Pamidronate: Usage, Efficacy, Precautions, and Adverse Effects

Overview:

Pamidronate, also known as Pamidronic acid or Pamidronate disodium, belongs to the group of medications called nitrogen-containing bisphosphonate. This drug was patented in 1971. Moreover, it received its FDA (United States Food and Drug Administration) approval for medical use in 1987. Pamidronate is primarily used to treat increased calcium concentration in the blood that might be resulted from certain types of cancerous conditions. It is also used in conjunction with chemotherapy for the treatment of bone damage caused due to multiple myeloma (cancer that develops in the plasma cells), or due to breast cancer that has metastasis (spread) to the bones. Pamidronate is also prescribed in the treatment of Paget’s disease (a condition characterized by soft, fragile, and weakened bones).

Drug Group:

Pamidronate comes in a class of drugs called nitrogen-containing bisphosphonates. Bisphosphonates possess two phosphonate groups. Bisphosphonates are a group of medications used for the treatment of osteoporosis. This works by preventing or slowing down the loss of bone density. Hence, they decrease the risk of spine and hip fractures. Bisphosphonates are the most commonly used osteoporosis medication.

Available Doses and Dosage Forms:

Pamidronate is to be administered through the intravenous (IV) route. The doctors inject and administer the drug into the vein of the patient. Pamidronate is available in various forms and strengths.

Powder for Reconstitution.

• 30 milligrams.

Pamidronate Disodium Injection Solution:

• 3 milligram per milliliter (mg/mL).

• 6 milligram per milliliter.

• 9 milligram per milliliter.

For Patients:

What Is Hypercalcemia of Malignancy?

Hypercalcemia refers to increased calcium levels in the blood. Hypercalcemia of malignancy is a typical manifestation found in people with advanced stages of cancer. Hypercalcemia of malignancy generally presents with signs of elevated calcium concentration. Individuals with hypercalcemia of malignancy are generally symptomatic. The common signs of hypercalcemia include the following:

• Nausea and vomiting.

• Loss of appetite.

• Headaches.

• Depression.

• Constipation.

• Abdominal pain.

• Confusion.

• Disorientation.

• Excessive thirst.

• Increased urination.

• Tiredness.

• Weakness.

• Muscle pain.

How Does Pamidronate Work?

Pamidronate sorts with the class of medications called bisphosphonates. This works by slowing down and preventing bone breakdown. It also helps increase bone density or thickness while reducing the quantity of calcium being released into the bloodstream from the bones.

What Are the Things to Inform the Doctor Before Taking the Drug?

• Inform the doctor whether one has an allergy to Pamidronate, Etidronate, Alendronate, Risedronate, Zoledronic acid, and Tiludronate. Also, inform the doctor if one is allergic to any other medication or other ingredients of Pamidronate injection.

• Inform the doctor about the medication one takes or plans to take. This includes all prescription medicines, over-the-counter medications, herbal products, nutritional supplements, and vitamins. Be certain to mention chemotherapy medications and any of the following oral steroid drugs: Dexamethasone, Prednisone, Methylprednisolone, and Thalidomide. The doctor might alter the dosage or assess conscientiously for any development of side effects.

• Many medications might interact with Pamidronate injection, so one should inform the doctor about all medications one takes.

• Inform the doctor if one is under radiation therapy.

• Inform the doctor about the medical condition one has had in the past few days. Be certain to inform if one has or has ever had seizures, liver disease, kidney problems, and thyroid surgery.

• Be sure to inform the healthcare provider if one is pregnant or has any plans for pregnancy. One should use an effective birth control method to prevent pregnancy while receiving Pamidronate treatment. Inform the doctor rightly if one gets pregnant during the treatment of Pamidronate. Discuss with the doctor if one has plans to become pregnant in the future, even after the cessation of treatment. Pamidronate might stay in the body for months and years even after one stops it.

• Pamidronate might cause serious jaw problems, particularly in those who have dental procedures. Inform the doctor before having any dental procedures while at Pamidronate treatment.

• The studies do not determine whether Pamidronate passes through human milk or whether it could harm the infant. However, one should not breastfeed while receiving Pamidronate treatment.

