Actonel

Name: Actonel

Is risedronate available as a generic drug?

GENERIC AVAILABLE: Yes

Actonel Dosage and Administration

General

  • Use adjunctively with other measures (e.g., weight-bearing exercise, reduction in smoking and alcohol use) to retard further bone loss.1 4

  • Supplemental calcium and vitamin D recommended if daily dietary intake is inadequate, particularly in patients with Paget’s disease of bone or receiving corticosteroids.1

Administration

Oral Administration

Administer risedronate sodium or risedronate sodium copackaged with calcium carbonate orally1 5 6 7 8 9 10 33 34 with a full glass (180–240 mL) of plain water ≥30 minutes before the first food or beverage of the day.1

Administer in an upright position (sitting or standing).1 Avoid lying down for ≥30 minutes following administration.1 (See Upper GI Effects under Cautions.)

Do not suck or chew tablets; potential for oropharyngeal irritation.1 (See Upper GI Effects under Cautions.)

Do not administer at the same time as other beverages, foods, antacids, or mineral supplements containing calcium, aluminum, or magnesium.1 5 33 34 (See Antacids or Mineral Supplements Containing Divalent Cations under Interactions.)

Missed dose in patients taking weekly 35-mg dose of risedronate sodium: take the missed dose the morning after it is remembered, then resume the regular weekly schedule.1 Do not take two 35-mg tablets on the same day.1

Missed dose of risedronate sodium (orange tablet) in patients taking weekly 35-mg dose copackaged with calcium carbonate (blue tablet): take missed dose the next morning, followed by resumption of the regular weekly schedule on the originally chosen day;34 do not take missed dose later on the same day.34 Take usual dose of calcium carbonate (blue tablet) with food later in the same day that the missed risedronate sodium tablet is taken.34 Do not take risedronate sodium and calcium carbonate at the same time.34 If a calcium carbonate tablet (days 2–7) is missed and it is remembered later the same day, take that tablet with food.34 If 1 day of calcium carbonate therapy is missed, take 2 tablets of calcium carbonate the next day at separate times of the day with food.34 Do not take more than 2 tablets of calcium carbonate on the same day unless directed by clinician.34

Missed dose in patients taking monthly 150-mg dose: If next scheduled dose is >7 days away, take the missed dose the morning after it is remembered and resume the regular schedule.1 If the next scheduled dose is 1–7 days away, maintain the regular schedule;1 do not take more than one 150-mg tablet within the same week.1

Missed dose(s) in patients taking 2 consecutive daily 75-mg doses each month and next scheduled dose is >7 days away: If one dose is missed, take the missed dose the morning after it is remembered, then resume the regular schedule.1 If both doses are missed, take one missed dose the morning after it is remembered and the next missed dose on the next consecutive morning, then resume the regular schedule.1 Do not take more than two 75-mg tablets within the same week.1

Missed dose(s) in patients taking 2 consecutive daily 75-mg doses each month and next scheduled dose is 1–7 days away: Maintain the regular schedule (i.e., wait until time of next month’s scheduled dose).1 Do not take more than two 75-mg tablets within the same week.1

Dosage

Available as risedronate sodium; dosage expressed in terms of the salt.18

Adults

Osteoporosis Prevention of Postmenopausal Osteoporosis Oral

Risedronate sodium: 5 mg once daily, 35 mg once weekly, or 150 mg monthly (given as a 150-mg tablet once monthly or a 75-mg tablet on 2 consecutive days each month).1

Risedronate sodium copackaged with calcium carbonate: 35 mg of risedronate sodium (orange tablet) once weekly (day 1), followed by 1.25 g of calcium carbonate (blue tablet containing 500 mg of elemental calcium) daily on days 2–7; treatment cycle repeated weekly.33 34 Each blister package contains enough tablets of each drug for four 7-day treatment cycles.33 34

Treatment in Postmenopausal Women Oral

Risedronate sodium: 5 mg once daily, 35 mg once weekly, or 150 mg monthly (given as a 150-mg tablet once monthly or a 75-mg tablet on 2 consecutive days each month).1

Risedronate sodium copackaged with calcium carbonate: 35 mg of risedronate sodium (orange tablet) once weekly (day 1), followed by 1.25 g of calcium carbonate (blue tablet containing 500 mg of elemental calcium) daily on days 2–7; treatment cycle repeated weekly.33 34 Each blister package contains enough tablets of each drug for four 7-day treatment cycles.33 34

Optimal duration of treatment not established.1 33 Safety and efficacy based on data supporting fracture reduction over 3 years of treatment.1 33 Reevaluate need for continued therapy periodically in all patients receiving bisphosphonates.1 33

