Pamidronate (Aredia) is a bisphosphonate that is administered as a slow intravenous infusion. It is used in the treatment and prevention of bone loss.

Pamidronate Uses:

• Hypercalcemia of malignancy:
  • Treatment of moderate or severe hypercalcemia due to malignancy, with or without bone metastases, in conjunction with optimal hydration.
• Osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma:
  • Use in the management of osteolytic lesions of multiple myeloma and osteolytic bone metastases of breast cancer in conjunction with standard antineoplastic therapy.
• Paget disease:
  • Moderate to severe Paget's disease of bone's treatment.
• Off Label Use of Pamidronate in Adults:
  • Prevention of bone loss associated with treatment in prostate cancer;
  • Hyperparathyroidism;
  • Symptomatic bone metastases of thyroid cancer

Pamidronate Dose in Adults

 Note: Single doses should not exceed 90 mg.

Pamidronate Dose in the treatment of Hypercalcemia of malignancy: 

• Moderate cancer-related hypercalcemia (corrected serum calcium: 12 to 13.5 mg/dL):
  • 60 to 90 mg Intravenous, as a single dose over 2 to 24 hours
• Severe cancer-related hypercalcemia (corrected serum calcium: >13.5 mg/dL):
  • 90 mg intravenous, as a single dose over 2 to 24 hours
• Re-treatment in patients who show an initial complete or partial response (allow at least 7 days to elapse prior to re-treatment):
  • Maybe treated at the same dose again, if serum calcium does not get back to normal or does not remain normal after initial treatment.

Pamidronate (Aredia) Dose in the treatment of Multiple myeloma for osteolytic bone lesions:

• • 90 mg intravenous over 4 hours once a month.
• Lytic bone disease: American Society of Clinical Oncology (ASCO) guidelines:
  • 90 mg intravenous over at least 2 hours every 3 to 4 weeks for up to 2 years;
  • less frequent dosing i.e once every 3 months may be considered in patients with stable/responsive disease (patients with no active disease and are on maintenance therapy);
  • discontinue the drug after 2 years in patients with responsive and/or stable disease;
  • resume therapy upon relapse with new-onset skeletal-related events.
• Newly diagnosed symptomatic multiple myeloma:
  • 30 mg intravenous over 2.5 hours once a month for at least 3 years (Gimsing 2010)

Pamidronate (Aredia) Dose in the treatment of osteolytic bone metastases in patients with breast cancer:

• • 90 mg intravenous over 2 hours every 3 to 4 weeks

Pamidronate (Aredia) Dose in the treatment of moderate to severe Pagets disease:

• • 30 mg intravenous over 4 hours daily for 3 consecutive days (total dose = 90 mg);
  • may repeat dose if clinically indicated

Pamidronate Dose in the treatment of Hyperparathyroidism (off-label): 

• • 15 to 90 mg intravenous as a single dose (Ammann 2003; Jansson 2004; Lu 2003);
  • may be repeated every 1 to 2 months or when hypercalcemia recurs (Jansson 1991; Torregrosa 2003).
  • The duration of treatment in clinical trials was up to 1 year (Torregrosa 2003).

Pamidronate dose for the prevention of androgen deprivation-induced osteoporosis (off-label):

• • 60 mg intravenous over 2 hours every 3 months (Smith 2001)

    Note: Due to the increased risk of nephrotoxicity, single doses should not exceed 90 mg.

Pamidronate Dose in Childrens

Pamidronate dose in the treatment of Hypercalcemia:

• Children and Adolescents:
  • • Dosing based on several case reports and retrospective studies for the treatment of hypercalcemia caused by malignancy and/or immobility.
    • Administer as a single infusion.
    • Repeat dose may be necessary if serum calcium does not return to normal or does not remain normal after initial treatment;
    • the reported interval for multiple doses is ≥24 hours.
  • Initial treatment:
    • 0.5 to 1 mg/kg Intravenous to a maximum dose of 90 mg.
  • Severe life-threatening:
    • 1.5 to 2 mg/kg Intravenous to a maximum dose of 90 mg;
    • in one case report, a higher dose of 4 mg/kg was used to treat a serum calcium concentration of 18.9 mg/dL associated with bone metastases in a 4-year child having non-Hodgkin lymphoma.