• Pamidronate injection treatment might cause severe muscle and bone pain. One begins to feel this pain within months, years, and even days after the first injection. Call and inform the doctor rightly if one experiences severe pain during Pamidronate treatment. The doctors might discontinue the treatment.

How Is Pamidronate Administered?

Pamidronate is typically administered by healthcare providers in hospital settings. So, one should not self-administer the drug.

• Pamidronate comes in a reconstituted powder that is to be mixed with liquid before intravenous administration.

• Pamidronate is administered or infused into a vein through an intravenous (IV) set.

• This medicine is administered slowly, and the total infusion could take 2 to 24 hours.

• The frequency and length of the infusion of Pamidronate will depend on the condition and its severity. This drug is given in a single dosage at a time for some individuals. In contrast, this medication can be repeatedly given for three days in succession or administered once every three to four weeks.

Important Considerations:

• One must keep assessing the kidney function and renal status while using Pamidronate.

• Addedly, one must pay attention to good oral hygiene practices and periodic dental hygiene examinations. Inform the dentist about Pamidronate therapy if one is about to undergo any dental procedure.

• The doctors might include calcium and vitamin D supplements along with Pamidronate treatment. One must take these supplements as directed by the doctor.

What Are the Side Effects of Pamidronate?

Pamidronate can induce certain unwanted side effects, though it is safe and effective to use. One should seek emergency medical help if they experience any signs of allergic reaction. The signs of allergic or hypersensitivity reactions to Pamidronate include the following.

• Hives.

• Rashes.

• Difficulty breathing.

• Swelling of the face.

• Swelling of the tongue.

• Swelling of the throat.

The common side effects of Pamidronate injection include the following:

• Fever.

• Headache.

• Bone or joint pain.

• Nausea.

• Vomiting.

• Increased blood pressure.

• Low calcium levels.

• Low phosphate levels.

• Low magnesium levels.

• Pain, redness, or lump under the skin tissue of the IV needle (injection site).

Serious Side Effects:

Pamidronate can cause serious side effects. One should reach out to the doctor directly if one experiences any of the following signs.

• High fever.

• Unusual and severe pain in the hip, thigh, and groin.

• Seizures.

• Kidney function problems like minimal urination, tiredness, shortness of breath, and swelling in the feet or ankles.

• Signs of low potassium include constipation, leg cramps, rapid heartbeat, increased thirst, increased urination, numbness, tingling sensation, and muscle weakness.

• Signs of low calcium levels include numbness, muscle pain, muscle spasms, and tingling sensation in fingers, toes, or mouth.

Dietary Considerations:

One can continue the routine classic diet habits unless the doctors address any restrictions. However, Pamidronate is part of a treatment containing diet changes, calcium supplements, and vitamin D supplements.

Missed Dose:

Call and inform the doctor if one misses the dosage or appointment for a Pamidronate injection. The doctor could fix the appointment for the missed one.

Overdose:

Overdose of Pamidronate is less likely to occur since it is usually administered in the office or clinical settings. However, seek emergency medical care or a poison control helpline in case of overdose.

For Doctors:

Clinical Data of Pamidronate

Generic Name: Pamidronate.

Other Names: Pamidronate disodium, Pamidronate disodium pentahydrate, or Pamidronic acid.

Drug Class: Nitrogen-containing bisphosphonate.

Route of Administration: Intravenous.

Chemical Formula: C3H11NO7P2.

Molar Mass: 235.069 g.mol -1.

What Are the Indications of Pamidronate?

Pamidronate is typically indicated for the treatment of moderate to severe forms of hypercalcemia of malignancy, moderate to severe types of Paget’s disease, osteolytic lesions of multiple myeloma, and osteolytic bone metastasis of bone cancer.

Dose and Dosing Consideration:

Hypercalcemia of Malignancy:

• 60 to 90 mg (milligrams) single dosage intravenous infusion for over two to 24 hours in case of moderate hypercalcemia.

• 90 mg single dosage intravenous infusion over two to 24 hours in severe hypercalcemia, whereas serum calcium level is above 13.5 mg/dL (milligram per decilitre).

• Longer infusion might decrease the risk of renal toxicity, particularly in people with pre-existing renal insufficiency.

• Treatment can be repeated after a minimum of seven days in individuals showing partial or favorable response, and the serum calcium level is not under the normal range.

