Risedronate

Risedronate may be found in some form under the following brand names:

• Actonel

• Atelvia

Before you receive risedronate, tell you doctor about all the medical conditions you have including if you have:

• swallowing problems
• stomach or digestive problems
• low blood calcium
• plans to have dental surgery or teeth removed
• kidney problems
• trouble absorbing minerals in your stomach or intestines (malabsorption syndrome)

Tell your doctor if you are pregnant or breastfeeding.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. 

Risedronate is in a group of medicines called bisphosphonates (bis FOS fo nayts). It alters the cycle of bone formation and breakdown in the body. Risedronate slows bone loss while increasing bone mass, which may prevent bone fractures.

Risedronate is used to treat or prevent osteoporosis in men and women. Risedronate is also used to treat Paget's disease of bone.

Risedronate may also be used for purposes not listed in this medication guide.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. Drink a full glass of milk and call your local poison control center or emergency room right away. Do not make yourself vomit and do not lie down.

Overdose symptoms may include nausea, heartburn, stomach pain, diarrhea, muscle cramps, numbness or tingling, tight muscles in your face, seizure (convulsions), irritability, and unusual thoughts or behavior.

Usual Adult Dose for Osteoporosis:

Treatment of Postmenopausal Osteoporosis:
Immediate release:
-5 mg orally once a day or
-35 mg orally once a week or
-75 mg orally on two consecutive days for a total of two tablets each month or
-150 mg orally once a month
Delayed release:
-35 mg orally once a week

Treatment to Increase Bone Mass in Men with Osteoporosis:
Immediate release:
-35 mg orally once a week

Treatment of Glucocorticoid-Induced Osteoporosis:
Immediate release:
-5 mg orally once a day

Comments:
-Refer to administration advice for details on how to take this drug.
-Reevaluate bisphosphonate therapy periodically.
-Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

Uses:
-Treatment to reduce the incidence of vertebral fractures and composite endpoint of nonvertebral osteoporosis-related fractures in postmenopausal women
-Treatment to increase bone mass in men with osteoporosis
-Treatment of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases

Usual Adult Dose for Prevention of Osteoporosis:

Prevention of Postmenopausal Osteoporosis:
-5 mg orally once a day or
-35 mg orally once a week or
-75 mg orally on two consecutive days for a total of two tablets each month or
-150 mg orally once a month

Prevention of Glucocorticoid-Induced Osteoporosis:
-5 mg orally once a week

Comments:
-Refer to administration advice for details on how to take this drug.
-Reevaluate bisphosphonate therapy periodically.
-Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

Uses:
-Prevention of osteoporosis in postmenopausal women
-Prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases

Usual Adult Dose for Paget's Disease:

-30 mg orally once a day for 2 months

Comments:
-Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase.
-For retreatment, the dose and duration of therapy are the same as for initial treatment.
-There is no data available on more than 1 course of retreatment.

Use: Treatment of Paget's disease of bone in men and women

Tell your doctor about all your current medicines and any you start or stop using, especially:

• aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs)--ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete. Other drugs may interact with risedronate, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

In the U.S.

• Actonel
• Atelvia

Available Dosage Forms:

• Tablet
• Tablet, Delayed Release

Therapeutic Class: Calcium Regulator

Chemical Class: Bisphosphonate

risedronate comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor if you have any questions.

If you are using the delayed-release tablets:

• Take it in the morning right after breakfast.
• Swallow the tablet whole with at least 4 ounces of plain water. Do not crush, chew, or cut it.

Take the regular tablets with a full glass (6 to 8 ounces) of plain water on an empty stomach. It should be taken as soon as you get out of bed in the morning at least 30 minutes before any food, beverage, or other medicines. Food and beverages (eg, mineral water, coffee, tea, or juice) will decrease the amount of risedronate absorbed by the body. Waiting longer than 30 minutes will allow more of the drug to be absorbed. Medicines such as antacids that contain calcium or calcium supplements also will decrease the absorption of risedronate.

Swallow the regular tablet whole. Do not suck or chew on the tablet because it may cause throat irritation.

Do not lie down for 30 minutes after taking risedronate. This will help risedronate reach your stomach faster. It also will help prevent irritation to your esophagus.

It is important that you eat a well-balanced diet with adequate amounts of calcium and vitamin D (found in milk or other dairy products). However, do not take any food, beverages, or calcium supplements within 30 minutes or longer after taking risedronate. To do so may keep risedronate from working properly.

Follow your dosing instructions given to you by your doctor closely. It may affect the way risedronate works if you do not. Do not stop using risedronate suddenly without asking your doctor.

