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| {{DrugProjectFormSinglePage
| | #REDIRECT [[Ibandronate]] |
| |authorTag={{DB}}
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| |genericName=Ibandronate sodium
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| |aOrAn=a
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| |drugClass=bone density conservation agent
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| |indicationType=treatment
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| |indication=osteoporosis
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| |adverseReactions=hypertension,abdominal pain, diarrhea, indigestion, nausea,
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| back ache, pain in limb, headache, bronchitis, upper respiratory infection
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| |blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
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| |blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
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| |fdaLIADAdult=====Treatment and Prevention of Postmenopausal Osteoporosis====
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| *BONIVA is indicated for the treatment and prevention of osteoporosis in postmenopausal women. BONIVA increases bone mineral density (BMD) and reduces the incidence of vertebral fractures.
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| '''Important Limitations of Use'''
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| *The optimal duration of use has not been determined. The safety and effectiveness of BONIVA 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.
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| *Dosing information:
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| :* The dose of BONIVA is one 150 mg tablet taken once monthly on the same date each month.
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| |offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Ibandronic acid in adult patients.
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| |offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Ibandronic acid in adult patients.
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| |offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Ibandronic acid in pediatric patients.
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| |offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Ibandronic acid in pediatric patients.
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| |contraindications=BONIVA is contraindicated in patients with the following conditions:
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| *Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.
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| *Inability to stand or sit upright for at least 60 minutes.
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| *Hypocalcemia.
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| *Known hypersensitivity to BONIVA or to any of its excipients. Cases of anaphylaxis have been reported.
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| |warnings='''Upper Gastrointestinal Adverse Reactions'''
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| *BONIVA, 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 BONIVA is given to patients with active upper gastrointestinal problems (such as known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers).
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| *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 BONIVA and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
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| *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 (6-8 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 BONIVA should be used under appropriate supervision.
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| *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.
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| '''Hypocalcemia and Mineral Metabolism'''
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| *Hypocalcemia has been reported in patients taking BONIVA. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting BONIVA therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate.
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| '''Musculoskeletal Pain'''
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| *Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking BONIVA and other bisphosphonates. 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.
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| '''Jaw Osteonecrosis'''
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| *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 BONIVA. 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), 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.
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| *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.
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| *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.
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| '''Atypical Subtrochanteric and Diaphyseal Femoral Fractures'''
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| *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.
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| *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.
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| *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.
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| '''Severe Renal Impairment'''
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| *BONIVA is not recommended for use in patients with severe renal impairment (creatinine clearance of less than 30 mL/min).
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| |clinicalTrials=*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.
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| '''Treatment and Prevention of Postmenopausal Osteoporosis'''
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| '''Daily Dosing'''
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| *The safety of BONIVA 2.5 mg once daily in the treatment and prevention of postmenopausal osteoporosis was assessed in 3577 patients aged 41 – 82 years. The duration of the trials was 2 to 3 years, with 1134 patients exposed to placebo and 1140 exposed to BONIVA 2.5 mg. 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.
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| *The incidence of all-cause mortality was 1% in the placebo group and 1.2% in the BONIVA 2.5 mg daily group. The incidence of serious adverse reactions was 20% in the placebo group and 23% in the BONIVA 2.5 mg daily group. The percentage of patients who withdrew from treatment due to adverse reactions was approximately 17% in both the BONIVA 2.5 mg 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 BONIVA than patients treated with placebo.
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| [[File:Boniva table 1.png|600px|thumbnail|left]]
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| {{clear}}
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| '''Gastrointestinal Adverse Reactions'''
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| *The incidence of selected gastrointestinal adverse reactions in the placebo and BONIVA 2.5 mg daily groups were: dyspepsia (10% vs. 12%), diarrhea (5% vs. 7%), and abdominal pain (5% vs. 6%).
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| '''Musculoskeletal Adverse Reactions'''
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| *The incidence of selected musculoskeletal adverse reactions in the placebo and BONIVA 2.5 mg daily groups were: back pain (12% vs. 14%), arthralgia (14% vs. 14%) and myalgia (5% vs. 6%).
