Adverse reactions that appear in other sections of the labeling include:
- Hypocalcemia and Mineral Metabolism [see WARNINGS AND PRECAUTIONS]
- Anaphylactic Reaction [see WARNINGS AND PRECAUTIONS]
- Renal Impairment [see WARNINGS AND PRECAUTIONS]
- Tissue Damage Related to Inappropriate Drug Administration [see WARNINGS AND PRECAUTIONS]
- Osteonecrosis of the Jaw [see WARNINGS AND PRECAUTIONS]
- Musculoskeletal Pain [see WARNINGS AND PRECAUTIONS]
- Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
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.
Quarterly Intravenous Injection
In a 1-year, double-blind, multicenter study comparing BONIVA Injection administered intravenously as 3 mg every 3 months to BONIVA 2.5 mg daily oral tablet in women with postmenopausal osteoporosis, the overall safety and tolerability profiles of the two dosing regimens were similar. The incidence of serious adverse reactions was 8.0% in the BONIVA 2.5 mg daily group and 7.5% in the BONIVA Injection 3 mg once every 3 months group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 6.7% in the BONIVA 2.5 mg daily group and 8.5% in the BONIVA Injection 3 mg every 3 months group. Table 1 lists the adverse reactions reported in greater than 2% of patients.
Table 1 : Adverse Reactions With an Incidence of at Least 2% in Patients Treated with BONIVA Injection (3 mg once every 3 months) or BONIVA Daily Oral Tablet (2.5 mg)
|Body System/Adverse Reaction||BONIVA 2.5 mg Daily (Oral) %
|BONIVA 3 mg every 3 months (Intravenous) %
|Infections and Infestations|
|Urinary Tract Infection||3||3|
|Upper Respiratory Tract Infection||3||1|
|Musculoskeletal and Connective Tissue Disorders|
|Pain in Extremity||2||3|
|Nervous System Disorders|
|General Disorders and Administration Site Conditions|
|Skin and Subcutaneous Tissue Disorders|
|* Combination of abdominal pain and abdominal pain upper
† Combination of influenza-like illness and acute phase reaction
‡ Combination of rash, rash pruritic, rash macular, dermatitis, dermatitis allergic, exanthema, erythema, rash papular, rash generalized, dermatitis medicamentosa, rash erythematous
Acute Phase Reaction-like Events
Symptoms consistent with acute phase reaction (APR) have been reported with intravenous bisphosphonate use. The overall incidence of patients with APR-like events was higher in the intravenous treatment group (4% in the BONIVA 2.5 mg daily oral tablet group vs. 10% in the BONIVA Injection 3 mg once every 3 months group). These incidence rates are based upon reporting of any of 33 potential APR-like symptoms within 3 days of an intravenous dose and lasting 7 days or less. In most cases, no specific treatment was required and the symptoms subsided within 24 to 48 hours.
Injection Site Reactions
Local reactions at the injection site, such as redness or swelling, were observed at a higher incidence in patients treated with BONIVA Injection 3 mg every 3 months (1.7%; 8/469) than in patients treated with placebo injections (0.2%; 1/465). In most cases, the reaction was of mild to moderate severity.
Daily Oral Tablet
The safety of BONIVA 2.5 mg once daily in the treatment and prevention of postmenopausal osteoporosis was assessed in 3577 patients aged 41 – 82 years. The duration of the trials was 2 to 3 years, with 1134 patients exposed to placebo and 1140 exposed to BONIVA 2.5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in these clinical trials. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily.
The incidence of all-cause mortality was 1% in the placebo group and 1.2% in the BONIVA 2.5 mg daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the BONIVA 2.5 mg daily oral tablet group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the placebo group and the BONIVA 2.5 mg daily oral tablet group. Table 2 lists adverse reactions from the Treatment and Prevention Studies reported in greater than or equal to 2% of patients and in more patients treated with BONIVA 2.5 mg daily oral tablet than patients treated with placebo.
Table 2 : Adverse Reactions Occurring at an Incidence greater than or equal to 2% and in More Patients Treated with BONIVA 2.5 mg Daily Oral Tablet than in Patients Treated with Placebo in the Osteoporosis Treatment and Prevention Studies
|Body System||Placebo %
|BONIVA 2.5 mg daily %
|Body as a Whole|
|Pain in Extremity||6||8|
|Urinary Tract Infection||4||6|
Gastrointestinal Adverse Reactions
The incidence of selected gastrointestinal adverse reactions in the placebo and BONIVA 2.5 mg daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%).
Musculoskeletal Adverse Reactions
The incidence of selected musculoskeletal adverse reactions in the placebo and BONIVA 2.5 mg daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%).
The following adverse reactions have been identified during post-approval use of BONIVA Injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity: Allergic reactions including anaphylaxis with fatalities, angioedema, asthma exacerbation, bronchospasm, and rash [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Hypocalcemia: Hypocalcemia [see WARNINGS AND PRECAUTIONS].
Renal Toxicity: Acute renal failure [see WARNINGS AND PRECAUTIONS].
Osteonecrosis of the Jaw: Osteonecrosis of the jaw [see WARNINGS AND PRECAUTIONS].
Musculoskeletal Pain: Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating [see WARNINGS AND PRECAUTIONS].
Atypical Femoral Shaft Fracture: Atypical, low-energy, or low-trauma fractures of the femoral shaft [see WARNINGS AND PRECAUTIONS].
Eye Inflammation: Iritis and uveitis. In some cases with other bisphosphonates, these events did not resolve until the bisphosphonate was discontinued.