Pamidronate

Pamidronate is an Bisphosphonate Derivative belonging to pharmacology class of Diphosphonate.

Pamidronate can be used in the treatment of Heterotopic ossification and Paget disease. Pamidronate increases bone mineral density in women with postmenopausal or steroid-induced osteoporosis.

It is Poorly absorbed from the GI tract. Bioavailability: Approx 1-3%.and Crosses the placenta. Plasma protein binding: Approx 54%and get excreted Via urine, approx 20-55% as unchanged drug. Elimination half-life: 21-35 hr. Pamidronate is available in the form of IV Solution.

The molecule is available in India, Japan, Germany, China.

Pamidronate is a nitrogen-containing bisphosphonate; it inhibits bone resorption by disrupting osteoclast activity.

Pamidronate can be used in the treatment of Hypercalcemia of malignancy, Osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma and Paget disease. Pamidronate increases bone mineral density in women with postmenopausal or steroid-induced osteoporosis.

IV: Infusion rate varies by indication. Longer infusion times (>2 hours) may reduce 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 at least 2 hours; if therapy is withheld due to renal toxicity, infuse over at least 4 hours upon reintroduction of treatment after renal recovery; infuse over 4 to 6 hours in patients with preexisting severe renal impairment and extensive bone disease.

Pamidronate is approved for use in the following clinical indications

Hypercalcemia of malignancy: Treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases, in conjunction with adequate hydration.

Osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma: Treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma in conjunction with standard antineoplastic therapy.

Paget disease: Treatment of patients with moderate to severe Paget disease of bone.

Although not approved there have been certain off labelled uses documented for Pamidronate which includes;

Hyperparathyroidism; Prostate cancer, bone loss associated with androgen deprivation therapy, prevention; Symptomatic bone metastases of thyroid cancer.

Pamidronate increases bone mineral density in women with postmenopausal or steroid-induced osteoporosis.

Breast cancer, osteolytic bone metastases: IV: 90 mg over at least 2 hours once every 3 or 4 weeks (maximum: 90 mg per dose).

Hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL [≥3 mmol/L]) (alternative agent):

Note: May also be used at the same doses for treatment of hypercalcemia due to excessive bone resorption from other causes (eg, granulomatous diseases, hyperparathyroidism, vitamin D intoxication) . Asymptomatic or mildly symptomatic patients with chronic hypercalcemia may not require immediate treatment unless albumin-corrected serum calcium level is >14 mg/dL (>3.5 mmol/L).

Albumin-corrected serum calcium level 12 to 13.5 mg/dL (3 to 3.4 mmol/L) and symptomatic: IV: 60 to 90 mg as a single dose over 2 to 24 hours (maximum: 90 mg per dose).

Albumin-corrected serum calcium level >13.5 mg/dL (>3.4 mmol/L): IV: 90 mg as a single dose over 2 to 24 hours (maximum: 90 mg per dose).

Re-treatment: IV: May re-treat at the same dose 7 days after the initial treatment if serum calcium does not return to normal or does not remain normal.

Hyperparathyroidism (off-label use): IV: 15 to 90 mg as a single dose (maximum: 90 mg per dose) ; may be repeated every 1 to 2 months or when hypercalcemia recurs . The treatment period in clinical trials was up to 1 year.

Multiple myeloma, osteolytic bone lesions: IV: 90 mg over 4 hours once monthly:

Lytic bone disease: American Society of Clinical Oncology (ASCO) guidelines: 90 mg over at least 2 hours once every 3 to 4 weeks for up to 2 years (maximum: 90 mg per dose); less frequent dosing (eg, once every 3 months) may be considered in patients with stable/responsive disease (patients with no active disease and are on maintenance therapy); discontinue after 2 years in patients with responsive and/or stable disease; resume therapy upon relapse with new-onset skeletal-related events.

Newly diagnosed, symptomatic (off-label dose): 30 mg over 2.5 hours once monthly for at least 3 years.

Paget disease (moderate to severe): IV: 30 mg over 4 hours once daily for 3 consecutive days (total dose = 90 mg); may re-treat at initial dose if clinically indicated.

Prostate cancer, bone loss associated with androgen deprivation therapy, prevention (alternative agent) (off-label use):

Note: For use in patients without bone metastases treated long-term with androgen deprivation therapy who are at elevated risk of osteoporotic fractures (according to a risk assessment tool).

IV: 60 mg over 2 hours once every 3 months. The optimal duration of therapy has not been established.

IV Solution

6mg/mL, 30 mg/10 mL; 90 mg/10 mL

IV Solution

Dose Adjustment in Kidney Patient:

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

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute or SCr >3 mg/dL:

Breast cancer, osteolytic bone metastases: Use is not recommended.