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| '''Ocular Adverse Events'''
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| *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 BONIVA 2.5 mg daily.
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| '''Monthly Dosing'''
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| *The safety of BONIVA 150 mg once monthly in the treatment of postmenopausal osteoporosis was assessed in a two year trial which enrolled 1583 patients aged 54 – 81 years, with 395 patients exposed to BONIVA 2.5 mg daily and 396 exposed to BONIVA 150 mg monthly. Patients with active or significant pre-existing gastrointestinal disease were excluded from this trial. Patients with dyspepsia or concomitant use of non-steroidal 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.
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| *After one year, the incidence of all-cause mortality was 0.3% in both the BONIVA 2.5 mg daily group and the BONIVA 150 mg monthly group. The incidence of serious adverse events was 5% in the BONIVA 2.5 mg daily group and 7% in the BONIVA 150 mg monthly group. The percentage of patients who withdrew from treatment due to adverse events was 9% in the BONIVA 2.5 mg daily group and 8% in the BONIVA 150 mg monthly group. Table 2 lists the adverse events reported in greater than or equal to 2% of patients.
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| [[File:Boniva table 2.png|600px|thumbnail|left]]
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| {{clear}}
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| '''Gastrointestinal Adverse Events'''
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| *The incidence of adverse events in the BONIVA 2.5 mg daily and BONIVA 150 mg monthly groups were: dyspepsia (7% vs. 6%), diarrhea (4% vs. 5%), and abdominal pain (5% vs. 8%).
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| '''Musculoskeletal Adverse Events'''
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| *The incidence of adverse events in the BONIVA 2.5 mg daily and BONIVA 150 mg monthly groups were: back pain (4% vs. 5%), arthralgia (4% vs. 6%) and myalgia (1% vs. 2%).
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| '''Acute Phase Reactions'''
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| *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 BONIVA 2.5 mg daily group and 9% in the BONIVA 150 mg 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 BONIVA 2.5 mg daily group and 2% in the BONIVA 150 mg monthly group.
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| '''Ocular Adverse Events'''
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| *Two patients who received BONIVA 150 mg once-monthly experienced ocular inflammation, one was a case of uveitis and the other scleritis.
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| *One hundred sixty (160) postmenopausal women without osteoporosis participated in a 1-year, double-blind, placebo-controlled study of BONIVA 150 mg once-monthly for prevention of bone loss. Seventy-seven subjects received BONIVA and 83 subjects received placebo. The overall pattern of adverse events was similar to that previously observed.
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| |postmarketing=*The following adverse reactions have been identified during postapproval use of BONIVA. 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.
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| '''Hypersensitivity'''
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| *Allergic reactions including anaphylactic reaction/shock; in some cases fatal, angioedema, bronchospasm, asthma exacerbations, and rash have been reported.
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| *'''Hypocalcemia'''
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| *Hypocalcemia has been reported in patients treated with BONIVA.
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| *'''Musculoskeletal Pain'''
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| *Bone, joint, or muscle pain (musculoskeletal pain), described as severe or incapacitating, has been reported.
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| *'''Jaw Osteonecrosis'''
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| *Osteonecrosis of the jaw has been reported in patients treated with BONIVA.
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| *'''Atypical Femoral Shaft Fracture'''
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| :*Atypical, low-energy, or low-trauma fractures of the femoral shaft.
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| |drugInteractions='''Calcium Supplements/Antacids'''
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| *Products containing calcium and other multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with absorption of BONIVA. Therefore, instruct patients to take BONIVA at least 60 minutes before any oral medications, including medications containing multivalent cations (such as antacids, supplements or vitamins). Also, patients should wait at least 60 minutes after dosing before taking any other oral medications (see Dosage and Administration [2.3]).
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| '''Aspirin/Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)'''
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| *Because aspirin, NSAIDs, and bisphosphonates are all associated with gastrointestinal irritation, caution should be exercised in the concomitant use of aspirin or NSAIDs with BONIVA.
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| '''H2 Blockers'''
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| *In healthy volunteers, co-administration with ranitidine resulted in a 20% increased bioavailability of ibandronate, which was not considered to be clinically relevant (see CLINICAL PHARMACOLOGY [12.3]).