Treatment in Men Oral

Men: 35 mg once weekly.1

Corticosteroid-induced Osteoporosis Prevention of Corticosteroid-induced Osteoporosis Oral

5 mg once daily.1

Continue risedronate as long as patient continues to receive corticosteroid therapy.21 57

Treatment of Corticosteroid-induced Osteoporosis Oral

5 mg once daily.1

Continue risedronate as long as patient continues to receive corticosteroid therapy.21 57

Paget’s Disease of Bone Oral

30 mg once daily for 2 months.1 2

Consider retreatment (same dosage and duration) after a 2-month posttreatment evaluation period if relapse occurs or if initial treatment failed to normalize serum alkaline phosphatase concentrations.1

Prescribing Limits

Adults

Paget’s Disease of Bone Oral

Safety and efficacy not established for >1 course of retreatment.1

Special Populations

Hepatic Impairment

Dosage adjustments not necessary.1

Renal Impairment

Dosage adjustments not necessary in patients with mild to moderate impairment (Clcr ≥30 mL/minute).1 Use not recommended in patients with severe impairment (Clcr <30 mL/minute).1

Geriatric Patients

Dosage adjustments not necessary in geriatric patients based solely on age.1

Actonel Pharmacokinetics

Absorption

Bioavailability

The mean absolute oral bioavailability is 0.63%.1

Onset

Reduction of bone turnover evident within 14 days of beginning therapy; maximal effects observed in about 6 months.1

Food

When administered 30 minutes or 1 hour prior to breakfast, the extent of absorption is reduced by 55 or 30%, respectively, compared to the fasting state.1 However, drug is effective when administered ≥30 minutes before breakfast.1

Distribution

Extent

Mean steady-state volume of distribution is 6.3 L/kg.1 In animal studies, 60% of a dose distributed into bone.1

Animal data indicate that the drug crosses placenta and is distributed into fetal bones.1

Distributed into milk in animals.1 Not known whether the drug is distributed into human milk.1

Plasma Protein Binding

About 24%.1

Elimination

Metabolism

There is no evidence of systemic metabolism.1

Elimination Route

Eliminated mainly in urine; only unabsorbed drug is excreted in feces.1

Half-life

Initial half-life is about 1.5 hours and terminal exponential half-life is 480 hours.1 The terminal half-life is thought to represent the dissociation of the drug from the surface of bone.1

Special Populations

Renal clearance is decreased by 70% in patients with severe renal impairment (i.e., Clcr <30 mL/minute).1

Before Using Actonel

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Use of risedronate is not indicated in children.

Appropriate studies have not been performed on the relationship of age to the effects of Actonel® with calcium in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of risedronate in the elderly.

Pregnancy

Pregnancy Category Explanation
All Trimesters C Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Esomeprazole

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Anemia or
  • Blood clotting problems or
  • Cancer or
  • Dental or tooth problems or
  • Dental procedures (eg, dental implants, tooth extraction) or
  • Infection or
  • Poor oral hygiene or
  • Surgery (eg, dental surgery)—May increase risk for severe jaw problems.
  • Esophagus (the tube that runs from your throat to your stomach) problems (eg, achalasia, stricture) or
  • Hypocalcemia (low calcium in the blood) or
  • Inability to stand or sit upright for at least 30 minutes or
  • Kidney problems, severe or
  • Trouble with swallowing—Should not be used in patients with these conditions.
  • Stomach or bowel problems (eg, Barrett's esophagus, duodenitis, gastritis, heartburn, inflammation of the esophagus, or ulcers)—Use with caution. May make these conditions worse.

Precautions While Using Actonel

It is important that your doctor check your progress at regular visits to make sure this medicine is working properly and watch for unwanted effects.

You should not take Actonel® tablets if you are also using Atelvia®.delayed-release tablets. These medicines should not be taken together because both medicines contain risedronate. Ask your doctor if you have any questions.

This medicine can irritate your esophagus. If you think this medicine has started to damage your esophagus, stop taking this medicine and call your doctor. Some symptoms of damage to the esophagus are heartburn (either new or worse than usual), pain when swallowing, pain in the center of your chest, trouble swallowing, or feeling that food gets stuck on the way to your stomach.

It is important that you tell all of your health care providers that you are taking risedronate. If you are having dental procedures done while taking risedronate you may have an increased chance of getting a severe problem of your jaw.

Make sure you tell your doctor about any new medical problems, especially with your teeth or jaws. Tell your doctor if you have severe bone, joint, or muscle pain while using this medicine.

