Pamidronic Acid

Pamidronate disodium is a potent inhibitor of osteoclastic bone resorption. It binds strongly to hydroxyapatite crystals in bone and inhibits both the formation and the dissolution of these crystals in vitro. It is a second-generation, nitrogen-containing bisphosphonate.

Mechanism of Action

• Bone binding: the inhibition of osteoclastic resorption in the body may be due, at least in part, to binding of the drug to the mineral of bone.
• Osteoclast precursors: pamidronate suppresses the access of osteoclast precursors to bone. The local, direct antiresorptive effect of bisphosphonate bound to bone appears to be the main mode of action in vitro and in vivo.
• Inside the osteoclast: released from bone during resorption, nitrogen-containing bisphosphonates are taken up by osteoclasts and inhibit the mevalonate pathway (farnesyl diphosphate synthase). This prevents prenylation of GTP-binding proteins such as Rap1, disrupts osteoclast function and leads to apoptosis.
• Tumour osteolysis: in experimental studies pamidronate inhibited tumour-induced osteolysis when given before or at the same time as inoculation or transplantation of tumour cells.
• Hypercalcaemia of malignancy: the biochemical changes are a fall in serum calcium and phosphate and, secondarily, a reduction in urinary excretion of calcium, phosphate and hydroxyproline. By controlling hypercalcaemia, pamidronate improves the glomerular filtration rate and lowers raised serum creatinine in most patients.
• Clinical effect: in trials in breast cancer patients on chemotherapy with predominantly lytic bone metastases, and in stage III multiple myeloma with osteolytic lesions, pamidronate prevented or delayed skeletal-related events (hypercalcaemia, fractures, radiotherapy, bone surgery, spinal cord compression) and reduced bone pain.

Pharmacokinetics

• Absorption: pamidronate is given by intravenous infusion, so absorption is complete at the end of the infusion.
• Distribution: plasma concentrations rise rapidly when the infusion starts and fall rapidly when it stops; the apparent plasma half-life is about 0.8 hours. Apparent steady state is reached with infusions longer than 2–3 hours. A 60 mg infusion over 1 hour gave peak plasma concentrations of about 10 nmol/mL, and apparent plasma clearance is about 180 mL/min. About the same percentage of each dose is retained in the body, so accumulation in bone depends only on the total cumulative dose, not on the capacity of bone. About 54% is bound to plasma proteins, a share that rises when calcium concentrations are abnormally high.
• Metabolism: pamidronate does not appear to be eliminated by biotransformation.
• Elimination: about 20–55% of the dose is recovered in urine within 72 hours as unchanged pamidronate, and the rest is retained in the body. The retained share does not depend on the dose (15–180 mg) or the infusion rate (1.25–60 mg/h). Urinary elimination is biexponential, with apparent half-lives of about 1.6 and 27 hours; apparent renal clearance is about 54 mL/min and tends to follow creatinine clearance.
• Special populations: because pamidronate is excreted unchanged mainly by the kidney, renal adverse reactions may be more likely in renal impairment. Pharmacokinetic studies indicate that no dose adjustment is needed in mild or moderate renal impairment or in mild to moderate hepatic impairment (see Administration and Dosage).

• Hypercalcaemia of malignancy: treatment of tumour-induced hypercalcaemia.
• Prevention of bone complications: pathological fractures, spinal compression, radiation or surgery to bone, and hypercalcaemia, in patients with breast cancer and bone metastases or with multiple myeloma and bone lesions, in addition to specific treatment of the tumour.

• Hypersensitivity to pamidronate, to other bisphosphonates or to any of the excipients.

Adverse reactions are usually mild and short-lived. The most common are asymptomatic hypocalcaemia, fever and flu-like symptoms (a rise in body temperature of 1–2 °C that can last up to 48 hours and usually resolves without treatment); the acute flu-like reactions usually occur only with the first infusion. Symptomatic hypocalcaemia is common, soft-tissue inflammation can occur at the infusion site, especially at higher doses, and osteonecrosis, first affecting the jaw, has been reported occasionally. Many of the reactions may be related to the underlying disease.

Very common (≥1/10): hypocalcaemia; hypophosphataemia; fever and flu-like symptoms, sometimes with malaise, rigors, fatigue and flushing.

