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Pamidronate Disodium

FDA Drug Information • Also known as: Pamidronate Disodium

Brand Names
Pamidronate Disodium
Route
INTRAVENOUS
Dosage Form
INJECTION, SOLUTION
Product Type
HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Pamidronate Disodium Injection is a bisphosphonate available in 30 mg and 90 mg vials for intravenous administration. Each mL of the 30 mg/10 mL vial contains 3 mg pamidronate disodium, 47 mg mannitol; water for injection, q.s.; and phosphoric acid to adjust pH 6.0 to 7.0. Each mL of the 90 mg/10 mL vial contains, 9 mg pamidronate disodium, 37.5 mg mannitol; water for injection, q.s.; and phosphoric acid to adjust pH 6.0 to 7.0. The pH of a 1% solution of pamidronate disodium in distilled water is approximately 8.3. Pamidronate disodium, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-1-hydroxypropylidene) bis-, disodium salt, and its structural formula is: Pamidronate disodium is a white powder. It is soluble in water and in 2N sodium hydroxide, sparingly soluble in 0.1N hydrochloric acid and in 0.1N acetic acid, and practically insoluble in organic solvents. Its molecular formula is C 3 H 9 NO 7 P 2 Na 2 and its molecular weight is 279.1 (calculated as the anhydrous form). structural formula

What Is Pamidronate Disodium Used For?

1 INDICATIONS AND USAGE Pamidronate disodium is a bisphosphonate indicated for the treatment of:

  • moderate or severe hypercalcemia associated with malignancy, with or without bone metastases ( 1.1 )
  • patients with moderate to severe Paget’s disease of bone ( 1.2 )
  • osteolytic bone metastases of breast cancer or osteolytic lesions of multiple myeloma, in conjunction with standard antineoplastic therapy ( 1.3 ) Limitations of use Safety and efficacy of pamidronate disodium in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions have not been established. ( 1.4 ) 1.1 Hypercalcemia of Malignancy Pamidronate disodium is indicated for the treatment of moderate or severe hypercalcemia associated with malignancy, with or without bone metastases. 1.2 Paget’s Disease Pamidronate disodium is indicated for the treatment of patients with moderate to severe Paget’s disease of bone. 1.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma Pamidronate disodium is indicated in conjunction with standard antineoplastic therapy, for the treatment of osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma [see Clinical Studies (14.3) ] . 1.4 Limitations of Use The safety and efficacy of pamidronate disodium in the treatment of hypercalcemia associated with hyperparathyroidism or with other non-tumor-related conditions has not been established.