This medicine could lower the amount of calcium in your blood. Call your doctor right away if you develop any signs of low calcium levels, such as muscle spasms or twitching, or numbness or tingling in your fingers, toes, or lips.

This medicine may increase your risk of developing fractures of the thigh bone. This may be more common if you use it for a long time. Check with your doctor right away if you have a dull or aching pain in the thighs, groin, or hips.

This medicine may interact with the dye used for bone scans.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

Indications and Usage for Actonel

Postmenopausal Osteoporosis

Actonel is indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, Actonel reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [see Clinical Studies (14.1, 14.2)].

Osteoporosis in Men

Actonel is indicated for treatment to increase bone mass in men with osteoporosis.

Glucocorticoid-Induced Osteoporosis

Actonel is indicated for the treatment and 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. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

Paget’s Disease

Actonel is indicated for treatment of Paget’s disease of bone in men and women.

Important Limitations of Use

The optimal duration of use has not been determined. The safety and effectiveness of Actonel for the treatment of osteoporosis are based on clinical data of three years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

Contraindications

Actonel is contraindicated in patients with the following conditions:

  • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1)]
  • Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2), Warnings and Precautions (5.1)]
  • Hypocalcemia [see Warnings and Precautions (5.2)]
  • Known hypersensitivity to Actonel or any of its excipients. Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported [see Adverse Reactions (6.2)]

Overdosage

Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind Actonel and reduce absorption of the drug.

In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia.

Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg, respectively. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m2).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 104-week carcinogenicity study, rats were administered daily oral doses up to approximately 8 times the maximum recommended human daily dose. There were no significant drug-induced tumor findings in male or female rats. The high dose male group was terminated early in the study (Week 93) due to excessive toxicity, and data from this group were not included in the statistical evaluation of the study results. In an 80-week carcinogenicity study, mice were administered daily oral doses approximately 6.5 times the human dose. There were no significant drug-induced tumor findings in male or female mice.

Mutagenesis

Risedronate did not exhibit genetic toxicity in the following assays: In vitro bacterial mutagenesis in Salmonella and E. coli (Ames assay), mammalian cell mutagenesis in CHO/HGPRT assay, unscheduled DNA synthesis in rat hepatocytes and an assessment of chromosomal aberrations in vivo in rat bone marrow. Risedronate was positive in a chromosomal aberration assay in CHO cells at highly cytotoxic concentrations (greater than 675 mcg/mL, survival of 6% to 7%). When the assay was repeated at doses exhibiting appropriate cell survival (29%), there was no evidence of chromosomal damage.

Impairment of Fertility

In female rats, ovulation was inhibited at an oral dose approximately 5 times the human dose. Decreased implantation was noted in female rats treated with doses approximately 2.5 times the human dose. In male rats, testicular and epididymal atrophy and inflammation were noted at approximately 13 times the human dose. Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses approximately 5 times the human dose. There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose approximately 8 times the human dose. These findings tended to increase in severity with increased dose and exposure time.

Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual doses were 24 mg/kg/day in rats, 32 mg/kg/day in mice, and 8, 16 and 40 mg/kg/day in dogs.

Animal Toxicology and/or Pharmacology

Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized rats and minipigs. Bone mass and biomechanical strength were increased dose-dependently at daily oral doses up to 4 and 25 times the human recommended oral dose of 5 mg for rats and minipigs, respectively. Risedronate treatment maintained the positive correlation between BMD and bone strength and did not have a negative effect on bone structure or mineralization. In intact dogs, risedronate induced positive bone balance at the level of the bone remodeling unit at oral doses ranging from 0.5 to 1.5 times the 5 mg/day human daily dose.

In dogs treated with an oral dose approximately 5 times the human daily dose, risedronate caused a delay in fracture healing of the radius. The observed delay in fracture healing is similar to other bisphosphonates. This effect did not occur at a dose approximately 0.5 times the human daily dose.

The Schenk rat assay, based on histologic examination of the epiphyses of growing rats after drug treatment, demonstrated that risedronate did not interfere with bone mineralization even at the highest dose tested, which was approximately 3500 times the lowest antiresorptive dose in this model (1.5 mcg/kg/day) and approximately 800 times the human daily dose of 5 mg. This indicates that Actonel administered at the therapeutic dose is unlikely to induce osteomalacia.

Dosing multiples provided above are based on the recommended human dose of 5 mg/day and normalized using body surface area (mg/m2).