Common (≥1/100 to <1/10): anaemia, thrombocytopenia, lymphocytopenia; hypokalaemia, hypomagnesaemia; symptomatic hypocalcaemia (paraesthesia, tetany), headache, insomnia, somnolence; conjunctivitis; hypertension; nausea, vomiting, anorexia, abdominal pain, diarrhoea, constipation, gastritis; rash; transient bone pain, arthralgia, myalgia, generalised pain; infusion site reaction (pain, redness, swelling, induration, phlebitis, thrombophlebitis); raised serum creatinine.

Uncommon (≥1/1,000 to <1/100): allergic and anaphylactic reactions, bronchospasm (dyspnoea), angioedema; seizures, agitation, dizziness, lethargy; uveitis (iritis, iridocyclitis); hypotension; dyspepsia; pruritus; muscle cramps; osteonecrosis; acute renal failure; abnormal liver function tests, raised serum urea.

Rare (≥1/10,000 to <1/1,000): focal segmental glomerulosclerosis, including the collapsing variant; nephrotic syndrome.

Very rare (<1/10,000): reactivation of herpes simplex and herpes zoster; leukopenia; anaphylactic shock; hyperkalaemia, hypernatraemia; confusion, visual hallucinations; scleritis, episcleritis, xanthopsia; osteonecrosis of the external auditory canal (a class effect of bisphosphonates); left ventricular failure (dyspnoea, pulmonary oedema) and congestive heart failure (oedema) due to fluid overload; adult respiratory distress syndrome, interstitial lung disease; haematuria, worsening of pre-existing kidney disease, renal tubular disorders, tubulointerstitial nephritis, glomerulonephropathy.

Not known: pseudotumour cerebri; orbital inflammation; atrial fibrillation; osteonecrosis of the jaw.

Important serious reactions are kidney damage, osteonecrosis of the jaw and of the external auditory canal, anaphylaxis and fluid overload. Osteonecrosis of the jaw has been reported mainly in cancer patients treated with bone-resorption inhibitors, many of whom were also receiving chemotherapy and corticosteroids and had signs of local infection including osteomyelitis; most reports followed tooth extractions or other dental procedures. In a trial comparing pamidronate 90 mg with zoledronic acid 4 mg, atrial fibrillation was reported in 2.2% (12/556) of the pamidronate group and 0.5% (3/563) of the zoledronic acid group; the mechanism is unknown.

• Other bisphosphonates, other antihypercalcaemic agents and calcitonin: using them together could cause hypocalcaemia with clinical symptoms (paraesthesia, tetany, hypotension). Pamidronate must not be given with other bisphosphonates, and other calcium-lowering agents given with it could cause significant hypocalcaemia. In severe hypercalcaemia, pamidronate has been combined successfully with calcitonin and mithramycin to speed and strengthen the calcium-lowering effect.
• Nephrotoxic medicines: use caution.
• Anti-angiogenic medicines: use caution, because a higher incidence of osteonecrosis of the jaw has been seen in patients treated with both.
• Thalidomide: in multiple myeloma, the risk of renal impairment may rise when pamidronate is combined with thalidomide.
• Antitumour medicines: pamidronate has been given with most of them without significant interactions.
• Bone scintigraphy: because pamidronate is taken up by bone, it could in theory interfere with bone scintigraphy.

Pamidronate is for intravenous infusion only and must never be given as a bolus injection. The solution must be diluted before use and infused slowly; compatibility and in-use stability are covered under Shelf Life. Patients should receive the package leaflet and the patient reminder card.

Infusion

• The infusion rate must never exceed 60 mg per hour (1 mg/min), and the concentration of pamidronate disodium in the infusion solution must not exceed 90 mg in 250 mL.
• In patients with established or suspected renal impairment, such as those with hypercalcaemia of malignancy or multiple myeloma, the rate should not exceed 22 mg per hour.
• To minimise local reactions, the cannula should be placed carefully in a relatively large vein.
• A single 90 mg dose is normally given as a 2-hour infusion in 250 mL of infusion solution. In multiple myeloma and in hypercalcaemia of malignancy, no more than 90 mg in 500 mL over 4 hours is recommended.

