Ibandronate Sodium Injection

Included as part of the PRECAUTIONS section.

Boniva®
(bon-EE-va)
(ibandronate) Injection for Intravenous Use

Read the Medication Guide that comes with BONIVA before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment. Talk to your doctor if you have any questions about BONIVA.

What is the most important information I should know about BONIVA?

BONIVA Injection is given in your vein (intravenously) and only given by a healthcare provider. Do not give BONIVA Injection to yourself.

BONIVA may cause serious side effects including:

1. Low calcium levels in your blood (hypocalcemia)
2. Severe allergic reaction (anaphylactic reaction)
3. Severe kidney problems
4. Severe jaw bone problems (osteonecrosis)
5. Bone, joint or muscle pain
6. Unusual thigh bone fractures

1. Low calcium levels in your blood (hypocalcemia).

BONIVA may lower the calcium levels in your blood. If you have low blood calcium before you start taking BONIVA, it may get worse during treatment. Your low blood calcium must be treated before you receive BONIVA. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:

• Spasms, twitches, or cramps in your muscles
• Numbness or tingling in your fingers, toes, or around your mouth

Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you receive BONIVA. Take calcium and vitamin D as your doctor tells you to.

2. Severe allergic reactions.

Some people who received BONIVA Injection had severe allergic reactions (anaphylactic reactions) that led to death. Get medical help right away if you have any of the symptoms of a serious allergic reaction such as:

• Swelling of your face, lips, mouth or tongue
• Trouble breathing
• Wheezing
• Severe itching
• Skin rash, redness or swelling
• Dizziness or fainting
• Fast heartbeat or pounding in your chest
• Sweating

3. Severe kidney problems.

Severe kidney problems, including kidney failure, may happen when you receive BONIVA. Your doctor should do blood tests to check your kidneys before you receive each dose of BONIVA.

4. Severe jaw bone problems (osteonecrosis).

Severe jaw bone problems may happen when you receive BONIVA. Your doctor may examine your mouth before you start BONIVA. Your doctor may tell you to see your dentist before you start BONIVA. It is important for you to practice good mouth care during treatment with BONIVA.

5. Bone, joint, or muscle pain.

Some people who receive BONIVA develop severe bone, joint, or muscle pain.

6. Unusual thigh bone fractures.

Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh.

Call your doctor right away if you have any of these side effects.

What is BONIVA?

BONIVA is a prescription medicine used to treat osteoporosis in women after menopause. BONIVA helps increase bone mass and helps reduce the chance of having a spinal fracture (break).

It is not known how long BONIVA works for the treatment of osteoporosis. You should see your doctor regularly to determine if BONIVA is still right for you.

It is not known if BONIVA is safe and effective in children.

Who should not receive BONIVA?

Do not receive BONIVA if you:

• Have low levels of calcium in your blood
• Are allergic to ibandronate sodium or any of the ingredients in BONIVA. See the end of this leaflet for a complete list of ingredients in BONIVA.

What should I tell my healthcare provider before receiving BONIVA?

Before you receive BONIVA, tell your doctor if you:

• Have low blood calcium
• Plan to have dental surgery or teeth removed
• Have kidney problems or other problems that may affect your kidneys
• Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome)
• Are pregnant or plan to become pregnant. It is not known if BONIVA can harm your unborn baby.
• Are breast-feeding or plan to breast-feed. It is not known if BONIVA passes into your milk and may harm your baby.

Tell your doctor and dentist about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.

How should I receive BONIVA?

• BONIVA Injection is given 1 time every 3 months by a healthcare provider.
• If you miss a dose of BONIVA, call your doctor or healthcare provider to schedule your next dose.

What are the possible side effects of BONIVA?

BONIVA may cause serious side effects.

• See “What is the most important information I should know about BONIVA?”

The most common side effects of BONIVA include:

• Pain in your bones, joints or muscles
• Back pain
• Abdominal pain
• Flu-like symptoms may happen within 3 days after you receive BONIVA. Symptoms include:
  • fever
  • chills
  • bone, joint, or muscle pain
  • fatigue

If you have flu-like symptoms, they should get better within 24 to 48 hours.