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Hypercalcemia of malignancy: 60 mg to 90 mg pamidronate disodium as a single dose infused over 2 hours to 24 hours for moderate hypercalcemia, or 90 mg as a single dose infused over 2 hours to 24 hours for severe hypercalcemia. If warranted, retreat after a minimum of 7 days. ( 2.1 )
  • Paget’s disease of bone: 30 mg pamidronate disodium daily as a 4-hour infusion on 3 consecutive days. ( 2.2 )
  • Osteolytic Bone Metastases of Breast Cancer: 90 mg pamidronate disodium as a 2-hour infusion every 3 to 4 weeks. Retreat after recovery of renal function. ( 2.3 )
  • Osteolytic Bone Lesions of Multiple Myeloma: 90 mg pamidronate disodium as a 4-hour infusion once every four weeks. Retreat after recovery of renal function. ( 2.3 )
  • Administer through a separate infusion line. Do not allow pamidronate disodium infusion to come in contact with any calcium or divalent cation-containing solutions. ( 2.6 ) 2.1 Hypercalcemia of Malignancy Vigorous saline hydration, should be initiated promptly along with pamidronate therapy and if possible the urine output should be about 2 L/day throughout treatment [see Warnings and Precautions (5.2) ] . Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment [see Warnings and Precautions (5.1) ] . Treatment should be withheld for renal deterioration. Moderate Hypercalcemia The recommended dose of pamidronate disodium in moderate hypercalcemia (corrected serum calcium* of approximately 12 mg/dL to 13.5 mg/dL) is 60 mg to 90 mg given as a single-dose, intravenous infusion over 2 hours to 24 hours. Longer infusions (i.e., greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal impairment. Severe Hypercalcemia The recommended dose of pamidronate disodium in severe hypercalcemia (corrected serum calcium* > 13.5 mg/dL) is 90 mg given as a single-dose, intravenous infusion over 2 to 24 hours. Longer infusions (i.e., greater than 2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency/impairment. *Albumin-corrected serum calcium = serum calcium, mg/dL + 0.8 (4.0-serum albumin, g/dL). Retreatment Retreatment with pamidronate disodium in patients who show complete or partial response initially may be carried out if serum calcium does not return to normal or remain normal after initial treatment. A minimum of 7 days between treatments is recommended to allow for full response to the initial dose. The dose and manner of retreatment is identical to that of the initial therapy. 2.2 Paget’s Disease The recommended dose of pamidronate disodium in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg. When clinically indicated, patients should be retreated at the dose of initial therapy. 2.3 Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: - Deterioration in renal function [see Warnings and Precautions (5.1) ] - Electrolyte disorders [see Warnings and Precautions (5.3) ] - Osteonecrosis of the jaw [see Warnings and Precautions (5.4) ] - Atypical fractures of the femur [see Warnings and Precautions (5.5) ] Most common adverse reactions per indication:

  • Hypercalcemia of malignancy (≥ 15%): Fever, nausea, infusion site reactions, hypocalcemia, hypophosphatemia ( 6.1 )
  • Paget’s disease (≥ 10%): Temperature increase, hypertension, arthrosis, bone pain, headache ( 6.1 )
  • Osteolytic bone metastases of breast cancer or osteolytic lesions of multiple myeloma (≥ 30%): Skeletal pain, nausea, anemia, fever, fatigue, vomiting, dyspnea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypercalcemia of Malignancy Transient elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of pamidronate disodium in 34% of patients in clinical trials. Local soft-tissue reactions (redness, swelling or induration and pain on palpation) at the site of catheter insertion were observed, most commonly in patients treated with 90 mg of pamidronate disodium. Symptomatic treatment resulted in resolution in all patients. Cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis and one case of uveitis upon separate rechallenges. Five of 231 patients (2%) who received pamidronate disodium while enrolled on controlled clinical trials for management of hypercalcemia were reported to have seizures, including two patients with pre-existing seizure disorders. One patient on the control (saline arm) also had a seizure. At least 15% of patients treated with pamidronate disodium for hypercalcemia of malignancy experienced the following adverse reactions during a clinical trial: General: Fluid overload, generalized pain Cardiovascular: Hypertension Gastrointestinal: Abdominal pain, anorexia, constipation, nausea, vomiting Genitourinary: Urinary tract infection Musculoskeletal: Bone pain Laboratory abnormality: Anemia, hypokalemia, hypomagnesemia, hypophosphatemia Table 1 lists the adverse reactions reported during comparative, controlled trials. Table 1: Adverse Reactions Reported in Three U.S. Controlled Clinical Trials Percent of Patients Pamidronate Disodium Etidronate Disodium Saline 60 mg over 4 hr 60 mg over 24 hr 90 mg over 24 hr 7.5 mg/kg x 3 days n = 23 n = 73 n = 17 n = 35 n = 23 General Edema 0 1 0 0 0 Fatigue 0 0 12 0 0 Fever 26 19 18 9 0 Infusion-site reaction 0 4 18 0 0 Moniliasis 0 0 6 0 0 Gastrointestinal Abdominal pain 0 1 0 0 0 Anorexia 4 1 12 0 0 Constipation 4 0 6 3 0 Diarrhea 0 1 0 0 0 Dyspepsia 4 0 0 0 0 Gastrointestinal hemorrhage 0 0 6 0 0 Nausea 4 0 18 6 0 Stomatitis 0 1 0 3 0 Vomiting 4 0 0 0 0 Respiratory Rales 0 0 6 0 0 Rhinitis 0 0 6 0 0 Upper respiratory infection 0 3 0 0 0 CNS Insomnia 0 1 0 0 0 Psychosis 4 0 0 0 0 Somnolence 0 1 6 0 0 Cardiovascular Atrial fibrillation 0 0 6 0 4 Atrial flutter 0 1 0 0 0 Cardiac failure 0 1 0 0 0 Hypertension 0 0 6 0 4 Syncope 0 0 6 0 0 Tachycardia 0 0 6 0 4 Endocrine Hypothyroidism 0 0 6 0 0 Hemic and Lymphatic Anemia 0 0 6 0 0 Leukopenia 4 0 0 0 0 Neutropenia 0 1 0 0 0 Thrombocytopenia 0 1 0 0 0 Musculoskeletal Myalgia 0 1 0 0 0 Urogenital Uremia 4 0 0 0 0 Laboratory Abnormalities Hypocalcemia 0 1 12 0 0 Hypokalemia 4 4 18 0 0 Hypomagnesemia 4 10 12 3 4 Hypophosphatemia 0 9 18 3 0 Paget’s Disease Adverse reactions that occurred in at least 5% of patients with...

