Bonviva

Each film-coated tablet contains Ibandronic acid 150 mg (equivalent to 168.75 mg of ibandronic acid, monosodium salt, monohydrate).
Excipients/Inactive Ingredients: Tablet core: Lactose monohydrate Ph. Eur./NF, Povidone Ph. Eur./USP, Microcrystalline cellulose Ph. Eur./NF, Crospovidone Ph. Eur./NF, Purified stearic acid Ph. Eur./NF, Colloidal anhydrous silica Ph. Eur./NF.
Tablet coat: Hypromellose Ph. Eur./USP, Titanium dioxide Ph. Eur./USP, Talc Ph. Eur./USP, 6,000 macrogol Ph. Eur./NF.

Pharmacology: Pharmacodynamics: The pharmacodynamic action of ibandronic acid is inhibition of bone resorption. In vivo, ibandronic acid prevents experimentally induced bone destruction caused by cessation of gonadal function, retinoids, tumors or tumor extracts.
In young (fast growing) rats, the endogenous bone resorption is also inhibited, leading to increased bone mass compared with untreated animals. Animal models confirm that ibandronic acid is a highly potent inhibitor of osteoclastic activity. In growing rats, there was no evidence of impaired mineralization even at doses greater than 5,000 times the dose required for osteoporosis treatment.
The high potency and therapeutic margin of ibandronic acid allows for more flexible dosing regimens and intermittent treatment with long drug-free intervals at comparatively low doses.
Both daily and intermittent (with prolonged dose-free intervals) long-term administration in rats, dogs and monkeys were associated with formation of new bone of normal quality and/or increased mechanical strength even in doses in excess of any pharmacologically intended dose, including the toxic range.
In humans, the efficacy of both daily and intermittent administration with a dose-free interval of 9-10 weeks of ibandronic acid was confirmed in a clinical trial (MF 4411), in which Ibandronic acid demonstrated anti-fracture efficacy.
Both daily and intermittent (with a drug-free interval of 9-10 weeks per quarter) oral doses of Ibandronic acid in postmenopausal women produced biochemical changes indicative of dose-dependent inhibition of bone resorption, including suppression of urinary biochemical markers of bone collagen degradation (such as deoxypyridinoline, and cross-linked C- and N-telopeptides of type I collagen).
Following treatment discontinuation, there is a reversion to the pathological pre-treatment rates of elevated bone resorption associated with postmenopausal osteoporosis.
The histological analysis of bone biopsies after two and three years of treatment of postmenopausal women showed bone of normal quality and no indication of a mineralization defect.
In a Phase 1 bioequivalence study conducted in 72 postmenopausal women receiving 150 mg orally every 28 days for a total of four doses, inhibition in serum CTX following the first dose was seen as early as 24 hours post-dose (median inhibition 28%), with median maximal inhibition (69%) seen 6 days later. Following the third and fourth dose, the median maximum inhibition 6 days post dose was 74% with reduction to a median inhibition of 56% seen 28 days following the fourth dose. With no further dosing, there is a loss of suppression of biochemical markers of bone resorption.
Mechanism of Action: Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group of bisphosphonates, which act on bone tissue and specifically inhibit osteoclast activity. It does not interfere with osteoclast recruitment. The selective action of ibandronic acid on bone tissue is based on the high affinity of this compound for hydroxyapatite, which represents the mineral matrix of the bone.