Some people have pain or a sore that will not heal in their mouth or jaw while they receive BONIVA. Tell your doctor or dentist if you have mouth or jaw problems.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of BONIVA. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1800-FDA-1088.

How should I store BONIVA if I need to pick it up from a pharmacy?

• Store BONIVA Injection at room temperature between 68°F and 77°F (20°C and 25°C).

Keep BONIVA Injection and all medicines out of the reach of children.

General information about the safe and effective use of BONIVA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BONIVA for a condition for which it was not prescribed. Do not give BONIVA to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about BONIVA. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about BONIVA that is written for health professionals.

What are the ingredients in BONIVA?

Active ingredient: ibandronate sodium

Inactive ingredients: sodium chloride, glacial acetic acid, sodium acetate and water

TERUMO® Surshield™
Safety Winged Infusion Set

Instructions for Use: IV Administration

Aseptic technique, proper skin preparation and continued protection of the site are essential. Observe Universal Precautions on all patients.

Caution: Keep hands behind the needle at all times during use and disposal.

Instructions for Device Assembly

1. Open the package.
2. Remove the rubber cap from the tip of the syringe containing the BONIVA Injection and the protective SV cap from hub at the end of the tubing opposite the butterfly needle.
3. Insert the tip of the syringe into the hub and twist as firm pressure is applied to assure a tight connection.
4. Proceed with priming and confirm that administration fluid comes from the needle.

Venipuncture and Administration

1. Flip the safety shield back away from the needle towards the tubing. Grasp wings securely.
2. Remove the needle protector. Caution: Care should be taken not to touch the needle.
3. Perform venipuncture and confirm proper positioning of the needle in the vein.
4. Carefully allow wings to return to starting position and conform to the shape of the skin.
5. Further secure the position of the winged infusion set per facility protocol.

After Use

1. Remove tape, if present, from wings.
2. Flip the safety shield forward toward the needle. Grasp a wing and the safety shield between your thumb and index finger. Completely remove the needle from the puncture site and apply digital pressure to the site using a sterile gauze pad held in the opposite hand (Fig. 1).
3. With the wing and shield between your thumb and index finger pinch together (or press the safety shield against a hard surface such as a bedside table) until an audible click is heard (Fig. 2).
4. Visually confirm activation of the safety feature (Fig. 3).
5. Dispose of used needles and materials following the policies and procedures of your facility, as well as and local regulations for “Sharps Disposal.”

You should not use this medication if you are allergic to ibandronate, or if you have severe kidney disease, low blood levels of calcium (hypocalcemia), or a problem with your esophagus (the tube that connects your mouth and stomach).

Do not take an ibandronate tablet if you cannot sit upright or stand for at least one full hour. Ibandronate can cause serious problems in the stomach or esophagus. You will need to stay upright for at least 60 minutes after taking this medication.

To make sure you can safely take ibandronate, tell your doctor if you have any of these other conditions:

• a vitamin D deficiency;
• kidney disease;
• an ulcer in your stomach or esophagus; or
• trouble swallowing.

Some people using medicines similar to ibandronate have developed bone loss in the jaw, also called osteonecrosis of the jaw. Symptoms of this condition may include jaw pain, swelling, numbness, loose teeth, gum infection, or slow healing after injury or surgery involving the gums.

You may be more likely to develop osteonecrosis of the jaw if you have cancer or have been treated with chemotherapy, radiation, or steroids. Other conditions associated with osteonecrosis of the jaw include blood clotting disorders, anemia (low red blood cells), and dental surgery or pre-existing dental problems.

FDA pregnancy category C. It is not known whether ibandronate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether ibandronate passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

If you take ibandronate tablets once daily: If you forget to take this medicine first thing in the morning, do not take it later in the day. Wait until the following morning to take the medicine and skip the missed dose. Do not take two (2) tablets in one day.

