Ibandronate Sodium (Page 2 of 7)

5.6 Musculoskeletal Pain

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking ibandronate and other bisphosphonates [see Adverse Reactions (6.2)]. 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 the bisphosphonate. A subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Discontinue ibandronate if severe symptoms develop.

5.7 Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Atypical, low-energy, or low-trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.

Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

6 ADVERSE REACTIONS

Adverse reactions that appear in other sections of the labeling include:

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Hypocalcemia and Mineral Metabolism [see Warnings and Precautions (5.1)]

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Anaphylactic Reaction [see Warnings and Precautions (5.2)]

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Renal Impairment [see Warnings and Precautions (5.3)]

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Tissue Damage Related to Inappropriate Drug Administration [see Warnings and Precautions (5.4)]

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Osteonecrosis of the Jaw [see Warnings and Precautions (5.5)]

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Musculoskeletal Pain [see Warnings and Precautions (5.6)]

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Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see Warnings and Precautions (5.7)]

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.

Quarterly Intravenous Injection –

In a 1-year, double-blind, multicenter study comparing ibandronate injection administered intravenously as 3 mg every 3 months to ibandronate 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% in the ibandronate 2.5 mg daily group and 7.5% in the ibandronate 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 ibandronate 2.5 mg daily group and 8.5% in the ibandronate 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 Ibandronate Injection (3 mg once every 3 months) or Ibandronate Daily Oral Tablet (2.5 mg)

* 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
Body System/Adverse Reaction	Ibandronate 2.5 mg Daily (Oral) % (n=465)	Ibandronate 3 mg every 3 months (Intravenous) % (n=469)
Infections and Infestations Influenza Nasopharyngitis Cystitis Gastroenteritis Urinary Tract Infection Bronchitis Upper Respiratory Tract Infection	8 6 3 3 3 3 3	5 3 2 2 3 2 1
Gastrointestinal Disorders Abdominal Pain * Dyspepsia Nausea Constipation Diarrhea Gastritis	6 4 4 4 2 2	5 4 2 3 3 2
Musculoskeletal and Connective Tissue Disorders Arthralgia Back Pain Localized Osteoarthritis Pain in Extremity Myalgia	9 8 2 2 1	10 7 2 3 3
Nervous System Disorders Dizziness Headache	3 3	2 4
PsychiatricDisorders Insomnia Depression	3 2	1 1
General Disorders and Administration Site Conditions Influenza-like Illness † Fatigue	1 1	5 3
Skin and Subcutaneous Tissue Disorders Rash ‡	3	2

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 ibandronate 2.5 mg daily oral tablet group vs. 10% in the ibandronate 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 ibandronate 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 ibandronate 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 ibandronate 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 ibandronate 2.5 mg daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the ibandronate 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 ibandronate 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 ibandronate 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 Ibandronate 2.5 mg Daily Oral Tablet than in Patients Treated with Placebo in the Osteoporosis Treatment and Prevention Studies

Body System	Placebo % (n=1134)	Ibandronate 2.5 mg daily % (n=1140)
Body as a Whole Back Pain Pain in Extremity Asthenia Allergic Reaction	12 6 2 2	14 8 4 3
Digestive System Dyspepsia Diarrhea Tooth Disorder Vomiting Gastritis	10 5 2 2 2	12 7 4 3 2
Musculoskeletal System Myalgia Joint Disorder Arthritis	5 3 3	6 4 3
Nervous System Headache Dizziness Vertigo	6 3 3	7 4 3
Respiratory System Upper Respiratory Infection Bronchitis Pneumonia Pharyngitis	33 7 4 2	34 10 6 3
Urogenital System Urinary Tract Infection	4	6

Gastrointestinal Adverse Reactions

The incidence of selected gastrointestinal adverse reactions in the placebo and ibandronate 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 ibandronate 2.5 mg daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%).