Ibandronic acid reduces bone resorption, with no direct effect on bone formation. In postmenopausal women, it reduces the elevated rate of bone turnover towards premenopausal levels, leading to a progressive net gain in bone mass.
Daily or intermittent administration of ibandronic acid results in reduced bone resorption as reflected in reduced levels of serum and urinary biochemical markers of bone turnover, increased BMD and a decreased incidence of fractures.
Clinical/Efficacy Studies: Treatment of postmenopausal osteoporosis: In the initial three-year, randomized, double-blind, placebo-controlled, fracture study (MF 4411), a statistically significant and medically relevant decrease in the incidence of new radiographic morphometric and clinical vertebral fractures was demonstrated. Ibandronic acid was evaluated at oral doses of 2.5 mg daily and 20 mg intermittently (20 mg every other day for 12 doses at the start of each 3-month cycle, followed by a 9-10 week drug-free interval).
Ibandronic acid was taken 60 minutes before the first food or drink of the day (post-dose fasting period). The study enrolled 2,946 women aged 55 to 80 years (2,928 were eligible for efficacy), who were at least 5 years postmenopausal, who had a lumbar spine BMD 2 to 5 SD below the premenopausal mean (T-score) in at least one vertebra [L1-L4], and who had one to four prevalent vertebral fractures. All patients received 500 mg calcium and 400 IU vitamin D daily.
Ibandronic acid showed a statistically significant and medically relevant reduction in the incidence of new vertebral fracture with both regimens tested. The 2.5 mg daily regimen reduced the occurrence of new radiographic vertebral fractures by 62% over the three year duration of the study. Clinical vertebral fractures were also reduced by 49%. The strong effect on vertebral fractures was furthermore reflected by a statistically significant reduction of height loss compared to placebo.
The anti-fracture effect was consistent over the duration of the study.
There was no indication of a waning of the effect over time.
Although the clinical fracture trial for ibandronic acid was not specifically designed to demonstrate fracture efficacy in non-vertebral fractures, a relative risk reduction of similar magnitude (69%) as demonstrated for vertebral fractures was observed for non-vertebral fractures in a subgroup of patients being at higher fracture risk (femoral neck BMD T-score <-3.0 SD).
The observation of non-vertebral fracture efficacy in high-risk subgroups is consistent with clinical trial findings for other bisphosphonates.
Three-year lumbar spine BMD increase compared to placebo was 5.3% for the daily regimen. Compared to baseline this increase was 6.5%.
Biochemical markers of bone turnover (such as urinary CTX and serum osteocalcin) showed the expected pattern of suppression to premenopausal levels and reached maximum suppression within a period of 3-6 months. A clinically meaningful reduction of 50% and 78% of biochemical markers of bone resorption was observed as early as one month after start of treatment with Ibandronic acid 2.5 mg daily and 20 mg intermittently, respectively.
Decreases in biochemical markers of bone resorption were evident within 7 days of starting treatment.
Ibandronic acid 150 mg once monthly: Bone mineral density: Ibandronic acid 150 mg once monthly was shown to be at least as effective as Ibandronic acid 2.5 mg daily at increasing BMD in a two year, double-blind, multicentre study (BM 16549) of postmenopausal women with osteoporosis (lumbar spine BMD T score below -2.5 SD at baseline). This was demonstrated in both the primary analysis at one year and in the confirmatory analysis at two years endpoint (Table 1). (See Table 1.)

