Ibandronate Sodium

Ibandronate is available as a white film-coated, capsule shaped tablet for once-monthly oral administration. One 150 mg film-coated tablet contains 168.75 mg ibandronate monosodium monohydrate, equivalent to 150 mg free acid. Ibandronate sodium tablets also contain the following inactive ingredients: ammonium hydroxide, black iron oxide, colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, shellac glaze and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The action of ibandronate on bone tissue 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

Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip, and wrist. The diagnosis can be confirmed by a finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. While osteoporosis occurs in both men and women, it is most common among women following menopause. In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50-year-old women will experience an osteoporosis-related fracture during their remaining lifetimes.

Ibandronate produced biochemical changes indicative of dose dependent inhibition of bone resorption, including decreases of biochemical markers of bone collagen degradation (such as deoxypyridinoline, and cross-linked C-telopeptide of Type I collagen) in the once-monthly doses from 100 mg to 150 mg in postmenopausal women.

In a one-year, study comparing once-monthly vs. once-daily oral dosing regimens, the median decrease from baseline in serum CTX values was -76% for patients treated with the 150 mg once-monthly regimen. In a one-year, prevention study comparing ibandronate 150 mg once-monthly to placebo, the median placebo-subtracted decrease in sCTX was -49.8%.

12.3 Pharmacokinetics

Absorption

The absorption of oral ibandronate occurs in the upper gastrointestinal tract. Plasma concentrations increase in a dose-linear manner up to 50 mg oral intake and increases nonlinearly above this dose.

Following oral dosing, the time to maximum observed plasma ibandronate concentrations ranged from 0.5 to 2 hours (median one hour) in fasted healthy postmenopausal women. The extent of absorption is impaired by food or beverages (other than plain water). The oral bioavailability of ibandronate is reduced by about 90% when ibandronate is administered concomitantly with a standard breakfast in comparison with bioavailability observed in fasted subjects. There is no meaningful reduction in bioavailability when ibandronate is taken at least 60 minutes before a meal. However, both bioavailability and the effect on bone mineral density (BMD) are reduced when food or beverages are taken less than 60 minutes following an ibandronate dose.

Distribution

After absorption, ibandronate either rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 L, and the amount of dose removed from the circulation via the bone is estimated to be 40% to 50% of the circulating dose. In vitro protein binding in human serum was 99.5% to 90.9% over an ibandronate concentration range of 2 to 10 ng/mL in one study and approximately 85.7% over a concentration range of 0.5 to 10 ng/mL in another study.

Metabolism

Ibandronate does not undergo hepatic metabolism and does not inhibit the hepatic cytochrome P450 system. Ibandronate is eliminated by renal excretion. Based on a rat study, the ibandronate secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other drugs. There is no evidence that ibandronate is metabolized in humans.

Elimination

The portion of ibandronate that is not removed from the circulation via bone absorption is eliminated unchanged by the kidney (approximately 50% to 60% of the absorbed dose). Unabsorbed ibandronate is eliminated unchanged in the feces.

The plasma elimination of ibandronate is multiphasic. Its renal clearance and distribution into bone accounts for a rapid and early decline in plasma concentrations, reaching 10% of the C_max within 3 or 8 hours after intravenous or oral administration, respectively. This is followed by a slower clearance phase as ibandronate redistributes back into the blood from bone. The observed apparent terminal half-life for ibandronate is generally dependent on the dose studied and on assay sensitivity. The observed apparent terminal half-life for the 150 mg ibandronate tablet upon oral administration to healthy postmenopausal women ranges from 37 to 157 hours.

Total clearance of ibandronate is low, with average values in the range 84 to 160 mL/min. Renal clearance (about 60 mL/min in healthy postmenopausal females) accounts for 50% to 60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal clearances likely reflects bone uptake of the drug.

Specific Populations

The pharmacokinetics of ibandronate has not been studied in patients less than 18 years of age.

Because ibandronate is not known to be metabolized, the only difference in ibandronate elimination for geriatric patients versus younger patients is expected to relate to progressive age related changes in renal function.

