Ibandren

Each tablet contains: Ibandronic sodium monohydrate 168.75 mg (as Ibandronic acid 150 mg).

Bisphosphonate.
Pharmacology: Pharmacodynamics: Osteoporosis is characterized by decreased bone mass and increased fracture risk, most commonly at the spine, hip and wrist. The diagnosis can be confirmed by a finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. While osteoporosis occurs in both men and women, it is most common among women following menopause. In healthy human, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly formed bone. In postmenopausal osteoporosis, bone resorption excess bone formation, leading to bone loss and increased risk of fracture. After menopause, the risk of fractures of the spine and hip increases; approximately 40% of 50-year-old women will experience and osteoporosis-related fracture during their remaining lifetimes.
IBANDREN 150 mg Film Coated Tablet produced biochemical changes indicative of dose dependent inhibition of bone resorption, including decreases of biochemical marker of bone collagen degradation (such as deoxypyridinoline, and cross-linked C-telopeptide of Type I collagen) in the daily dose range of 0.25 mg to 5 mg and once-monthly doses from 100 mg to 150 mg in postmenopausal women.
Treatment with 2.5 mg daily IBANDREN 150 mg Film Coated Tablet resulted in decreases in biochemical markers of bone turnover, including urinary C-terminal telopeptide of Type I collagen (uCTX) and serum osteocalcin, to levels similar to those in premenopausal women. Changes in markers of bone formation were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and formation. Treatment with 2.5 mg daily IBANDREN 150 mg Film-Coated Tablet decreased levels of uCTX within 1 month of starting treatment and decreased levels of osteocalcin within 3 months. Bone turnover markers reached a nadir of approximately 64% below baseline values by 6 months of treatment and remained stable with continued treatment up to 3 years. Following treatment discontinuation, there is a return to pretreatment baseline rates of elevated bone resorption associated with postmenopausal osteoporosis.
In a 1-year, study comparing once-monthly vs. once-daily oral dosing regimens, the median decrease from baseline in serum CTX values was -76% for patients treated with the 150 mg once-monthly regimen and -67% for patients treated with the 2.5 mg daily regimen. In a 1-year, prevention study comparing IBANDREN 150 mg Film Coated Tablet once-monthly to placebo, the median placebo-subtracted decrease in sCTX was -49.8%.
Pharmacokinetics: Absorption: The absorption of oral Ibandronate occurs in the upper gastrointestinal tract. Plasma concentrations increase in a dose-linear manner up to 50 mg oral intake and increases nonlinearly above this dose. Following oral dosing, the time to maximum observed plasma Ibandronate concentrations ranged from 0.5 to 2 hours (median 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 IBANDREN 150 mg Film Coated Tablet 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 mean. However, both bioavailability and the effect on bone mineral density (BMD) are reduced when food or beverages are taken less than 60 minutes following an Ibandronate dose.
Distribution: After absorption, Ibandronate either rapidly binds to bone or is excreted into urine. In humans, the apparent terminal volume of distribution is at least 90 L, and the amount of dose removed from the circulation via the bone is estimated to be 40% to 50% of the calculating dose. In vitro protein binding in human serum was 99.5% to 90.0% over an Ibandronate concentration range of 2 to 10 ng/mL in one study and approximately 85.7% over a concentration range of 0.5 to 10 ng/mL in another study.
Metabolism: Ibandronate does not undergo hepatic metabolism and does not inhibit the hepatic cytochrome P450 system. Ibandronate is eliminated by renal excretion. Based on a rat study, the Ibandronate secretory pathway does not appear to include known acidic or basic transport systems involved in the excretion of other drugs. There is no evidence that Ibandronate is metabolized in humans.
Elimination: The portion of Ibandronate that is not removed from the circulation via bone absorption is eliminated unchanged by the kidney (approximately 50% to 60% of the absorbed dose). Unabsorbed Ibandronate is eliminated unchanged in the feces. The plasma elimination of Ibandronate is multiphasic. Its renal clearance and distribution into bone accounts for a rapid and early decline in plasma concentrations, reaching 10% of the Cmax within 3 or 8 hours after intravenous or oral administration, respectively. This is followed by a slower clearance phase as terminal half-life for Ibandronate is generally dependent on the dose studied on assay sensitivity. The observed apparent terminal half-life for the 150 mg Ibandronate Film Coated Tablet upon oral administration to healthy postmenopausal women ranges from 37 to 157 hours. Total clearance of Ibandronate is low, with average values in the range 84 to 160 mL/min. Renal clearance (about 60 mL/min in healthy postmenopausal females) accounts for 50% to 60% of total clearance and is related to creatinine clearance. The difference between the apparent total and renal appearances likely reflects bone uptake of the drug.
Toxicology: Preclinical Safety Data: Carcinogenesis: In a 104-week carcinogenicity, 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 (exposure 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-daily 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, 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 those findings to humans is unknown.
Mutagenesis: There was no evidence for a mutagenic or clastogenic potential of ibandronate in the following assays: In vitro bacterial mutagenesis assay in Salmonella typhimurium and Escherichia coli (Ames test), mammalian cell mutagenesis assay in Chinese hamster V79 cells, and chromosomal aberration test in human peripheral lymphocytes, each with and without metabolic activation. Ibandronate was not genotoxic in the in vivo mouse micronucleus tests for chromosomal damage.
Impairment of Fertility: In female rats treated from 14 days prior to mating through gestation, decreases in fertility, corpora lutea, and implantation sites were observed at an oral dose of 16 mg/kg/-day (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).
Animal Reproductive and Development Toxicity: In female rats given or as 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 Reference ID: 3728047 13 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 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 post implantation loss was observed in rats treated from 14 days before mating throughout lactation or during gestation, only at doses causing maternal dystocia and parturient 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 in inhibition of skeletal calcium mobilization resulting in hypocalcemia and dystocia.
Exposure of pregnant rats during the period of organogenesis resulted in an increased fetal incidence of RPU (Renal Pelvis Ureter) syndrome at oral doses greater than or equal to 10 mg/kg/day (greater than or equal to 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).
In pregnant rabbits given oral dose 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 mg and greater than or equal to 4 times the recommended human once-monthly oral dose of 150 mg, based on body surface are comparison, mg/m²). The deaths occurred prior to parturition and were associated with lung edema and hemorrhage. No significant fetal anomalies were observed.