Clinical Studies

Treatment of Osteoporosis in Postmenopausal Women

The fracture efficacy of Actonel 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 4000 postmenopausal women under similar protocols. The Multinational study (VERT MN) (Actonel 5 mg, N = 408) was conducted primarily in Europe and Australia; a second study was conducted in North America (VERT NA) (Actonel 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 1000 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 pre-existing 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. Actonel 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.

Table 3 The Effect of Actonel on the Risk of Vertebral Fractures
   Proportion of Patients
with Fracture (%)a
 
 

a Calculated by Kaplan-Meier methodology.

 
VERT NA
 Placebo
N = 678
 Actonel 5 mg
N = 696
 Absolute Risk
Reduction (%)
 Relative Risk
Reduction (%)
 New and Worsening        
       0 - 1 Year  7.2  3.9  3.3  49
       0 - 2 Years  12.8  8.0  4.8  42
       0 - 3 Years  18.5  13.9  4.6  33
 New        
       0 - 1 Year  6.4  2.4  4.0  65
       0 - 2 Years  11.7  5.8  5.9  55
       0 - 3 Years  16.3  11.3  5.0  41
 
VERT MN
 Placebo
N = 346
 Actonel 5 mg
N = 344
 Absolute Risk
Reduction (%)
 Relative Risk
Reduction (%)
 New and Worsening        
       0 - 1 Year  15.3  8.2  7.1  50
       0 - 2 Years  28.3  13.9  14.4  56
       0 - 3 Years  34.0  21.8  12.2  46
 New        
       0 - 1 Year  13.3  5.6  7.7  61
       0 - 2 Years  24.7  11.6  13.1  59
       0 - 3 Years  29.0  18.1  10.9  49

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. Actonel 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 Nonvertebal 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 Actonel 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), Actonel 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.

Table 4 Mean Percent Increase in BMD from Baseline in Patients Taking Actonel 5 mg or Placebo at Endpointa
     VERT MNb  VERT NAb  BMD MNc  BMD NAc
     Placebo
N = 323
 5 mg
N = 323
 Placebo
N = 599
 5 mg
N = 606
 Placebo
N = 161
 5 mg
N = 148
 Placebo
N = 191
 5 mg
N = 193
    aThe endpoint value is the value at the study's last time point for all patients who had BMD measured at that time; otherwise the last post-baseline BMD value prior to the study's last time point is used.
    bThe duration of the studies was 3 years.
    cThe duration of the studies was 1.5 to 2 years.
    * BMD of the midshaft radius was measured in a subset of centers in VERT MN (placebo, N = 222; 5 mg, N = 214) and VERT NA (placebo, N = 310; 5 mg, N = 306).
    ND = analysis not done
   Lumbar Spine  1.0  6.6  0.8  5.0  0.0  4.0  0.2  4.8
   Femoral Neck  -1.4  1.6  -1.0  1.4  -1.1  1.3  0.1  2.4
   Femoral Trochanter  -1.9  3.9  -0.5  3.0  -0.6  2.5  1.3  4.0
   Midshaft Radius  -1.5*  0.2*  -1.2*  0.1*  ND  ND

Actonel 35 mg once-a-week (N = 485) was shown to be non-inferior to Actonel 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 4.0% (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 Actonel 75 mg two consecutive days per month (N = 616) was shown to be non-inferior to Actonel 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.

Actonel 150 mg once-a-month (N = 650) was shown to be non-inferior to Actonel 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% (3.0, 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 Actonel (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 Actonel-treated women. These findings demonstrate that bone formed during Actonel 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 Actonel 5 mg. Mineralizing surface decreased moderately in Actonel-treated patients (median percent change: placebo, -21%; Actonel 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 Actonel and placebo-treated groups lost height during the studies. Patients who received Actonel 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 Actonel 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 Actonel 5 mg daily group.

Prevention of Osteoporosis in Postmenopausal Women

The safety and effectiveness of Actonel 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 (Actonel 5 mg, N = 129). All patients in this study received supplemental calcium 1000 mg/day. Increases in BMD were observed as early as 3 months following initiation of Actonel treatment. Actonel 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). Actonel 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 Actonel 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 Actonel 35 mg once-a-week for the prevention postmenopausal osteoporosis were demonstrated in a 1-year, double-blind, placebo-controlled study of 278 patients (Actonel 35 mg, N = 136). All patients were supplemented with 1000 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). Actonel 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%). Actonel 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 -1.00%; risedronate +0.22%), and trochanter of +1.8% (placebo -0.74%; risedronate +1.07%).

Combined Administration with Hormone Replacement Therapy

The effects of combining Actonel 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.

