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warnings and cautions
5 WARNINGS AND PRECAUTIONS Enter section text here Severe irritation of the upper gastrointestinal (GI) mucosa can occur. Dosing instructions should be followed and caution should be used in patients with active upper GI disease. Discontinue use if new or worsening symptoms occur. ( 5.1 ) Hypocalcemia may worsen during treatment. Correct hypocalcemia before use. ( 5.2 ) Severe bone, joint, and muscle pain may occur. Consider discontinuing use if symptoms develop. ( 5.3 ) Osteonecrosis of the jaw has been reported. ( 5.4 ) 5.1 Upper Gastrointestinal Adverse Reactions BONIVA, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when BONIVA is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue BONIVA and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6-8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see DOSAGE AND ADMINISTRATION [2.2] ) . In patients who cannot comply with dosing instructions due to mental disability, therapy with BONIVA should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials. 5.2 Hypocalcemia and Mineral Metabolsim Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting BONIVA therapy. Adequate intake of calcium and vitamin D is important in all patients to prevent hypocalcemia (see DOSAGE AND ADMINISTRATION [2.3] ) . Hypocalcemia following dosing has been reported postmarketing. 5.3 Musculoskeletal Pain Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking BONIVA and other bisphosphonates (see ADVERSE REACTIONS [6] ) . The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop. 5.4 Jaw Osteonecrosis Osteonecrosis, primarily in the jaw, has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Known risk factors for osteonecrosis include a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, radiotherapy, corticosteroids), and co-morbid disorders (e.g., anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally (see ADVERSE REACTIONS [6.2] ) . For patients who develop osteonecrosis of the jaw (ONJ) while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. 5.5 Severe Renal Impairment BONIVA is not recommended for use in patients with severe renal impairment (creatinine clearance of <30 mL/min).
6 ADVERSE REACTIONS Enter section text here The most common adverse reactions (>5%) are back pain, dyspepsia, pain in extremity, diarrhea, headache, and myalgia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Treatment and Prevention of Postmenopausal Osteoporosis Daily Dosing 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 IU 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 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. Table 1 lists adverse events from the treatment and prevention studies reported in ≥2% of patients and more frequently in patients treated daily with BONIVA than patients treated with placebo. Table 1 Adverse Events Occurring at a Frequency ≥2% and More Frequently in 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 Gastrointestinal Adverse Events The incidence of adverse events 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 Events The incidence of adverse events 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%). Ocular Adverse Events Reports in the medical literature indicate that bisphosphonates may be associated with ocular inflammation such as iritis 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. Monthly Dosing The safety of BONIVA 150 mg once monthly in the treatment of postmenopausal osteoporosis was assessed in a two year trial which enrolled 1583 patients aged 54 – 81 years, with 395 patients exposed to BONIVA 2.5 mg daily and 396 exposed to BONIVA 150 mg monthly. Patients with active or significant pre-existing gastrointestinal disease were excluded from this trial. Patients with dyspepsia or concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in this study. All patients received 500 mg calcium plus 400 IU vitamin D supplementation daily. After one year, the incidence of all-cause mortality was 0.3% in both the BONIVA 2.5 mg daily group and the BONIVA 150 mg monthly group. The incidence of serious adverse events was 5% in the BONIVA 2.5 mg daily group and 7% in the BONIVA 150 mg monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the BONIVA 2.5 mg daily group and 8% in the BONIVA 150 mg monthly group. Table 2 lists the adverse events reported in ≥2% of patients. Table 2 Adverse Events with an Incidence of at Least 2% in Patients Treated with BONIVA 2.5 mg Daily or 150 mg Once-Monthly for Treatment of Postmenopausal Osteoporosis 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 Pain * 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 Illness † 0.8 3.3 Skin and Subcutaneous Tissue Disorders Rash ‡ 1.3 2.3 Psychiatric Disorders Insomnia 0.8 2.0 * Combination of abdominal pain and abdominal pain upper † Combination of influenza-like illness and acute phase reaction ‡ Combination of rash pruritic, rash macular, rash papular, rash generalized, rash erythematous, dermatitis, dermatitis allergic, dermatitis medicamentosa, erythema and exanthem Gastrointestinal Adverse Events The incidence of adverse events in the BONIVA 2.5 mg daily and BONIVA 150 mg monthly groups were: dyspepsia (7% vs. 6%), diarrhea (4% vs. 5%), and abdominal pain (5% vs. 8%). Musculoskeletal Adverse Events The incidence of adverse events in the BONIVA 2.5 mg daily and BONIVA 150 mg monthly groups were: back pain (4% vs. 5%), arthralgia (4% vs. 6%) and myalgia (1% vs. 2%). Acute Phase Reactions Symptoms consistent with acute phase reactions have been reported with bisphosphonate use. Over the two years of the study, the overall incidence of acute phase reaction symptoms was 3% in the BONIVA 2.5 mg daily group and 9% in the BONIVA 150 mg monthly group. These incidence rates are based on the reporting of any of 33 acute-phase reaction like symptoms within 3 days of the monthly dosing and lasting 7 days or less. Influenza like illness was reported in no patients in the BONIVA 2.5 mg daily group and 2% in the BONIVA 150 mg monthly group. Ocular Adverse Events Two patients who received BONIVA 150 mg once-monthly experienced ocular inflammation, one was a case of uveitis and the other scleritis. One hundred sixty (160) postmenopausal women without osteoporosis participated in a 1-year, double-blind, placebo-controlled study of BONIVA 150 mg once-monthly for prevention of bone loss. Seventy-seven subjects received BONIVA and 83 subjects received placebo. The overall pattern of adverse events was similar to that previously observed. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of BONIVA. 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, angioedema, bronchospasm and rash have been reported ( see CONTRAINDICATIONS [4] ). Hypocalcemia Hypocalcemia has been reported in patients treated with BONIVA ( see WARNINGS AND PRECAUTIONS [5.2] ). Musculoskeletal Pain Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating, has been reported ( see WARNINGS AND PRECAUTIONS [5.3] ). Jaw Osteonecrosis Osteonecrosis of the jaw has been reported in patients treated with BONIVA ( see WARNINGS AND PRECAUTIONS [5.4] ).