Treatment and prevention of Postmenopausal Osteoporosis.

Take one IBANDREN 150mg Film Coated Tablet once a month on the same date each month. It should be taken with sufficient water in the morning. 1 hour before the first food or drink (other than water) of the day or any other oral medicine or supplementation including calcium antacids or vitamins to maximize absorption and clinical benefit.
It should be taken with sufficient water (180-240 mL) while standing or sitting in an upright position for 1 hour to reduce the potential for esophageal irritation. Avoid lying down for 1 hour after taking IBANDREN 150 mg Film Coated Tablet.
Avoid taking it with mineral water because it may interrupt with the absorption of ibandronate sodium.
In case a dose is missed, patients should be instructed to take one IBANDREN 150 mg Film Coated Tablet in 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 tablets within the same week.
Patients should receive supplemental calcium and/or Vitamin D if dietary intake is inadequate.

No specific information is available on the treatment of overdose. However, based on knowledge of this class 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 IBANDREN 150 mg Film Coated Tablet. Due to the risk of esophageal irritation, vomiting should not be induced, and the patient should remain fully upright. Dialysis would not be beneficial.

Patients who have hypersensitivity to Ibandronic acid of any ingredients contained in Ibandren 150 mg Film-Coated Tablet.
Patients with incurable hypocalcemia.
Patients who are unable to stand or sit upright for 1 hour at least.
Patients with abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.
Patients who have genetic factor related to lactose such as galactose intolerance, Lapp lactase deficiency and glucose-galactose malabsorption.

Upper Gastrointestinal Adverse Reactions: IBANDREN 150 mg Film Coated Tablet, like other biphosphates 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 IBANDREN 150 mg Film Coated Tablet is given to patients with active upper gastrointestinal problems. 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 biphosphates. 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 IBANDREN 150 mg Film Coated Tablet 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 (6-8 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. In patients who cannot comply with dosing instructions due to mental disability, therapy with IBANDREN 150 mg Film Coated Tablet should be used under appropriate supervision. There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and within complications, although no increased risk was observed in controlled clinical trials.
Hypocalcemia and Mineral Metabolism: Hypocalcemia has been reported in patients taking IBANDREN 150 mg Film Coated Tablet. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting IBANDREN 150 mg Film Coated Tablet therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate.
Musculoskeletal Pain: Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking IBANDREN 150 mg Film Coated Tablet and other bisphosphonates. The time to insert 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 re-challenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.
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 IBANDREN 150 mg Film Coated Table. 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, diagnosis of cancer, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders. The risk for 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 judgement 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.
Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Atypical, low-energy, or low-trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patient. 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 the evidence of comminution. Casualty 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 month 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 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 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.
Severe Renal Impairment: IBANDREN 150 mg Film Coated Tablet is not recommended for use in patients with severe renal impairment (creatinine clearance of less than 30 mL/min).
Effects on ability to drive and use machine (if applicable): On the basis of pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is expected that Ibandronic acid has no or negligible influence on the availability of to drive and use machines.
Use in Children: Safety of administration of IBANDREN 150 mg Film Coated Tablet is not demonstrated for children under 18 years old.
Use in the Elderly: No dose adjustment needed for Elderly.