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Furthermore, Ibandronic acid 150 mg once monthly was proven superior to Ibandronic acid 2.5 mg daily for increases in lumbar spine BMD in a prospectively planned analysis at one year, p=0.002, and at two years, p<0.001.
At one year (primary analysis), 91.3% (p=0.005) of patients receiving Ibandronic acid 150 mg once monthly had a lumbar spine BMD increase above or equal to baseline (BMD responders), compared with 84.0% of patients receiving Ibandronic acid 2.5 mg daily. At two years, 93.5% (p=0.004) and 86.4% of patients receiving Ibandronic acid 150 mg once monthly or Ibandronic acid 2.5 mg daily, respectively, were responders.
For total hip BMD, 90.0% (p<0.001) of patients receiving Ibandronic acid 150 mg once monthly and 76.7% of patients receiving Ibandronic acid 2.5 mg daily had total hip BMD increases above or equal to baseline at one year. At two years 93.4% (p<0.001) of patients receiving Ibandronic acid 150 mg once monthly and 78.4%, of patients receiving Ibandronic acid 2.5 mg daily had total hip BMD increases above or equal to baseline.
When a more stringent criterion is considered, which combines both lumbar spine and total hip BMD, 83.9% (p<0.001) and 65.7% of patients receiving Ibandronic acid 150 mg once monthly or Ibandronic acid 2.5 mg daily, respectively, were responders at one year. At two years, 87.1% (p<0.001) and 70.5%, of patients met this criterion in the 150 mg monthly and 2.5 mg daily arms respectively.
Biochemical markers of bone turn-over Clinically meaningful reductions in serum CTX levels were observed at all time points measured, i.e. months 3, 6, 12 and 24. After one year (primary analysis) the median relative change from baseline was -76% for Ibandronic acid 150 mg once monthly and -67% for Ibandronic acid 2.5 mg daily.
At two years the median relative change was -68% and -62%, in the 150 mg monthly and 2.5 mg daily arms respectively.
At one year, 83.5% (p= 0.006) of patients receiving Ibandronic acid 150 mg once monthly and 73.9% of patients receiving Ibandronic acid 2.5 mg daily were identified as responders (defined as a decrease ≥50% from baseline).
At two years 78.7% (p=0.002) and 65.6% of patients were identified as responders in the 150 mg monthly and 2.5 mg daily arms respectively.
Based on the results of study BM 16549, Ibandronic acid 150 mg once monthly is expected to be at least as effective in preventing fractures as Ibandronic acid 2.5 mg daily.
Pharmacokinetics: The pharmacological effects of ibandronic acid are not directly related to actual plasma concentrations. This was demonstrated by various studies in animals and in humans, in which equivalent efficacy of ibandronic acid was demonstrated following either daily or intermittent regimens, consisting of a drug-free interval of several weeks (at least 6 weeks in rats, at least 11 weeks in dogs, at least 30 days in monkeys, and at least 9.5 weeks in humans) provided the same total dose was administered over this period.
Absorption: The absorption of ibandronic acid in the upper gastrointestinal tract is rapid after oral administration and plasma concentrations increase in a dose-proportional manner up to 50 mg oral intake, with greater than dose-proportional increases seen above this dose. Maximum observed plasma concentrations were reached within 0.5 to 2 hours (median 1 hour) in the fasted state and absolute bioavailability was about 0.6%. The extent of absorption is impaired when taken together with food or beverages (other than plain water). Bioavailability is reduced by about 90% when ibandronic acid is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects. There is no meaningful reduction in bioavailability provided ibandronic acid is taken 60 minutes before a meal. Both bioavailability and BMD gains are reduced when food or beverage are taken less than 60 minutes after Ibandronic acid.
Distribution: After initial systemic exposure, ibandronic acid 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 reaching the bone is estimated to be 40-50% of the circulating dose.
Protein binding in human plasma is low (approximately 85% bound at therapeutic concentrations), and thus there is a low potential for drug-drug interaction due to displacement.
Metabolism: There is no evidence that ibandronic acid is metabolized in animals or humans.
Elimination: The absorbed fraction of ibandronic acid is removed from the circulation via bone absorption (40-50%) and the remainder is eliminated unchanged by the kidney.
The unabsorbed fraction of ibandronic acid is eliminated unchanged in the feces.
The range of observed apparent half-lives is broad and dependent on dose and assay sensitivity, but the apparent terminal half-life is generally in the range of 10-72 hours.
Early plasma levels fall quickly reaching 10% of peak values within 3 and 8 hours after intravenous or oral administration respectively.
Total clearance of ibandronic acid is low with average values in the range 84-160 ml/min.
Renal clearance (about 60 ml/min in healthy postmenopausal females) accounts for 50-60% of total clearance and is related to creatinine clearance.
The difference between the apparent total and renal clearances is considered to reflect the uptake by bone.
Pharmacokinetics in Special Populations: Gender: Bioavailability and pharmacokinetics of ibandronic acid are similar in both men and women.
Race: There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronic acid disposition. There are few data available on patients of African origin.
Patients with renal impairment: Renal clearance of ibandronic acid in patients with various degrees of renal impairment is linearly related to creatinine clearance (CLcr). No dosage adjustment is necessary for patients with mild or moderate renal impairment (CLcr >30 ml/min), as shown in study BM 16549 where the majority of patients fell into these categories.
Subjects with severe renal impairment (CLcr ≤30 ml/min) receiving oral administration of 10 mg ibandronic acid daily for 21 days, had 2-3 fold higher plasma concentrations than subjects with normal renal function (total clearance = 129 ml/min). Total clearance of ibandronic acid was reduced to 44 ml/min in the subjects with severe renal impairment.
After i.v. administration of 0.5 mg, total, renal, and non-renal clearances decreased by 67%, 77% and 50%, respectively, in subjects with severe renal impairment.
However, there was no reduction in tolerability associated with the increase in exposure.
Patients with hepatic impairment: There are no pharmacokinetic data for ibandronic acid in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronic acid which is not metabolized but is cleared by renal excretion and by uptake into bone. Therefore, dosage adjustment is not necessary in patients with hepatic impairment. Further, as protein binding of ibandronic acid is low (85%) at therapeutic concentrations, hypoproteinemia in severe liver disease is unlikely to lead to clinically significant increases in free plasma concentration.
Elderly: In a multivariate analysis age was not found to be an independent factor of any of the pharmacokinetic parameters studied. As renal function decreases with age, this is the only factor to take into consideration (see Patients with renal impairment as previously mentioned).
Children: There are no data on the use of Ibandronic acid in patients less than 18 years old.
Toxicology: Preclinical Safety: Toxic effects in animals were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