    • Drug Interactions

    7 DRUG INTERACTIONS

  • Nephrotoxic drugs: Use with caution. ( 7.1 )
  • Thalidomide: Increased risk of renal dysfunction in patients with multiple myeloma. ( 7.2 ) 7.1 Nephrotoxic Drugs Caution is indicated when pamidronate disodium is used with other potentially nephrotoxic drugs. 7.2 Thalidomide In multiple myeloma patients, the risk of renal deterioration may be increased when pamidronate disodium is used in combination with thalidomide. 7.3 Loop Diuretics Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of pamidronate disodium.

    • Contraindications

    4 CONTRAINDICATIONS Pamidronate disodium is contraindicated in patients with hypersensitivity to pamidronate disodium, other bisphosphonates, or mannitol. Reactions to pamidronate disodium injection and to mannitol have included anaphylaxis. Hypersensitivity to pamidronate, other bisphosphonates, or mannitol ( 4 )

    Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , pamidronate disodium can cause fetal harm when administered to a pregnant woman. Available data from case reports with pamidronate disodium use in pregnant women are insufficient to inform a drug-associated risk. Administration of pamidronate to pregnant rats and rabbits resulted in maternal toxicity and embryo-fetal effects (see Data ) . Bisphosphonates, such as pamidronate disodium, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In animal reproduction studies, intravenous administration of pamidronate to pregnant rats and rabbits during the period of organogenesis resulted in maternal toxicity and embryo-fetal effects at doses of 0.6 to 8.3 times the highest recommended human dose for a single intravenous infusion.

    Overdosage

    10 OVERDOSAGE Cases of drug overdose have been reported in hypercalcemia patients treated with total doses of 225 mg to 300 mg pamidronate disodium given over 2.5 to 4 days. All patients survived, but all developed hypocalcemia that required intravenous and/or oral administration of calcium. If overdosage occurs, treat symptomatic hypocalcemia patients with short-term intravenous 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 [see Dosage and Administration (2.5) and Warnings and Precautions (5.1) ] . 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, occurring about 6 hours after the first infusion. Fever and hypotension reversed with steroid therapy.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Pamidronate Disodium Injection is available as follows: 30 mg/10 mL (3 mg/mL) single-dose vial as a clear-colorless solution containing 30 mg of pamidronate disodium and 470 mg of mannitol in 10 mL water for injection. NDC 67457-430-10 Carton of 1 single-dose vial 90 mg/10 mL (9 mg/mL) single-dose vial as a clear-colorless solution containing 90 mg of pamidronate disodium and 375 mg of mannitol in 10 mL water for injection. NDC 67457-446-10 Carton of 1 single-dose vial Storage: Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.