FDA Label for Ibandronate Sodium

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 increases bone mineral density (BMD) and reduces the incidence of vertebral fractures [seeClinical Studies(14)] .

1.2 Important Limitations Of Use

The safety and effectiveness of ibandronate sodium 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.

2.1 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 use only.

2.2 Dosage Information

The recommended dose of ibandronate sodium injection for the treatment of postmenopausal osteoporosis is 3 mg (ibandronate) 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 [seeWarnings 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 [seeWarnings 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) [seeWarnings and Precautions (5.3)andClinical 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) [seeClinical Pharmacology (12.3)] .

3 Dosage Forms And Strengths

Ibandronate Sodium Injection is supplied as a kit containing:

• a 3 mg/3 mL single-use prefilled syringe. Each syringe delivers 3.0 mL solution containing 3.375 mg ibandronate sodium monohydrate, equivalent to 3 mg ibandronate free acid; sodium chloride, 25.800 mg; glacial acetic acid, 1.530 mg; sodium acetate, 0.612 mg and water for injection, quantity sufficient to 3 mL.
• a 25-gauge, 3/4 inch needle with wings, needle-stick protection device, and a 30.48 cm plastic tubing for attachment

4 Contraindications

Ibandronate Sodium 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. [seeWarnings and Precautions (5.2) , Adverse Reactions (6.2) ]

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 [ seeAdverse 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 [ seeAdverse 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ibandronate sodium injection. 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 with fatalities, angioedema, asthma exacerbation, bronchospasm, rash, Stevens-Johnson syndrome, erythema multiforme, and dermatitis bullous [seeContraindications (4),Warnings and Precautions (5.2)] .

Hypocalcemia : Hypocalcemia [seeWarnings and Precautions (5.1)].

Renal Toxicity : Acute renal failure [seeWarnings and Precautions (5.3)].

Osteonecrosis of the Jaw : Osteonecrosis of the jaw and other oro-facial sites, including the external auditory canal [seeWarnings and Precautions (5.5)] .

Musculoskeletal Pain : Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating [seeWarnings and Precautions (5.6)] .

Atypical Femoral Shaft Fracture : Atypical, low-energy, or low-trauma fractures of the femoral shaft [seeWarnings and Precautions (5.7) ].

Eye Inflammation : Iritis and uveitis. In some cases with other bisphosphonates, these events did not resolve until the bisphosphonate was discontinued.

7.1 Melphalan/Prednisolone

Intravenous ibandronate (6 mg) did not interact with intravenous melphalan (10 mg/m ² ) or oral prednisolone (60 mg/m ² ). [SeeClinical Pharmacology (12.3)]

7.2 Tamoxifen

There was no interaction between oral 30 mg tamoxifen and intravenous 2 mg ibandronate.

[SeeClinical Pharmacology (12.3)]

7.3 Bone Imaging Agents

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ibandronate sodium have not been performed.

8.2 Lactation

Risk Summary

Ibandronate Sodium is not indicated for use in women of reproductive potential. There is no information on the presence of ibandronate in human milk, the effects of ibandronate on the breastfed infant, or the effects of ibandronate on milk production. Ibandronate is present in rat milk ( see Data ). The clinical relevance of this data is unclear.

Data

Animal Data

In lactating rats treated with intravenous doses of 0.08 mg/kg, ibandronate was present in breast milk at concentrations of 8.1 to 0.4 ng/mL from 2 to 24 hours after dose administration. Concentrations in milk averaged 1.5 times plasma concentrations.

8.4 Pediatric Use

Safety and effectiveness of ibandronate sodium in pediatric patients have not been established.

8.5 Geriatric Use

Of the patients receiving ibandronate sodium injection 3 mg (ibandronate) every 3 months for 1 year, 51% were over 65 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity in some older individuals cannot be ruled out.

8.6 Renal Impairment

Ibandronate Sodium Injection should not be administered to patients with severe renal impairment (creatinine clearance less than 30 mL/min) [seeWarnings and Precautions (5.3)] .

10 Overdosage

No cases of overdose were reported in premarketing studies with ibandronate sodium injection. Overdosage with intravenous bisphosphonates may result in hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.

Dialysis would not be beneficial unless it is administered within 2 hours following the overdose.

11 Description

Ibandronate Sodium is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. The chemical name for ibandronate sodium is 3-( N -methyl- N -pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate with the molecular formula C ₉ H ₂₂ NO ₇ P ₂ Na•H ₂ O and a molecular weight of 359.24. Ibandronate sodium is a white- to off-white powder. It is freely soluble in water and practically insoluble in organic solvents. Ibandronate sodium has the following structural formula:

c988dc8-e4af-400a-b47d-debbe71e9ba2 - fig 01

Ibandronate Sodium Injection is intended for intravenous administration only. Ibandronate Sodium Injection is available as a sterile, clear, colorless, ready-to-use solution in a prefilled syringe that delivers 3.375 mg of ibandronate monosodium salt monohydrate in 3 mL of solution, equivalent to a dose of 3 mg ibandronate free acid. Inactive ingredients include sodium chloride, glacial acetic acid, sodium acetate and water.

