Adronil™

  • [ Ibandronate Sodium ]

     Description:

    Adronil is a nitrogen-containing bisphosphonate.

    Type of Dosage Form:

    Film coated tablets.

    Route of Administration:

    Oral.

    Qualitative and Quantitative Composition:

    Active ingredient: Ibandronate sodium monohydrate One 150 mg film-coated tablet contains 168.75 mg of Ibandronate sodium monohydrate equivalent to 150 mg of ibandronate.

    Mechanism of Action:

    Ibandronate sodium is a highly potent bisphosphonate belonging to the nitrogen-containing group of bisphosphonates, which act on bone tissue and specifically inhibit osteoclastic activity. It does not interfere with osteoclast recruitment. The selective action of ibandronate sodium on bone tissue is based on the high affinity of this compound for hydroxyapatite, which represents the mineral matrix of the bone.

    Ibandronate sodium 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 ibandronate sodium 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.

    Therapeutic Indication(s):

    Adronil 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  total bone density (T-score <-2.5) and the presence or history of osteoporotic fracture, or total bone density (T-score <-2.5 ) in the absence of documented pre-existing osteoporotic fracture. 

    Dosage and Administration 

    The recommended dose of Adronil for treatment is one 150 mg film-coated tablet once a month. The tablet should preferably be taken on the same date of each month. Adronil should be taken 60 minutes before the first food or drink (other than water) of the day 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 Adronil.

    Plain water is the only drink that should be taken with Adronil. 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 take supplemental calcium or vitamin D if dietary intake is inadequate.

    If once-monthly dose is missed, patients should be instructed to take one Adronil 150 mg 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 move taking their dose once a month on their originally scheduled date.

    If the next scheduled dose is within 7 days, patients should wait until the 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.

    Patients with renal impairment: No dosage adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal or greater than 30 ml/min. Below 30 ml/min creatinine clearance, the decision to administer Adronil should be based on an individual risk-benefit assessment.

    Elderly: No dosage adjustment is necessary.

    Children: Safety and efficacy have not been established in patients less than 18 years old.

     Contraindications:

    Adronil is contraindicated in patients with known hypersensitivity to ibandronate sodium or to any of the excipients. Adronil 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 Adronil. Adronil is contraindicated in renal failure.

    Warnings and Precautions

    General

    Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Adronil therapy. Adequate intake of calcium and vitamin D is important in all patients.

    Bisphosphonates have been associated with dysphagia, esophagitis and esophageal or gastric ulcers. Therefore, patients should pay particular attention and be able to comply with the dosing instructions.

    Physicians should be alert to signs or symptoms signaling a possible esophageal reaction during therapy, and patients should be instructed to discontinue Adronil and seek medical attention if they develope symptoms of esophageal irritation

    Since NSAIDs and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant medication with Adronil.

    Osteonecrosis of the jaw has been reported in patients treated with bisphosphonates. Most cases have been reported in cancer patients undergoing dental procedures, but some have occurred in patients with postmenopausal osteoporosis or other diagnosis. Known risk factors for osteonecrosis of the jaw include a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy, corticosteroids), and co-morbid disorders (eg, anemia, coagulopathy, infection, pre-existing dental disease). Most reported cases have been in patients treated with bisphosphonates intravenously but some have been treated orally.

    For patients who develope osteonecrosis of the jaw (ONJ) 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.

    Ability to Drive and Use Machines:

    No studies on the effects on the ability to drive and use machines have been performed.
     

    Interactions with other Medicinal Products and other Forms of Interaction

    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 Ibandronate 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 Adronil. Therefore, patients must wait 60 minutes after taking Adronil 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 ibandronate 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 ibandronate, no dosage adjustment is required when Adronil 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 ibandronate 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 ibandronate is therefore unlikely to displace other drugs.

    Ibandronate 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 ibandronate 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 ibandronate sodium, 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 ibandronate 150 mg once monthly was similar to that in patients treated with ibandronate 2.5 mg daily.

    Use in Special Populations

    Pregnancy

    Pregnancy category C

    Adronil should not be used during pregnancy as no adequate data is available.

    Nursing Mothers:

    Adronil should not be used during lactation as no adequate data is available on humans.

    Pediatric Use:

    Refer to special dosage instructions

    Geriatric Use:

    Refer to special dosage instructions

    Renal Impairment:

    Refer to special dosage instructions

    Hepatic Impairment:

    Refer to special dosage instructions 

    Overdose:

    No specific information is available on the treatment of overdosage with Adronil. 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 Adronil. Owing to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright.

     PHARMACODYNAMIC PROPERTIES AND EFFECTS:

    The pharmacodynamic action of ibandronate sodium is inhibition of bone resorption. In vivo, ibandronate sodium 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 ibandronate sodium 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 ibandronate sodium 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 or 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 ibandronate sodium was confirmed in a clinical trial (MF 4411), in which as no adequate data is available demonstrated anti-fracture efficacy. Both daily and intermittent (with a drug-free interval of 9-10 weeks per quarter) oral doses of as no adequate data is available 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.

    PHARMACOKINETICS 

    Absorption

    The absorption of ibandronate sodium 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 ibandronate sodium is administered with a standard breakfast in comparison with bioavailability seen in fasted subjects. There is no meaningful reduction in bioavailability provided ibandronate sodium 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 Ibandronate.

    Distribution

    After initial systemic exposure, ibandronate sodium 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 ibandronate sodium is metabolized in animals or humans.

    Elimination

    The absorbed fraction of ibandronate sodium is removed from the circulation via bone absorption (40-50%) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronate sodium is eliminated unchanged in the feaces.

    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 ibandronate sodium 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 ibandronate sodium are similar in both men and women.

    Race

    There is no evidence for clinically relevant interethnic differences between Asians and Caucasians in ibandronate sodium disposition. There are few data available on patients of African origin.

    Patients with renal impairment

    Renal clearance of ibandronate sodium 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 ibandronate sodium 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 ibandronate sodium 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 ibandronate sodium in patients who have hepatic impairment. The liver has no significant role in the clearance of ibandronate sodium 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 ibandronate sodium 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', mentioned above).

    Children

    There are no data on the use of Adronil in patients less than 18 years old. 

    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.

     Carcinogenicity

    No indication of carcinogenic and genotoxic potential has been observed.

     Storage

    Store at room temperature (15 C 30 C)

    To be sold on prescription of a registered medical practitioner only.

    Keep all medicines out of reach of the children.

    Protect from moisture, freezing, excessive heat and sunlight.



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