Tell your doctor if you do weight-bearing exercises, smoke or drink excessively. Your doctor will need to take these into consideration in deciding your dose.

Dosing

The dose of risedronate will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of risedronate. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (delayed-release tablets):
  • For treatment of postmenopausal osteoporosis:
    • Adults—35 milligrams (mg) once a week, taken right after breakfast.
    • Children—Use is not recommended.
• For oral dosage form (tablets):
  • For prevention and treatment of corticosteroid-induced osteoporosis:
    • Adults—5 milligrams (mg) once a day at least 30 minutes before the first food or drink of the day other than water.
    • Children—Use is not recommended.
  • For prevention and treatment of postmenopausal osteoporosis:
    • Adults—5 milligrams (mg) once a day or 35 mg once-a-week at least 30 minutes before the first food or drink of the day other than water. Alternatively, you may take one 75 mg tablet per day for two consecutive days each month or 150 mg tablet once a month.
    • Children—Use is not recommended.
  • For treatment of osteoporosis in men:
    • Adults—35 milligrams (mg) once a week at least 30 minutes before the first food or drink of the day other than water.
    • Children—Use is not recommended. .
  • For treatment of Paget's disease of the bone:
    • Adults—30 milligrams (mg) once a day at least 30 minutes before the first food or drink of the day other than water for two months. Your doctor may tell you to repeat this dose.
    • Children—Use is not recommended.

Missed Dose

If you miss a dose of risedronate, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

For patients taking the delayed-release tablets: If you missed taking it once a week, take 1 tablet on the morning that you remember. Do not take two tablets on the same day. Return to your regular schedule the following week.

For patients taking the regular tablets each day: If you miss a dose or forget to use your medicine in the morning, skip the missed dose and take your medicine the next morning. Do not take two tablets on the same day. Return to your regular schedule the next day.

If you are on a weekly schedule and miss a dose of the regular tablets, take it the next morning after you remember. Resume your usual schedule taking the medicine on your chosen day the next week.

For patients taking the regular tablets on two consecutive days each month, and the next month's scheduled doses are more than 7 days away: If both tablets are missed, take the first tablet on the morning after the day it is remembered. Take the second tablet on the next morning. If only one tablet is missed, take the missed tablet on the morning after the day it is remembered. Return to your regular schedule the following month. Do not take more than two tablets within 7 days.

For patients taking the regular tablets on two consecutive days each month, and the next month's scheduled doses are 1 to 7 days away: Wait until the next month and take the tablets on the scheduled days. Return to your regular schedule the following month. Do not take more than two tablets within 7 days.

For patients taking the regular tablets once a month and the next month's scheduled dose is more than 7 days away: Take it the next morning after you remember. Resume your usual schedule taking the medicine on your chosen day the following month. Do not take more than 1 tablet within 7 days.

For patients taking the regular tablets once a month and the next month's scheduled dose is 1 to 7 days away: Wait until the next month and take the tablet on the scheduled day of the month. Resume your usual schedule taking the medicine on your chosen day the following month. Do not take more than 1 tablet within 7 days.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain
• skin rash

• Abdominal or stomach pain (severe)
• belching
• bone pain
• cramping of the stomach
• trouble swallowing

• Red, sore eyes

• Bone, joint, or muscle pain, severe and occasionally incapacitating
• chest pain
• heartburn
• pain or burning in the throat
• sores, ulcers, or white spots on the lips or tongue or inside the mouth
• vomiting

Get emergency help immediately if any of the following symptoms of overdose occur:

• Confusion
• convulsions
• difficulty with breathing
• irregular heartbeats
• muscle cramps in the hands, arms, feet, legs, or face
• numbness and tingling around the mouth, fingertips, or feet
• shortness of breath
• tremor

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Back pain
• cough or hoarseness
• diarrhea
• fever or chills
• headache
• joint pain
• lower back or side pain
• painful or difficult urination

• Acid or sour stomach
• bladder pain
• bloody or cloudy urine
• blurred vision or change in vision
• body aches or pains
• congestion
• constipation
• difficult, burning, or painful urination
• difficulty with moving
• dizziness
• dry eyes
• dryness or soreness of the throat
• frequent urge to urinate
• general feeling of discomfort or illness
• indigestion
• leg cramps
• muscle pain or stiffness
• nausea
• nervousness
• pain, swelling, or redness in the joints
• pounding in the ears
• ringing in the ears
• runny nose
• slow or fast heartbeat
• stomach discomfort or upset
• swelling of the feet or lower legs
• tender swollen glands in the neck
• voice changes
• weakness

• Fainting
• fear
• itching skin
• loss of appetite
• pale skin
• passing of gas
• redness, swelling, or soreness of the tongue
• sneezing
• stomach fullness
• tightness in the chest
• troubled breathing
• troubled breathing with exertion
• unusual bleeding or bruising
• unusual tiredness or weakness
• wheezing

• Eye pain
• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs
• muscle pain
• redness of the eye
• sensitivity of the eye to light
• skin blisters
• tearing

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (for example, Cytochrome P450).

Calcium Supplements/Antacids

Coadministration of Risedronate sodium and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of Risedronate sodium.

Hormone Replacement Therapy

One study of about 500 early postmenopausal women has been conducted to date in which treatment with Risedronate sodium 5 mg daily plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, Risedronate sodium may be used concomitantly with hormone replacement therapy.

Aspirin/Nonsteroidal Anti-Inflammatory Drugs

Of over 5,700 patients enrolled in the Risedronate sodium Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in placebo-treated patients (24.8%) was similar to that in Risedronate sodium-treated patients (24.5%).

H2 Blockers and Proton Pump Inhibitors (PPIs)

Of over 5,700 patients enrolled in the Risedronate sodium Phase 3 osteoporosis studies, 21% used H2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in Risedronate sodium-treated patients.

Mechanism of Action

Risedronate sodium has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Risedronate sodium inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that Risedronate sodium treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

Pharmacodynamics

Risedronate sodium treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Risedronate sodium to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation). At the 5 mg dose, decreases in deoxypyridinoline/creatinine were evident within 14 days of treatment. Changes in bone formation markers were observed later than changes in resorption markers, as expected, due to the coupled nature of bone resorption and bone formation; decreases in bone-specific alkaline phosphatase of about 20% were evident within 3 months of treatment. Bone turnover markers reached a nadir of about 40% below baseline values by the sixth month of treatment and remained stable with continued treatment for up to 3 years. Bone turnover is decreased as early as 14 days and maximally within about 6 months of treatment, with achievement of a new steady-state that more nearly approximates the rate of bone turnover seen in premenopausal women. In a 1-year study comparing daily versus weekly oral dosing regimens of Risedronate sodium for the treatment of osteoporosis in postmenopausal women, Risedronate sodium 5 mg daily and Risedronate sodium 35 mg once-a-week decreased urinary collagen cross-linked N-telopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the Risedronate sodium 5 mg daily and Risedronate sodium 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with Risedronate sodium 5 mg daily or Risedronate sodium 75 mg two consecutive days per month, urinary collagen cross-linked N-telopeptide was decreased by 54% and 52%, respectively, and serum bone-specific alkaline phosphatase was reduced by 36% and 35%, respectively. In a 1–year study comparing Risedronate sodium 5 mg daily versus Risedronate sodium 150 mg once-a-month in women with postmenopausal osteoporosis, urinary collagen cross-linked N-telopeptide was decreased by 52% and 49%, respectively, and serum bone-specific alkaline phosphatase was reduced by 31% and 32%, respectively.

Osteoporosis in Men

In a 2-year study of men with osteoporosis, treatment with Risedronate sodium 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; Risedronate sodium 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; Risedronate sodium 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; Risedronate sodium 35 mg 25%) for the bone formation marker serum bone-specific alkaline phosphatase.

Glucocorticoid-Induced Osteoporosis

Osteoporosis with glucocorticoid use occurs as a result of inhibited bone formation and increased bone resorption resulting in net bone loss. Risedronate sodium decreases bone resorption without directly inhibiting bone formation.

In two 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, Risedronate sodium 5 mg decreased urinary collagen cross-linked N-telopeptide (a marker of bone resorption), and serum bone-specific alkaline phosphatase (a marker of bone formation) by 50% to 55% and 25% to 30%, respectively, within 3 to 6 months after initiation of therapy.

Paget's Disease

Paget's disease of bone is a chronic, focal skeletal disorder characterized by greatly increased and disordered bone remodeling. Excessive osteoclastic bone resorption is followed by osteoblastic new bone formation, leading to the replacement of the normal bone architecture by disorganized, enlarged, and weakened bone structure.

In pagetic patients treated with Risedronate sodium 30 mg daily for 2 months, bone turnover returned to normal in a majority of patients as evidenced by significant reductions in serum alkaline phosphatase (a marker of bone formation), and in urinary hydroxyproline/creatinine and deoxypyridinoline/creatinine (markers of bone resorption).

Pharmacokinetics

Absorption

Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (Tmax) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 mg to 30 mg; multiple dose, from 2.5 mg to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution.

Food Effect

The extent of absorption of a 30 mg dose (three 10 mg tablets) when administered 0.5 hours before breakfast is reduced by 55% compared to dosing in the fasting state (no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces the extent of absorption by 30% compared to dosing in the fasting state. Dosing either 0.5 hours prior to breakfast or 2 hours after dinner (evening meal) results in a similar extent of absorption. Risedronate sodium is effective when administered at least 30 minutes before breakfast. 

Distribution

The mean steady-state volume of distribution for Risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] Risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of Risedronate in soft tissues was in the range of 0.001% to 0.01%.

Metabolism

There is no evidence of systemic metabolism of Risedronate.

Excretion

 In young healthy subjects, approximately half of the absorbed dose of Risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting nonrenal clearance or clearance due to adsorption to bone. The renal clearance is not concentration dependent, and there is a linear relationship between renal clearance and creatinine clearance. Unabsorbed drug is eliminated unchanged in feces. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV=25%), and mean total clearance was 73 mL/min (CV=15%).

Specific Populations

Pediatric: Risedronate sodium is not indicated for use in pediatric patients [see Pediatric Use (8.4)].

Gender: Bioavailability and pharmacokinetics following oral administration are similar in men and women.

Geriatric: Bioavailability and disposition are similar in elderly (greater than 60 years of age) and younger subjects. No dosage adjustment is necessary.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Impairment: Risedronate is excreted unchanged primarily via the kidney. As compared to persons with normal renal function, the renal clearance of Risedronate was decreased by about 70% in patients with creatinine clearance of approximately 30 mL/min. Risedronate sodium is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min. 

Hepatic Impairment: No studies have been performed to assess Risedronate's safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in rat, dog, and human liver preparations. Insignificant amounts (less than 0.1% of intravenous dose) of drug are excreted in the bile in rats. Therefore, dosage adjustment is unlikely to be needed in patients with hepatic impairment.

Drug Interactions: No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes (Cytochrome P450) [see Drug Interactions (7)]. 

Treatment of Osteoporosis in Postmenopausal Women

The fracture efficacy of Risedronate sodium 5 mg daily in the treatment of postmenopausal osteoporosis was demonstrated in 2 large, randomized, placebo-controlled, double-blind studies that enrolled a total of almost 4,000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (Risedronate sodium 5 mg, N = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (Risedronate sodium 5 mg, N = 821). Patients were selected on the basis of radiographic evidence of previous vertebral fracture, and therefore, had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in VERT MN, and 2.5 in VERT NA, with a broad range of baseline BMD levels. All patients in these studies received supplemental calcium 1,000 mg/day. Patients with low 25-hydroxyvitamin D3 levels (approximately 40 nmol/L or less) also received supplemental vitamin D 500 international units/day.


Effect on Vertebral Fractures
Fractures of previously undeformed vertebrae (new fractures) and worsening of preexisting vertebral fractures were diagnosed radiographically; some of these fractures were also associated with symptoms (that is, clinical fractures). Spinal radiographs were scheduled annually and prospectively planned analyses were based on the time to a patient's first diagnosed fracture. The primary endpoint for these studies was the incidence of new and worsening vertebral fractures across the period of 0 to 3 years. Risedronate sodium 5 mg daily significantly reduced the incidence of new and worsening vertebral fractures and of new vertebral fractures in both VERT NA and VERT MN at all time points (Table 3). The reduction in risk seen in the subgroup of patients who had 2 or more vertebral fractures at study entry was similar to that seen in the overall study population.

Effect on Osteoporosis-Related Nonvertebral Fractures
In VERT MN and VERT NA, a prospectively planned efficacy endpoint was defined consisting of all radiographically confirmed fractures of skeletal sites accepted as associated with osteoporosis. Fractures at these sites were collectively referred to as osteoporosis-related nonvertebral fractures. Risedronate sodium 5 mg daily significantly reduced the incidence of nonvertebral osteoporosis-related fractures over 3 years in VERT NA (8% versus 5%; relative risk reduction 39%) and reduced the fracture incidence in VERT MN from 16% to 11%. There was a significant reduction from 11% to 7% when the studies were combined, with a corresponding 36% reduction in relative risk. Figure 1 shows the overall results as well as the results at the individual skeletal sites for the combined studies.

Figure 1 Nonvertebral Osteoporosis-Related Fractures Cumulative Incidence Over 3 Years Combined VERT MN and VERT NA

Effect on Bone Mineral Density

The results of 4 randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that Risedronate sodium 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 4 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo. In both VERT studies (VERT MN and VERT NA), Risedronate sodium 5 mg daily produced increases in lumbar spine BMD that were progressive over the 3 years of treatment, and were statistically significant relative to baseline and to placebo at 6 months and at all later time points.

ND = analysis not done

Risedronate sodium 35 mg once-a-week (N = 485) was shown to be non-inferior to Risedronate sodium 5 mg daily (N = 480) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 4% (3.7, 4.3; 95% confidence interval [CI]) in the 5 mg daily group (N = 391) and 3.9% (3.6, 4.3; 95% CI) in the 35 mg once-a-week group (N = 387) and the mean difference between 5 mg daily and 35 mg once-a-week was 0.1% (-0.4, 0.6; 95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites.

In a double-blind, multicenter study of postmenopausal women with osteoporosis, treatment with Risedronate sodium 75 mg two consecutive days per month (N = 616) was shown to be non-inferior to Risedronate sodium 5 mg daily (N = 613). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at 1 year were 3.6% (3.3, 3.9; 95% CI) in the 5 mg daily group (N = 527) and 3.4% (3.1, 3.7; 95% CI) in the 75 mg two days per month group (N = 524) with a mean difference between groups being 0.2%   (-0.2, 0.6; 95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites.

Risedronate sodium 150 mg once-a-month (N = 650) was shown to be non-inferior to Risedronate sodium 5 mg daily (N = 642) in a 1-year, double-blind, multicenter study of postmenopausal women with osteoporosis. The primary efficacy analysis was conducted in all randomized patients with baseline and post-baseline lumbar spine BMD values (modified intent-to-treat population) using last observation carried forward. The mean increases from baseline in lumbar spine BMD at 1 year were 3.4% (3, 3.8; 95% CI) in the 5 mg daily group (N = 561), and 3.5% (3.1, 3.9; 95% CI) in the 150 mg once-a-month group (N = 578) with a mean difference between groups being -0.1% (-0.5, 0.3; 95% CI). The results of the completers analysis were consistent with the primary efficacy analysis. The 2 treatment groups were also similar with regard to BMD increases at other skeletal sites.

Histology/Histomorphometry 
Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received placebo or daily Risedronate sodium (2.5 mg or 5 mg) for 2 to 3 years. Histologic evaluation (N = 103) showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in Risedronate sodium-treated women. These findings demonstrate that bone formed during Risedronate sodium administration is of normal quality. The histomorphometric parameter mineralizing surface, an index of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 21 treated with placebo and 23 patients treated with Risedronate sodium 5 mg. Mineralizing surface decreased moderately in Risedronate sodium-treated patients (median percent change: placebo, -21%; Risedronate sodium 5 mg, -74%), consistent with the known effects of treatment on bone turnover.

Effect on Height 
In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. Both Risedronate sodium and placebo-treated groups lost height during the studies. Patients who received Risedronate sodium had a statistically significantly smaller loss of height than those who received placebo. In VERT MN, the median annual height change was -2.4 mm/yr in the placebo group compared to -1.3 mm/yr in the Risedronate sodium 5 mg daily group. In VERT NA, the median annual height change was -1.1 mm/yr in the placebo group compared to -0.7 mm/yr in the Risedronate sodium 5 mg daily group.

Prevention of Osteoporosis in Postmenopausal Women

The safety and effectiveness of Risedronate sodium 5 mg daily for the prevention of postmenopausal osteoporosis were demonstrated in a 2-year, double-blind, placebo-controlled study of 383 postmenopausal women (age range 42 to 63 years) within three years of menopause (Risedronate sodium 5 mg, N = 129). All patients in this study received supplemental calcium 1,000 mg/day. Increases in BMD were observed as early as 3 months following initiation of Risedronate sodium treatment. Risedronate sodium 5 mg daily produced significant mean increases in BMD at the lumbar spine, femoral neck, and trochanter compared to placebo at the end of the study (Figure 2). Risedronate sodium 5 mg daily was also effective in patients with lower baseline lumbar spine BMD (more than 1 SD below the premenopausal mean) and in those with normal baseline lumbar spine BMD. Bone mineral density at the distal radius decreased in both Risedronate sodium and placebo-treated women following 1 year of treatment.

Figure 2 Change in BMD from Baseline 2-Year Prevention Study

The safety and effectiveness of Risedronate sodium 35 mg once-a-week for the prevention postmenopausal osteoporosis were demonstrated in a 1-year, double-blind, placebo-controlled study of 278 patients (Risedronate sodium 35 mg, N = 136). All patients were supplemented with 1,000 mg elemental calcium and 400 international units vitamin D per day. The primary efficacy measure was the percent change in lumbar spine BMD from baseline after 1 year of treatment using LOCF (last observation carried forward). Risedronate sodium 35 mg once-a-week resulted in a statistically significant mean difference from placebo in lumbar spine BMD of +2.9% (least square mean for placebo -1.05%; Risedronate +1.83%). Risedronate sodium 35 mg once-a-week also showed a statistically significant mean difference from placebo in BMD at the total proximal femur of +1.5% (placebo -0.53%; Risedronate +1.01%), femoral neck of +1.2% (placebo -1%; Risedronate +0.22%), and trochanter of +1.8% (placebo -0.74%; Risedronate +1.07%).

Combined Administration with Hormone Replacement Therapy

The effects of combining Risedronate sodium 5 mg daily with conjugated estrogen 0.625 mg daily (N = 263) were compared to the effects of conjugated estrogen alone (N = 261) in a 1-year, randomized, double-blind study of women ages 37 to 82 years, who were on average 14 years postmenopausal. The BMD results for this study are presented in Table 5.

Values shown are mean (± SEM) percent change from baseline.

Histology/Histomorphometry

Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received Risedronate sodium 5 mg plus estrogen or estrogen alone once daily for 1 year. Histologic evaluation (N = 47) demonstrated that the bone of patients treated with Risedronate sodium plus estrogen was of normal lamellar structure and normal mineralization. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 12 patients treated with Risedronate sodium plus estrogen and 12 treated with estrogen alone. Mineralizing surface decreased in both treatment groups (median percent change: Risedronate sodium plus estrogen, -79%; estrogen alone, -50%), consistent with the known effects of these agents on bone turnover.

Men with Osteoporosis

The effects of Risedronate sodium 35 mg once-a-week on BMD were examined in a 2-year, double-blind, placebo-controlled, multinational study in 285 men with osteoporosis (Risedronate sodium, N = 192). The patients had a mean age of 61 years (range 36 to 84 years) and 95% were Caucasian. At baseline, mean lumbar spine T-score was -3.2 and mean femoral neck T-score was -2.4. All patients in the study had either, 1) a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or 2) a BMD T-score less than or equal to -1 at the femoral neck and less than or equal to -2.5 at the lumbar spine. All patients were supplemented with calcium 1,000 mg/day and vitamin D 400 to 500 international units/day. Risedronate sodium 35 mg once-a-week produced significant mean increases in BMD at the lumbar spine, femoral neck, trochanter, and total hip compared to placebo after 2 years of treatment (treatment difference: lumbar spine, 4.5%; femoral neck, 1.1%; trochanter, 2.2%; total proximal femur, 1.5%).

Glucocorticoid-Induced Osteoporosis

Bone Mineral Density

Two 1-year, double-blind, placebo-controlled trials in patients who were taking greater than or equal to 7.5 mg/day of prednisone or equivalent demonstrated that Risedronate sodium 5 mg daily was effective in the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who were either initiating or continuing glucocorticoid therapy. The efficacy of Risedronate sodium therapy for glucocorticoid-induced osteoporosis beyond one year has not been studied.

The prevention study enrolled 228 patients (Risedronate sodium 5 mg, N = 76) (18 to 85 years of age), each of whom had initiated glucocorticoid therapy (mean daily dose of prednisone 21 mg) within the previous 3 months (mean duration of use prior to study 1.8 months) for rheumatic, skin, and pulmonary diseases. The mean lumbar spine BMD was normal at baseline (average T-score -0.7). All patients in this study received supplemental calcium 500 mg/day. By the third month of treatment, and continuing through the year-long treatment, the placebo group experienced losses in BMD at the lumbar spine, femoral neck, and trochanter, while BMD was maintained or increased in the Risedronate sodium 5 mg group. At each skeletal site there were statistically significant differences between the placebo group and the Risedronate sodium 5 mg group at all timepoints (Months 3, 6, 9, and 12). The treatment differences increased with continued treatment. Although BMD increased at the distal radius in the Risedronate sodium 5 mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and Risedronate sodium 5 mg after 1 year were 3.8% at the lumbar spine, 4.1% at the femoral neck, and 4.6% at the trochanter, as shown in Figure 3. The results at these skeletal sites were similar to the overall results when the subgroups of men and postmenopausal women, but not premenopausal women, were analyzed separately. Risedronate sodium was effective at the lumbar spine, femoral neck, and trochanter regardless of age (less than 65 vs. greater than or equal to 65), gender, prior and concomitant glucocorticoid dose, or baseline BMD. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

The treatment study of similar design enrolled 290 patients (Risedronate sodium 5 mg, N = 100) (19 to 85 years of age) with continuing, long-term (greater than or equal to 6 months) use of glucocorticoids (mean duration of use prior to study 60 months; mean daily dose of prednisone 15 mg) for rheumatic, skin, and pulmonary diseases. The baseline mean lumbar spine BMD was low (1.63 SD below the young healthy population mean), with 28% of the patients more than 2.5 SD below the mean. All patients in this study received supplemental calcium 1,000 mg/day and vitamin D 400 international units/day.

After 1 year of treatment, the BMD of the placebo group was within 1% of baseline levels at the lumbar spine, femoral neck, and trochanter. Risedronate sodium 5 mg increased BMD at the lumbar spine (2.9%), femoral neck (1.8%), and trochanter (2.4%). The differences between Risedronate sodium and placebo were 2.7% at the lumbar spine, 1.9% at the femoral neck, and 1.6% at the trochanter as shown in Figure 4. The differences were statistically significant for the lumbar spine and femoral neck, but not at the femoral trochanter. Risedronate sodium was similarly effective on lumbar spine BMD regardless of age (less than 65 vs. greater than or equal to 65), gender, or pre-study glucocorticoid dose. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

Figure 3 Change in BMD from Baseline Patients Recently Initiating Glucocorticoid Therapy

Figure 4 Change in BMD from Baseline Patients on Long-Term Glucocorticoid Therapy

Vertebral Fractures

In the prevention study of patients initiating glucocorticoids, the incidence of vertebral fractures at 1 year was reduced from 17% in the placebo group to 6% in the Risedronate sodium group. In the treatment study of patients continuing glucocorticoids, the incidence of vertebral fractures was reduced from 15% in the placebo group to 5% in the Risedronate sodium group (Figure 5). The statistically significant reduction in vertebral fracture incidence in the analysis of the combined studies corresponded to an absolute risk reduction of 11% and a relative risk reduction of 70%. All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (that is, clinical fractures).

Figure 5 Incidence of Vertebral Fractures in Patients Initiating or Continuing Glucocorticoid Therapy

Histology/Histomorphometry

Bone biopsies from 40 patients on glucocorticoid therapy were obtained at endpoint. Patients had received placebo or daily Risedronate sodium (2.5 mg or 5 mg) for 1 year. Histologic evaluation (N = 33) showed that bone formed during treatment with Risedronate sodium was of normal lamellar structure and normal mineralization, with no bone or marrow abnormalities observed. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 10 patients treated with Risedronate sodium 5 mg. Mineralizing surface decreased 24% (median percent change) in these patients. Only a small number of placebo-treated patients had both baseline and post-treatment biopsy samples, precluding a meaningful quantitative assessment.

Treatment of Paget's Disease

The efficacy of Risedronate sodium was demonstrated in 2 clinical studies involving 120 men and 65 women. In a double-blind, active-controlled study of patients with moderate-to-severe Paget's disease (serum alkaline phosphatase levels of at least 2 times the upper limit of normal), patients were treated with Risedronate sodium 30 mg daily for 2 months or etidronate disodium 400 mg daily for 6 months. At Day 180, 77% (43/56) of Risedronate sodium-treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10.5% (6/57) of patients treated with etidronate disodium (p less than 0.001). At Day 540, 16 months after discontinuation of therapy, 53% (17/32) of Risedronate sodium-treated patients and 14% (4/29) of etidronate disodium-treated patients with available data remained in biochemical remission.

During the first 180 days of the active-controlled study, 85% (51/60) of Risedronate sodium-treated patients demonstrated a greater than or equal to 75% reduction from baseline in serum alkaline phosphatase excess (difference between measured level and midpoint of the normal range) with 2 months of treatment compared to 20% (12/60) in the etidronate disodium-treated group with 6 months of treatment (p less than 0.001). Changes in serum alkaline phosphatase excess over time (shown in Figure 6) were significant following only 30 days of treatment, with a 36% reduction in serum alkaline phosphatase excess at that time compared to only a 6% reduction seen with etidronate disodium treatment at the same time point (p less than 0.01).

Figure 6 Mean Percent Change from Baseline in Serum Alkaline Phosphatase Excess by Visit

Response to Risedronate sodium therapy was similar in patients with mild to very severe Paget's disease. Table 6 shows the mean percent reduction from baseline at Day 180 in excess serum alkaline phosphatase in patients with mild, moderate, or severe disease.

Response to Risedronate sodium therapy was similar between patients who had previously received anti-pagetic therapy and those who had not. In the active-controlled study, 4 patients previously non-responsive to 1 or more courses of anti-pagetic therapy (calcitonin, etidronate disodium) responded to treatment with Risedronate sodium 30 mg daily (defined by at least a 30% change from baseline). Each of these patients achieved at least 90% reduction from baseline in serum alkaline phosphatase excess, with 3 patients achieving normalization of serum alkaline phosphatase levels.

Histomorphometry of the bone was studied in 14 patients with bone biopsies: 9 patients had biopsies from pagetic bone lesions and 5 patients from non-pagetic bone. Bone biopsy results in non-pagetic bone did not reveal osteomalacia, impairment of bone remodeling, or induction of a significant decline in bone turnover in patients treated with Risedronate sodium.

• Bisphosphonate Derivative

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). However, dosage adjustment unlikely because risedronate is not metabolized by the liver.

Store at 20°C to 25°C (68°F to 77°F).

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, diarrhea, back pain, or flu-like symptoms. Have patient report immediately to prescriber signs of low calcium (muscle cramps or spasms, numbness and tingling, or seizures); black, tarry, or bloody stools; angina; coughing up blood; severe nausea; severe vomiting; vomiting blood; severe abdominal pain; heartburn; dysphagia; painful swallowing; pharyngitis; severe bone pain; severe joint pain; severe muscle pain; groin, hip, or thigh pain; severe headache; severe dizziness; vision changes; difficult urination; painful urination; eye pain; eye irritation; jaw pain or edema, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Administration advice:
-The delayed release tablets should be taken immediately following breakfast to avoid risk of abdominal pain.
-The immediate release tablets should be taken at least 30 minutes before the first food or drink of the day other than water.
-Food and other medications should not be taken for at least 30 minutes after taking the immediate release tablet.
-Tablets should be swallowed whole while in upright position, and with 8 to 6 ounces (immediate release) or 4 ounces (delayed release) of plain water; avoid laying down for 30 minutes after taking this drug.
-Tablets should not be chewed or sucked (potential for oropharyngeal ulceration), cut, or crushed.
-Supplemental calcium and vitamin D is recommended if dietary intake is inadequate.
-Calcium supplements, antacids, magnesium-based supplements or laxatives, iron preparations, vitamins, and any other medication should be taken at a different time of the day to avoid interference with the drug's absorption.

Missed Doses:
Immediate release:
If a dose of 35 mg once-a-week is missed:
-Take 1 tablet on the morning after remembering and return to take 1 tablet once-a-week as originally scheduled; two doses should not be taken on the same day.

If one or both tablets of 75 mg on two consecutive days per month dose are missed, and the next month's scheduled doses are more than 7 days away:
-If both tablets are missed, take one 75 mg tablet in the morning after remembering and then the other tablet on the next consecutive morning.
-If only one 75 mg tablet is missed, take the missed tablet in the morning after remembering; return to take one 75 mg tablet on two consecutive days per month as originally scheduled. No more than two 75 mg tablets should be taken within 7 days.

If one or both tablets of 75 mg on two consecutive days per month dose are missed, and the next month's scheduled doses are within 7 days:
-Wait until their next month's scheduled doses and then continue taking 75 mg tablet on two consecutive days per month as originally scheduled.

If the dose of 150 mg once-a-month is missed, and the next month's scheduled dose is more than 7 days away:
-Take the missed tablet in the morning after remembering and then return to take 150 mg once-a-month tablet as originally scheduled. No more than one 150 mg tablet should be taken within 7 days.

If the dose of 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days:
-Wait until their next month's scheduled dose and then continue taking 150 mg once-a-month tablet as originally scheduled.

Delayed release:
-If the once-weekly dose is missed, take one dose on the morning after remembering; two doses should not be taken on the same day.
-Resume the next dose on its regular schedule.

Limitations of Use:
-The optimal therapy duration of use has not been determined.
-The safety and effectiveness of this drug for the treatment of osteoporosis are based on three years duration.
-All patients on bisphosphonate therapy should reevaluated therapy on a periodic basis.
-Patients at low-risk for fracture should consider discontinuation of therapy after 3 to 5 years of use.
-If therapy is discontinued, reevaluate risk for fracture periodically.

Monitoring:
-Hematologic: Blood calcium levels
-Musculoskeletal: Bone, joint, or muscle pain

Patient advice:
-Patients should read the Medication Guide before starting therapy and each time the prescription is renewed.
-Instruct patients that the brands Atelvia and Actonel contain the same ingredient and should not be taken together.
-Patients should pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions.
-Consult a physician if symptoms of difficulty or pain upon swallowing, retrosternal pain or severe persistent or worsening heartburn develop before continuing taking this drug.

Risedronate starts to effect markers that reflect bone resorption within 14 days of treatment, reaching a maximal effect on all markers reflecting bone turnover within six months. Effects remain stable following continued treatment for up to three years. Food can decrease absorption of risedronate by up to 55%.

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