Ibandronate Sodium: Package Insert and Label Information

IBANDRONATE SODIUM — ibandronate sodium tablet, film coated
Aurobindo Pharma Limited

1 INDICATIONS AND USAGE

1.1 Treatment and Prevention of Postmenopausal Osteoporosis

Ibandronate sodium tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women. Ibandronate sodium tablets increase bone mineral density (BMD) and reduce the incidence of vertebral fractures.

1.2 Important Limitations of Use

The optimal duration of use has not been determined. The safety and effectiveness of ibandronate sodium tablets for the treatment of osteoporosis are based on clinical data of three years duration. 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 DOSAGE AND ADMINISTRATION

2.1 Dosage Information

The dose of ibandronate sodium is one 150 mg tablet taken once monthly on the same date each month.

2.2 Important Administration Instructions

Instruct Patients to do the following:

  • Take ibandronate sodium tablets at least 60 minutes before the first food or drink (other than water) of the day or before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, (see DRUG INTERACTIONS [7.1]). Avoid the use of water with supplements including mineral water because they may have a higher concentration of calcium.
  • Swallow ibandronate sodium tablets whole with a full glass of plain water (6 to 8 oz) while standing or sitting in an upright position to reduce the potential for esophageal irritation. Avoid lying down for 60 minutes after taking ibandronate sodium tablets (see WARNINGS AND PRECAUTIONS [5.1]). Do not chew or suck the tablet because of a potential for oropharyngeal ulceration.
  • Do not eat, drink anything except plain water, or take other medications for at least 60 minutes after taking ibandronate sodium tablets.

2.3 Recommendations for Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Avoid the use of calcium supplements within 60 minutes of ibandronate sodium tablets administration because co-administration of ibandronate sodium tablets and calcium may interfere with the absorption of ibandronate sodium (see DRUG INTERACTIONS [7.1]).

2.4 Administration Instructions for Missed Once-Monthly Doses

If the once-monthly dose is missed, instruct patients to do the following:

  • If the next scheduled ibandronate sodium tablets day is more than 7 days away, take one ibandronate sodium tablet 150 mg (ibandronate) in the morning following the date that it is remembered.
  • If the next scheduled ibandronate sodium tablets day is only 1 to 7 days away, wait until the subsequent month’s scheduled ibandronate sodium tablets day to take their tablet.

For subsequent monthly doses for both of the above scenarios, instruct patients to return to their original schedule by taking one ibandronate sodium tablet 150 mg (ibandronate) every month on their previous chosen day.

3 DOSAGE FORMS AND STRENGTHS

Ibandronate sodium tablets, 150 mg: white to off-white, film-coated, caplet shaped, biconvex tablets debossed with ‘X’ on one side and ‘78’ on the other side.

4 CONTRAINDICATIONS

Ibandronate sodium tablets are contraindicated in patients with the following conditions:

5 WARNINGS AND PRECAUTIONS

5.1 Upper Gastrointestinal Adverse Reactions


Ibandronate sodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when ibandronate sodium is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers).
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue ibandronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient (see DOSAGE AND ADMINISTRATION [2.2]). In patients who cannot comply with dosing instructions due to mental disability, therapy with ibandronate sodium should be used under appropriate supervision.
There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.

5.2 Hypocalcemia and Mineral Metabolism

Hypocalcemia has been reported in patients taking ibandronate sodium. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting ibandronate sodium therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate (see DOSAGE AND ADMINISTRATION [2.3]).

5.3 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]). 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. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.

5.4 Jaw Osteonecrosis


Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including ibandronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.

For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.

Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.

5.5 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.

5.6 Severe Renal Impairment

Ibandronate sodium is not recommended for use in patients with severe renal impairment (creatinine clearance of less than 30 mL/min).

6 ADVERSE REACTIONS

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.

Treatment and Prevention of Postmenopausal Osteoporosis

Daily Dosing The safety of ibandronate sodium 2.5 mg (ibandronate) 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 sodium 2.5 mg (ibandronate). Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors and H2 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 sodium 2.5 mg (ibandronate) daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the ibandronate sodium 2.5 mg (ibandronate) daily group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the ibandronate sodium 2.5 mg (ibandronate) daily group and the placebo group. Table 1 lists adverse reactions from the treatment and prevention studies reported in greater than or equal to 2% of patients and more frequently in patients treated daily with ibandronate sodium than patients treated with placebo.

Table 1 Adverse Reactions Occurring at an Incidence Greater Than or Equal to 2% and in More Patients Treated with Ibandronate Sodiu m Than in Patients Treated with Placebo Daily in the Osteoporosis Treatment and Prevention Studies

Body System Placebo % (n=1134) Ibandronate Sodium 2.5 mg (ibandronate) % (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 sodium 2.5 mg (ibandronate) 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 sodium 2.5 mg (ibandronate) daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%).

