IBANDRONATE SODIUM: Package Insert and Label Information

IBANDRONATE SODIUM — ibandronate sodium injection, solution
Sun Pharmaceutical Industries, Inc.

1 INDICATIONS AND USAGE

1.1 Treatment of Postmenopausal Osteoporosis

Ibandronate sodium injection is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, ibandronate sodium injection increases bone mineral density (BMD) and reduces the incidence of vertebral fractures [see Clinical Studies (14)].

1.2 Important Limitations of Use


The safety and effectiveness of ibandronate sodium injection for the treatment of osteoporosis are based on clinical data of one year duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions


Ibandronate sodium injection must be administered intravenously only by a health care professional. Care must be taken not to administer intra-arterially or paravenously as this could lead to tissue damage [see Warnings and Precautions (5.4)].

  • Appropriate medical support and monitoring measures should be readily available when ibandronate sodium injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment [see Warnings and Precautions (5.2)].
  • Visually inspect the liquid in the vial for particulate matter and discoloration before administration. Do not use vials with particulate matter or discoloration.
  • Discard any unused portion.
  • Do not mix with calcium-containing solutions or other intravenously administered drugs.
  • Vials are for single use only.

2.2 Dosage Information


The recommended dose of ibandronate sodium injection for the treatment of postmenopausal osteoporosis is 3 mg every 3 months administered intravenously over a period of 15 to 30 seconds. Do not administer more frequently than once every 3 months.

2.3 Laboratory Testing and Oral Examination Prior to Administration


Prior to administration of each dose obtain a serum creatinine [see Warnings and Precautions (5.3)]. Given that bisphosphonates have been associated with osteonecrosis of the jaw (ONJ), perform a routine oral examination prior to administration of ibandronate sodium injection.

2.4 Calcium and Vitamin D Supplementation


Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. [see Warnings and Precautions (5.1)].

2.5 Dosing After Missed Dose


If the dose is missed, administer as soon as it can be re-scheduled. Thereafter, ibandronate sodium injection should be scheduled every 3 months from the date of the last injection.

2.6 Dosage Modifications in Patients with Renal Impairment


Do not administer to patients with severe renal impairment (creatinine clearance less than 30 mL/minute) [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. No dose adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min) [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Ibandronate sodium injection is supplied in a 3 mg/3 mL single-dose vial.

4 CONTRAINDICATIONS


Ibandronate sodium injection is contraindicated in patients with the following conditions:

  • Hypocalcemia [see Warnings and Precautions (5.1)]
  • Known hypersensitivity to ibandronate sodium injection or to any of its excipients. Cases of anaphylaxis, including fatal events, have been reported. [see Warnings and Precautions (5.2), Adverse Reactions (6.2)]

5 WARNINGS AND PRECAUTIONS

5.1 Hypocalcemia and Mineral Metabolism


Ibandronate sodium injection may cause a decrease in serum calcium values. Treat hypocalcemia, hypovitaminosis D, and other disturbances of bone and mineral metabolism before starting ibandronate sodium injection therapy.Adequate intake of calcium and vitamin D is important in all patients. It is recommended that patients receive supplemental calcium and vitamin D if dietary intake is inadequate.

5.2 Anaphylactic Reaction

Cases of anaphylaxis, including fatal events, have been reported in patients treated with ibandronate sodium injection.Appropriate medical support and monitoring measures should be readily available when ibandronate sodium injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment.

5.3 Renal Impairment

Treatment with intravenous bisphosphonates has been associated with renal toxicity manifested as deterioration in renal function and acute renal failure. Although no cases of acute renal failure were observed in controlled clinical trials in which intravenous ibandronate sodium was administered as a 15- to 30-second bolus, acute renal failure has been reported postmarketing. Do not administer ibandronate sodium injection to patients with severe renal impairment (creatinine clearance less than 30 mL/min).Obtain serum creatinine prior to each ibandronate sodium injection. After ibandronate sodium injection, assess renal function, as clinically appropriate, in patients with concomitant diseases or taking medications that have the potential for adverse effects on the kidney. Ibandronate sodium injection should be withheld in patients with renal deterioration.

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 injection 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 injection 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 every 3 months to ibandronate sodium tablets 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% in the ibandronate sodium tablets 2.5 mg (ibandronate) daily group and 7.5% in the ibandronate sodium 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 sodium tablets 2.5 mg (ibandronate) daily group and 8.5% in the ibandronate sodium 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 Sodium Injection (3 mg once every 3 months) or Ibandronate Sodium Tablets 2.5 mg (ibandronate) Daily Oral Tablet
Body System/Adverse Reaction Ibandronate Sodium Tablets 2.5 mg (ibandronate) Daily (Oral) % (n=465) Ibandronate Sodium Injection3 mg 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

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 sodium tablets 2.5 mg (ibandronate) daily oral tablet group vs. 10% in the ibandronate sodium 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 sodium 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 sodium tablets 2.5 mg (ibandronate) once daily in the treatment and prevention of postmenopausal osteoporosis was assessed in 3,577 patients aged 41 to 82 years. The duration of the trials was 2 to 3 years, with 1,134 patients exposed to placebo and 1,140 exposed to ibandronate sodium tablets 2.5 mg (ibandronate). Patients with preexisting 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 sodium tablets 2.5 mg (ibandronate) daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the ibandronate sodium tablets 2.5 mg (ibandronate) 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 sodium tablets 2.5 mg (ibandronate) 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 sodium tablets 2.5 mg (ibandronate) 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 Sodium Tablets 2.5 mg (ibandronate) Daily Oral Tablet than in Patients Treated with Placebo in the Osteoporosis Treatment and Prevention Studies
Body System Placebo % (n=1,134) Ibandronate Sodium Tablets 2.5 mg (ibandronate) daily % (n=1,140)
Body as a Whole
Back Pain 12 14
Pain in Extremity 6 8
Asthenia 2 4
Allergic Reaction 2 3
Digestive System
Dyspepsia 10 12
Diarrhea 5 7
Tooth Disorder 2 4
Vomiting 2 3
Gastritis 2 2
Musculoskeletal System
Myalgia 5 6
Joint Disorder 3 4
Arthritis 3 3
Nervous System
Headache 6 7
Dizziness 3 4
Vertigo 3 3
Respiratory System
Upper Respiratory Infection 33 34
Bronchitis 7 10
Pneumonia 4 6
Pharyngitis 2 3
Urogenital System
Urinary Tract Infection 4 6

Gastrointestinal Adverse Reactions

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

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