Pamidronate is a medication belonging to a class of drugs known as bisphosphonates. It's primarily used in the treatment of osteoporosis, a condition characterized by weakened bones prone to fractures. Bisphosphonates like pamidronate work by inhibiting the breakdown of bone tissue, thus helping to maintain or increase bone density and reduce the risk of fractures.

Aside from osteoporosis, pamidronate is also used to treat other conditions involving abnormal bone metabolism, such as Paget's disease (a chronic bone disorder), hypercalcemia (elevated levels of calcium in the blood), and bone metastases (cancer that has spread to the bones).

A second-generation injectable bisphosphonate used to treat and prevent osteoporosis is pamidronate (Aredia). Patients with Paget's disease and malignant hypercalcemia are also treated with it. The bones become less brittle as a result of the calcium being removed from the blood and deposited there. It could, however, cause low serum calcium levels. Patients receiving treatment for osteoporosis must take calcium and vitamin D supplements.

Pamidronate (Aredia) Uses:

• Hypercalcemia of malignancy:
  • Pamidronate is used to treat moderate to severe hypercalcemia linked to cancer, whether or not bone metastases are present. But concurrent hydration is necessary.
• Osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma:
  • In addition to conventional antineoplastic therapy, it is also utilised to treat multiple myeloma osteolytic lesions and osteolytic bone metastases from breast cancer.
• Off Label Use of Pamidronate in Adults:
  • prevention of bone loss brought on by the treatment of prostate cancer with androgen deprivation.
    Hyperparathyroidism.
    thyroid cancer bone metastases with symptoms.
• Paget disease:
  • Patients with mild to severe Paget disease of the bone may also benefit from using it.

Pamidronate (Aredia) Dose in Adult

Note: Single dose should not exceed 90 mg.

Pamidronate Dose in the therapy of Hypercalcemia of malignancy: 

• When treating moderate cancer-related hypercalcemia, doctors usually give 60 to 90 mg of pamidronate through an IV over 2 to 24 hours if the corrected serum calcium level is between 12 to 13.5 mg/dL.
• For severe cases where the corrected serum calcium is higher than 13.5 mg/dL, a single dose of 90 mg of pamidronate is typically administered over 2 to 24 hours.
• If the patient responds well to the initial treatment, but the hypercalcemia comes back, doctors may wait at least 7 days before considering re-treatment. If needed, they can give the same dose of pamidronate again if the serum calcium levels don't return to normal or stay normal after the first treatment.

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Pamidronate (Aredia) Dose in the therapy of Multiple myeloma, osteolytic bone lesions:

• The usual dose of pamidronate administered intravenously is 90 mg given over 4 hours.
• This treatment is typically given once a month.

Lytic bone disease:

• For lytic bone disease, according to the American Society of Clinical Oncology (ASCO) guidelines, pamidronate is administered at a dose of 90 mg over at least 2 hours, once every 3 to 4 weeks for up to 2 years.
• After this period, doctors may consider less frequent dosing, such as once every 3 months, especially for patients with stable or responsive disease.
• If the disease remains stable or responsive, treatment can be discontinued after 2 years.
• However, if there's a relapse with new bone-related events, therapy can be resumed.

Newly diagnosed, symptomatic (off-label dose):

• For newly diagnosed, symptomatic multiple myeloma (an off-label use), a different dosing regimen may be employed.
• In this case, the dose is typically 30 mg over 2.5 hours, once monthly for at least 3 years.

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Pamidronate Dose in the treatment of osteolytic bone metastases Breast cancer:

• Use pamidronate intravenously.
• The typical dose is 90 milligrams given over a 2-hour period, once every three to four weeks.

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Pamidronate Dose in the therapy of Paget disease (moderate to severe):

• The usual treatment involves pamidronate given intravenously.
• Doctors typically administer a dose of 30 mg over a 4-hour period once daily for 3 consecutive days.
• This totals to a dose of 90 mg over the course of the treatment.
• If necessary, the same initial dose can be repeated if there's a clinical need for it.

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

• Pamidronate is typically administered intravenously.
• The dose can vary, ranging from 15 to 90 mg as a single dose.
• This dosage may be repeated every 1 to 2 months or when hypercalcemia recurs.
• Clinical trials have shown treatment periods lasting up to 1 year.

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Pamidronate (Aredia) Dose in the therapy of preventing androgen deprivation-induced osteoporosis (off-label): Males:

• Typically in males, pamidronate is administered intravenously.
• The usual dose is 60 mg given over a 2-hour period, once every 3 months.