Ibandronic acid 150 mg is indicated for the treatment of postmenopausal osteoporosis, to reduce the risk of fractures.
Treatment of Osteoporosis: Osteoporosis may be confirmed by the finding of low bone mass (T score <-2.0 SD) and the presence or history of osteoporotic fracture, or a low bone mass (T-score -2.5 SD) in the absence of documented pre-existing osteoporotic fracture.

Standard Dosage: The recommended dose of Ibandronic acid for treatment is one 150 mg film-coated tablet once a month. The tablet should preferably be taken on the same date each month.
Ibandronic acid should be taken 60 minutes before the first food or drink (other than water) of the day (see Interactions) or any other oral medication or supplementation (including calcium): Tablets should be swallowed whole with a full glass of plain water (180 to 240 ml) while the patient is sitting or standing in an upright position. Patients should not lie down for 60 minutes after taking Ibandronic acid.
Plain water is the only drink that should be taken with Ibandronic acid. Please 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.
Patients should receive supplemental calcium or vitamin D if dietary intake is inadequate.
In case a once-monthly dose is missed, patients should be instructed to take one Ibandronic acid 150 mg tablet the morning after the tablet is remembered, unless the time to the next scheduled dose is within 7 days. Patients should then return to taking their dose once a month on their originally scheduled date.
If the next scheduled dose is within 7 days, patients should wait until their next dose and then continue taking one tablet once a month as originally scheduled.
Patients should not take two 150 mg tablets within the same week.
Special Dosage Instructions: Patients with hepatic impairment: No dosage adjustment is necessary (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Patients with renal impairment: No dosage adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is ≥30 ml/min.
Below 30 ml/min creatinine clearance, the decision to administer Ibandronic acid should be based on an individual risk-benefit assessment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Elderly: No dosage adjustment is necessary.
Children: Safety and efficacy have not been established in patients less than 18 years old.

No specific information is available on the treatment of overdosage with Ibandronic acid. However, oral overdosage may result in upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer. Milk or antacids should be given to bind Ibandronic acid. Owing to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.

Ibandronic acid is contraindicated in patients with known hypersensitivity to ibandronic acid or to any of the excipients. Ibandronic acid is contraindicated in patients with uncorrected hypocalcemia. As with all bisphosphonates indicated in the treatment of osteoporosis, pre-existing hypocalcemia needs to be corrected before initiating therapy with Ibandronic acid. As with several bisphosphonates, Ibandronic acid is contraindicated in patients with abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia (see Precautions). Ibandronic acid is contraindicated in patients who are unable to stand or sit upright for at least 60 minutes (see Dosage & Administration and Precautions).

Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Ibandronic acid therapy.
Adequate intake of calcium and vitamin D is important in all patients.
Orally administered bisphosphonates may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and apotential for worsening of the underlying disease, caution should be used when Ibandronic acid is given to patients with active upper gastrointestinal problems (e.g. known Barrett's esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers).
Adverse experiences such as esophagitis, esophageal ulcers and esophageal erosions, in some cases severe and requiring hospitalization, rarely with bleeding or followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. The risk of severe esophageal adverse experiences appears to be greater in patients who do not comply with the dosing instruction and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Patients should pay particular attention and be able to comply with the dosing instructions (see Dosage & Administration).
Physicians should be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue Ibandronic acid and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
While no increased risk was observed in controlled clinical trials there have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications. Since NSAIDs and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant medication with Ibandronic acid.
Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. Most cases have been in cancer patients undergoing dental procedures, but some have occurred in patients with postmenopausal osteoporosis or other diagnoses. Known risk factors for osteonecrosis of the jaw include a diagnosis of cancer, concomitant therapies (e.g., chemotherapy, including angiogenesis inhibitors, radiotherapy, corticosteroids), and co-morbid disorders (e.g., anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases have been in patients treated with bisphosphonates intravenously but some have been in patients treated orally.
For patients who develop osteonecrosis of the jaw while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit-risk assessment.
Cases of osteonecrosis of other oro-facial sites including the external auditory canal have also been reported in patients treated with bisphosphonates including IBN. Risk factors are similar as for ONJ. Other risk factors may include repetitive minor trauma (e.g., habitual cotton bud use). The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who present with ear symptoms including chronic ear infections.
Atypical fractures of the femur: Atypical subtrochanteric and diaphyseal femoral fractures have been reported with bisphosphonate therapy, primarily in patients receiving long-term treatment for osteoporosis. These transverse or short oblique fractures can occur anywhere along the femur from just below the lesser trochanter to just above the supracondylar flare. These fractures occur after minimal or no trauma and some patients experience thigh or groin pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. Discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment.
During bisphosphonate treatment patients should be advised to report any thigh, hip or groin pain and any patient presenting with such symptoms should be evaluated for an incomplete femur fracture.
Renal impairment: Due to limited clinical experience, Ibandronic acid (Bonviva) is not recommended for patients with a creatinine clearance below 30 ml/min.
Galactose intolerance: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. medicinal product.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.