Paget’s Disease:

• 30 mg intravenous infusion of Pamidronate over four hours once daily for three consecutive days is recommended for Paget’s disease.

Osteolytic Bone Metastasis of Breast Cancer:

• The recommended dosage is 90 mg intravenous infusion of Pamidronate for over two hours thrice daily for three weeks.

Osteolytic Bone Lesions of Multiple Myeloma:

• The recommended dosage is 90 mg intravenous infusion of Pamidronate for over four hours once a month.

Storage:

It is not recommended to store Pamidronate powder for reconstitution exceeding 30 degrees Celsius (86 degrees Fahrenheit).

Associated Conditions:

• Hypercalcemia of malignancy.

• Osteolytic lesion.

• Paget’s disease.

• Osteolytic bone metastasis.

What Are the Pharmacological Aspects of Pamidronate?

Pharmacodynamics:

Pamidronic acid belongs to second-generation nitrogen-containing bisphosphonates. So, it inhibits osteoclast-stimulated and mediated bone loss. It possesses an extensive therapeutic index with a longer duration of action. So, it can be administered every three to four weeks under several indications. Pamidronate carries the risk of adverse effects like elevated blood urea nitrogen concentration, nephrotoxicity, and renal tubular necrosis.

Mechanism of Action:

Bisphosphonates bind to the hydroxyapatite crystals after being carried to the bone. Osteoclasts undergo bone resorption, which further results in local acidification with the release of bisphosphonates. The bisphosphonates released are carried into the osteoclast through fluid-phase endocytosis. As a result, endocytic vesicles also become acidified.

Osteoclasts are the bone cells that mediate the resorption of bone. These osteoclasts adhere to the bone resulting in the formation of podosomes (a ring structure of F-actin). Any interference or disruption to the podosomes can precipitate the osteoclasts to dissociate from the bone. This action helps prevent bone resorption.

Pamidronate is a second-generation bisphosphate that contains nitrogens. The nitrogen-containing bisphosphonates are known to trigger the apoptosis (cell death) of hematopoietic tumor cells. This works by inhibiting the significant components of farnesyl diphosphate, farnesyl diphosphate synthase, and geranylgeranyl diphosphate. These components are vital for the post-translational prenylation of guanosine triphosphate (GTP)- binding proteins such as Rap1. So, diminished or lack of prenylation influences the function and Rap1, leading to apoptosis. Pamidronate, in addition to the activated caspases, contributes to apoptosis.

Distribution:

• The protein binding capacity of Pamidronate is approximately 54 percent in serum.

• The mean, standard deviation with body retention of Pamidronate is estimated to be about 54 and 16 percent of the dose in 120 hours.

Metabolism:

• The drug Pamidronate is not metabolized in vivo.

• It exclusively undergoes elimination by means of renal excretion.

Elimination:

• Pamidronate is eliminated in urine.

• The mean, standard dose of about 16 percent was excreted in the urine in unchanged form within 120 hours following the administration of 30, 60, and 90 mg of the drug Pamidronate disodium in four hours and another 90 mg dosage of Pamidronate disodium in 24 hours.

• So, the accretive urinary excretion was linearly dependent on the dose of Pamidronate.

Half-Life and Clearance:

• The mean elimination half-life of Pamidronate is about 28 + 7 hours.

• The mean total clearance of the drug Pamidronate is about 107 + 50 mL/min (milliliters per minute), and the mean renal clearance is about 49 + 28 mL/min.

Toxicity:

• People with Pamidronate overdose encounter fever, hypocalcemia, taste perversion, and hypotension.

• Overdose of Pamidronate can be effectively managed by appropriate and supportive treatment measures. This chiefly includes the administration of intravenous calcium and steroids.

What Are the Contraindications of Pamidronate?

• Pamidronate disodium is strictly contraindicated in people having clinically significant hypersensitivity reactions to Pamidronate disodium or other bisphosphonates.

• It is also contraindicated in people hypersensitive to excipients (substances present along the active ingredients) like mannitol.