Multiple myeloma (and extensive bone disease): 90 mg (or consider a reduced initial dose) over 4 to 6 hours once every 3 to 4 weeks.

Other indications: Clinical judgement should determine whether the potential benefit outweighs the potential risk.

Hemodialysis, intermittent (thrice weekly): Avoid use; consider alternative agents. Limited data suggests that reduced pamidronate doses (30 to 60 mg) with slower infusion rates (over 4 to 6 hours) may be considered when other agents are not available ; use with caution and only when potential benefits outweigh risks.

Peritoneal dialysis: Avoid use; consider alternative agents. Limited data suggests that reduced pamidronate doses (30 to 60 mg) may be considered when other agents are not available. Prolonged infusion (over 4 to 6 hours) should be considered as well . Monitor closely; nephrotoxicity is a concern as this patient population often has residual kidney function . Use with caution and only if potential benefit outweighs the potential risk .

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

Osteolytic bone lesions/metastases : Treatment should be withheld for deterioration in renal function (increase of SCr ≥0.5 mg/dL in patients with normal baseline [SCr <1.4 mg/dL] or ≥1 mg/dL in patients with abnormal baseline [SCr ≥1.4 mg/dL]). Resumption of therapy may be considered when serum creatinine returns to within 10% of baseline.

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

Renal deterioration without an apparent cause: Withhold therapy; may resume at the prior dose when renal function returns to within 10% of baseline.

Unexplained albuminuria >500 mg/24 hours: Withhold dose until returns to baseline, then recheck every 3 to 4 weeks; consider reinitiating at a dose not to exceed 90 mg every 4 weeks and with a longer infusion time of at least 4 hours.

Dose Adjustment in Hepatic Patient:

Mild to moderate impairment: No dosage adjustment necessary.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling

Dose Adjustment in Pediatric Patient:

Hypercalcemia: Limited data available: Children and Adolescents: Dosing based on several case reports and retrospective studies for treatment of hypercalcemia due to malignancy and/or immobility. Administer as a single infusion. Retreatment may be necessary if serum calcium does not return to normal or does not remain normal after initial treatment; reported interval for multiple doses is ≥24 hours.

Initial treatment: IV: 0.5 to 1 mg/kg; maximum dose: 90 mg

Severe, life-threatening: IV: 1.5 to 2 mg/kg; maximum dose: 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 old child with non-Hodgkin lymphoma

Osteogenesis imperfecta: Limited data available: Note: Reported dosing regimens variable (ie, weight-directed vs BSA-directed); duration of treatment has not been established; however, the most benefit has been shown to occur in the first 2 to 4 years of treatment .

Weight-directed dosing:

Infants and Children <2 years: IV: Initial: 0.25 mg/kg 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: IV: Initial: 0.38 mg/kg 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 once 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: IV: Initial: 0.5 mg/kg once on day 1, then 1 mg/kg/dose daily days 2 and 3 of the first cycle, then 1 mg/kg/dose once 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: IV: Initial: 10 mg/m²/dose once a month for 3 months, then increase to 20 mg/m²/dose once a month for 3 months, then increase to 30 mg/m²/dose once a month for subsequent doses; maximum dose: 40 mg/m²/dose was used in six patients after 1-2 years due to skeletal pain and less bone mineral gain; improvements in mobility and vertebral height was noted in patients who received this regimen for 3 to 6 years (n=11, median age at initiation of therapy: 3.6 months, range: 3 to 13 months); another study used the same dosing in 14 prepubescent patients with mild disease

Osteopenia associated with cerebral palsy (nonambulatory): Limited data available; dosing regimens variable: Children and Adolescents: IV: Initial: 1 mg/kg/dose daily for 3 days; administer every 3 to 4 months; minimum dose: 15 mg; maximum dose: 35 mg. Dosing based on two trials; the first included 14 pediatric patients (age range: 6 to 16 years, treatment group: n=7), and reported an increase in bone mineral density; therapy was used in combination with calcium and vitamin D supplementation. In the other trial (n=25, age range: 3 to 19 years), a decreased incidence of fractures was noted after 1 year of therapy. A lower dose was used in a trial of 23 pediatric patients (age range: 4 to 17 years); the initial dose was 0.37 mg/kg on day 1, followed by 0.75 mg/kg on day 2, then 0.75 mg/kg/dose once daily for 2 days was used for subsequent cycles; cycles were repeated every 4 months for 1 year; maximum single dose: 45 mg.

Multiple myeloma or metastatic bone lesions from solid tumors or Paget disease: Take adequate daily calcium and vitamin D supplement (if patient is not hypercalcemic).

Pamidronate may be contraindicated in the following conditions:

Clinically significant hypersensitivity to pamidronate, other bisphosphonates, or any component of the formulation.

