IBANDRO

Ibandronic Acid (As Sodium Monohydrate)

150 mg Film-Coated Tablets

PRESENTATION

Dosage Form: Film-Coated Tablet

Strength: 150 mg 

Generic Name: Ibandronic Acid (As Sodium Monohydrate).

Packing: Blister

Pack Size:1*1

CLINICAL PARTICULARS

Therapeutic Indications

• Treatment of osteoporosis in postmenopausal women at increased risk of fracture.

*A reduction in the risk of vertebral fractures has been demonstrated, efficacy on femoral    neck fractures has not been established.

Posology And Method of Administration

Posology

The recommended dose 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 after an overnight fast (at least 6 hours) and 1 hour before the first food or drink (other than water) of the day or any other oral medicinal products or

supplementation (including calcium).

In case a 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 tablets within the same week.

Patients should receive supplemental calcium and / or vitamin D if dietary intake is inadequate.

The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of Ibandronic Acid on an individual patient basis, particularly after 5 or more years of use.

Special Populations

• Patients With Renal Impairment

Ibandronic Acid is not recommended for patients with a creatinine clearance below 30 ml/min due to limited clinical experience.

No dose adjustment is necessary for patients with mild or moderate renal impairment where creatinine clearance is equal or greater than 30 ml/min.

• Patients With Hepatic Impairment

No dose adjustment is required.

• Elderly Population (>65 years)

No dose adjustment is required.

• Pediatric Population

There is no relevant use of Ibandronic Acid in children below 18 years, and Ibandronic Acid was not studied in this population.

Method of Administration

• For oral use.

• Tablets should be swallowed whole with a glass of water (180 to 240 ml) while the patient is sitting or standing in an upright position.
• Water with a high concentration of calcium should not be used. If there is a concern regarding potentially high levels of calcium in the tap water (hard water), it is advised to use bottled water with a low mineral content.
• Patients should not lie down for 1 hour after taking Ibandronic Acid.
• Water is the only drink that should be taken with Ibandronic Acid.
• Patients should not chew or suck the tablet, because of a potential for oropharyngeal ulceration.

CONTRAINDICATIONS

• Hypersensitivity to Ibandronic acid or to any of the excipients.
• Hypocalcemia
• Abnormalities of the esophagus delay esophageal emptying such as stricture or achalasia.
• Inability to stand or sit upright for at least 60 minutes.

Special Warnings and Precautions for Use

• Hypocalcemia

Existing hypocalcemia must be corrected before starting Ibandronic Acid therapy. Other disturbances of bone and mineral metabolism should also be effectively treated. Adequate intake of calcium and vitamin D is important in all patients.

• Gastrointestinal Irritation

Orally administered bisphosphonates 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 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 reactions 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 to and be able to comply with the dosing instructions.

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 Nonsteroidal Anti-Inflammatory medicinal products and bisphosphonates are both associated with gastrointestinal irritation, caution should be taken during concomitant administration.

• Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) has been reported very rarely in the post marketing setting in patients receiving Ibandronic Acid for osteoporosis.

The start of treatment or of a new course of treatment should be delayed in patients with unhealed open soft tissue lesions in the mouth.

A dental examination with preventive dentistry and an individual benefit-risk assessment is

recommended prior to treatment with Ibandronic Acid in patients with concomitant risk factors.

The following risk factors should be considered when evaluating a patient’s risk of developing ONJ:

• Potency of the medicinal product that inhibits bone resorption (higher risk for highly potent compounds), route of administration (higher risk for parenteral administration) and cumulative dose of bone resorption therapy.

• Cancer, co-morbid conditions (e.g. Anemia, Coagulopathies, Infection), smoking Concomitant therapies: corticosteroids, chemotherapy, angiogenesis inhibitors, radiotherapy to head and neck.

• Poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, invasive dental procedures e.g. tooth extractions.

All patients should be encouraged to maintain good oral hygiene, undergo routine dental check-ups, and immediately report any oral symptoms such as dental mobility, pain or swelling, or non-healing of sores or discharge during treatment with Ibandronic Acid. While on treatment, invasive dental procedures should be performed only after careful consideration and be avoided in close proximity to Ibandronic Acid administration.

The management plan for the patients who develop ONJ should be set up in close collaboration

between the treating physician and a dentist or oral surgeon with expertise in ONJ. Temporary

interruption of Ibandronic Acid treatment should be considered until the condition resolves and contributing risk factors are mitigated where possible.

