Clinical Studies

Hypercalcemia of Malignancy

Transient mild elevation of temperature by at least 1°C was noted 24 to 48 hours after administration of Aredia in 34% of patients in clinical trials. In the saline trial, 18% of patients had a temperature elevation of at least 1°C 24 to 48 hours after treatment.

Drug-related local soft-tissue symptoms (redness, swelling or induration and pain on palpation) at the site of catheter insertion were most common in patients treated with 90 mg of Aredia. Symptomatic treatment resulted in rapid resolution in all patients.

Rare 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 Aredia during the four U.S. controlled hypercalcemia clinical studies were reported to have had seizures, 2 of whom had preexisting seizure disorders. None of the seizures were considered to be drug-related by the investigators. However, a possible relationship between the drug and the occurrence of seizures cannot be ruled out. It should be noted that in the saline arm 1 patient (4%) had a seizure.

There are no controlled clinical trials comparing the efficacy and safety of 90-mg Aredia over 24 hours to 2 hours in patients with hypercalcemia of malignancy. However, a comparison of data from separate clinical trials suggests that the overall safety profile in patients who received 90-mg Aredia over 24 hours is similar to those who received 90-mg Aredia over 2 hours. The only notable differences observed were an increase in the proportion of patients in the Aredia 24-hour group who experienced fluid overload and electrolyte/mineral abnormalities.

At least 15% of patients treated with Aredia for hypercalcemia of malignancy also experienced the following adverse events 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

Many of these adverse experiences may have been related to the underlying disease state. The following table lists the adverse experiences considered to be treatment-related during comparative, controlled U.S. trials.

Treatment-Related Adverse Experiences Reported in Three U.S. Controlled Clinical Trials

Paget's Disease

Transient mild elevation of temperature > 1°C above pretreatment baseline was noted within 48 hours after completion of treatment in 21% of the patients treated with 90 mg of Aredia in clinical trials.

Drug-related musculoskeletal pain and nervous system symptoms (dizziness, headache, paresthesia, increased sweating) were more common in patients with Paget's disease treated with 90 mg of Aredia than in patients with hypercalcemia of malignancy treated with the same dose.

Adverse experiences considered to be related to trial drug, which occurred in at least 5% of patients with Paget's disease treated with 90 mg of Aredia in two U.S. clinical trials, were fever, nausea, back pain, and bone pain.

At least 10% of all Aredia-treated patients with Paget's disease also experienced the following adverse experiences during clinical trials:

Cardiovascular: Hypertension

Musculoskeletal: Arthrosis, bone pain

Nervous system: Headache

Most of these adverse experiences may have been related to the underlying disease state.

Osteolytic Bone Metastases of Breast Cancer and Osteolytic Lesions of Multiple Myeloma

The most commonly reported ( > 15%) adverse experiences occurred with similar frequencies in the Aredia- and placebo-treatment groups, and most of these adverse experiences may have been related to the underlying disease state or cancer therapy.

Commonly Reported Adverse Experiences in Three U.S. Controlled Clinical Trials

Of the toxicities commonly associated with chemotherapy, the frequency of vomiting, anorexia, and anemia were slightly more common in the Aredia patients whereas stomatitis and alopecia occurred at a frequency similar to that in placebo patients. In the breast cancer trials, mild elevations of serum creatinine occurred in 18.5% of Aredia patients and 12.3% of placebo patients. Mineral and electrolyte disturbances, including hypocalcemia, were reported rarely and in similar percentages of Aredia-treated patients compared with those in the placebo group. The reported frequencies of hypocalcemia, hypokalemia, hypophosphatemia, and hypomagnesemia for Aredia-treated patients were 3.3%, 10.5%, 1.7%, and 4.4%, respectively, and for placebo-treated patients were 1.2%, 12%, 1.7%, and 4.5%, respectively. In previous hypercalcemia of malignancy trials, patients treated with Aredia (60 or 90 mg over 24 hours) developed electrolyte abnormalities more frequently (see ADVERSE REACTIONS, Hypercalcemia of Malignancy).

Arthralgias and myalgias were reported slightly more frequently in the Aredia group than in the placebo group (13.6% and 26% vs 10.8% and 20.1%, respectively).

In multiple myeloma patients, there were five Aredia-related serious and unexpected adverse experiences. Four of these were reported during the 12-month extension of the multiple myeloma trial. Three of the reports were of worsening renal function developing in patients with progressive multiple myeloma or multiple myeloma-associated amyloidosis. The fourth report was the adult respiratory distress syndrome developing in a patient recovering from pneumonia and acute gangrenous cholecystitis. One Aredia-treated patient experienced an allergic reaction characterized by swollen and itchy eyes, runny nose, and scratchy throat within 24 hours after the sixth infusion.

In the breast cancer trials, there were four Aredia-related adverse experiences, all moderate in severity, that caused a patient to discontinue participation in the trial. One was due to interstitial pneumonitis, another to malaise and dyspnea. One Aredia patient discontinued the trial due to a symptomatic hypocalcemia. Another Aredia patient discontinued therapy due to severe bone pain after each infusion, which the investigator felt was trial-drug-related.

Renal Toxicity

In a study of the safety and efficacy of Aredia 90 mg (2-hour infusion) vs Zometa 4 mg (15- minute infusion) in bone metastases patients with multiple myeloma or breast cancer, renal deterioration was defined as an increase in serum creatinine of 0.5 mg/dL for patients with normal baseline creatinine ( < 1.4 mg/dL) or an increase of 1.0 mg/dL for patients with an abnormal baseline creatinine ( ≥ 1.4 mg/dL). The following are data on the incidence of renal deterioration in patients in this trial. See table below.

Incidence of Renal Function Deterioration in Multiple Myeloma and Breast Cancer Patients with Normal and Abnormal Serum Creatinine at Baseline*

Post-Marketing Experience

The following adverse reactions have been reported in post-marketing use: General: reactivation of Herpes simplex and Herpes zoster, influenza-like symptoms; CNS: confusion and visual hallucinations, sometimes in the presence of electrolyte imbalance; Skin: rash, pruritus; Special senses:conjunctivitis; Renal: focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome; Laboratory abnormalities: hyperkalemia, hypernatremia, hematuria. Rare instances of allergic manifestations have been reported, including hypotension, dyspnea, or angioedema, and, very rarely, anaphylactic shock. Aredia is contraindicated in patients with clinically significant hypersensitivity to Aredia or other bisphosphonates (see CONTRAINDICATIONS).

Cases of osteonecrosis (primarily of the jaws) have been reported since market introduction. Osteonecrosis of the jaws has other well documented multiple risk factors. It is not possible to determine if these events are related to Aredia or other bisphosphonates, to concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), to patient's underlying disease, or to other comorbid risk factors (e.g., anemia, infection, preexisting oral disease). (See PRECAUTIONS.)

Concomitant administration of a loop diuretic had no effect on the calcium-lowering action of Aredia.

Caution is indicated when Aredia is used with other potentially nephrotoxic drugs.

In multiple myeloma patients, the risk of renal dysfunction may be increased when Aredia is used in combination with thalidomide.

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