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| '''Drug/Laboratory Test Interactions'''
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| *Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ibandronate have not been performed.
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| |FDAPregCat=C
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| |useInPregnancyFDA=*There are no adequate and well-controlled studies in pregnant women. BONIVA should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
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| *Bisphosphonates are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established.
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| *In female rats given ibandronate orally at doses greater than or equal to 3 times human exposure at the recommended daily oral dose of 2.5 mg or greater than or equal to 1 times human exposure at the recommended once-monthly oral dose of 150 mg beginning 14 days before mating and continuing through lactation, maternal deaths were observed at the time of delivery in all dose groups. Perinatal pup loss in dams given 45 times human exposure at the recommended daily dose and 13 times the recommended once-monthly dose was likely related to maternal dystocia. Calcium supplementation did not completely prevent dystocia and periparturient mortality in any of the treated groups at greater than or equal to 16 times the recommended daily dose and greater than or equal to 4.6 times the recommended once-monthly dose. 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 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 equivalent to human exposure at the recommended daily and greater than or equal to 4 times the recommended once-monthly dose. 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.
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| *Exposure of pregnant rats during the period of organogenesis resulted in an increased fetal incidence of RPU (renal pelvis ureter) syndrome at oral doses 30 times the human exposure at the recommended daily oral dose of 2.5 mg and greater than or equal to 9 times the recommended once-monthly oral dose of 150 mg. Impaired pup neuromuscular development (cliff avoidance test) was observed at 45 times human exposure at the daily dose and 13 times the once-monthly dose.
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| *In pregnant rabbits treated orally with ibandronate during gestation at doses greater than or equal to 8 times the recommended human daily oral dose of 2.5 mg and greater than or equal to 4 times the recommended human once-monthly oral dose of 150 mg, dose-related maternal mortality was observed in all treatment groups. The deaths occurred prior to parturition and were associated with lung edema and hemorrhage. No significant fetal anomalies were observed.
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| |useInNursing=*It is not known whether BONIVA is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BONIVA is administered to a nursing woman. In lactating rats treated with intravenous doses, ibandronate was present in breast milk from 2 to 24 hours after dose administration. Concentrations in milk averaged 1.5 times plasma concentrations.
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| |useInPed=*Safety and effectiveness in pediatric patients have not been established.
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| |useInGeri=*Of the patients receiving BONIVA 2.5 mg daily in postmenopausal osteoporosis studies, 52% were over 65 years of age, and 10% were over 75 years of age. Of the patients receiving BONIVA 150 mg once-monthly in the postmenopausal osteoporosis 1-year study, 52% were over 65 years of age, and 9% were over 75 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.
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| |useInRenalImpair=*BONIVA is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).
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| |administration='''Dosage Information'''
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| *The dose of BONIVA is one 150 mg tablet taken once monthly on the same date each month.
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| '''Important Administration Instructions'''
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| Instruct Patients to do the following:
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| *Take BONIVA 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.
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| *Swallow BONIVA 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 BONIVA. Do not chew or suck the tablet because of a potential for oropharyngeal ulceration.
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| *Do not eat, drink anything except plain water, or take other medications for at least 60 minutes after taking BONIVA.
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| '''Recommendations for Calcium and Vitamin D Supplementation'''
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| *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 BONVIA administration because co-administration of BONIVA and calcium may interfere with the absorption of ibandronate sodium.
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| '''Administration Instructions for Missed Once-Monthly Doses'''
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| *If the once-monthly dose is missed, instruct patients to do the following:
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| :*If the next scheduled BONIVA day is more than 7 days away, take one BONIVA 150 mg tablet in the morning following the date that it is remembered.
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| :*If the next scheduled BONIVA day is only 1 to 7 days away, wait until the subsequent month's scheduled BONIVA day to take their tablet.
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| *For subsequent monthly doses for both of the above scenarios, instruct patients to return to their original schedule by taking one BONIVA 150 mg tablet every month on their previous chosen day.
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| '''DOSAGE FORMS AND STRENGTHS'''
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| *BONIVA 150 mg tablets: white, oblong, engraved with "BNVA" on one side and "150" on the other side.