Osteonecrosis of the External Auditory Canal

Osteonecrosis of the external auditory canal has been reported with bisphosphonates, mainly in

association with long-term therapy. Possible risk factors for osteonecrosis of the external auditory canal include steroid use and chemotherapy and/or local risk factors such as infection or trauma. The possibility of osteonecrosis of the external auditory canal should be considered in patients receiving bisphosphonates who are 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 of having 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.

Atypical Fractures of Other Long Bones

Atypical fractures of other long bones, such as the ulna and tibia have also been reported in patients receiving long-term treatment. As with atypical femoral fractures, these fractures occur after minimal, or no trauma and some patients experience prodromal pain prior to presenting with a complete fracture. In cases of ulna fracture, this may be associated with repetitive stress loading associated with the long-term use of walking aids.

Renal Impairment

Due to limited clinical experience, Ibandronic Acid is not recommended for patients with 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.

Interaction With Other Medicinal Products and Other Forms of Interaction

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 aluminums,

magnesium, iron), are likely to interfere with absorption of Ibandronic Acid, which is consistent with findings in animal studies. Therefore, patients should fast overnight (at least 6 hours) before taking Ibandronic Acid and continue fasting for 1 hour following intake of Ibandronic Acid.

Interactions With Other Medicinal Products

Metabolic interactions are not 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. Ibandronic acid is eliminated by renal excretion only and does not undergo any biotransformation.

Calcium supplements, antacids and some oral medicinal products containing multivalent cations

Calcium supplements, antacids and some oral medicinal products containing multivalent cations (such as aluminum, magnesium, iron) are likely to interfere with the absorption of Ibandronic Acid. Therefore, patients should not take other oral medicinal products for at least 6 hours before taking Ibandronic Acid and for 1 hour following intake of Ibandronic Acid.

Acetylsalicylic Acid and NSAIDs

Since Acetylsalicylic acid, Nonsteroidal Anti-Inflammatory medicinal products (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 compared 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 was similar to that in patients treated with ibandronic acid 2.5 mg daily.

In healthy male volunteers and postmenopausal women, intravenous administration of ranitidine

caused an increase in ibandronic acid bioavailability of about 20 %, probably because 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.

Fertility, Pregnancy and Lactation

Pregnancy

Ibandronic Acid is only for use in postmenopausal women and must not be taken by women of childbearing potential.

There are no adequate data from the use of ibandronic acid in pregnant women. Studies in rats have shown some reproductive toxicity. The potential risk for humans is unknown. Ibandronic Acid should not be used during pregnancy.

Breast-Feeding

It is not known whether ibandronic acid is excreted in human milk. Studies in lactating rats have

demonstrated the presence of low levels of ibandronic acid in the milk following intravenous

administration. Ibandronic Acid should not be used during breast-feeding.

Fertility

There is no data on the effects of ibandronic acid from humans. In reproductive studies in rats by the oral route, ibandronic acid decreased fertility. In studies in rats using the intravenous route, ibandronic acid decreased fertility at high daily doses.

Effects On Ability to Drive and Use Machines

Based on the pharmacodynamic and pharmacokinetic profile and reported adverse reactions, it is

expected that Ibandronic Acid has no or negligible influence on the ability to drive and use machines.

UNDESIRABLE EFFECTS

Summary of the safety profile

The most serious reported adverse reactions are anaphylactic reaction/shock, atypical fractures of the femur, osteonecrosis of the jaw, gastrointestinal irritation, ocular inflammation.

Frequency categories are defined using the following convention: very common (>1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions occurring in postmenopausal women receiving Ibandronic Acid 150 mg once monthly

*See further information below

†Identified in post-marketing experience.

OVERDOSE

No specific information is available on the treatment of overdose with Ibandronic Acid.

However, based on knowledge of this class of compounds, oral overdose may result in upper

gastrointestinal adverse reactions (such as upset stomach, dyspepsia, esophagitis, gastritis, or ulcer) or hypocalcemia. Milk or antacids should be given to bind Ibandronic Acid, and any adverse reactions treated

symptomatically. Owing to the risk of esophageal irritation, vomiting should not be induced, and the patient should remain fully upright.

PHARMACOLOGICAL PROPERTIES

• Pharmacodynamic Properties

Pharmacotherapeutic group: Medicinal products for treatment of bone diseases, bisphosphonates,

Mechanism of Action

Ibandronic acid is a highly potent bisphosphonate belonging to the nitrogen-containing group of

bisphosphonates, which act selectively on bone tissue and specifically inhibit osteoclast activity

without directly affecting bone formation. It does not interfere with osteoclast recruitment. Ibandronic acid leads to progressive net gains in bone mass and a decreased incidence of fractures through the reduction of elevated bone turnover towards premenopausal levels in postmenopausal women.

Pharmacodynamic Effects

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, endogenous bone resorption is also inhibited, leading to increased normal bone mass compared with untreated animals.

• Pharmacokinetic Properties

The primary pharmacological effects of ibandronic acid on bone are not directly related to actual

plasma concentrations, as demonstrated by various studies in animals and humans.

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 fast state and absolute bioavailability was about 0.6 %. The extent of absorption is impaired when taken together with food or beverages (other than 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 the first food of the day. Both bioavailability and BMD gains are reduced when food or beverage is taken less than 60 minutes after ibandronic acid is ingested.

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 approximately 85 % - 87 % (determined in vitro at therapeutic concentrations), and thus there is a low potential for interaction with other medicinal products due to displacement.

Biotransformation

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

(estimated to be 40-50 % in postmenopausal women) and the remainder is eliminated unchanged by the kidney. The unabsorbed fraction of ibandronic acid is eliminated unchanged in the feces.

The range of apparent half-life observed is broad, the apparent terminal half-life is generally in the range of 10-72 hours. As the values calculated are largely a function of the duration of study, the dose used, and assay sensitivity, the true terminal half-life is likely to be substantially longer, in common with other bisphosphonates. 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.

The secretory pathway appears not to include known acidic or basic transport systems involved in the excretion of other active substances. In addition, ibandronic acid does not inhibit the major human hepatic P450 isoenzymes and does not induce the hepatic cytochrome P450 system in rats.

Pharmacokinetics in Special Clinical Situations

Gender

Bioavailability and pharmacokinetics of ibandronic acid are similar in men and women.

Race

There is no evidence for any clinically relevant inter-ethnic differences between Asians and

Caucasians are 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.

No dose adjustment is necessary for patients with mild or moderate renal impairment (CLcr equal or greater than 30 ml/min), as shown in study BM 16549 where most patients had mild to moderate renal impairment.

Subjects with severe renal failure (CLcr less than 30 ml/min) receiving daily oral administration of 10 mg ibandronic acid for 21 days, had 2-3-fold higher plasma concentrations than subjects with normal renal function and total clearance of ibandronic acid was 44 ml/min. After intravenous administration of 0.5 mg, total, renal, and non-renal clearances decreased by 67 %, 77 % and 50 %, respectively, in subjects with severe renal failure but there was no reduction in tolerability associated with the increase in exposure. Due to the limited clinical experience, Ibandronic Acid is not recommended in patients with severe renal impairment. The pharmacokinetics of ibandronic acid was not assessed in patients with end-stage renal disease managed by other than hemodialysis. The pharmacokinetics of ibandronic acid in these patients are unknown, and ibandronic acid should not be used under these circumstances.

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, dose adjustment is not necessary for patients with hepatic impairment.

Elderly Population

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.

Pediatric Population

There is no data on the use of Ibandronic Acid in these age groups.

Preclinical Safety Data

Toxic effects, e.g. signs of renal damage, were observed in dogs only at exposures considered

sufficiently more than the maximum human exposure indicating little relevance to clinical use.

Mutagenicity/Carcinogenicity:

No indication of carcinogenic potential was observed. Tests for genotoxicity revealed no evidence of genetic activity for ibandronic acid.

Reproductive Toxicity:

There was no evidence for a direct fetal toxic or teratogenic effect of ibandronic acid in orally treated rats and rabbits and there were no adverse effects on the development in F1 offspring in rats at an extrapolated exposure of at least 35 times above human exposure. In reproductive studies in rats the oral route effects on fertility consisted of increased preimplantation losses at dose levels of 1 mg/kg/day and higher. In reproductive studies in rats by the intravenous route, ibandronic acid decreased sperm counts at doses of 0.3 and 1 mg/kg/day and decreased fertility in males at 1 mg/kg/day and in females at 1.2 mg/kg/day. Adverse effects of ibandronic acid in reproductive toxicity studies in the rat were those observed with bisphosphonates as a class. They include fewer implantation sites, interference with natural delivery (dystocia), and an increase in visceral variations (renal pelvis ureter syndrome).

Special Precautions for Storage

This medicinal product does not require any special storage conditions.