Pamidronate (Aredia) Dose in Children

Note: Single dosages shouldn't exceed 90 mg due to the increased risk of nephrotoxicity.

Pamidronate (Aredia) Dose in the treatment of Hypercalcemia: 

For children and adolescents with hypercalcemia due to conditions like cancer or immobility, the dosage of pamidronate is determined based on limited data from case reports and retrospective studies. It's given as a single infusion, and retreatment may be needed if the serum calcium levels don't return to normal after the initial treatment, with a reported interval for multiple doses of at least 24 hours.

For the initial treatment:

• Intravenous (IV) administration is used.
• The dose typically ranges from 0.5 to 1 mg per kilogram of body weight, with a maximum dose of 90 mg.

In severe, life-threatening cases:

• The IV dose is higher, ranging from 1.5 to 2 mg per kilogram of body weight, with a maximum dose of 90 mg.
• In extreme cases, such as when calcium levels are dangerously high, a higher dose of up to 4 mg per kilogram of body weight has been reported in some case studies.

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Pamidronate (Aredia) Dose in the treatment of Osteogenesis imperfecta:

In the treatment of osteogenesis imperfecta (OI), dosing regimens for pamidronate can vary, and the duration of treatment hasn't been firmly established. However, the most benefit seems to occur in the first 2 to 4 years of treatment.

For weight-directed dosing:

• For infants and children under 2 years old: The initial dose is 0.25 mg per kilogram of body weight once on day 1, followed by 0.5 mg/kg/day on days 2 and 3 of the first cycle, then 0.5 mg/kg/day for 3 days for subsequent cycles. This cycle is repeated every 2 months, aiming for a total yearly dose of 9 mg/kg.
• For children aged 2 to 3 years: The initial dose is 0.38 mg/kg once on day 1, followed by 0.75 mg/kg/day on days 2 and 3 of the first cycle, then 0.75 mg/kg/day for 3 days for subsequent cycles. This cycle is repeated every 3 months, aiming for a total yearly dose of 9 mg/kg.
• For children over 3 years old and adolescents: The initial dose is 0.5 mg/kg once on day 1, followed by 1 mg/kg/day on days 2 and 3 of the first cycle, then 1 mg/kg/day for 3 days for subsequent cycles. This cycle is repeated every 4 months, aiming for a total yearly dose of 9 mg/kg.

Alternatively, for BSA-directed dosing:

• Initial dose: 10 mg per square meter of body surface area once a month for 3 months, then increased to 20 mg/m² once a month for 3 months, then increased to 30 mg/m² once a month for subsequent doses. In some cases, a maximum dose of 40 mg/m² was used after 1-2 years due to skeletal pain and less bone mineral gain.

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Pamidronate Dose in the treatment of Osteopenia associated with cerebral palsy in non-ambulatory patients:

For treating osteopenia associated with cerebral palsy in non-ambulatory children and adolescents, dosing with pamidronate can vary due to limited data:

• Initial IV dose: 1 mg per kilogram of body weight per dose daily for 3 days.
• Administration frequency: Every 3 to 4 months.
• Minimum dose: 15 mg; Maximum dose: 35 mg.

This dosing regimen is based on trials involving pediatric patients:

• In one trial with 14 pediatric patients (ages 6 to 16), pamidronate, along with calcium and vitamin D supplementation, showed an increase in bone mineral density.
• Another trial with 25 patients (ages 3 to 19) showed a decreased incidence of fractures after 1 year of therapy.
• In a different trial with 23 pediatric patients (ages 4 to 17), a lower initial dose of 0.37 mg/kg on day 1, followed by 0.75 mg/kg on day 2, then 0.75 mg/kg/day for 2 days for subsequent cycles was used. Cycles were repeated every 4 months for 1 year, with a maximum single dose of 45 mg.

Pregnancy Risk Factor D

• Bisphosphonates, such as those used for treating bone conditions, carry a Pregnancy Risk Factor D due to adverse effects seen in animal studies.
• While it's unclear if these drugs cross the placenta, they are expected to reach the fetus since they integrate into the bone and release slowly over time.
• Although there isn’t conclusive evidence that bisphosphonates cause fetal harm when used during pregnancy, caution is advised.
• Generally, it's recommended to stop bisphosphonate therapy as early as possible before a planned pregnancy, especially in women of childbearing age, unless necessary for preventing rapid bone loss.
• Additionally, there's a risk of newborns having low calcium levels if exposed to bisphosphonates in the womb, so monitoring after birth is important.

