IBANDRONATE SODIUM (Page 2 of 8)

5.4 Tissue Damage Related to Inappropriate Drug Administration

Ibandronate Sodium Injection must only be administered intravenously. Care must be taken not to administer ibandronate sodium injection intra-arterially or paravenously as this could lead to tissue damage.

Do not administer ibandronate sodium injection by any other route of administration. The safety and efficacy of ibandronate sodium injection following non-intravenous routes of administration have not been established.

5.5 Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates, including ibandronate sodium injection. Most cases have been in cancer patients treated with intravenous bisphosphonates undergoing dental procedures. Some cases have occurred in patients with postmenopausal osteoporosis treated with either oral or intravenous bisphosphonates. A routine oral examination should be performed by the prescriber prior to initiation of bisphosphonate treatment. Consider a dental examination with appropriate preventive dentistry prior to treatment with bisphosphonates in patients with a history of concomitant risk factors (e.g., cancer, chemotherapy, angiogenesis inhibitors, radiotherapy, corticosteroids, poor oral hygiene, pre-existing dental disease or infection, anemia, coagulopathy). Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. The risk of ONJ may increase with duration of exposure to bisphosphonates.

While on treatment, patients with concomitant risk factors should avoid invasive dental procedures if possible. For patients who develop 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. The clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment [ see Adverse Reactions (6.1) ].

5.6 Musculoskeletal Pain

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking ibandronate sodium 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 sodium 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:

• Hypocalcemia and Mineral Metabolism [ see Warnings and Precautions (5.1) ]
• Anaphylactic Reaction [ see Warnings and Precautions (5.2) ]
• Renal Impairment [ see Warnings and Precautions (5.3) ]
• Tissue Damage Related to Inappropriate Drug Administration [ see Warnings and Precautions (5.4) ]
• Osteonecrosis of the Jaw [ see Warnings and Precautions (5.5) ]
• Musculoskeletal Pain [ see Warnings and Precautions (5.6) ]
• 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 sodium injection administered intravenously as 3 mg (ibandronate) every 3 months to ibandronate sodium 2.5 mg (ibandronate) 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 ibandronate sodium 2.5 mg (ibandronate) daily group and 7.5% in the ibandronate sodium injection 3 mg (ibandronate) once every 3 months group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 6.7% in the ibandronate sodium 2.5 mg (ibandronate) daily group and 8.5% in the ibandronate sodium injection 3 mg (ibandronate) 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 Sodium Injection (3 mg ibandronate once every 3 months) or Ibandronate Sodium Daily Oral Tablet (2.5 mg ibandronate)

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