Concerns related to adverse effects:

• Bone fractures: Atypical femur fractures (AFF) have been reported in patients receiving bisphosphonates. The fractures include subtrochanteric femur (bone just below the hip joint) and diaphyseal femur (long segment of the thigh bone). Some patients experience prodromal pain weeks or months before the fracture occurs. It is unclear if bisphosphonate therapy is the cause for these fractures; atypical femur fractures have also been reported in patients not taking bisphosphonates, and in patients receiving glucocorticoids. Patients receiving long-term (>3 to 5 years) bisphosphonate therapy may be at an increased risk. Patients presenting with thigh or groin pain with a history of receiving bisphosphonates should be evaluated for femur fracture. Consider interrupting bisphosphonate therapy in patients who develop a femoral shaft fracture; assess for fracture in the contralateral limb.

• Musculoskeletal pain: Infrequently, severe (and occasionally debilitating) bone, joint, and/or muscle pain have been reported during bisphosphonate treatment. The onset of pain ranged from a single day to several months. Consider discontinuing therapy in patients who experience severe symptoms; symptoms usually resolve upon discontinuation. Some patients experienced recurrence when rechallenged with same drug or another bisphosphonate; avoid use in patients with a history of these symptoms in association with bisphosphonate therapy.

• Electrolyte abnormalities: Use has been associated with asymptomatic electrolyte abnormalities (including hypophosphatemia, hypokalemia, hypomagnesemia, and hypocalcemia). Rare cases of symptomatic hypocalcemia, including tetany, have been reported.

• Myelosuppression: Patients with preexisting anemia, leukopenia, or thrombocytopenia should be closely monitored during the first 2 weeks of treatment.

• Osteonecrosis of the jaw: Osteonecrosis of the jaw (ONJ), also referred to as medication-related osteonecrosis of the jaw (MRONJ), has been reported in patients receiving bisphosphonates. Known risk factors for MRONJ include invasive dental procedures (eg, tooth extraction, dental implants, boney surgery), cancer diagnosis, concomitant therapy (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, ill-fitting dentures, and comorbid disorders (anemia, coagulopathy, infection, preexisting dental or periodontal disease). Risk may increase with increased duration of bisphosphonate use and/or may be reported at a greater frequency based on tumor type (eg, advanced breast cancer, multiple myeloma). According to a position paper by the American Association of Maxillofacial Surgeons (AAOMS), MRONJ has been associated with bisphosphonates and other antiresorptive agents (denosumab), and antiangiogenic agents (eg, bevacizumab, sunitinib) used for the treatment of osteoporosis or malignancy; risk is significantly higher in cancer patients receiving antiresorptive therapy compared to patients receiving osteoporosis treatment (regardless of medication used or dosing schedule). MRONJ risk is also increased with monthly IV antiresorptive therapy compared to the minimal risk associated with oral bisphosphonate use, although risk appears to increase with oral bisphosphonates when duration of therapy exceeds 4 years. The AAOMS suggests that if medically permissible, initiation of IV bisphosphonates for cancer therapy should be delayed until optimal dental health is attained (if extractions are required, antiresorptive therapy should delayed until the extraction site has mucosalized or until after adequate osseous healing). Once IV bisphosphonate therapy is initiated for oncologic disease, procedures that involve direct osseous injury and placement of dental implants should be avoided. Patients developing ONJ during therapy should receive care by an oral surgeon .

• Renal deterioration: Single pamidronate doses should not exceed 90 mg. Initial or single doses have been associated with renal deterioration, progressing to renal failure and dialysis. Glomerulosclerosis (focal segmental) with or without nephrotic syndrome has also been reported. Longer infusion times (>2 hours) may reduce the risk for renal toxicity, especially in patients with pre-existing renal insufficiency. Withhold pamidronate treatment (until renal function returns to baseline) in patients with evidence of renal deterioration.

There is no sufficient scientific evidence traceable regarding use and safety of Pamidronate in concurrent use with alcohol.

It is not known if pamidronate is present in breast milk.

Pamidronate was not detected in the milk of a breastfeeding female receiving pamidronate 30 mg IV monthly (therapy started ~6 months postpartum). Following the first infusion, milk was pumped and collected for 0 to 24 hours and 25 to 48 hours and each day pooled for analysis. Pamidronate readings were below the limit of quantification (<0.4 micromole/L). During therapy, breast milk was pumped and discarded for the first 48 hours following each infusion prior to resuming breastfeeding. The infant was breastfed >80% of the time; adverse events were not observed in the breastfed infant. Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.

Pregnancy Category D

There are no adequate and well-controlled studies in pregnant women.