Warnings and Precautions:

Bisphosphonates like Pamidronate are incorporated into the bone matrix with a gradual release mechanism. The warnings and precautions of Pamidronate disodium include the following:

Renal Impairment:

• Bisphosphonates have been typically associated with renal toxicity, particularly focal segmental glomerulosclerosis. The clinical manifestations of Pamidronate-mediated renal toxicity include renal function impairment, renal function deterioration, nephrotic syndrome, and complete renal failure.

• Renal failure has been particularly reported in people with single-dose Pamidronate disodium administration. Many people showed mild and slow improvement in renal function after the discontinuation of the drug.

• Single dose Pamidronate disodium should not be administered with an excess of 90 mg dosage. This might result in clinically significant renal function decline and deterioration.

• Consider serum creatinine monitoring before each administration of treatment.

• Withhold or temporarily discontinue the Pamidronate treatment until renal status reverts to the baseline in people having deterioration in renal function.

• Pamidronate disodium should not be administered in people with severe renal impairment for the management of osteolytic bone metastasis.

Electrolyte Disorders:

• Pamidronate disodium treatment has been associated with reports of asymptomatic hypokalemia, hypophosphatemia, hypocalcemia, and Hypomagnesemia. Symptomatic hypocalcemia, including tetany associated with Pamidronate therapy, has been reported in rare instances.

• Hence, assess the serum concentration of phosphate, magnesium, potassium, and calcium before and after the initiation of Pamidronate treatment.

• Short-term calcium therapy is recommended if hypocalcemia results.

• Consider oral calcium and vitamin D supplements in the absence of hypercalcemia. This might decrease the risk of low calcium serum concentration or hypocalcemia.

Osteonecrosis of Jaw:

• Osteonecrosis of the jaw (ONJ) has been chiefly reported in people with cancer who undergo intravenous bisphosphonate therapy. Nevertheless, many were also under corticosteroids and chemotherapy. These might increase the risk of ONJ.

• Post-marketing reports show evidence of a higher frequency of ONJ in certain types of tumors like multiple myeloma and advanced breast cancer. ONJ has also been predominantly associated with dental extraction, local traumas, and periodontal diseases.

• Local infections have occurred with ONJ. This chiefly includes osteomyelitis. So, it is strictly recommended that patients maintain good oral hygiene and undergo periodic dental examinations before the initiation of Pamidronate treatment. Preventive dental measures should be taken into consideration prior to initiation of treatment.

• Ask patients to avoid invasive dental procedures during Pamidronate treatment. Dental surgery and invasive dental procedures might exacerbate ONJ if people develop it while on Pamidronate treatment.

• The clinical data does not recommend if the discontinuation of bisphosphonate therapy can reduce the risk of ONJ for those requiring dental treatments.

• However, clinical judgment should be based on the assessment obtained from individuals' benefits and risks.

Femur Fractures:

• Atypical femur fractures have been reported in people receiving bisphosphonates. The fractures include atypical diaphyseal and subtrochanteric fractures. These kinds of fractures can occur in the femoral shaft below the lesser trochanter to supracondylar flare, showing transverse or oblique orientation. However, such fractures show no comminution.

• The atypical femoral fractures might occur with minimal or no trauma. However, individuals could encounter groin pain before having a total femoral fracture. The femoral fractures associated with bisphosphonates are generally bilateral. Hence, consider contra lateral femur examination in individuals who have suffered a femoral shaft fracture.

• Evaluate atypical fracture in individuals with a history of bisphosphonates therapy presenting with groin or thigh pain even in the exclusion of trauma.

• Poor healing has been reported with these atypical femoral fractures.

• Discontinue Pamidronate treatment in individuals having greater suspicion for atypical femur fracture. But, the clinical data does not suggest whether the risk of fracture remains even after the discontinuation of the therapy.

What Are the Drug Interactions of Pamidronate?

Pamidronate is known to interact with certain drugs, showing adverse reactions. Pamidronate shows no severe interaction with other drugs. However, Pamidronate is known to show moderate interactions with the drugs that are listed below:

• Aluminum hydroxide.

• Calcium citrate.

• Calcium chloride.

• Calcium gluconate.

• Dichlorphenamide.

• Calcium acetate.

• Calcium carbonate.

• Sodium citrate.

• Tenofovir.

• Sodium bicarbonate.

Pamidronate shows minor interactions with certain drugs:

• Entecavir.

• Teriparatide.

• Foscarnet.