Pregnancy Category - C.
Do not take IBANDREN 150 mg Film Coated Tablet if the patient is pregnant or breast-feeding. It is not known whether IBANDREN 150 mg Film Coated Tablet is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when IBANDREN 150 mg Film Coated Tablet is administered to a nursing woman. In lactating rats treated with intravenous doses, Ibandronate was present in breast milk from 2-24 hours after dose administration. Concentrations in milk averaged 1.5 times plasma concentration.

Esophagus problems: Some people who take IBANDREN 150 mg Film Coated Tablet may develop problems in the esophagus. These problems include irritation, inflammation, or ulcers of the esophagus which may sometime bleed. It is important to take IBANDREN 150 mg Film Coated Tablet exactly as prescribed to help lower the chance of getting esophagus problems. Stop taking IBANDREN 150 mg Film Coated Tablet and call the doctor right away if the patient gets chest pain, new or worsening heartburn, or have trouble or pain when swallowing.
Low Calcium levels in the blood (Hypocalcemia): IBANDREN 150 mg Film Coated Tablet may lower the calcium levels in the blood. If the patient has low blood calcium before starting to take IBANDREN 150 mg Film Coated Tablet, it may get worse during treatment. The low blood calcium must be treated before taking IBANDREN 150 mg Film Coated Tablet. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call the doctor right away if the patient has symptoms of low blood calcium such as: Spasms, twitches, or cramps in the muscles, numbness or tingling in the finger, toes, or around the mouth. The doctor may prescribe calcium and vitamin D to help prevent low calcium levels in the blood.
Bone, joint or muscle pain: Some people who take IBANDREN 150 mg Film Coated Tablet develop severe bone, joint or muscle pain.
Severe jaw bone problems (Osteonecrosis): Severe jaw bone problems may happen when the patient takes IBANDREN 150 mg Film Coated Tablet.
The doctor may examine the mouth or the doctor may tell the patient to see the dentist before starting IBANDREN 150 mg Film Coated Tablet.
Unusual thigh bone fractures: Some people developed unusual fractures in their thigh bone. Symptoms of fracture may include new or unusual pain in the hip, groin or thigh.
Common Side effects: Back pain, Heartburn, Stomach area (abdominal) pain, pain in the arms and legs, diarrhea, headache, muscle pain, flu-like symptoms.
The patient may get allergic reactions such as hives, breathing difficulties, swelling of the face, lips, tongue or throat, or feeling faint. Tell the doctor if the patient experiences any side effect that is bothersome, although these are not all the possible side effects. For more information, ask the doctor or pharmacist.

Medicinal Product-Food Interaction: Oral bioavailability of Ibandronic acid is generally reduced in the presence of food. In particular, products containing calcium, including milk and other multivalent cations (such as aluminum, magnesium, iron), are likely to interfere with absorption of Ibandronic acid, which is consistent in animal studies. Patients should fast overnight (at least 6 hours) before taking Ibandronic acid and continue fasting for 1 hour following the intake of Ibandronic acid.
Interactions with other Medicinal Products: Metabolic interactions are not considered likely, since Ibandronic acid does not inhibit the major hepatic P450 isoenzymes and have been shown not to induce the hepatic cytochrome P450 system in rats. Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.
Acetylsalicylic acid and NSAIDs: Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and bisphosphonates are associated with gastrointestinal irritation. Caution should be taken during concomitant administration.
H2 blockers or Proton Pump Inhibitors: Of over 1500 patients enrolled in study BM 16549 comparing monthly with daily dosing regimens of Ibandronic acid, 14% and 18% of patients used histamine (H2) blockers or Proton Pump Inhibitors after one and two years, respectively. Among these patients, the incidence of upper gastrointestinal events in the patients treated with Ibandronic acid 150 mg once monthly is similar to that in patients treated with Ibandronic acid 2.5 mg daily. In healthy male volunteers and postmenopausal women, intravenous administration of ranitidine cause and increase in Ibandronic acid bioavailability of about 20%, probably as a result of reduced gastric acidity. However, since this increase is within the normal variability of the bioavailability of Ibandronic acid, no dose adjustment is considered necessary when Ibandronic acid is administered with H2-antagonists or other active substances which increase gastric pH.

Store at temperatures not exceeding 30°C.
Shelf Life: 36 months from the manufacturing date.

Agents Affecting Bone Metabolism

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

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