The bioavailability and pharmacokinetics of ibandronate are similar in both men and women.

Pharmacokinetic differences due to race have not been studied.

Renal clearance of ibandronate in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).

Following a single dose of 0.5 mg ibandronate by intravenous administration, patients with CLcr 40 to 70 mL/min had 55% higher exposure (AUC_∞) than the exposure observed in subjects with CLcr greater than 90 mL/min. Patients with CLcr less than 30 mL/min had more than a 2-fold increase in exposure compared to the exposure for healthy subjects (see Dosage and Administration [2.4]).

No studies have been performed to assess the pharmacokinetics of ibandronate in patients with hepatic impairment because ibandronate is not metabolized in the human liver.

Drug Interaction Studies

Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron), including milk, food, and antacids are likely to interfere with absorption of ibandronate, which is consistent with findings in animal studies.

A pharmacokinetic interaction study in healthy volunteers demonstrated that 75 mg ranitidine (25 mg injected intravenously 90 and 15 minutes before and 30 minutes after ibandronate administration) increased the oral bioavailability of 10 mg ibandronate by about 20%. This degree of increase is not considered to be clinically relevant.

13 NONCLINICAL TOXICOLOGY

13.1 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 male and female Wistar rats (systemic cumulative exposures up to 3.5 and 2 times, respectively, human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). 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 male and female NMRI mice (cumulative exposures up to 135 and 20 times, respectively, human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). 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 (cumulative monthly exposures in males and females up to 70 and 115 times, respectively, human exposure at the recommended dose of 150 mg, based on AUC comparison). A dose-related increased incidence of adrenal subcapsular adenoma/carcinoma was observed in female mice, which was statistically significant at 80 mg/kg/day (115 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). The relevance of these findings to humans is unknown.

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 were observed at an oral dose of 16 mg/kg/day (13 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison).

13.2 Animal Reproductive and Developmental Toxicology

In female rats given oral doses of 1, 4, or 16 mg/kg/day beginning 14 days before mating and continuing through lactation, maternal deaths were observed at the time of delivery in all dose groups (greater than or equal to 1 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). Perinatal pup loss in dams given 16 mg/kg/day (13 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison) was likely related to maternal dystocia. In pregnant rats given oral doses of 6, 20, or 60 mg/kg/day during gestation, calcium supplementation (32 mg/kg/day by subcutaneous injection from gestation day 18 to parturition) did not completely prevent dystocia and periparturient mortality in any of the treated groups (greater than or equal to 4.6 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). A low incidence of postimplantation loss was observed in rats treated from 14 days before mating throughout lactation or during gestation, only at doses causing maternal dystocia and periparturient mortality. In pregnant rats dosed orally with 1, 5, or 20 mg/kg/day from gestation day 17 through lactation day 21 (following closure of the hard palate through weaning), maternal toxicity, including dystocia and mortality, fetal perinatal and postnatal mortality, were observed at doses greater than or equal to 5 mg/kg/day (equivalent to human exposure at greater than or equal to 4 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). 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 oral doses greater than or equal to 10 mg/kg/day (greater than or equal to 9 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison). Impaired pup neuromuscular development (cliff avoidance test) was observed at 16 mg/kg/day when dams were dosed from 14 days before mating through lactation (13 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison).

In pregnant rabbits given oral doses of 1, 4, or 20 mg/kg/day during gestation, dose related maternal mortality was observed in all treatment groups (greater than or equal to 4 times the recommended human once-monthly oral dose of 150 mg, based on body surface area comparison, mg/m²). The deaths occurred prior to parturition and were associated with lung edema and hemorrhage. No significant fetal anomalies were observed.

13.3 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 administered at therapeutic doses is unlikely to induce osteomalacia.

Long-term once-monthly intermittent administration of ibandronate to ovariectomized rats or monkeys was associated with suppression of bone turnover and increases in bone mass. In both rats and monkeys, vertebral BMD, trabecular density, and biomechanical strength were increased dose-dependently at cumulative monthly doses up to 8 times (rat) or 6 times (monkey) the recommended human once-monthly oral dose of 150 mg, based on body surface area (mg/m²) or AUC comparison. In monkeys, 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.