If you take ibandronate tablets once a month: If you forget to take ibandronate on your scheduled day, take it first thing in the morning on the day after you remember the missed dose. Then return to your regular monthly schedule on your chosen dose day. If your next scheduled dose is less than 7 days away, wait until then to take the medicine and skip the missed dose. Do not take two (2) tablets in one week.

If you receive ibandronate injections every 3 months: Call your doctor for instructions if you miss an appointment for your injection.

Do not take any other medicines including vitamins, calcium, or antacids for at least 60 minutes before or after taking an ibandronate tablet.

Avoid milk and other dairy products for at least 60 minutes after taking ibandronate (except in the case of overdose as stated above).

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.

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 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 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

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)].

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 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.

Pregnancy

Risk Summary

Ibandronate sodium is not indicated for use in women of reproductive potential. There are no data with ibandronate sodium use in pregnant women to inform any drug-associated risks.

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 (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.

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.

Pediatric Use

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

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.

Renal Impairment

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 104-week carcinogenicity study, doses of 3, 7, or 15 mg/kg/day were administered by oral gavage to Wistar rats (systemic exposures in males and females up to 3 and 1 times, respectively, human exposure). There were no significant drug-related tumor findings in male or female rats. In a 78-week carcinogenicity study, doses of 5, 20, or 40 mg/kg/day were administered by oral gavage to NMRI mice (exposures in males and females up to 96 and 14 times, respectively, human exposure). There were no significant drug-related tumor findings in male or female mice. In a 90-week carcinogenicity study, doses of 5, 20, or 80 mg/kg/day were administered in the drinking water to NMRI mice. A dose-related increased incidence of adrenal subcapsular adenoma/carcinoma was observed in female mice, which was statistically significant at 80 mg/kg/day (32 to 51 times human exposure). The relevance of these findings to humans is unknown.

Exposure multiples comparing human and rodent doses were calculated using human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison.

Mutagenesis

There was no evidence for a mutagenic or clastogenic potential of ibandronate in the following assays: in vitro bacterial mutagenesis assay in Salmonella typhimurium and Escherichia coli (Ames test), mammalian cell mutagenesis assay in Chinese hamster V79 cells, and chromosomal aberration test in human peripheral lymphocytes, each with and without metabolic activation. Ibandronate was not genotoxic in the in vivo mouse micronucleus tests for chromosomal damage.

Impairment of Fertility

In female rats treated from 14 days prior to mating through gestation, decreases in fertility, corpora lutea and implantation sites, and increased preimplantation loss were observed at an intravenous dose of 1.2 mg/kg/day (117 times human exposure). In male rats treated for 28 days prior to mating, a decrease in sperm production and altered sperm morphology were observed at intravenous doses greater than or equal to 0.3 mg/kg/day (greater than or equal to 40 times human exposure).

Exposure multiples comparing human and rat doses were calculated using human exposure at the recommended intravenous dose of 3 mg every 3 months, based on cumulative AUC comparison.

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 1,000 times the lowest antiresorptive dose of 0.005 mg/kg/day in this model, and 5,000 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 every 3 months, based on cumulative dose normalized for body surface area (mg/m2) and area under the curve (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.

Treatment of Postmenopausal Osteoporosis

Quarterly Intravenous Injection

The effectiveness and safety of Ibandronate Sodium Injection 3 mg (ibandronate) once every 3 months were demonstrated in a randomized, double-blind, multinational, noninferiority study in 1358 women with postmenopausal osteoporosis (L2-L4 lumbar spine BMD, T-score below -2.5 SD at baseline). The control group received ibandronate 2.5 mg daily oral tablets. The primary efficacy parameter was the relative change from baseline to 1 year of treatment in lumbar spine BMD, which was compared between the intravenous injection and the daily oral treatment groups. All patients received 400 international units vitamin D and 500 mg calcium supplementation per day.

