ADVERSE REACTIONS
Daily Dosing
Daily treatment with oral BONIVA was studied in over 3900 patients in postmenopausal osteoporosis trials of up to 3 years duration. The overall adverse event profile of BONIVA 2.5 mg once daily in these studies was similar to that of placebo.
Treatment and Prevention of Postmenopausal Osteoporosis
Most adverse events were mild or moderate and did not lead to discontinuation. The incidence of serious adverse events was 20% in the placebo group and 23% in the BONIVA 2.5 mg daily group. The percentage of patients who withdrew from treatment due to adverse events was approximately 17% in both the BONIVA 2.5 mg daily group and the placebo group. Overall, and according to body system, there was no difference between BONIVA and placebo, with adverse events of the digestive system being the most common reason for withdrawal.
Table 3 lists adverse events from the Treatment and Prevention Studies reported in ≥2% of patients and in more patients treated daily with BONIVA than patients treated with placebo. Adverse events are shown without attribution of causality.
Table 3 Adverse Events Occurring at a Frequency ≥2% and in More Patients Treated with BONIVA than in Patients Treated with Placebo Daily in the Osteoporosis Treatment and Prevention Studies | Body System | Placebo
%
(n=1134) | BONIVA 2.5 mg
%
(n=1140) |
|---|
| Body as a Whole | | |
| Back Pain | 12.2 | 13.5 |
| Pain in Extremity | 6.4 | 7.8 |
| Infection | 3.4 | 4.3 |
| Asthenia | 2.3 | 3.5 |
| Allergic Reaction | 1.9 | 2.5 |
| Digestive System | | |
| Dyspepsia | 9.8 | 11.9 |
| Diarrhea | 5.0 | 6.8 |
| Tooth Disorder | 2.3 | 3.5 |
| Vomiting | 2.1 | 2.7 |
| Gastritis | 1.9 | 2.2 |
| Metabolic and Nutritional Disorders | | |
| Hypercholesterolemia | 4.2 | 4.8 |
| Musculoskeletal System | | |
| Myalgia | 5.1 | 5.7 |
| Joint Disorder | 3.3 | 3.6 |
| Arthritis | 2.7 | 3.2 |
| Nervous System | | |
| Headache | 5.8 | 6.5 |
| Dizziness | 2.6 | 3.7 |
| Vertigo | 2.5 | 3.0 |
| Nerve Root Lesion | 1.9 | 2.2 |
| Respiratory System | | |
| Upper Respiratory Infection | 33.2 | 33.7 |
| Bronchitis | 6.8 | 10.0 |
| Pneumonia | 4.3 | 5.9 |
| Pharyngitis | 1.5 | 2.5 |
| Urogenital System | | |
| Urinary Tract Infection | 4.2 | 5.5 |
Once-Monthly Dosing
In a 1-year, double-blind, multicenter study comparing BONIVA 2.5 mg once daily and BONIVA 150 mg once monthly in women with postmenopausal osteoporosis, the overall safety and tolerability profiles of the two oral dosing regimens were similar. The incidence of serious adverse events was 4.8% in the BONIVA 2.5 mg daily group and 7.1% in the BONIVA 150 mg once-monthly group. The percentage of patients who withdrew from treatment due to adverse events was approximately 8.9% in the BONIVA 2.5 mg daily group and 7.8% in the BONIVA 150 mg once-monthly group. Table 4 lists the adverse events reported in ≥2% of patients without attribution of causality.
Table 4 Adverse Events With an Incidence of at Least 2% in Patients Treated with BONIVA 150 mg Once Monthly or 2.5 mg Daily | Body System/Adverse Event | BONIVA
2.5 mg Daily
%
(n=395) | BONIVA
150 mg Monthly
%
(n=396) |
|---|
| Vascular Disorders | | |
| Hypertension | 7.3 | 6.3 |
| Gastrointestinal Disorders | | |
| Dyspepsia | 7.1 | 5.6 |
| Nausea | 4.8 | 5.1 |
| Diarrhea | 4.1 | 5.1 |
| Constipation | 2.5 | 4.0 |
| Abdominal PainCombination of abdominal pain and abdominal pain upper | 5.3 | 7.8 |
| Musculoskeletal and Connective Tissue Disorders | | |
| Arthralgia | 3.5 | 5.6 |
| Back Pain | 4.3 | 4.5 |
| Pain in Extremity | 1.3 | 4.0 |
| Localized Osteoarthritis | 1.3 | 3.0 |
| Myalgia | 0.8 | 2.0 |
| Muscle Cramp | 2.0 | 1.8 |
| Infections and Infestations | | |
| Influenza | 3.8 | 4.0 |
| Nasopharyngitis | 4.3 | 3.5 |
| Bronchitis | 3.5 | 2.5 |
| Urinary Tract Infection | 1.8 | 2.3 |
| Upper Respiratory Tract Infection | 2.0 | 2.0 |
| Nervous System Disorders | | |
| Headache | 4.1 | 3.3 |
| Dizziness | 1.0 | 2.3 |
| General Disorders and Administration Site Conditions | | |
| Influenza-like IllnessCombination of influenza-like illness and acute phase reaction | 0.8 | 3.3 |
| Skin and Subcutaneous Tissue Disorders | | |
| RashCombination of rash pruritic, rash macular, rash papular, rash generalized, rash erythematous, dermatitis, dermatitis allergic, dermatitis medicamentosa, erythema and exanthem | 1.3 | 2.3 |
| Psychiatric Disorders | | |
| Insomnia | 0.8 | 2.0 |
Patients with a previous history of gastrointestinal disease, including patients with peptic ulcer without recent bleeding or hospitalization and patients with dyspepsia or reflux controlled by medication, were included in the once-monthly treatment study. For these patients, there was no difference in upper gastrointestinal adverse events with the 150 mg once-monthly regimen compared to the 2.5 mg once-daily regimen.
Ocular Adverse Events
Reports in the medical literature indicate that bisphosphonates may be associated with ocular inflammation such as uveitis and scleritis. In some cases, these events did not resolve until the bisphosphonate was discontinued. There were no reports of ocular inflammation in studies with BONIVA 2.5 mg daily. Two patients who received BONIVA once monthly experienced ocular inflammation, one was a case of uveitis and the other scleritis.
Laboratory Test Findings
In the 3-year treatment study with BONIVA 2.5 mg daily, there were no clinically significant changes from baseline values or shifts in any laboratory variable for each of the treatment groups. As expected with bisphosphonate treatment, a decrease in total alkaline phosphatase levels was seen in the active treatment groups compared to placebo. There was no difference compared with placebo for laboratory abnormalities indicative of hepatic or renal dysfunction, hypocalcemia, or hypophosphatemia. Similarly, no changes were noted for the 150 mg once-monthly administration in the 1-year study.
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