14 CLINICAL STUDIES

14.1 Treatment of Postmenopausal Osteoporosis

Once-Monthly Dosing

The effectiveness and safety of ibandronate once-monthly were demonstrated in a randomized, double-blind, multinational, noninferiority trial in 1,602 women aged 54 to 81 years, who were on average 18 years postmenopause, and had L2-L4 lumbar spine BMD T-score below -2.5 SD at baseline. The main outcome measure was the comparison of the percentage change from baseline in lumbar spine BMD after one year of treatment with once-monthly ibandronate (100 mg, 150 mg) to daily ibandronate (2.5 mg). All patients received 400 international units vitamin D and 500 mg calcium supplementation per day.

Ibandronate 150 mg once-monthly (n = 327) was shown to be noninferior to ibandronate 2.5 mg daily (n = 318) in lumbar spine BMD in a one-year, double-blind, multicenter study of women with postmenopausal osteoporosis. In the primary efficacy analysis (per-protocol population), the mean increases from baseline in lumbar spine BMD at one year were 3.86% (95% CI: 3.40%, 4.32%) in the 2.5 mg daily group and 4.85% (95% CI: 4.41%, 5.29%) in the 150 mg once-monthly group; the mean difference between 2.5 mg daily and 150 mg once-monthly was 0.99% (95% CI: 0.38%, 1.60%), which was statistically significant (p = 0.002). The results of the intent-to-treat analysis were consistent with the primary efficacy analysis. The 150 mg once-monthly group also had consistently higher BMD increases at the other skeletal sites compared to the 2.5 mg daily group.

Daily Dosing

The effectiveness and safety of ibandronate were demonstrated in a randomized, double-blind, placebo-controlled, multinational study (Treatment Study) of 2,946 women aged 55 to 80 years, who were on average 21 years postmenopause, who had lumbar spine BMD 2 to 5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had 1 to 4 prevalent vertebral fractures. Ibandronate 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 Fracture Incidence

Ibandronate 2.5 mg daily significantly reduced the incidence of new vertebral (primary efficacy measure) and of new and worsening vertebral fractures. Over the course of the 3-year study, the risk for vertebral fracture was 9.6% in the placebo-treated women and 4.7% in the women treated with ibandronate 2.5 mg (p < 0.001) (see Table 2).

Table 2 Effect of Ibandronate on the Incidence of Vertebral Fracture in the 3-Year Osteoporosis Treatment StudyThe endpoint value is the value at the study's last time point, 3 years, for all patients who had a fracture identified at that time; otherwise, the last postbaseline value prior to the study's last time point is used.

	Proportion of Patients with Fracture (%)
	Placebo n = 975	Ibandronate 2.5 mg Daily n = 977	Absolute Risk Reduction (%) 95% CI	Relative Risk Reduction (%) 95% CI
New Vertebral Fracture	9.6	4.7	4.9	52p = 0.0003 vs. placebo
0 to 3 Year			(2.3, 7.4)	(29, 68)
New and Worsening Vertebral Fracture	10.4	5.1	5.3	52
0 to 3 Year			(2.6, 7.9)	(30, 67)
Clinical (Symptomatic) Vertebral Fracture	5.3	2.8	2.5	49
0 to 3 Year			(0.6, 4.5)	(14, 69)

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 [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 nonvertebral sites: pelvis, femur, wrist, forearm, rib, and hip.

Bone Mineral Density (BMD)

Ibandronate 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 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 2.5 mg daily ibandronate compared with 1.4% in the placebo group. Table 3 displays the significant increases in BMD seen at the lumbar spine, total hip, femoral neck, and trochanter compared to placebo.

Table 3 Mean Percent Change in BMD from Baseline to Endpoint in Patients Treated Daily with Ibandronate 2.5 mg or Placebo in the 3-Year Osteoporosis Treatment StudyThe endpoint value is the value at the study's last time point, 3 years, for all patients who had BMD measured at that time; otherwise, the last postbaseline value prior to the study's last time point is used.