Pamidronate dose in the treatment of Osteogenesis imperfecta:

Note:

• Reported dosing regimens are variable (ie, weight-directed vs BSA-directed);
• duration of treatment has not been defined.
• however, most benefit has been reported to occur in the first 2 to 4 years of treatment.
• Weight-directed dosing:
  • Infants and Children <2 years:
    • Initial:
      • 0.25 mg/kg Intravenous once on day 1,
      • then 0.5 mg/kg/dose daily days 2 and 3 of the first cycle,
      • then 0.5 mg/kg/dose once daily for 3 days for subsequent cycles;
      • cycles are repeated every 2 months for a total yearly dose of 9 mg/kg.
  • Children 2 to 3 years:
    • Initial:
      • 0.38 mg/kg Intravenous once on day 1,
      • then 0.75 mg/kg/dose daily days 2 and 3 of the first cycle,
      • then 0.75 mg/kg/dose daily for 3 days for subsequent cycles;
      • cycles are repeated every 3 months for a total yearly dose of 9 mg/kg
  • Children >3 years and Adolescents:
    • Initial:
      • 0.5 mg/kg Intravenous once on day 1,
      • then 1 mg/kg/dose daily on day 2 and 3 of the first cycle,
      • then 1 mg/kg/dose daily for 3 days for subsequent cycles;
      • cycles are repeated every 4 months for a total yearly dose of 9 mg/kg
• BSA-directed dosing:
  • Infants, Children, and Adolescents:
    • Initial:
      • 10 mg/m /dose Intravenous every month for 3 months,
      • then increase to 20 mg/m²/dose every month for 3 months,
      • then increase to 30 mg/m² /dose every month for subsequent doses to a maximum dose of 40 mg/m² /dose was used in six patients after 1-2 years due to skeletal pain and less bone mineral gain;

Pamidronate dose in the treatment of Osteopenia associated with cerebral palsy (nonambulatory):

• Children and Adolescents:
  • Initial:
    • 1 mg/kg/dose Intravenous daily for 3 days;
    • administer every 3 to 4 months;
    • minimum dose: 15 mg;
    • maximum dose: 35 mg.

Pregnancy Risk Factor D

• In animal reproduction studies, adverse events were noted.
• Although it is unknown if bisphosphonates cross into the placenta, it is possible that fetal exposure to them is possible.
• Bisphosphonates are absorbed into bone matrix and slowly released over a period of time.
• The dose and duration of therapy will determine how much is available in the systemic circulation.
• Theoretically, there could be a risk for the fetus if the therapy is completed during pregnancy.
• However, data do not support the claim that pregnancy with bisphosphonates increases the likelihood of fetal complications.
• Researchers recommend that pregnant women stop taking bisphosphonate therapy before they have a planned pregnancy.
• Premenopausal women should only be used for rare occasions, such as when there is rapid bone loss.
• After in-utero exposure tobisphosphonate has been reported as having low calcium levels.
• It is important that exposed infants be monitored for hypocalcemia following birth.

Pamidronate use during breastfeeding:

• It is unknown if pamidronate can be found in breast milk.
• A breastfeeding woman who received pamidronate 30mg IV monthly (therapy began 6 months after birth) did not have any signs of pamidronate in her milk.
• After the first infusion, milk is pumped and collected for 0-24 hours and 25-48 hours respectively. Each day is then pooled for analysis.
• Pamidronate was found to be below the limit for quantification (0.4 micromoles/L).
• Breast milk was removed from the infants during therapy.
• Breastfeeding was done for >80% of the time. No adverse events were reported.
• It is recommended to monitor the serum calcium levels of breastfed infants.
• The potential for severe side effects in breastfed babies makes drug manufacturers recommend that you decide whether to discontinue breastfeeding or stop using the drug.