Pamidronate use during breastfeeding:

• It's uncertain whether pamidronate passes into breast milk.
• A study found that pamidronate wasn't detected in the milk of a woman who received monthly intravenous doses of 30 mg while breastfeeding, starting around 6 months after giving birth.
• After each infusion, the woman pumped and discarded breast milk for the first 48 hours before resuming breastfeeding.
• Despite this precaution, the infant was breastfed most of the time without any reported adverse effects.
• However, because serious adverse reactions in breastfed infants can't be ruled out, the manufacturer advises weighing the importance of treatment for the mother against the potential risks to the infant, suggesting a decision to either discontinue breastfeeding or the drug.
• Monitoring the serum calcium levels of breastfed infants is also recommended for safety.

Pamidronate (Aredia) Dose in Kidney Disease:

Exclusion from Trials:

• Patients with serum creatinine >3 mg/dL were not included in clinical trials.
• Limited data for patients with creatinine clearance (CrCl) <30 mL/minute.

Dosing Adjustments Before Starting Pamidronate:

• Bone Metastases: Not recommended for patients with severe renal impairment.
• Other Conditions: Use clinical judgment to decide if the treatment's benefits outweigh the risks.
• Multiple Myeloma with Severe Renal Impairment:
  • Recommended dose is 90 mg over 4 to 6 hours, or consider a lower starting dose.

Adjustments During Pamidronate Therapy if Renal Toxicity Develops:

• Bone Metastases:
  • Stop treatment if serum creatinine increases by ≥0.5 mg/dL (normal baseline) or ≥1 mg/dL (abnormal baseline).
  • Consider resuming therapy when serum creatinine is within 10% of baseline.
• Multiple Myeloma:
  • Stop therapy if there's unexplained renal deterioration; may resume at previous dose when renal function is nearly back to baseline.
  • If albuminuria exceeds 500 mg/24 hours without explanation, withhold dose until it returns to baseline, monitor every 3 to 4 weeks, and consider restarting at no more than 90 mg every 4 weeks, extending infusion time to at least 4 hours.

Pamidronate (Aredia) Dose in Liver disease:

• Mild to Moderate Hepatic Impairment: No change in dosage is necessary.
• Severe Hepatic Impairment: No specific dosage adjustments are recommended by the manufacturer because this condition has not been studied.

Common Side Effects of Pamidronate (Aredia):

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

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
• Gastrointestinal:
  • Constipation
  • Gastrointestinal haemorrhage
  • Diarrhoea
  • Stomatitis
• Genitourinary:
  • Uremia
• Hematologic & oncologic:
  • Leukopenia
  • Neutropenia
  • Thrombocytopenia
• Infection:
  • Candidiasis
• Neuromuscular & skeletal:
  • Arthropathy
  • Back pain
• Renal:
  • Renal insufficiency

• Respiratory:
  • Rales
  • Rhinitis

Side effects of Pamidronate (Aredia) Frequency not defined:

• Endocrine & metabolic:
  • Hypervolemia

Contraindications to Pamidronate (Aredia):

• Pamidronate should not be used by anyone who has a severe allergy to pamidronate itself, other medicines in the same family (bisphosphonates), or any ingredient in the drug's formulation.
• In Canada, there are extra restrictions: it should not be used by pregnant or breastfeeding women, but these restrictions are not mentioned in the U.S. labeling.

Warnings and precautions

Bone fractures:

• Atypical femur fractures (AFF), occurring in the bone just below the hip joint (subtrochanteric) or in the long segment of the thigh bone (diaphyseal), have been reported in patients who take bisphosphonates.
• Some patients report pain in the thigh or groin area weeks or months before the fracture happens.
• It's not clear if bisphosphonate therapy directly causes these fractures since similar fractures have also occurred in patients who do not take these drugs and those who use glucocorticoids.
• However, the risk seems to increase with long-term use of bisphosphonates, typically over 3 to 5 years.
• If a patient on bisphosphonates reports thigh or groin pain, doctors should check for a femur fracture.
• In cases where such a fracture is confirmed, it might be advisable to pause the bisphosphonate treatment and also check the other thigh bone for fractures.

Musculoskeletal pain

• Severe and sometimes debilitating pain in the bones, joints, or muscles has been reported infrequently in patients undergoing bisphosphonate therapy.
• This pain can start as quickly as one day after beginning treatment or as late as several months into it.
• If a patient experiences severe symptoms, consider stopping the therapy; typically, the symptoms will resolve after the medication is discontinued.
• Some patients have reported that the pain returned when they started taking the same or a different bisphosphonate again.
• Therefore, it's recommended to avoid using bisphosphonates in patients who have previously experienced these pain symptoms with such treatments.