	Placebo	Ibandronate 2.5 mg Daily
Lumbar Spine	1.4 (n = 693)	6.4 (n = 712)
Total Hip	-0.7 (n = 638)	3.1 (n = 654)
Femoral Neck	-0.7 (n = 683)	2.6 (n = 699)
Trochanter	0.2 (n = 683)	5.3 (n = 699)

Bone Histology

The effects of ibandronate 2.5 mg daily 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.

14.2 Prevention of Postmenopausal Osteoporosis

Once-Monthly Dosing

The safety and effectiveness of ibandronate 150 mg once-monthly for the prevention of postmenopausal osteoporosis were demonstrated in a randomized, double-blind, placebo-controlled one-year study (Monthly Prevention Study) of 160 postmenopausal women with low bone mass at baseline (T-score of -1 to -2.5). Women, aged 46 to 60 years, were on average 5.4 years postmenopause. All women received 400 international units of vitamin D and 500 mg calcium supplementation daily.

The primary efficacy measure was the relative change in BMD at the lumbar spine after one year of treatment. Ibandronate 150 mg once-monthly resulted in a mean increase in lumbar spine BMD of 4.12% (95% confidence interval 2.96 - 5.28) compared with placebo following one year of treatment (p < 0.0001), based on a 3.73% and -0.39% mean change in BMD from baseline in the 150 mg once-monthly ibandronate and placebo treatment groups, respectively. BMD at other skeletal sites was also increased relative to baseline values.

Daily Dosing

The safety and effectiveness of ibandronate 2.5 mg daily for the prevention of postmenopausal osteoporosis were demonstrated in a randomized, double-blind, placebo-controlled 2-year study (Prevention Study) of 653 postmenopausal women without osteoporosis at baseline. Women were aged 41 to 82 years, were on average 8.5 years postmenopause, and had lumbar spine BMD T-scores greater than -2.5. Women were stratified according to time since menopause (1 to 3 years, greater than 3 years) and baseline lumbar spine BMD (T-score: greater than -1, -1 to -2.5). The study compared daily ibandronate at three dose levels (0.5 mg, 1.0 mg, 2.5 mg) with placebo. All women received 500 mg of supplemental calcium per day.

The primary efficacy measure was the change in BMD of lumbar spine after 2 years of treatment. Ibandronate 2.5 mg daily resulted in a mean increase in lumbar spine BMD of 3.1% compared with placebo following 2 years of treatment. Increases in BMD were seen at 6 months and at all later time points. Irrespective of the time since menopause or the degree of preexisting bone loss, treatment with ibandronate resulted in a higher BMD response at the lumbar spine compared with placebo across all four baseline strata [time since menopause (1 to 3 years, greater than 3 years) and baseline lumbar spine BMD (T-score: greater than -1, -1 to -2.5)].

Compared with placebo, treatment with ibandronate 2.5 mg daily increased BMD of the total hip by 1.8%, the femoral neck by 2%, and the trochanter by 2.1%.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Ibandronate Sodium Tablets are available containing 168.75 mg of ibandronate sodium monohydrate equivalent to 150 mg of free acid.

The 150 mg tablets are white film-coated, capsule shaped, unscored tablets imprinted with G over I-150 in black ink on one side of the tablet and blank on the other side.  They are available as follows:

NDC 0378-5215-53
cartons of 3 blister packs containing one tablet each

16.2 Storage and Handling

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

PHARMACIST: Dispense a Medication Guide with each prescription.

17 PATIENT COUNSELING INFORMATION

“See FDA-approved patient labeling (Medication Guide)”

17.1 Information for Patients

Instruct patients to read the Medication Guide carefully before taking ibandronate sodium tablets and to re-read it each time the prescription is renewed because it contains important information the patient should know about ibandronate sodium tablets. The Medication Guide also includes the dosing instructions in order to maximize absorption and clinical benefit.