Bolus intravenous studies conducted in rats and rabbits determined that pamidronate disodium produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. As it has been shown that pamidronate disodium can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women during pregnancy.

Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systematic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.

Food and/or supplements decrease the absorption and bioavailability of the drug. Management: Administer tablet on an empty stomach with a full glass of plain water or fruit juice (6 to 8 oz) 2 hours before food. Avoid administering foods/supplements with calcium, iron, or magnesium within 2 hours of drug. Do not take with mineral water or other beverages.

The adverse reactions related to Pamidronate can be categorized as

Common Adverse effects:

Renal toxicity, fever and flu-like symptoms, CNS effects (e.g. agitation, confusion, dizziness

Less Common Adverse effects:

Lethargy, insomnia, somnolence), seizures, hallucinations, hypocalcemia, hypophosphatemia, hypomagnesaemia, hypokalemia, hypotension, HTN, anemia

Rare Adverse effects:

Hypernatremia, hyperkalemia, bronchospasm, interstitial pneumonitis.

The clinically relevant drug interactions of Pamidronate is briefly summarized here:

Enhanced hypo calcemic effect w/ aminoglycosides. Increased nephrotoxic effect w/ thalidomide.

Enhanced adverse effects w/ NSAIDs.

Synergistic effect w/ calcitonin in patients w/ severe hypercalcaemia.

Concomitant use w/ other bisphosphonates, other antihypercalcaemic agents and calcitonin may lead to hypocalcaemia w/ associated clinical symptoms (e.g. paraesthesia, tetany, hypotension).

The most common side effects of Pamidronate includes: Renal toxicity, fever and flu-like symptoms, CNS effects (e.g. agitation, confusion, dizziness.

Pregnancy Category D

• There are no adequate and well-controlled studies in pregnant women.
• Bolus intravenous studies conducted in rats and rabbits determined that pamidronate disodium produces maternal toxicity and embryo/fetal effects when given during organogenesis at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion. As it has been shown that pamidronate disodium can cross the placenta in rats and has produced marked maternal and nonteratogenic embryo/fetal effects in rats and rabbits, it should not be given to women during pregnancy.
• Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systematic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.

Labor and Delivery

• There is no FDA guidance on use of Pamidronate during labor and delivery.

Nursing Mothers

• It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Pamidronate disodium is administered to a nursing woman.

Pediatric Use

• Safety and effectiveness in pediatric patients have not been established. Pediatric patients have been treated with Pamidronate disodium, at doses recommended for adults, to prevent heterotopic ossifications or soft tissue calcifications. A rachitic syndrome has been reported infrequently at doses of 10 mg/kg/day and more for prolonged periods approaching or exceeding a year. The epiphyseal radiologic changes associated with retarded mineralization of new osteoid and cartilage, and occasional symptoms reported, have been reversible when medication is discontinued.

Geriatric Use

• Clinical studies of Pamidronate disodium did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. As stated in PRECAUTIONS, Pamidronate disodium dosage should be reduced when reductions in glomerular filtration rates are present. In addition, patients with renal impairment should be closely monitored.

Gender

There is no FDA guidance on the use of Pamidronate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Pamidronate with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Pamidronate in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Pamidronate in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Pamidronate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Pamidronate in patients who are immunocompromised.

Acute Overdose

There have been several cases of drug maladministration of intravenous pamidronate disodium in hypercalcemia patients with total doses of 225 mg to 300 mg given over 21/2 to 4 days. All of these patients survived, but they experienced hypocalcemia that required intravenous and/or oral administration of calcium. Single doses of pamidronate disodium should not exceed 90 mg and the duration of the intravenous infusion should be no less than 2 hours.

In addition, one obese woman (95 kg) who was treated with 285 mg of pamidronate disodium/day for 3 days experienced high fever (39.5°C), hypotension (from 170/90 mmHg to 90/60 mmHg), and transient taste perversion, noted about 6 hours after the first infusion. The fever and hypotension were rapidly corrected with steroids.

If overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated with short-term intravenous calcium.

Pharmacodynamics:

Pamidronate inhibits bone resorption and decreases mineralization by suppressing the accession of osteoclast precursors onto the bone, thus preventing transformation into mature, absorbing osteoclasts.

Pharmacokinetics:

Absorption: Poorly absorbed from the GI tract. Bioavailability: Approx 1-3%.

Distribution: Crosses the placenta. Plasma protein binding: Approx 54%.

Metabolism: Not metabolised.

Excretion: Via urine, approx 20-55% as unchanged drug. Elimination half-life: 21-35 hr.

1. https://www.uptodate.com/contents/ Pamidronate -drug-information?search= Pamidronate &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Pamidronate _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Pamidronate ?type=full&mtype=generic#mechanism-of-action