Pamidronate dose in Kidney Disease:

• Patients with serum creatinine >3 mg/dL were excluded from clinical trials;
• there are only limited pharmacokinetic data in patients with CrCl <30 mL/minute.

Dosing adjustment in patients with renal impairment prior to initiating pamidronate treatment:

• Treatment of bone metastases:
  • Use is not recommended in patients with severe renal impairment.
• Renal impairment in indications other than bone metastases:
  • Use clinical judgment to determine if benefits outweigh potential risks.
• Multiple myeloma:
  • Severe renal impairment (serum creatinine >3 mg/dL or CrCl <30 mL/minute) and extensive bone disease:
  • Recommended dose: 90 mg over 4 to 6 hours or consider a reduced initial dose.

Dosing adjustment in patients who develop renal toxicity during pamidronate therapy:

• In patients with bone metastases, treatment should be withheld for deterioration in renal function in case of:
  • increase of serum creatinine ≥0.5 mg/dL in patients with normal baseline [serum creatinine <1.4 mg/dL] or
  • ≥1 mg/dL in patients with abnormal baseline [serum creatinine ≥1.4 mg/dL].
• Resumption of therapy may be considered when serum creatinine lowers to within 10% of baseline.

Multiple myeloma: American Society of Clinical Oncology (ASCO) guidelines:

• Renal deterioration without an apparent cause, then Withhold therapy; may resume at the prior dose when the renal function returns to within 10% of baseline.
• Albuminuria >500 mg/24 hours (unexplained):
  • Withhold dose until returns to normal baseline, then monitor every 3 to 4 weeks; consider re-initiating at a dose not to exceed 90 mg every 4 weeks and with a prolonged infusion time of at least 4 hours

Pamidronate Dose in Liver disease:

• Mild to moderate impairment:
  • No dosage adjustment is necessary.
• Severe impairment:
  • There are no dosage adjustments provided in the manufacturer’s labeling or it has not been studied.

   Common Side Effects of Pamidronate (Aredia):

• Central nervous system:
  • Fatigue
  • Headache
  • Insomnia
  • Anxiety
  • Pain
• Endocrine & metabolic:
  • Hypophosphatemia
  • Hypokalemia
  • Hypocalcemia
  • Hypomagnesemia
• Gastrointestinal:
  • Nausea
  • Vomiting
  • Anorexia
  • Abdominal Pain
  • Dyspepsia
• Genitourinary:
  • Urinary tract infection
• Hematologic & oncologic:
  • Anemia
  • Metastases
  • Granulocytopenia
• Local:
  • Infusion site reaction
• Neuromuscular & skeletal:
  • Myalgia
  • Weakness
  • Ostealgia
  • Arthralgia
• Renal:
  • Increased serum creatinine
• Respiratory:
  • Dyspnea
  • Upper Respiratory Tract Infection
  • Cough
  • Sinusitis
  • Pleural Effusion
• Miscellaneous:
  • Fever

Less Common Side Effects of Pamidronate (Aredia):

• Cardiovascular:
  • Atrial fibrillation
  • Hypertension
  • Syncope
  • Tachycardia
  • Atrial Flutter
  • Cardiac failure
  • Edema
• Central nervous system:
  • Drowsiness
  • Psychosis
• Endocrine & metabolic:
  • Hypothyroidism
  • Hypervolemia
• Gastrointestinal:
  • Constipation
  • Gastrointestinal hemorrhage
  • Diarrhea
  • Stomatitis
• Genitourinary:
  • Uremia
• Hematologic & oncologic:
  • Leukopenia
  • Neutropenia
  • Thrombocytopenia
• Infection:
  • Candidiasis
• Neuromuscular & skeletal:
  • Arthropathy
  • Back pain
• Renal:
  • Renal insufficiency

