at dose of 90 mg with scheduled chemotherapy)
Multiple Myeloma:
Intravenous: 90 mg over 4 hours every 4 weeks
|
Toxicity
|
Action
|
|
Osteonecrosis of jaw
|
Refer patient to dentist or dental surgeon; hold until recovery. |
|
Atypical fractures of the femur |
Consider discontinuing
|
|
Severe musculoskeletal pain
|
|
|
Ocular symptoms other than uncomplicated conjunctivitis |
Refer to ophthalmologist; consider discontinuing. |
|
Nephrotoxicity
|
Hold until recovered to within 10% of baseline |
AUC is increased in mild to moderate hepatic impairment but not considered clinically relevant; no dosage adjustment is required. No data available in patients with severe hepatic dysfunction and so should be used with caution.
Patients with severe renal impairment (< 30mL/min) have 3 times higher pamidronate exposure than those with normal renal function.
|
Baseline
|
During Treatment
|
||
|
Level
|
Action
|
Level/change
|
Action
|
|
Clcr > 90 mL/min
|
No adjustment needed
|
Creatinine ↑ of 44 µmol/L if normal baseline
|
Hold until returns to within 10% of baseline
|
|
Clcr 30-90 mL/min
|
Do not exceed infusion rate of 22.5 mg/h
|
Creatinine ↑ of 88 µmol/L if abnormal baseline
|
|
|
Clcr < 30 mL/min
or
Creatinine
> 440 µmol/L (TIH) or
> 180 µmol/L (myeloma)
|
Only use for life-threatening hypercalcemia where the benefit exceeds risk |
Clcr < 30 mL/min
or
Creatinine
> 440 µmol/L (TIH) or
> 180 µmol/L (myeloma)
|
Only use for life-threatening hypercalcemia where the benefit exceeds risk
|
No data available.
Safety and efficacy not established. Not recommended for use in children.
- Pamidronate must not be mixed with calcium-containing solutions (e.g., Ringer's solution).
- Pamidronate is generally mixed in 250-500mL solution (D5W or NS) and infused IV over 2-4 hours (refer to Dosing section).
- According to the product monograph, it is recommended not to exceed 90 mg in 500 mL over 4 hours (i.e. 22.5 mg/h infusion rate) in multiple myeloma and tumour-induced hypercalcemia.
- Pamidronate must never be given as a bolus injection because of the risk of thrombophlebitis, severe local reactions and renal failure; it should always be diluted and administered as a slow IV infusion.
- All patients, especially those who are dehydrated or hypercalcemic, must be adequately rehydrated prior to treatment with pamidronate.
- Store unopened vials at room temperature (15-25°C). Protect vials from heat.
- Patients with known or suspected hypersensitivity to pamidronate, or any of its components, or to other bisphosphonates
- Pregnant and/or breastfeeding women
- Pamidronate should not be given together with other bisphosphonates to treat hypercalcemia, since the combined effects of these agents are unknown.
- Patients must be adequately hydrated throughout treatment, but special care should be taken in the elderly and patients with cardiac disease, to prevent fluid overload and cardiac failure.
- Avoid in patients with severe renal impairment, except in life-threatening cases of hypercalcemia.
- Use with caution in patients with risk factors for ONJ (see adverse effects description section).
- Patients should not drive, operate machinery or perform tasks that require alertness if they experience somnolence and/or dizziness after infusion.
Other Drug Properties:
-
Carcinogenicity:
No
-
Mutagenicity:
No
-
Fetotoxicity:
Yes
Pamidronate can cause bone mineralization defects during organogenesis in animals.
-
Teratogenicity:
Yes
Pamidronate is contraindicated for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose (general recommendation).
-
Breastfeeding:
Contraindicated
-
Fertility effects:
Probable
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Anti-angiogenic drugs | ↑ risk of ONJ | Additive | Caution |
| Calcitonin | Significant ↓ in Ca | Synergistic | Caution |
| Nephrotoxic drugs | Renal impairment | Additive | Avoid, use with caution |
| Thalidomide | Renal impairment | Unknown | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Dental examination with appropriate preventative dentistry before starting treatment. Regular dental check- ups and avoidance of invasive dental surgery during treatment. |
|
Renal function tests |
Baseline and at each visit |
Electrolytes, including corrected serum calcium, phosphates, magnesium, and serum albumin |
Baseline and as clinically indicated |
Fluid balance (urine output, daily weights), especially in patients with pre-existing renal disease or risk of renal impairment |
As clinically indicated |
Clinical toxicity assessment (including flu-like syndrome, hypersensitivity, hydration status, pain, dental, otic, and ocular effects) |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
CBC, in patients with anemia, leukopenia, or thrombocytopenia |
Baseline and at each visit |
CCO Practice Guideline: Use of Bisphosphonates in Women with Breast Cancer.
CCO Practice Guideline: The Role of Bisphosphonates in the Management of Skeletal Complications for Patients with Multiple Myeloma.
Fitton A, McTavish D. Pamidronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs 1991;41(2):289-318.
Ifosfamide: AHFS Drug Information [Internet]; 2010 [cited 2012 April 4].
Lacy MO, Dispenzieri A, Gertz MA, et al. Mayo Clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 2006;81(8):1047-53.
Product Monograph: Pamidronate disodium for injection. Hospira Healthcare Corp. Mar 30, 2017.
Product Monograph: Pamidronate disodium for injection. Pfizer Canada, Dec 11, 2018.
Product Monograph: Pamidronate disodium for injection. Fresenius Kabi Canada Ltd., March 12, 2019.
January 2024 Modified Dosing and Administration guidelines sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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