Ibandronate sodium injection is a bisphosphonate indicated for the treatment of osteoporosis in postmenopausal women. (1.1) 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 (1.2)
1.1Treatment 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) ] .
1.2Important 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.
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) ] Hypocalcemia (4) Hypersensitivity to ibandronate sodium injection (4)
Warnings and precautions
Hypocalcemia can worsen. Correct hypocalcemia prior to use. Adequately supplement patients with calcium and vitamin D (5.1) Anaphylaxis , including fatal events, has been reported. (5.2) 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) Tissue Damage with Inappropriate Drug Administration can occur. Do not administer ibandronate sodium injection intra-arterially or paravenously. (5.4) Osteonecrosis of the jaw (ONJ) has been reported. (5.5) Severe Bone, Joint, and/or Muscle Pain may occur, consider discontinuing use if symptoms occur. (5.6) Atypical Fractures Including Femoral Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture.
Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered. (5.7)
5.1Hypocalcemia 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.
5.2Anaphylactic 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.
5.3Renal 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 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.
5.4Tissue 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) ].
5.6Musculoskeletal 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.
5.7Atypical Fractures Including Femoral Fractures
Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported during treatment with bisphosphonates, including ibandronate sodium in patients with osteoporosis. Atypical femur and other fractures most commonly occur with minimal or no trauma to the affected area. These fractures occurred anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are traverse or short oblique in orientation without evidence of comminution.
Atypical fractures of other bones have also been reported. They may be bilateral. These fractures can also occur in osteoporotic patients who have not been treated with bisphosphonates. Concomitant treatment with glucocorticoids may also induce these fractures. Prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs was reported by patients.
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. Bony pain in other locations should also be considered for evaluation of atypical fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb.
Risk/benefit of continuing bisphosphonate therapy should be re-evaluated in these patients and interruption of bisphosphonate therapy should be considered.
Interactions
7.1Melphalan/Prednisolone
Intravenous ibandronate (6 mg) did not interact with intravenous melphalan (10 mg/m 2 ) or oral prednisolone (60 mg/m 2 ). [ See Clinical Pharmacology (12.3) ]
7.2Tamoxifen
There was no interaction between oral 30 mg tamoxifen and intravenous 2 mg ibandronate. [ see Clinical Pharmacology (12.3) ]
7.3Bone Imaging Agents
Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ibandronate have not been performed.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Ibandronate is not indicated for use in women of reproductive potential. There are no data with ibandronate use in pregnant women to inform any drug-associated risks. In reproductive toxicity studies in the rat, ibandronate 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 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 ( see Data ).
Data Animal Data 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.
Adverse reactions
The following clinically significant adverse drug reactions are described elsewhere in the labeling: 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 Fractures Including Femoral Fractures [see Warnings and Precautions (5.7)] The most frequently reported adverse reactions (>5%) are arthralgia, back pain, and abdominal pain.
(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 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 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 2.5 mg 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 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 Sodium Injection 3 mg every 3 months (Intravenous) % (n = 469) 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 2.5 mg 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 2.5 mg once daily in the treatment and prevention of postmenopausal osteoporosis was assessed in 3577 patients aged 41 to 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 H 2 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 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 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%).
6.2Postmarketing Experience
The following adverse reactions have been identified during post-approval use of ibandronate sodium injection or bisphosphonate products. 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 [ see Contraindications (4) , Warnings and Precautions (5.2) ] .
Hypocalcemia : Hypocalcemia [ see Warnings and Precautions (5.1) ]. Renal Toxicity : Acute renal failure [ see Warnings and Precautions (5.3) ]. Osteonecrosis of the Jaw : Osteonecrosis of the jaw and other oro-facial sites, including the external auditory canal [ see Warnings and Precautions (5.5) ]. Musculoskeletal : Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions (5.6)] ; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions (5.7)] .
Eye Inflammation : Iritis and uveitis. In some cases with other bisphosphonates, the
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Composition
Active ingredients
IBANDRONATE SODIUM EQ 3MG BASE/3ML
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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