Ibandronic acid should not be used during pregnancy.
Pregnancy: There was no evidence for a direct fetal toxic or teratogenic effect of ibandronic acid in daily orally treated rats and rabbits and there were no adverse effects on the development in F1 offspring in rats. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as a class. They include a decreased number of implantation sites, interference with natural delivery (dystocia), and an increase in visceral variations (renal pelvis ureter syndrome). Specific studies for the monthly regimen have not been performed.
There is no clinical experience with Ibandronic acid in pregnant women.
Lactation: In lactating rats treated with 0.08 mg/kg/day i.v. ibandronic acid, the highest concentration of ibandronic acid in breast milk was 8.1 ng/ml and was seen in the first 2 hours after i.v. administration. After 24 hours, the concentration in milk and plasma was similar, and corresponded to about 5% of the concentration measured after 2 hours. It is not known whether Ibandronic acid is excreted in human milk.

Experience from Clinical Trials: Treatment of postmenopausal osteoporosis: Once-monthly dosing: In a two-year study in postmenopausal women with osteoporosis (BM 16549) the overall safety of Ibandronic acid 150 mg once monthly and Ibandronic acid 2.5 mg daily was similar. The overall proportion of patients who experienced an adverse drug reaction, i.e. adverse event with a possible or probable relationship to trial medication, was 22.7% and 25.0% for Ibandronic acid 150 mg once monthly and 21.5% and 22.5% for Ibandronic acid 2.5 mg daily after one and two years, respectively. The majority of adverse drug reactions were mild to moderate in intensity. Most cases did not lead to cessation of therapy.
Tables 2 and 3 list adverse drug reactions occurring in more than 1% of patients treated with Ibandronic acid 150 mg monthly or 2.5 mg daily in study BM 16549 and in patients treated with Ibandronic acid 2.5 mg daily in study MF 4411. The tables show the adverse drug reactions in the two studies that occurred with a higher incidence than in patients treated with placebo in study MF 4411. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Data at one year from BM 16549 are represented in Table 2 and cumulative data for the two years from BM 16549 are represented in Table 3. (See Tables 2 and 3.)