Myelosuppression

• Patients who already have conditions like anemia, leukopenia (low white blood cell count), or thrombocytopenia (low platelet count) need careful monitoring in the initial two weeks of treatment to watch for any worsening of these conditions.

An abnormality in the electrolyte:

• The use of certain medications can lead to changes in electrolyte levels in the body, including decreases in phosphate, potassium, magnesium, and calcium levels, which usually do not cause symptoms.
• However, there have been rare cases where low calcium levels have led to symptoms such as muscle cramps and spasms, known as tetany.

Osteonecrosis in the jaw:

• Osteonecrosis of the jaw (ONJ), also known as medication-related osteonecrosis of the jaw (MRONJ), can occur in patients taking bisphosphonates.
• Risk factors for MRONJ include invasive dental procedures, cancer diagnosis, concurrent therapies like chemotherapy or corticosteroids, poor oral hygiene, and certain medical conditions.
• The risk may increase with longer use of bisphosphonates, especially in cancer patients.
• The American Association of Maxillofacial Surgeons advises delaying IV bisphosphonate therapy until dental health is optimal and avoiding certain dental procedures once treatment begins.
• Patients who develop ONJ during treatment should receive care from an oral surgeon.

Renal deterioration:

• It's important not to exceed a single pamidronate dose of 90 mg because higher doses have been linked to kidney problems, including renal deterioration that could lead to kidney failure and the need for dialysis.
• Some cases have also involved glomerulosclerosis, a kidney condition that can cause nephrotic syndrome.
• To lower the risk of kidney issues, longer infusion times (more than 2 hours) are recommended, especially for patients with existing kidney problems.
• If there are signs of kidney deterioration, pamidronate treatment should be stopped until kidney function returns to normal.

Breast cancer (metastatic).

• The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) updated guidelines recommend starting a bone-modifying agent (BMA), like denosumab, pamidronate, or zoledronic acid, for breast cancer patients whose cancer has spread to the bone.
• They suggest that any of these BMAs can be used, as there's no clear evidence favoring one over the others.
• While the best length of BMA treatment isn't defined, the guidelines suggest continuing it indefinitely.
• However, BMAs aren't typically used alone for pain relief; other pain management methods like medication, radiation therapy, or surgery are also recommended.
• These guidelines match the prescribing details for BMAs, including dosing, adjusting doses for kidney function, infusion times, preventing and managing jaw bone problems, and monitoring lab results.

Hypercalcemia in malignancy (HCM).

• In treating hypercalcemia of malignancy (HCM), it's crucial to ensure patients are adequately hydrated, aiming for a urine output of about 2 liters per day.
• However, it's essential to avoid excessive hydration, especially in patients with heart failure, as it can lead to fluid overload.
• Balancing hydration is key to managing HCM effectively.

Hypoparathyroidism:

• Patients with hypoparathyroidism, especially those with a history of thyroid surgery, should be approached with caution when considering pamidronate treatment.
• Thyroid surgery can sometimes lead to relative hypoparathyroidism, where the parathyroid glands don't function as well as they should.
• This condition can make patients more prone to experiencing hypocalcemia (low calcium levels) when using pamidronate.
• Therefore, close monitoring of calcium levels is necessary in such patients to prevent complications.

Multiple myeloma

• In multiple myeloma patients, especially those with Bence-Jones proteinuria and dehydration, it's important to ensure adequate hydration before starting therapy.
• According to updated guidelines from the American Society of Clinical Oncology (ASCO), bisphosphonate therapy, like pamidronate or zoledronic acid, should be considered for patients with evidence of bone damage seen in imaging.
• It can also be used for pain management related to bone issues or as an add-on therapy for fractures.
• However, it's not recommended for certain conditions like solitary plasmacytoma or early myeloma without bone damage.
• Treatment typically lasts up to 2 years, with consideration given to stopping if the disease is stable or responsive.
• For patients with severe kidney problems and extensive bone disease, pamidronate at a reduced initial dose may be used.
• Monitoring for albuminuria is important, and treatment adjustments should be made if necessary.
• The guidelines also align with recommendations for dosing, adjusting for kidney function, infusion times, preventing jaw bone problems, and lab monitoring.