• Respiratory:
  • Rales
  • Rhinitis

Contraindication to Pamidronate (Aredia):

• Hypersensitivity clinically to pamidronate or other bisphosphonates or any component of this formulation is contraindicated.
• Pregnancy
• Breastfeeding

Warnings and precautions

• Bone fractures:
  • Patients receiving bisphosphonates have had atypical femur fractures (AFF).
  • These fractures are caused by subtrochanteric and diaphyseal bone fragments.
  • Few patients feel prodromal pain for weeks or months before a fracture occurs.
  • These fractures may be caused by bisphosphonate therapy.
  • Patients not receiving bisphosphonates or those who are taking glucocorticoids have also reported atypical fractures of the femur.
  • Long-term bisphosphonate therapy, i.e. >3 to 5 Years, may increase the risk for patients.
  • Patients who present with groin or thigh pain and have had bisphosphonate treatment should be evaluated for a femur fracture.
  • Patients with a fracture of the femoral shaft should not receive bisphosphonate therapy.
  • Examine the contralateral limb for fractures.
• Musculoskeletal pain
  • Bisphosphonate treatment can sometimes cause severe, sometimes debilitating, bone, joint and/or muscular pain.
  • It can last from one day to several years.
  • If you experience severe symptoms, discontinue therapy. Most cases resolve within a few days.
  • Recurrences may occur in some patients if the same drug is administered again or another bisphosphonate.
  • Patients who have had these symptoms before should not take these drugs.
• An abnormality in the electrolyte:
  • The use of this product has been linked to asymptomatic electrolyte imbalances (hypophosphatemia, hypomagnesemia and hypocalcemia).
  • There have been rare cases of hypocalcemia symptomatic, which includes tetany.
• Myelosuppression
  • Patients with anemia, leukopenia or thrombocytopenia must be closely monitored for the first two weeks.
• Osteonecrosis in the jaw:
  • Patients who have received bisphosphonates have been known to suffer from medication-related osteonecrosis (MRONJ), also called Osteonecrosis (ONJ).
  • MRONJ is a known risk factor
    • invasive dental procedures (eg, tooth extraction, dental implants, boney surgery),
    • cancer diagnosis,
    • Concomitant therapy (eg chemotherapy, corticosteroids or angiogenesis inhibitors)
    • poor oral hygiene,
    • ill-fitting dentures,
    • and comorbid conditions (anemia.coagulopathy.infection, preexisting periodontal or dental disease).
  • There is a possibility that the risk of developing breast cancer may rise if you use bisphosphonate for longer periods and/or report your tumor at a higher frequency depending on the type of tumor (eg, multiple myeloma, advanced breast carcinoma).
  • According to a position paper by the American Association of Maxillofacial Surgeons, Medication-related osteonecrosis of the jaw (MRONJ) has been associated with bisphosphonates and other antiresorptive agents like denosumab, and anti-angiogenic agents (eg, bevacizumab, sunitinib) which are used for the treatment of osteoporosis or malignancy;
  • Patients with malignancy who receive antiresorptive treatment are at greater risk than patients with osteoporosis treatment.
  • This is independent of the medication or dosing schedule.
  • MRONJ risk increases with monthly IV antiresorptive therapy, compared to the lower risk associated with oral bisphosphonate therapy.
  • However, the risk seems to increase with oral bisphosphonate therapy that lasts more than 4 years.
  • According to the AAOMS, if there is no medical harm, IV bisphosphonates should be initiated until optimal dental health has been attained.
  • If extractions are necessary, antiresorptive therapy should not be initiated until the extraction site is mucosalized, or after adequate osseous healing.
  • After IV bisphosphonate therapy has been started for cancerous diseases, any interventions that cause direct bone injury should be avoided.
  • An oro-dental surgeon should be consulted if a patient develops ONJ from treatment with these.
• Renal deterioration:
  • Doses of pamidronate should not exceed 90mg.
  • Initial or single doses of dialysis have been linked to renal deterioration and progression to renal failure.
  • Glomerulosclerosis (focal Segmental) has been reported with or without nephrotic Syndrome.