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| |overdose=No specific information is available on the treatment of overdosage of BONIVA. However, based on knowledge of this class of compounds, oral *Overdosage may result in hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, dyspepsia, esophagitis, gastritis, or ulcer. Milk or antacids should be given to bind BONIVA. Due to the risk of esophageal irritation, vomiting should not be induced, and the patient should remain fully upright. Dialysis would not be beneficial.
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| |mechAction=*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.
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| |structure=*BONIVA (ibandronate sodium) is a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption. The chemical name for ibandronate sodium is 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate with the molecular formula C9H22NO7P2Na•H2O and a molecular weight of 359.24. Ibandronate sodium is a white- to off-white powder. It is freely soluble in water and practically insoluble in organic solvents. Ibandronate sodium has the following structural formula:
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| [[File:Ibandronate str.png|600px|thumbnail|left]] | |
| {{clear}}
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| *BONIVA is available as a white, oblong, 150 mg film-coated 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. BONIVA also contains the following inactive ingredients: lactose monohydrate, povidone, microcrystalline cellulose, crospovidone, purified stearic acid, colloidal silicon dioxide, and purified water. The tablet film coating contains hypromellose, titanium dioxide, talc, polyethylene glycol 6000, and purified water.
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| |PK='''Absorption'''
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| *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.
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| *Following oral dosing, the time to maximum observed plasma ibandronate concentrations ranged from 0.5 to 2 hours (median 1 hour) in fasted healthy postmenopausal women. The mean oral bioavailability of 2.5 mg ibandronate was about 0.6% compared to intravenous dosing. 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 BONIVA 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.
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| '''Distribution'''
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| *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.
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| '''Metabolism'''
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| *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.
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| '''Elimination'''
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| *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.
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| *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 Cmax 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.
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| *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.
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| '''Specific Populations'''
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| '''Pediatrics'''
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| *The pharmacokinetics of ibandronate has not been studied in patients less than 18 years of age.
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| '''Geriatric'''
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| *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.
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| '''Gender'''
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| *The bioavailability and pharmacokinetics of ibandronate are similar in both men and women.
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| '''Race'''
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| *Pharmacokinetic differences due to race have not been studied.
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| '''Renal Impairment'''
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| *Renal clearance of ibandronate in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr).
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| *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 two-fold increase in exposure compared to the exposure for healthy subjects.
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| '''Hepatic Impairment'''
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| *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.
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| '''Drug Interaction Studies'''
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| *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.
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| '''H2 Blockers'''
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| *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.
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| |nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
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| '''Carcinogenesis'''
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| *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 exposures up to 12 and 7 times, respectively, human exposure at the recommended daily oral dose of 2.5 mg, and 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 (exposures up to 475 and 70 times, respectively, human exposure at the recommended daily oral dose of 2.5 mg and 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 (220 to 400 times human exposure at the recommended daily oral dose of 2.5 mg and 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.
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| '''Mutagenesis'''
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| *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.
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| '''Impairment of Fertility'''
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| *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 (45 times human exposure at the recommended daily oral dose of 2.5 mg and 13 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison).
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| '''Animal Reproductive and Developmental Toxicology'''
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| *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 3 times human exposure at the recommended daily oral dose of 2.5 mg or 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 (45 times human exposure at the recommended daily oral dose of 2.5 mg and 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 16 times human exposure at the recommended daily oral dose of 2.5 mg and 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 the recommended daily oral dose of 2.5 mg and 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.
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| *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 30 times human exposure at the recommended daily oral dose of 2.5 mg and 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 (45 times human exposure at the recommended daily oral dose of 2.5 mg and 13 times human exposure at the recommended once-monthly oral dose of 150 mg, based on AUC comparison).
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| *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 8 times the recommended human daily oral dose of 2.5 mg and 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.
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| '''Animal Pharmacology'''
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| *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 BONIVA administered at therapeutic doses is unlikely to induce osteomalacia.
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| *Long-term daily or 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 doses up to 15 times the recommended human daily oral dose of 2.5 mg, or 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.
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| |alcohol=Alcohol-Ibandronic acid interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
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| }}
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