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Adverse drug reactions occurring at a frequency of less than or equal to 1%: The following list provides information on adverse drug reactions (considered possibly or probably related to treatment by the investigator) reported in study MF 4411 occurring more frequently with Ibandronic acid 2.5 mg daily than with placebo and study BM 16549 occurring more frequently with Ibandronic acid 150 mg once monthly than with Ibandronic acid 2.5 mg daily. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness: Uncommon (1/100 - 1/1,000): Gastrointestinal Disorders: gastritis, oesophagitis including Oesophageal ulcerations or strictures, vomiting, dysphagia.
Nervous System Disorders: dizziness.
Musculoskeletal and Connective Tissue Disorders: back pain.
Rare (1/1,000 - 1/10,000): Gastrointestinal Disorders: duodenitis.
Immune System Disorders: hypersensitivity reactions.
Skin and Subcutaneous Tissue Disorders: angioedema, face oedema, urticaria.
Patients with a previous history of gastrointestinal disease including patients with peptic ulcer without recent bleeding or hospitalisation, and patients with dyspepsia or reflux controlled by medication were included in the once monthly treatment study.
For these patients, there was no difference in the incidence of upper gastrointestinal adverse events with the 150 mg once monthly regimen compared to the 2.5 mg daily regimen.
Abnormal laboratory findings: In the pivotal three-year study with Ibandronic acid 2.5 mg daily (MF 4411) there was no difference compared with placebo for laboratory abnormalities indicative of hepatic or renal dysfunction, impaired hematologic system, hypocalcemia or hypophosphatemia. Similarly, no differences were noted between the groups in study BM 16549 after one and two years.
Osteonecrosis of jaw: Osteonecrosis of the jaw and other oro-facial sites, including the external auditory canal, has been reported very rarely in patients treated with ibandronic acid (see Precautions). The majority of the reports refer to cancer patients, but such cases have also been reported in patients treated for osteoporosis.
Osteonecrosis of the jaw is generally associated with tooth extraction and/or local infection (including osteomyelitis). Diagnosis of cancer, chemotherapy, radiotherapy, corticosteroids and poor oral hygiene are also deemed as risk factors (see Precautions).
Ocular inflammation: Ocular inflammation events such as uveitis, episcleritis and scleritis have been reported with ibandronic acid. In some cases, these events did not resolve until the ibandronic acid was discontinued.
Anaphylactic reaction/shock: Cases of anaphylactic reaction/shock, including fatal events, have been reported in patients treated with intravenous ibandronic acid.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
The patient must seek medical attention immediately at the first sign of any adverse drug reaction.
Post Marketing: Musculoskeletal and connective tissue disorders: Osteonecrosis of the jaw has been reported very rarely in patients treated with ibandronic acid (refer to Precautions).

Drug-Food Interactions: Products containing calcium and other multivalent cations (such as aluminium, magnesium, iron), including milk and food, are likely to interfere with absorption of Ibandronic acid which is consistent with findings in animal studies. Therefore, with such products, including food, intake must be delayed for 60 minutes following oral administration.
Drug-Drug Interactions: It is likely that calcium supplements, antacids and some oral medications containing multivalent cations (such as aluminium, magnesium, iron) are likely to interfere with the absorption of Ibandronic acid.
Therefore, patients must wait 60 minutes after taking Ibandronic acid before taking other oral medications.
Pharmacokinetic interaction studies in postmenopausal women have demonstrated the absence of any interaction potential with tamoxifen or hormone replacement therapy (estrogen). No interaction was observed when co-administered with melphalan/prednisolone in patients with multiple myeloma.
In healthy male volunteers and postmenopausal women, i.v. ranitidine caused an increase in ibandronic acid bioavailability of about 20%, probably as a result of reduced gastric acidity. However, since this increase is within the normal range of the bioavailability of ibandronic acid, no dosage adjustment is required when Ibandronic acid is administered with H2-antagonists or other drugs which increase gastric pH.
In relation to disposition, no drug interactions of clinical significance are considered likely, since ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and has been shown not to induce the hepatic cytochrome P450 system in rats. Furthermore, plasma protein binding is low at therapeutic concentrations and ibandronic acid is therefore unlikely to displace other drugs. Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.
The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other drugs.
In a one-year study in postmenopausal women with osteoporosis (BM16549), the incidence of upper gastrointestinal events in patients concomitantly taking aspirin or NSAIDs was similar in patients taking Ibandronic acid 2.5 mg daily or 150 mg once monthly.
Of over 1500 patients enrolled in study BM 16549 comparing monthly with daily dosing regimens of ibandronic acid, 14% of patients used histamine (H2) blockers or proton pump inhibitors. Among these patients, the incidence of upper gastrointestinal events in the patients treated with Ibandronic acid 150 mg once monthly was similar to that in patients treated with Ibandronic acid 2.5 mg daily.

Disposal of Unused/Expired Medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection systems" if available in the location.

Store at temperatures not exceeding 30°C.

Planning When To Take Ibandronic Acid Tablet: The dose of Ibandronic acid 150 mg is one tablet once a month.
Choose one day of the month that will be easy to remember: either the same date (such as the 1st of each month); or the same day (such as the first Sunday of each month).
Use the peel-off stickers to mark the dates on your calendar. Once you've taken your tablet, put a tick in the box on the sticker.
It is important to keep taking Ibandronic acid tablet 150 mg every month. Remember to contact your doctor when you need a new prescription.

Agents Affecting Bone Metabolism

M05BA06 - ibandronic acid ; Belongs to the class of bisphosphonates. Used in the treatment of bone diseases.

Rx