12.1 Mechanism Of Action

The action of ibandronate on bone is based on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Ibandronate inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

12.2 Pharmacodynamics

In studies of postmenopausal women, ibandronate sodium injection at doses of 0.5 mg to 3 mg produced biochemical changes indicative of inhibition of bone resorption, including decreases of biochemical markers of bone collagen degradation (cross-linked C-telopeptide of Type I collagen [CTX]). Changes in markers of bone formation (osteocalcin) were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation.

Year 1 results from an efficacy and safety study comparing ibandronate sodium injection 3 mg (ibandronate) every 3 months and ibandronate sodium 2.5 mg (ibandronate) daily oral tablet demonstrated that both dosing regimens significantly suppressed serum CTX levels at Months 3, 6, and 12. The median pre-dose or trough serum CTX levels in the intent-to-treat population reached a nadir of 57% (ibandronate sodium injection) and 62% (ibandronate sodium 2.5 mg (ibandronate) tablets) below baseline values by Month 6, and remained stable at Month 12 of treatment.

13.2 Animal Pharmacology

Animal studies have shown that ibandronate is an inhibitor of osteoclast-mediated bone resorption. In the Schenk assay in growing rats, ibandronate inhibited bone resorption and increased bone volume, based on histologic examination of the tibial metaphyses. There was no evidence of impaired mineralization at the highest dose of 5 mg/kg/day (subcutaneously), which is 1000 times the lowest antiresorptive dose of 0.005 mg/kg/day in this model, and 5000 times the optimal antiresorptive dose of 0.001 mg/kg/day in the aged ovariectomized rat. This indicates that ibandronate sodium injection administered at a therapeutic dose is unlikely to induce osteomalacia.

Long-term daily or intermittent administration of ibandronate to ovariectomized rats or monkeys was associated with suppression of bone turnover and increases in bone mass. Vertebral BMD, trabecular density, and biomechanical strength were increased dose-dependently in rats and monkeys, at doses up to 8 to 4 times the human intravenous dose of 3 mg ibandronate every 3 months, based on cumulative dose normalized for body surface area (mg/m ² ) and AUC comparison, respectively. Ibandronate maintained the positive correlation between bone mass and strength at the ulna and femoral neck. New bone formed in the presence of ibandronate had normal histologic structure and did not show mineralization defects.

16.1 How Supplied

Ibandronate Sodium Injection is supplied as a kit containing a 3 mg (ibandronate)/3 mL single-use, clear glass, 5 mL (5 cc) prefilled syringe, a 25-gauge, 3/4 inch needle with wings, needle-stick protection device, and a 30.48 cm plastic tubing for attachment (NDC 51224-008-01). Each syringe delivers 3 mL solution containing 3.375 mg ibandronate sodium monohydrate, equivalent to 3 mg ibandronate free acid; sodium chloride, 25.8 mg; glacial acetic acid, 1.53 mg; sodium acetate, 0.612 mg and water for injection, quantity sufficient to 3 mL.

The tip cap of the prefilled syringe may contain natural rubber.

16.2 Storage And Handling

Store at 25°C (77°F); excursions permitted between 15 and 30°C (59 and 86°F) [see USP Controlled Room Temperature].

17 Patient Counseling Information

"See FDA-approved patient labeling (Medication Guide) "

Inform patients that ibandronate sodium injection must be administered intravenously by a health care professional.

Patients should be instructed to read the Medication Guide carefully before ibandronate sodium is administered and to re-read it each time the prescription is renewed because it contains important information the patient should know about ibandronate sodium.

Inform patients that ibandronate sodium injection is administered once every 3 months. If the dose is missed, the injection should be administered as soon as it can be rescheduled. Thereafter, injections should be scheduled every 3 months from the date of the last injection. Do not administer ibandronate sodium injection more frequently than once every 3 months.

Inform patients that they should take supplemental calcium and vitamin D if their dietary intake is inadequate [seeWarnings and Precautions (5.1) ] .

Inform patients ibandronate sodium injection should not be administered to patients with creatinine clearance less than 30 mL/min. A serum creatinine should be measured prior to each dose [seeWarnings and Precautions (5.3) ] .

Inform patients that the most common side effects of ibandronate sodium include arthralgia, back pain, hypertension, and abdominal pain. Flu-like symptoms (acute phase reaction) may occur within 3 days following infusion, and usually subside within 24-48 hours without specific therapy.

Inform patients that there have been reports of persistent pain and/or a non-healing sore of the mouth or jaw, primarily in patients treated with bisphosphonates for other illnesses. If they experience these symptoms, they should inform their physician or dentist.

Inform patients that severe bone, joint, and/or muscle pain have been reported in patients taking bisphosphonates, including ibandronate sodium. Patients should report severe symptoms if they develop.

Inform patients that atypical femur fractures in patients on bisphosphonate therapy have been reported. Patients should report new thigh or groin pain and undergo evaluation to rule out a femoral fracture.