• •Ibandronate sodium tablets should be taken at least 60 minutes before the first food or drink (other than water) of the day and before taking any oral medication or supplementation including calcium, antacids or vitamins (see Drug Interactions [7.1]).
• •To facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation, ibandronate sodium tablets should be swallowed whole with a full glass of plain water (6 to 8 oz) while the patient is standing or sitting in an upright position. Patients should not lie down for 60 minutes after taking ibandronate sodium tablets.
• •Patients should not eat, drink anything except for water, or take other medications for 60 minutes after taking ibandronate sodium tablets.
• •Plain water is the only drink that should be taken with ibandronate sodium tablets. Note that some mineral waters may have a higher concentration of calcium and therefore should not be used.
• •Patients should not chew or suck the tablet because of a potential for oropharyngeal ulceration.
• •The ibandronate 150 mg tablet should be taken on the same date each month (i.e., the patient’s ibandronate day).
• •The patient must not take two 150 mg tablets within the same week.
• •If the once-monthly dose is missed, and the patient’s next scheduled ibandronate day is more than 7 days away, the patient should be instructed to take one ibandronate 150 mg tablet in the morning following the date that it is remembered (see Dosage and Administration [2.3]). The patient should then return to taking one ibandronate 150 mg tablet every month in the morning of their chosen day, according to their original schedule.
• •If the once-monthly dose is missed, and the patient’s next scheduled ibandronate day is only 1 to 7 days away, the patient must wait until the subsequent month’s scheduled ibandronate day to take their tablet. The patient should then return to taking one ibandronate 150 mg tablet every month in the morning of their chosen day, according to their original schedule.

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate. Intake of supplemental calcium and vitamin D should be delayed for at least 60 minutes following oral administration of ibandronate sodium tablets in order to maximize absorption of ibandronate sodium tablets.

Physicians should be alert to signs or symptoms signaling a possible esophageal reaction during therapy, and patients should be instructed to discontinue ibandronate sodium tablets and seek medical attention if they develop symptoms of esophageal irritation such as new or worsening dysphagia, pain on swallowing, retrosternal pain, or heartburn.

MEDICATION GUIDE
IBANDRONATE SODIUM TABLETS
(eye ban′ droe nate soe′ dee um)
150 mg

Read the Medication Guide that comes with ibandronate 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 your treatment. Talk to your doctor if you have any questions about ibandronate sodium tablets.

What is the most important information I should know about ibandronate sodium tablets?

Ibandronate sodium tablets may cause serious side effects including:

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

1. Esophagus problems.

Some people who take ibandronate sodium tablets may develop problems in the esophagus (the tube that connects the mouth and the stomach). These problems include irritation, inflammation, or ulcers of the esophagus which may sometimes bleed.

• • It is important that you take ibandronate sodium tablets exactly as prescribed to help lower your chance of getting esophagus problems (see the section “How should I take ibandronate sodium tablets?”).
• • Stop taking ibandronate sodium tablets and call your doctor right away if you get chest pain, new or worsening heartburn, or have trouble or pain when you swallow.

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

Ibandronate sodium tablets may lower the calcium levels in your blood. If you have low blood calcium before you start taking ibandronate sodium tablets, it may get worse during treatment. Your low blood calcium must be treated before you take ibandronate sodium tablets. 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 take ibandronate sodium tablets. Take calcium and vitamin D as your doctor tells you to.

3. Bone, joint, or muscle pain.

Some people who take ibandronate sodium tablets develop severe bone, joint, or muscle pain.

4. Severe jaw bone problems (osteonecrosis).

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

5. 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 ibandronate?

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

It is not known how long ibandronate sodium tablets work for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if ibandronate sodium tablets are still right for you.

It is not known if ibandronate sodium tablets are safe and effective in children.

Who should not take ibandronate sodium tablets?

Do not take ibandronate sodium tablets if you:

• •Have certain problems with your esophagus, the tube that connects your mouth with your stomach
• •Cannot stand or sit upright for at least 60 minutes
• •Have low levels of calcium in your blood
• •Are allergic to ibandronate sodium tablets or any of its ingredients. A list of ingredients is at the end of this leaflet

What should I tell my doctor before taking ibandronate sodium tablets?