Hypercalcaemia of Malignancy

• Rehydrate with 0.9% w/v sodium chloride solution before and during treatment.
• The total dose per treatment course depends on the initial serum calcium. The ranges apply to uncorrected values and also to serum- or albumin-corrected values in rehydrated patients:
  • up to 3.0 mmol/L (up to 12.0 mg%): 15–30 mg;
  • 3.0–3.5 mmol/L (12.0–14.0 mg%): 30–60 mg;
  • 3.5–4.0 mmol/L (14.0–16.0 mg%): 60–90 mg;
  • above 4.0 mmol/L (above 16.0 mg%): 90 mg.
• The total dose can be given as one infusion or as several infusions over 2–4 consecutive days. The maximum dose per treatment course is 90 mg, for the first and for repeat courses.
• Serum calcium usually falls significantly within 24–48 hours and normalises within 3–7 days. If normal calcium is not reached in that time, a further dose may be given. The duration of response varies and treatment can be repeated when hypercalcaemia returns; clinical experience suggests that efficacy may fall as the number of treatments increases.

Bone Complications

• Stage III multiple myeloma: 90 mg every 4 weeks.
• Osteolytic lesions with bone metastases of breast cancer: 90 mg every 4 weeks. The doses can also be given every 3 weeks to coincide with chemotherapy.

Special Populations

• Renal impairment: no dose adjustment in mild (creatinine clearance 61–90 mL/min) or moderate (30–60 mL/min) impairment, but the infusion rate should not exceed 90 mg over 4 hours (about 22 mg per hour). Pamidronate must not be given in severe impairment (creatinine clearance below 30 mL/min) unless life-threatening hypercalcaemia of malignancy makes the benefit outweigh the risk. Serum creatinine should be checked before each dose. In patients treated for bone metastases or multiple myeloma who show clear deterioration of renal function, treatment should be withheld until renal function is back within 10% of baseline. In the clinical trial behind this advice, deterioration meant a rise of 0.5 mg/dL in patients with normal baseline creatinine, or of 1.0 mg/dL in patients with abnormal baseline creatinine.
• Hepatic impairment: no adjustment in mild to moderate impairment. Pamidronate has not been studied in severe hepatic impairment, so no specific recommendation can be made.
• Children and adolescents: there is no clinical experience under 18 years.

Supervision, Hydration and Monitoring

Pamidronate should be given under the supervision of a physician with equipment to monitor clinical and biochemical effects. It can cause eye irritation. It must never be given as a bolus, because of the risk of severe local reactions and thrombophlebitis. In initial treatment of hypercalcaemia of malignancy, intravenous rehydration to maintain urine output is essential, but overhydration must be avoided, especially in patients on diuretics. In patients with heart disease, especially the elderly, extra saline can cause heart failure, and fever (flu-like symptoms) may add to this. Serum calcium and phosphate must be monitored closely after starting. Patients who have had thyroid surgery may be especially prone to hypocalcaemia from relative hypoparathyroidism. Patients with anaemia, leukopenia or thrombocytopenia need regular blood counts.

Kidney Toxicity

Bisphosphonates, including pamidronate, are associated with kidney toxicity that shows as impaired renal function and possible renal failure. After a first or single dose, renal deterioration, progression to renal failure and dialysis have been described. If renal function worsens during treatment, the infusion should be stopped. Renal impairment, including renal failure, has also been reported after long-term treatment in multiple myeloma, but progression of the disease or other complications were present, so a causal link is unproven. Single doses must not exceed 90 mg and the recommended infusion rate must be kept. Serum creatinine and blood urea nitrogen and the clinical state of renal function should be assessed before each dose, especially in patients on frequent infusions over a long time and in those with kidney disease or a tendency to renal dysfunction, such as multiple myeloma or hypercalcaemia of malignancy. Fluid balance (urine output, daily weights) should also be watched closely.

Hepatic Impairment

Pamidronate has not been studied in severe hepatic impairment, so no specific recommendation can be given.

Calcium and Vitamin D

Patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium and vitamin D deficiency, should be given oral calcium and vitamin D supplements to minimise the risk of hypocalcaemia when they are not hypercalcaemic.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw has been reported uncommonly in clinical trials and after marketing in patients given pamidronate.