  • Patients with pre-existing renal impairment may be at greater risk of developing renal toxicities if they receive longer infusions (>2 hours).
  • Patients with severe renal impairment should be advised to stop taking pamidronate until their renal function is back to normal.
• Breast cancer (metastatic).
  • American Society of Clinical Oncology/Cancer Care Ontario (CCO), updated guidelines regarding the role and effects of bone-modifying agents (BMAs), in metastatic breast cancer patients.
  • These guidelines recommend that patients with metastatic breast cancer to their bones be treated with a BMA (denosumab pamidronate, and zoledronic Acid).
  • A BMA should not be deemed superior to another if there are sufficient evidence to support the recommendation.
  • It is unknown exactly how long BMA therapy should be continued. However, guidelines recommend that BMA therapy be continued for at least one year.
  • BMAs have a modest analgesic effect and should not be used for pain management.
  • Supportive care, analgesics and adjunctive therapies, radiation therapy and surgery should also be considered.
  • ASCO/CCO guidelines include information regarding dosing, renal dosage adjustments and infusion times. They also provide guidance in monitoring laboratory parameter recommendations.
• Hypercalcemia in malignancy (HCM).
  • Treatment requires adequate hydration, i.e. urine output of approximately 2 L/day.
  • Avoid overhydration, especially for patients with heart disease.
• Hypoparathyroidism:
  • Patients with a history or thyroid surgery should be cautious.
  • They may have relative hypoparathyroidism which can predispose them to pamidronate-related Hypocalcemia.
• Multiple myeloma
  • Patients suffering from Bence-Jones proteinuria or dehydration need to be properly hydrated before starting therapy.
  • American Society of Clinical Oncology has revised guidelines for bone-modifying agents (BMAs), in multiple myeloma.
  • Patients with radiographic evidence or imaging of lytic bone disease should start bisphosphonate (pamidronate, zoledronic Acid) therapy.
  • Patients with osteolytic pain or patients who are in imminent danger of fractures may consider bisphosphonates.
  • These guidelines recommend IV bisphosphonates for patients with multiple myeloma (osteoporosis), but not radiographic evidence of lytic bones disease.
  • Patients with solitary plasmacytoma or smoldering (asymptomatic) bisphosphonates should not be used.
  • Monoclonal Gammopathy of Undetermined Significance is not recommended if osteopenia (osteoporosis), is also present.
  • Guidelines recommend that patients with stable/responsive diseases receive monthly treatment for up to 2 years.
  • Patients with stable/responsive conditions may need less frequent dosing.
  • Consider quitting after 2 years in stable and responsive patients. If a new-onset skeletal event occurs, re-initiate if necessary.
  • ASCO guidelines can be viewed in conjunction with prescribing information regarding dosing, renal dosage adjustments and infusion times, prevention of osteonecrosis and management, as well as monitoring laboratory parameter recommendations.
  • The guidelines recommend that patients suffering from severe bone disease and renal disease should receive pamidronate in a 90 mg dose over 4 to 6 hours.
  • Preexisting renal disease should not be considered.
  • Every 3 to 6 Months, monitor for albuminuria.
  • Patients with undiagnosed albuminuria greater than 500 mg/24 hours should be withheld from receiving any doses until the level is back to baseline. After that, recheck every 3-4 weeks.
  • Pamidronate can be reinitiated at a dosage not exceeding 90 mg every four weeks, with an infusion time of at least 4 hours.
• Renal impairment
  • Clinical trials were not conducted on patients with serum creatinine levels greater than 3 mg/dL.
  • Patients with CrCl >30 mL/minute have limited data.
  • Before starting treatment, it is important to determine the level of serum creatinine.
  • Patients with severe renal impairment should not be treated for bone metastases.
  • If you have other indications than bone metastases for which you are evaluating the benefits, it is important to use your clinical judgement to decide if there are any risks for patients with renal impairment.

