Ibandronate Sodium

Ibandronate Sodium Injection is a bisphosphonate indicated for the treatment of osteoporosis in postmenopausal women. (

Limitations of Use

Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use (

• 3 mg every 3 months administered intravenously over a period of 15 to 30 seconds (
  
  
  
  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.
  )
  
  
• Dosing Instructions:
  
  
  
  • Only administer intravenously by a health care professional. (
    
    
    
    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 prefilled syringe for particulate matter and discoloration before administration. Do not use prefilled syringes with particulate matter or discoloration.
    • Administer only with the enclosed needle.
    • Discard any unused portion.
    • Do not mix with calcium-containing solutions or other intravenously administered drugs.
    • Prefilled syringes are for single dose only.
    )
    
    
    
  • Do not mix with calcium-containing solutions or other intravenously administered drugs. (
    
    
    
    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 prefilled syringe for particulate matter and discoloration before administration. Do not use prefilled syringes with particulate matter or discoloration.
    • Administer only with the enclosed needle.
    • Discard any unused portion.
    • Do not mix with calcium-containing solutions or other intravenously administered drugs.
    • Prefilled syringes are for single dose only.
    )
    
    
    
  • Do not administer more frequently than once every 3 months. (
    
    
    
    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.
    )
    
    
    
• Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate

Ibandronate Sodium Injection is supplied as a kit containing:

• a 3 mg/3 mL single-dose prefilled syringe.
• a 25-gauge, 3/4 inch needle with wings, needle-stick protection device, and a 9 cm plastic tubing for attachment

In reproductive toxicity studies in the rat, Ibandronate Sodium caused obstruction of labor, with maternal periparturient mortality, pup loss and reduced pup weight at greater than or equal to 2 times human exposure at the recommended human intravenous dose of 3 mg. Abnormal pup odontogeny was observed at greater than or equal to 18 times human exposure. In rats dosed during pregnancy, kidney developmental toxicity occurred in offspring at greater than or equal to 47 times human exposure. Also, fetal weight and pup growth were reduced at greater than or equal to 5 times human exposure. In reproductive studies in the rabbit, Ibandronate Sodium caused maternal mortality, reduced maternal body weight gain, decreased litter size due to increased resorption rate, and decreased fetal weight at 19 times the recommended human dose

In pregnant rats given intravenous doses producing greater than or equal to 2 times human exposure from Day 17 post-coitum until Day 20 post-partum, ibandronate treatment resulted in dystocia, maternal mortality, and early postnatal pup loss in all dose groups. Reduced body weight at birth was observed at greater than or equal to 4 times the human exposure. Pups exhibited abnormal odontogeny that decreased food consumption and body weight gain at greater than or equal to 18 times human exposure. Periparturient mortality has also been observed with other bisphosphonates and appears to be a class effect related to inhibition of skeletal calcium mobilization resulting in hypocalcemia and dystocia.

Exposure of pregnant rats during the period of organogenesis resulted in an increased fetal incidence of RPU (renal pelvis ureter) syndrome at an intravenous dose producing greater than or equal to 47 times human exposure. In this spontaneous delivery study, dystocia was counteracted by perinatal calcium supplementation. In rat studies with intravenous dosing during gestation, fetal weight and pup growth were reduced at doses producing greater than or equal to 5 times human exposure.

In pregnant rabbits given intravenous doses during the period of organogenesis, maternal mortality, reduced maternal body weight gain, decreased litter size due to increased resorption rate, and decreased fetal weight were observed at 19 times the recommended human intravenous dose.

Exposure multiples for the rat studies were calculated using human exposure at the recommended intravenous dose of 3 mg every 3 months and were based on cumulative area under the curve (AUC) comparison. Exposure multiples for the rabbit study were calculated for the recommended human intravenous dose of 3 mg every 3 months and were based on cumulative dose/[body surface area] comparison. Doses in pregnant animals were 0.05, 0.1, 0.15, 0.3, 0.5 or 1 mg/kg/day in rats, and 0.03, 0.07, or 0.2 mg/kg/day in rabbits.

• Hypocalcemia
  can worsen. Correct hypocalcemia prior to use.
  
  
  
  
  Adequately supplement patients with calcium and vitamin D (
  
  
  
  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.
  )
  
  
• Anaphylaxis
  , including fatal events, has been reported. (
  
  
  
  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.
  )
  
  
• Renal Toxicity
  may be greater in patients with underlying renal impairment. Do not administer Ibandronate Sodium Injection to patients with severe renal impairment (creatinine clearance less than 30 mL/min). Monitor serum creatinine prior to each dose. (
  
  
  
  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.
  )
  
  
• Tissue Damage with Inappropriate Drug Administration
  can occur. Do not administer Ibandronate Sodium Injection intra-arterially or paravenously. (
  
  
  
  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.
  )
  
  
• Osteonecrosis of the jaw (ONJ)
  has been reported. (
  
  
  
  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)

  ].
  )
  
  
• Severe Bone, Joint, and/or Muscle Pain
  may occur, consider discontinuing use if symptoms occur. (
  
  
  
  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.
  )
  
  
• Atypical Femur Fractures
  have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture. (
  
  
  
  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.
  )