Renal impairment

• In patients with kidney problems, it's essential to monitor their serum creatinine levels before each treatment session.
• For bone metastases, using pamidronate isn't advised in those with severe kidney impairment.
• However, in cases unrelated to bone metastases, doctors should carefully weigh the benefits against potential risks when considering treatment for patients with kidney issues.
• Since there's limited data available for patients with very low kidney function, close monitoring and clinical judgment are crucial for managing pamidronate therapy in these individuals.

Monitoring parameters:

• Serum Creatinine: Check before each treatment session.
• Serum Electrolytes: Including calcium, phosphate, magnesium, and potassium.
• CBC with Differential: Regular monitoring, especially in patients with pre-existing blood disorders.
• Hypocalcemia: Monitor for at least 2 weeks after therapy.
• Dental Examination: Conduct prior to therapy, especially for patients at risk of osteonecrosis, including cancer patients.

Monitoring Parameters for Specific Conditions

Multiple Myeloma

• Serum Creatinine: Check before each dose.
• Serum Calcium: Regular monitoring.
• Vitamin D Levels: Intermittent assessment.
• Albuminuria: Spot urine sample every 3 to 6 months; consider 24-hour urine collection if unexplained albuminuria.

Paget Disease

• Serum Total Alkaline Phosphatase: Assess at 6 to 12 weeks for initial response, then potentially at 6 months.
• Biochemical Markers of Bone Turnover: Consider monitoring in patients with abnormal liver or biliary tract function or when early assessment of treatment response is needed.
• Serum Calcium, Phosphorus, and Magnesium: Regular monitoring.
• Symptoms: Watch for hypocalcemia symptoms and pain, especially post-treatment.

Prostate Cancer (Androgen Deprivation Therapy)

• Bone Mineral Density (BMD): Monitor every 18 to 24 months.

How to administer Pamidronate (Aredia)?

Infusion Rates for Pamidronate Therapy

• Hypercalcemia of Malignancy: Infuse over 2 to 24 hours.
• Osteolytic Bone Lesions with Metastatic Breast Cancer: Infuse over 2 hours.
• Paget Disease: Infuse over 4 hours.
• Osteolytic Bone Lesions with Multiple Myeloma: Infuse over 4 hours.

Recommendations for Specific Conditions

• Multiple Myeloma (ASCO Guidelines):
  • Infuse over at least 2 hours.
  • If therapy is withheld due to renal toxicity, infuse over at least 4 hours upon reintroduction after renal recovery.
  • Infuse over 4 to 6 hours in patients with preexisting severe renal impairment and extensive bone disease.

Mechanism of action of Pamidronate (Aredia):

• Pamidronate belongs to a group of medications called nitrogen-containing bisphosphonates.
• It works by inhibiting bone resorption, which is the process of breaking down bone tissue.
• By doing so, it reduces mineralization and disrupts the activity of osteoclasts, cells responsible for breaking down bone tissue.

The beginning of action:

• Hypercalcemia of Malignancy (HCM)
  • Children: Around 48 hours for reduction of albumin-corrected serum calcium.
  • Adults: Less than or equal to 24 hours for a decrease in albumin-corrected serum calcium, with maximum effect within 7 days.
• Paget Disease: Approximately 1 month for a ≥50% decrease in serum alkaline phosphatase. Maximum effect is seen within 7 days for HCM.

Duration

• HCM: Typically lasts 7 to 14 days.
• Paget Disease: Can range from 1 to 372 days.

Absorption

• Poorly absorbed from the gastrointestinal tract.

Distribution

• 38% to 70% distribution over 120 hours.

Metabolism

• Not metabolized.

Half-Life Elimination

• Approximately 28 ± 7 hours.

Excretion

• Biphasic excretion, with around 30% to 62% excreted unchanged in urine within 120 hours. Excretion may be lower in patients with renal dysfunction.

International Brand Names of Pamidronate:

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

Pamidronate Brand Names in Pakistan:

Pamidronate Injection 15 Mg in Pakistan
Aminomux	Seignior Pharma
Aredia	Novartis Pharma (Pak) Ltd

 

Pamidronate 30 mg injection in Pakistan
Aminomux	Seignior Pharma
Osteopam	Consolidated Chemical Laboratories (Pvt) Ltd.
Pamidria	A. J. Mirza Pharma (Pvt) Ltd
Pamisole	Atco Laboratories Limited

 

Pamidronate 60 mg injection in Pakistan
Pamidria	A. J. Mirza Pharma (Pvt) Ltd

 

Pamidronate Injection 90 mg in Pakistan
Aminomux	Seignior Pharma
Osteopam	Consolidated Chemical Laboratories (Pvt) Ltd.
Pamidria	A. J. Mirza Pharma (Pvt) Ltd