Pamidronate: Drug Interaction

Monitoring parameters:

• Serum creatinine (prior to each treatment);
• serum electrolytes, including calcium, phosphate, magnesium, and potassium;
• CBC with differential;
• monitor for hypocalcemia for at least 2 weeks after therapy;
• dental exam and preventive dentistry prior to therapy for patients at risk of osteonecrosis, including all cancer patients;
• patients with pre-existing anemia, leukopenia, or thrombocytopenia should be closely monitored during the first 2 weeks of treatment;
• in addition, monitor urine albumin every 3 to 6 months in multiple myeloma patients

Multiple myeloma:

• Monitor serum creatinine (prior to each dose),
• serum calcium (regularly);
• vitamin D levels (intermittently),
• spot urine sample for albuminuria (every 3 to 6 months;
• for unexplained albuminuria, obtain 24-hour urine collection to assess urinary albumin;
• reassess every 3 to 4 weeks with 24-hour urine collection for total protein and urine protein electrophoresis until renal function returns to baseline).

Prostate cancer:

• Androgen deprivation therapy (ADT)-associated osteoporosis:
• Monitor BMD every 18 to 24 months.

How to administer Pamidronate (Aredia)?

• Intravenous: Infusion rate varies by indication.
• Longer infusion times (>2 hours) may lower the risk for renal toxicity, especially in patients with preexisting renal insufficiency.
• The manufacturer recommends infusing over 2 to 24 hours for hypercalcemia of malignancy;
  • over 2 hours for osteolytic bone lesions with metastatic breast cancer;
  • and over 4 hours for Paget disease and for osteolytic bone lesions with multiple myeloma.
  • ASCO guidelines for bisphosphonate use in multiple myeloma recommend infusing pamidronate over 2 hours at least;
  • if therapy is withheld due to renal toxicity, infuse over 4 hours at least upon reintroduction of treatment after renal improvment.
  • infuse over 4 to 6 hours in patients with preexisting severe renal parameters derrangment and extensive bone disease presence.

Mechanism of action of Pamidronate (Aredia):

• Pamidronate, a bisphosphonate containing nitrogen, is what you are looking for.
• It inhibits bone resorption, decreases mineralization, and disrupts osteoclast activity.

The beginning of action:

• Hypercalcemia in malignancy (HCM).
• Reduced serum calcium that has been albumin corrected
  • Children: 48 Hours
  • Adults: For a decrease of albumin-corrected se calcium, it takes =24 hours
  • maximum effect: <=7 days
• Paget disease
  • In less than a month, a decrease of >=50% in serum alkalinephosphatase has been observed
  • Maximum Effect: Hypercalcemia in malignancy: =7 Days

Time:

• Hypercalcemia in malignancy: 7-14 days
• Paget disease: 1- 372 days

Absorption:

• Poorly from your GI tract

Distribution

• 38% to 70% in 120 hours

Metabolism:

• Not metabolized

Half-life elimination:

• 28 +- 7 Hours

Excretion:

• Is Biphasic; urine (30% - 62% excreted unchanged drug; lower for patients with renal impairment) within 120hrs   

International Brands of Pamidronate:

• Aredia
• Pamidronate Disodium Omega
• PMS-Pamidronate
• VAL-Pamidronate Disodium
• Aminomux
• Aredia
• Biodronate
• Pamidria
• Pamidrom
• Pamidron
• Pamired
• Pamisol
• Pamitor
• Panolin
• Panorin

Pamidronate Disodium Pentahydrate Brand Names in Pakistan: