OSTEOS

Risedronic acid is a third generation bisphosphonate that is used for the treatment of some forms of osteoperosis and Paget's disease Label 1, 2.

It functions by preventing resorption of bone Label 1.

Risedronic acid is indicated for the treatment of osteoperosis in men, treatment of Paget's disease, treatment and prevention of osteoperosis in postmenopausal women, and treatment and prevention of glucocorticoid-induced osteoperosis Label.

Risedronate is a pyridine-based bisphosphonate that inhibits bone resorption caused by osteoclasts Label.

Oral bioavailability is 0.63% and maximum absorption is approximately 1 hour after dosing Label.

Administration half and hour before a meal reduces bioavailability by 55% compared to fasting and dosing 1 hour before a meal reduces bioavailability by 30% Label.

Risedronic acid is not likely not metabolized before elimination Label.

P-C-P group of bisphosphonates is resistant to chemical and enzymatic hydrolysis preventing metabolism of the molecule 1.

Risedronate is excreted by the kidneys and the unabsorbed dose is eliminated in the feces Label.

The initial half life of risedronic acid is approximately 1.5 hours 3, with a terminal half life of 561 hours Label.

Mean renal clearance was 52 mL/min and mean total clearance was 73 mL/min Label.

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In clinical trials, over 10% of patients experienced back pain, arthralgia, abdominal pain, and dyspepsia Label.

Less commonly, patients experience angioedema, generalized rash, bullous skin reactions, iritis, and uveitis Label.

Patients experiencing an overdose may experience a decrease in serum calcium and phosphorus Label.

Patients can be given milk or antacids to bind the drug and reduce its absorption Label.

In more severe cases, patients may require gastric lavage and intravenous calcium Label.

A lethal dose in rats is equivalent to 320-620 times the human dose based on surface area Label.

Risedronate sodium delayed-release tablets contraindicated in patients with the following conditions: 1.

Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia 2.

Inability to stand or sit upright for at least 30 minutes 3.

Hypocalcemia 4.

Known hypersensitivity to any component of this product.

Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported.

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia.

• Inability to stand or sit upright for at least 30 minutes.

• Known hypersensitivity to any component of this product.

• Take risedronate sodium delayed-release tablets in the morning immediately following breakfast with at least 4 ounces of plain water.

• Avoid lying down for 30 minutes after taking risedronate sodium delayed-release tablets.

• Take risedronate sodium delayed-release tablets in the morning immediately following breakfast.

Risedronate sodium delayed-release tablets should be taken immediately following breakfast and not under fasting conditions because of a higher risk of abdominal pain if taken before breakfast when fasting.

• Swallow risedronate sodium delayed-release tablets whole while in an upright position and with at least 4 ounces of plain water to facilitate delivery to the stomach.

Avoid lying down for 30 minutes after taking the medication.

• Do not chew, cut, or crush risedronate sodium delayed-release tablets. 2.3 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of risedronate sodium delayed-release tablets. 2.4 Administration Instructions for Missed Doses If the once-weekly dose is missed, instruct patients to take one tablet on the morning after they remember and return to taking one tablet once-a-week, as originally scheduled on their chosen day. Patients should not take two tablets on the same day.

Risedronate sodium delayed-release tablets are: 35 mg, oval-shaped, yellow colored coated tablets with ‘S’ imprinted on one side and plain on the other side.

NDC 63304-440-09 Blister pack of 4 tablets.

Store at 20º.

• 25º C (68º - 77º F) .

Available data on use of risedronate sodium in pregnant women are insufficient to inform drug-associated risk of adverse maternal or fetal outcomes.

Discontinue risedronate sodium when pregnancy is recognized.

In animal reproduction studies, daily oral administration of risedronate to pregnant rats during organogenesis decreased neonatal survival and body weight at doses approximately and 26 times, respectively, the highest recommended human daily dose of 30 mg (based on body surface area, mg/m 2 ), the dose indicated for treatment of Paget’s disease.

A low incidence of cleft palate was observed in fetuses of dams treated at doses approximately equal to the 30 mg human daily dose.

Delayed skeletal ossification was observed in fetuses of dams treated at approximately 2.5 to 5 times the 30 mg human daily dose.

Periparturient mortality due to maternal hypocalcemia occurred in dams and neonates upon daily oral administration of risedronate to pregnant rats during mating and/or gestation starting at doses equivalent to the 30 mg daily human dose.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of weeks to years.

The amount of bisphosphonate incorporated into adult bone available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use.

Consequently, based on mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy.

The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.

All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and to 20%, respectively.

Data Animal data

In animal studies, pregnant rats received risedronate sodium during organogenesis at doses to 26 times the human Paget’s disease dose of 30 mg/day (based on body surface area, mg/m 2 ).

Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose.

A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose.

The number of fetuses exhibiting incomplete ossification of sternebrae or skull of dams treated with approximately 2.5 times the human dose was significantly increased compared to controls.

Both incomplete ossification and unossified sternebrae were increased in fetuses of dams treated with oral doses approximately 5 times the human dose.

No significant ossification effects were seen in fetuses of rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested).

However, 1 of 14 litters were aborted and of 14 litters were delivered prematurely.

Periparturient mortality due to maternal hypocalcemia occurred in dams and neonates when pregnant rats were treated daily during mating and/or gestation with oral doses equivalent to the human dose or higher.

Risedronate sodium is not indicated for use in pediatric patients.

The safety and effectiveness of risedronate sodium immediate-release was assessed in a one-year, randomized, double-blind, placebo-controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI).

The enrolled population was predominantly patients with mild OI (85% Type-I), aged to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls).

Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose.

After one year, an increase in lumbar spine BMD in the risedronate sodium immediate-release group compared to the placebo group was observed.

However, treatment with risedronate sodium immediate-release did not result in a reduction in the risk of fracture in pediatric patients with OI.

In risedronate sodium immediate-release treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12.

The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis.

However, there was an increased incidence of vomiting compared to placebo.

In this study, vomiting was observed in 15% of children treated with risedronate sodium immediate-release and 6% of patients treated with placebo.

Other adverse reactions reported in greater than or equal to 10% of patients treated with risedronate sodium immediate-release and with a higher frequency than placebo were: pain in the extremity (21% with risedronate sodium immediate-release versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%).

Of the patients receiving risedronate sodium in postmenopausal osteoporosis studies, 59% were and over, while 13% were and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.