• Start of treatment, or of a new course, should be delayed in patients with open, unhealed soft-tissue lesions in the mouth, except in a medical emergency.
• A dental examination with appropriate preventive dentistry and an individual benefit-risk assessment is recommended before treatment in patients with concomitant risk factors.
• Risk factors include: the potency of the bisphosphonate (higher with highly potent compounds), parenteral route (higher) and cumulative dose; cancer, concomitant conditions (anaemia, coagulopathies, infection) and smoking; concomitant chemotherapy, anti-angiogenic medicines, head and neck radiotherapy and corticosteroids; a history of dental disease, poor oral hygiene, periodontal disease, invasive dental procedures such as extractions, and poorly fitting dentures.
• All patients should keep good oral hygiene, have regular dental check-ups and report at once any oral symptom such as tooth mobility, pain, swelling, sores that do not heal or discharge. During treatment, invasive dental procedures should be done only after careful consideration and avoided close to a pamidronate dose. Dental procedures can worsen osteonecrosis of the jaw, and no data show that stopping the bisphosphonate lowers the risk in patients who need them.
• The plan for a patient who develops osteonecrosis of the jaw should be made with a dentist or maxillofacial surgeon experienced in it, and temporary interruption of pamidronate should be considered until it resolves and the risk factors are reduced where possible.

Osteonecrosis of the External Auditory Canal

This has been reported with bisphosphonates, mainly after long-term treatment. Possible risk factors are steroid use, chemotherapy and local factors such as infection or trauma. It should be considered in patients on bisphosphonates with ear symptoms such as chronic ear infections.

Musculoskeletal Pain

After marketing, severe and occasionally incapacitating bone, joint or muscle pain has been reported infrequently with bisphosphonates, including pamidronate. Onset ranged from one day to several months after starting. Most patients improved after stopping, and symptoms returned in some when the same or another bisphosphonate was restarted.

Atypical Femoral Fractures

Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonates, mainly in patients on long-term treatment for osteoporosis. They can occur after minimal or no trauma, and some patients have thigh or groin pain, often with stress-fracture imaging, weeks to months before a complete fracture. They are often bilateral, so the opposite femur should be examined, and healing is often poor. Patients should report any thigh, hip or groin pain, and an incomplete femoral fracture should be looked for. Interruption of the bisphosphonate should be considered in suspected cases, based on an individual benefit-risk assessment.

Pregnancy and Breastfeeding

• Pregnancy: there are no clinical data. There is no unequivocal evidence of teratogenicity in animals, but pamidronate may pose a risk to the foetus or newborn through its action on calcium homeostasis, and in animals it caused defects in bone mineralisation, especially of the long bones, with angular distortion. The risk to humans is unknown. Pamidronate should not be given to pregnant women except for life-threatening hypercalcaemia.
• Breastfeeding: very limited experience indicates pamidronate levels in breast milk below the detection limit, and oral absorption is poor. Breastfeeding is nevertheless not recommended during treatment, because experience is limited and pamidronate strongly affects bone mineralisation.

Sodium

Each maximum dose (90 mg) contains less than 1 mmol (23 mg) of sodium, so the medicine is essentially sodium-free. If 0.9% sodium chloride solution is used to dilute it, the sodium dose received will be higher.

Effect on Driving

Somnolence or dizziness can occur after the infusion. Patients affected should not drive, use potentially dangerous machines or do other activities that could be hazardous because of reduced alertness.

Do not store the vials above 25 °C. For storage after dilution, see Shelf Life. The vials are clear glass, in cartons of 1, 4 or 5 vials depending on the strength and size, and not all pack sizes may be marketed.

3 years. After dilution in 0.9% sodium chloride or 5% glucose solution, chemical and physical stability in use has been shown for 24 hours when stored at 2–8 °C. From a microbiological point of view, the product should be used immediately; if it is not, the user is responsible for in-use storage times and conditions, which should not exceed 24 hours at 2–8 °C.

Prescription only (Rx). Pamidronic acid is given as a slow intravenous infusion under the supervision of a physician with equipment to monitor clinical and biochemical effects, so it is supplied to the hospital or clinic that administers it.