Before you start ibandronate sodium tablets, be sure to talk to your doctor if you:

• •Have problems with swallowing
• •Have stomach or digestive problems
• •Have low blood calcium
• •Plan to have dental surgery or teeth removed
• •Have kidney problems
• •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 ibandronate sodium tablets can harm your unborn baby.
• •Are breast-feeding or plan to breast-feed. It is not known if ibandronate 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. Certain medicines may affect how ibandronate sodium tablets work.

Especially tell your doctor if you take:

• •antacids
• •aspirin
• •nonsteroidal anti-inflammatory (NSAID) medicines

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

How should I take ibandronate sodium tablets?

• •Take ibandronate sodium tablets exactly as your doctor tells you.
• • Ibandronate sodium tablets work only if taken on an empty stomach.
• •Take one ibandronate sodium tablet, after you get up for the day and before taking your first food, drink, or other medicine.
• •Take ibandronate sodium tablets while you are sitting or standing.
• • Do not chew or suck on a tablet of ibandronate.
• •Swallow ibandronate sodium tablet with a full glass (6 to 8 oz) of plain water only.
• •Do not take ibandronate sodium tablets with mineral water, coffee, tea, soda, or juice.

After swallowing ibandronate sodium tablet, wait at least 60 minutes:

• •Before you lie down. You may sit, stand or walk, and do normal activities like reading.
• •Before you take your first food or drink except for plain water.
• •Before you take other medicines, including antacids, calcium, and other supplements and vitamins.

Do not lie down for at least 60 minutes after you take ibandronate sodium tablets, and do not eat your first food of the day for at least 60 minutes after you take ibandronate sodium tablets.

If you miss a dose of ibandronate sodium tablets, do not take it later in the day. Call your doctor for instructions.

If you take too much ibandronate, call your doctor. Do not try to vomit. Do not lie down.

What are the possible side effects of ibandronate sodium tablets?

Ibandronate sodium tablets may cause serious side effects.

• •See “What is the most important information I should know about ibandronate sodium tablets?”

The most common side effects of ibandronate sodium tablets are:

• •Back pain
• •Heartburn
• •Stomach area (abdominal) pain
• •Pain in your arms and legs
• •Diarrhea
• •Headache
• •Muscle pain
• •Flu-like symptoms

You may get allergic reactions, such as hives, breathing difficulties, swelling of your face, lips, tongue or throat, or feeling faint.

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 ibandronate sodium tablets. 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 1-800-FDA-1088.

How do I store ibandronate sodium tablets?

• •Store ibandronate sodium tablets at 20° to 25°C (68° to 77°F).
• •Keep ibandronate sodium tablets in a tightly closed container.

Keep ibandronate sodium tablets and all medicines out of the reach of children.

General information about the safe and effective use of ibandronate sodium tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ibandronate sodium tablets for a condition for which it was not prescribed. Do not give ibandronate sodium tablets 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 ibandronate sodium tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ibandronate sodium tablets that is written for health professionals.

For more information call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in ibandronate sodium tablets?

Active ingredient: ibandronate sodium

Inactive ingredients: ammonium hydroxide, black iron oxide, colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, shellac glaze and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Manufactured in India by:
Mylan Laboratories Limited
Hyderabad — 500 034, India
Code No.: MH/DRUGS/25/NKD/89

REVISED SEPTEMBER 2013
IBAN:R3

PRINCIPAL DISPLAY PANEL - 150 mg

NDC 0378-5215-53

Once-Monthly
Ibandronate
Sodium
Tablets
150 mg*

PHARMACIST: Dispense the enclosed
Medication Guide to each patient.

Rx only      3 PACKS (ONE TABLET PER PACK)

*Each film-coated tablet contains 168.75 mg ibandronate
monosodium monohydrate equivalent to 150 mg free acid.

Usual Dosage: See accompanying prescribing information.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room
Temperature.]

Keep this and all medication out of the reach of children.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Made in India

Code No.: MH/DRUGS/25/NKD/89

www.mylan.com

M:5215:3C:R1