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adverse reactions
ADVERSE REACTIONS 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. 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 Edema 0 1 0 0 0 Fatigue 0 0 12 0 0 Fever 26 19 18 9 0 Fluid overload 0 0 0 6 0 Infusion-site reaction 0 4 18 0 0 Moniliasis 0 0 6 0 0 Rigors 0 0 0 0 4 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 Dyspnea 0 0 0 3 0 Rales 0 0 6 0 0 Rhinitis 0 0 6 0 0 Upper respiratory infection 0 3 0 0 0 CNS Anxiety 0 0 0 0 4 Convulsions 0 0 0 3 0 Insomnia 0 1 0 0 0 Nervousness 0 0 0 0 4 Psychosis 4 0 0 0 0 Somnolence 0 1 6 0 0 Taste perversion 0 0 0 3 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 Abnormal liver function 0 0 0 3 0 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 Asthenia 16.1 17.1 25.6 19.2 22.2 18.5 Fatigue 31.7 28.3 40.3 28.8 37.2 29.0 Fever 38.5 38 38.1 32.1 38.5 34 Metastases 1.0 3.0 31.3 24.4 20.5 17.5 Pain 13.2 11.8 15.0 18.1 14.3 16.1 Digestive System Anorexia 17.1 17.1 31.1 24.9 26.0 22.3 Constipation 28.3 31.7 36.0 38.6 33.2 35.1 Diarrhea 26.8 26.8 29.4 30.6 28.5 29.7 Dyspepsia 17.6 13.4 18.3 15.0 22.6 17.5 Nausea 35.6 37.4 63.5 59.1 53.5 51.8 Pain Abdominal 19.5 16.0 24.3 18.1 22.6 17.5 Vomiting 16.6 19.8 46.3 39.1 35.7 32.8 Hemic and Lymphatic Anemia 47.8 41.7 39.5 36.8 42.5 38.4 Granulocytopenia 20.5 15.5 19.3 20.5 19.8 18.8 Thrombocytopenia 16.6 17.1 12.5 14.0 14.0 15.0 Musculoskeletal System Arthralgias 10.7 7.0 15.3 12.7 13.6 10.8 Myalgia 25.4 15.0 26.4 22.5 26 20.1 Skeletal Pain 61.0 71.7 70.0 75.4 66.8 74 CNS Anxiety 7.8 9.1 18.0 16.8 14.3 14.3 Headache 24.4 19.8 27.2 23.6 26.2 22.3 Insomnia 17.1 17.2 25.1 19.4 22.2 19.0 Respiratory System Coughing 26.3 22.5 25.3 19.7 25.7 20.6 Dyspnea 22.0 21.4 35.1 24.4 30.4 23.4 Pleural Effusion 2.9 4.3 15.0 9.1 10.7 7.5 Sinusitis 14.6 16.6 16.1 10.4 15.6 12.0 Upper Respiratory Tract Infection 32.2 28.3 19.6 20.2 24.1 22.9 Urogenital System Urinary Tract Infection 15.6 9.1 20.2 17.6 18.5 15.6 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 (%) Normal 20/246 (8.1%) 23/246 (9.3%) Abnormal 2/22 (9.1%) 1/26 (3.8%) Total 22/268 (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 during post-approval use of Aredia. Because these reports are from a population of uncertain size and are subject to confounding factors, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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, orbital inflammation; Renal and urinary disorders: focal segmental glomerulosclerosis including the collapsing variant, nephrotic syndrome; renal tubular disorders (RTD); tubulointerstitial nephritis, and glomerulonephropathies. 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). Respiratory, thoracic and mediastinal disorders: adult respiratory distress syndrome (ARDS), interstitial lung disease (ILD). Musculoskeletal and connective tissue disorders: severe and occasionally incapacitating bone, joint, and/or muscle pain. Cases of osteonecrosis (primarily involving the jaw) have been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Aredia. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Data suggest a greater frequency of reports of ONJ in certain cancers, such as advanced breast cancer and multiple myeloma. The majority of the reported cases are in cancer patients following invasive dental procedures, such as tooth extraction. It is therefore prudent to avoid invasive dental procedures as recovery may be prolonged. (See PRECAUTIONS.) Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, including Aredia. (See PRECAUTIONS.)