Ocular Adverse Events

Reports in the medical literature indicate that bisphosphonates may be associated with ocular inflammation such as iritis and scleritis. In some cases, these events did not resolve until the bisphosphonate was discontinued. There were no reports of ocular inflammation in studies with ibandronate sodium 2.5 mg (ibandronate) daily.
Monthly Dosing
The safety of ibandronate sodium 150 mg (ibandronate) once monthly in the treatment of postmenopausal osteoporosis was assessed in a two year trial which enrolled 1583 patients aged 54 to 81 years, with 395 patients exposed to ibandronate sodium 2.5 mg (ibandronate) daily and 396 exposed to ibandronate sodium 150 mg (ibandronate) monthly. Patients with active or significant pre-existing gastrointestinal disease were excluded from this trial. Patients with dyspepsia or concomitant use of nonsteroidal anti-inflammatory drugs, proton pump inhibitors and H2 antagonists were included in this study. All patients received 500 mg calcium plus 400 international units vitamin D supplementation daily.

After one year, the incidence of all-cause mortality was 0.3% in both the ibandronate sodium 2.5 mg (ibandronate) daily group and the ibandronate sodium 150 mg (ibandronate) monthly group. The incidence of serious adverse events was 5% in the ibandronate sodium 2.5 mg (ibandronate) daily group and 7% in the ibandronate sodium 150 mg (ibandronate) monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the ibandronate sodium 2.5 mg (ibandronate) daily group and 8% in the ibandronate sodium 150 mg (ibandronate) monthly group. Table 2 lists the adverse events reported in greater than or equal to 2% of patients.

Table 2 Adverse Events with an Incidence of at Least 2% in Patients Treated with Ibandronate Sodium 2.5 mg (ibandronate) Daily or Ibandronate Sodium 150 mg (ibandronate) Once-Monthly for Treatment of Postmenopausal Osteoporosis
Body System/Adverse Event Ibandronate Sodium2.5 mg (ibandronate) Daily% (n=395) Ibandronate Sodium 150 mg (ibandronate) Monthly % (n=396)
a Combination of abdominal pain and abdominal pain upperb Combination of influenza-like illness and acute phase reaction c Combination of rash pruritic, rash macular, rash papular, rash generalized, rash erythematous, dermatitis, dermatitis allergic, dermatitis medicamentosa, erythema and exanthema
Vascular Disorders
Hypertension 7.3 6.3
Gastrointestinal Disorders
Dyspepsia 7.1 5.6
Nausea 4.8 5.1
Diarrhea 4.1 5.1
Constipation 2.5 4
Abdominal Paina 5.3 7.8
Musculoskeletal and Connective Tissue Disorders
Arthralgia 3.5 5.6
Back Pain 4.3 4.5
Pain in Extremity 1.3 4
Localized Osteoarthritis 1.3 3
Myalgia 0.8 2
Muscle Cramp 2 1.8
Infections and Infestations
Influenza 3.8 4
Nasopharyngitis 4.3 3.5
Bronchitis 3.5 2.5
Urinary Tract Infection 1.8 2.3
Upper Respiratory Tract Infection 2 2
Nervous System Disorders
Headache 4.1 3.3
Dizziness 1 2.3
General Disorders and Administration Site Conditions
Influenza-like Illnessb 0.8 3.3
Skin and Subcutaneous Tissue Disorders
Rashc 1.3 2.3
Psychiatric Disorders
Insomnia 0.8 2

Gastrointestinal Adverse Events
The incidence of adverse events in the ibandronate sodium 2.5 mg (ibandronate) daily and ibandronate sodium 150 mg (ibandronate) monthly groups were: dyspepsia (7% vs. 6%), diarrhea (4% vs. 5%), and abdominal pain (5% vs. 8%).
Musculoskeletal Adverse Events

The incidence of adverse events in the ibandronate sodium 2.5 mg (ibandronate) daily and ibandronate sodium 150 mg (ibandronate) monthly groups were: back pain (4% vs. 5%), arthralgia (4% vs. 6%) and myalgia (1% vs. 2%).
Acute Phase Reactions
Symptoms consistent with acute phase reactions have been reported with bisphosphonate use. Over the two years of the study, the overall incidence of acute phase reaction symptoms was 3% in the ibandronate sodium 2.5 mg (ibandronate) daily group and 9% in the ibandronate sodium 150 mg (ibandronate) monthly group. These incidence rates are based on the reporting of any of 33 acute-phase reaction like symptoms within 3 days of the monthly dosing and lasting 7 days or less. Influenza like illness was reported in no patients in the ibandronate sodium 2.5 mg (ibandronate) daily group and 2% in the ibandronate sodium 150 mg (ibandronate) monthly group.

Ocular Adverse Events

Two patients who received ibandronate sodium 150 mg (ibandronate) once-monthly experienced ocular inflammation, one was a case of uveitis and the other scleritis. One hundred sixty (160) postmenopausal women without osteoporosis participated in a 1-year, double-blind, placebo-controlled study of ibandronate sodium 150 mg (ibandronate) once-monthly for prevention of bone loss. Seventy-seven subjects received ibandronate sodium and 83 subjects received placebo. The overall pattern of adverse events was similar to that previously observed.

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