Effect on BMD

In the intent-to-treat (ITT) efficacy analysis, the least-squares mean increase at 1 year in lumbar spine BMD in patients (n=429) treated with Ibandronate Sodium Injection 3 mg (ibandronate) once every 3 months (4.5%) was statistically superior to that in patients (n=434) treated with daily oral tablets (3.5%). The mean difference between groups was 1.1% (95% confidence interval: 0.5%, 1.6%; p<0.001; see Figure 1). The mean increase from baseline in total hip BMD at 1 year was 2.1% in the Ibandronate Sodium Injection 3 mg (ibandronate) once every 3 months group and 1.5% in the ibandronate 2.5 mg daily oral tablet group. Consistently higher BMD increases at the femoral neck and trochanter were also observed following Ibandronate Sodium Injection 3 mg (ibandronate) once every 3 months compared to ibandronate 2.5 mg daily oral tablet.

Figure 1 Mean Percent Change (95% Confidence Interval) from Baseline in Lumbar Spine BMD at One Year in Patients Treated with Ibandronate 2.5 mg Daily Oral Tablet or Ibandronate Sodium Injection 3 mg (ibandronate) Once Every 3 Months

Bone Histology

The histological analysis of bone biopsies after 22 months of treatment with 3 mg intravenous ibandronate every 3 months (n=30) or 23 months of treatment with 2 mg intravenous ibandronate every 2 months (n=27) in women with postmenopausal osteoporosis showed bone of normal quality and no indication of a mineralization defect.

Daily Oral Tablets

The effectiveness and safety of ibandronate sodium daily oral tablets were demonstrated in a randomized, double-blind, placebo-controlled, multinational study (Treatment Study) of 2946 women aged 55 to 80 years, who were on average 21 years postmenopause, who had a lumbar spine BMD 2 to 5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. Ibandronate sodium was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently. The main outcome measure was the occurrence of new radiographically diagnosed, vertebral fractures after 3 years of treatment. The diagnosis of an incident vertebral fracture was based on both qualitative diagnosis by the radiologist and quantitative morphometric criterion. The morphometric criterion required the dual occurrence of two events: a relative height ratio or relative height reduction in a vertebral body of at least 20%, together with at least a 4 mm absolute decrease in height. All women received 400 international units vitamin D and 500 mg calcium supplementation per day.

Effect on Vertebral Fracture

Ibandronate 2.5 mg daily oral tablet significantly reduced the incidence of new vertebral fractures compared to placebo. Over the course of the 3-year study, the risk for new vertebral fracture was 9.6% in the placebo-treated women and 4.7% in the women treated with ibandronate 2.5 mg daily oral tablet (p<0.001) (see Table 3).

Effect on Nonvertebral Fractures

Ibandronate 2.5 mg daily did not reduce the incidence of nonvertebral fractures (secondary efficacy measure). There was a similar number of nonvertebral osteoporotic fractures at 3 years reported in women treated with ibandronate 2.5 mg daily oral tablet [9.1%, (95% CI: 7.1%, 11.1%)] and placebo [8.2%, (95% CI: 6.3%, 10.2%)]. The two treatment groups were also similar with regard to the number of fractures reported at the individual non-vertebral sites: pelvis, femur, wrist, forearm, rib, and hip.

Effect on BMD

Ibandronate 2.5 mg daily oral tablet significantly increased BMD at the lumbar spine and hip relative to treatment with placebo. In the 3-year osteoporosis treatment study, ibandronate 2.5 mg daily oral tablet produced increases in lumbar spine BMD that were progressive over 3 years of treatment and were statistically significant relative to placebo at 6 months and at all later time points. Lumbar spine BMD increased by 6.4% after 3 years of treatment with ibandronate 2.5 mg daily oral tablet compared with 1.4% in the placebo group (p<0.0001). Table 4 displays the significant increases in BMD seen at the lumbar spine, total hip, femoral neck, and trochanter compared to placebo.

Bone Histology

The effects of ibandronate 2.5 mg daily oral tablet on bone histology were evaluated in iliac crest biopsies from 16 women after 22 months of treatment and 20 women after 34 months of treatment. The histological analysis of bone biopsies showed bone of normal quality and no indication of osteomalacia or a mineralization defect.