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Aredia (Pamidronate Disodium) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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 
Percent of Patients
Aredia®
Etidronate Disodium    Saline
60 mg
over 4 hr   
n=23    
60 mg
over 24 hr   
n=73   
90 mg
over 24 hr   
n=17   
7.5 mg/kg  
x 3 days
n=35   
n=23
General
Edema01000
Fatigue001200
Fever26191890
Fluid overload00060
Infusion-site reaction041800
Moniliasis00600
Rigors00004
Gastrointestinal
Abdominal pain01000
Anorexia411200
Constipation40630
Diarrhea01000
Dyspepsia40000
Gastrointestinal hemorrhage00600
Nausea401860
Stomatitis01030
Vomiting40000
Respiratory
Dyspnea00030
Rales00600
Rhinitis00600
Upper respiratory infection03000
CNS
Anxiety00004
Convulsions00030
Insomnia01000
Nervousness00004
Psychosis40000
Somnolence01600
Taste perversion00030
Cardiovascular
Atrial fibrillation00604
Atrial flutter01000
Cardiac failure01000
Hypertension00604
Syncope00600
Tachycardia00604
Endocrine
Hypothyroidism00600
Hemic and Lymphatic
Anemia00600
Leukopenia40000
Neutropenia01000
Thrombocytopenia01000
Musculoskeletal
Myalgia01000
Urogenital
Uremia40000
Laboratory Abnormalities
Hypocalcemia011200
Hypokalemia441800
Hypomagnesemia4101234
Hypophosphatemia091830
Abnormal liver function00030

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
Aredia®
90 mg
over 4 hours   
N=205
%
Placebo   
N=187
%
Aredia®
90 mg
over 2 hours   
N=367
%
Placebo   
N=386
%
All
Aredia®  
90 mg
N=572
%
Placebo
N=573
%
General
Asthenia16.117.125.619.222.218.5
Fatigue31.728.340.328.837.229.0
Fever38.53838.132.138.534
Metastases1.03.031.324.420.517.5
Pain13.211.815.018.114.316.1
Digestive System
Anorexia17.117.131.124.926.022.3
Constipation28.331.736.038.633.235.1
Diarrhea26.826.829.430.628.529.7
Dyspepsia17.613.418.315.022.617.5
Nausea35.637.463.559.153.551.8
Pain Abdominal19.516.024.318.122.617.5
Vomiting16.619.846.339.135.732.8
Hemic and Lymphatic
Anemia47.841.739.536.842.538.4
Granulocytopenia20.515.519.320.519.818.8
Thrombocytopenia16.617.112.514.014.015.0
Musculoskeletal System
Arthralgias10.77.015.312.713.610.8
Myalgia25.415.026.422.52620.1
Skeletal Pain61.071.770.075.466.874
CNS
Anxiety7.89.118.016.814.314.3
Headache24.419.827.223.626.222.3
Insomnia17.117.225.119.422.219.0
Respiratory System
Coughing26.322.525.319.725.720.6
Dyspnea22.021.435.124.430.423.4
Pleural Effusion2.94.315.09.110.77.5
Sinusitis14.616.616.110.415.612.0
Upper Respiratory Tract
   Infection
32.228.319.620.224.122.9
Urogenital System
Urinary Tract Infection15.69.120.217.618.515.6

      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*
Patient Population/Baseline Creatinine  Aredia® 90 mg/2 hours  Zometa® 4 mg/15 minutes
n/N(%)n/N(%)
Normal20/246(8.1%)23/246(9.3%)
Abnormal2/22(9.1%)1/26(3.8%)
Total22/268(8.2%)24/272(8.8%)

*Patients were randomized following the 15-minute infusion amendment for the Zometa arm.

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.)

Drug label data at the top of this Page last updated: 2008-01-24

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