Table 5 Percent Change from Baseline in BMD After 1 Year of Treatment
   Estrogen 0.625 mg
N = 261
 Actonel 5 mg +
Estrogen 0.625 mg
N = 263
 

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

 Lumbar Spine  4.6 ± 0.20  5.2 ± 0.23
 Femoral Neck  1.8 ± 0.25  2.7 ± 0.25
 Femoral Trochanter  3.2 ± 0.28  3.7 ± 0.25
 Midshaft Radius  0.4 ± 0.14  0.7 ± 0.17
 Distal Radius  1.7 ± 0.24  1.6 ± 0.28

Histology/Histomorphometry

Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received Actonel 5 mg plus estrogen or estrogen-alone once daily for 1 year. Histologic evaluation (N = 47) demonstrated that the bone of patients treated with Actonel 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 Actonel plus estrogen and 12 treated with estrogen-alone. Mineralizing surface decreased in both treatment groups (median percent change: Actonel plus estrogen, -79%; estrogen-alone, -50%), consistent with the known effects of these agents on bone turnover.

Men with Osteoporosis

The effects of Actonel 35 mg once-a-week on BMD were examined in a 2-year, double-blind, placebo-controlled, multinational study in 285 men with osteoporosis (Actonel, 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 1000 mg/day and vitamin D 400 to 500 international units/day. Actonel 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 Actonel 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 Actonel therapy for glucocorticoid-induced osteoporosis beyond one year has not been studied.

The prevention study enrolled 228 patients (Actonel 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 Actonel 5 mg group. At each skeletal site there were statistically significant differences between the placebo group and the Actonel 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 Actonel 5 mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and Actonel 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. Actonel 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 (Actonel 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 1000 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. Actonel 5 mg increased BMD at the lumbar spine (2.9%), femoral neck (1.8%), and trochanter (2.4%). The differences between Actonel 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. Actonel 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 Actonel 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 Actonel 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 Actonel (2.5 mg or 5 mg) for 1 year. Histologic evaluation (N = 33) showed that bone formed during treatment with Actonel 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 Actonel 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 Actonel 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 Actonel 30 mg daily for 2 months or Didronel (etidronate disodium) 400 mg daily for 6 months. At Day 180, 77% (43/56) of Actonel-treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10.5% (6/57) of patients treated with Didronel (p less than 0.001). At Day 540, 16 months after discontinuation of therapy, 53% (17/32) of Actonel-treated patients and 14% (4/29) of Didronel-treated patients with available data remained in biochemical remission.

During the first 180 days of the active-controlled study, 85% (51/60) of Actonel-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 Didronel-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 Didronel 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 Actonel 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.

Table 6 Mean Percent Reduction from Baseline at Day 180 in Total Serum Alkaline Phosphatase Excess by Disease Severity
   Actonel 30 mg  Didronel 400 mg
 Subgroup:
Baseline Disease
Severity (AP)
 n  Baseline
Serum
AP (U/L)*
 Mean
% Reduction
 n  Baseline
Serum
AP (U/L)*
 Mean
% Reduction
 

*Values shown are mean ± SEM; ULN = upper limit of normal.

 greater than 2, less than 3x ULN  32  271.6 ± 5.3  -88.1  22  277.9 ± 7.45  -44.6
 greater than or equal to 3, less than 7x ULN  14  475.3 ± 28.8  -87.5  25  480.5 ± 26.44  -35.0
 greater than or equal to 7x ULN  8  1336.5 ± 134.19  -81.8  6  1331.5 ± 167.58  -47.2

Response to Actonel 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, Didronel) responded to treatment with Actonel 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 Actonel.

Principal display panel

NDC 0430-0471-15
Actonel® (risedronate sodium) tablets
5 mg x 30 Tablets

Actonel Overview

Actonel is a prescription medication used to treat conditions in which bones become weak and break easily such as osteoporosis and Paget's disease.

Actonel belongs to a group of drugs called bisphosphonates that work by preventing bone breakdown and increasing bone density. 

The medication comes in the form of a tablet. Depending on which dose you take, Actonel is taken daily, weekly, or monthly.

Common side effects include back and joint pain, stomach area (abdominal) pain, and heartburn. Actonel can cause esophagus (tube connecting the throat to the stomach) problems and low calcium levels in your blood (hypocalcemia).

Actonel Drug Class

Actonel is part of the drug class:

  • Bisphosphonates

For the Consumer

Applies to risedronate: oral tablet, oral tablet delayed release

Along with its needed effects, risedronate (the active ingredient contained in Actonel) 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 while taking risedronate:

More common
  • Abdominal or stomach pain
  • skin rash
Less common
  • Abdominal or stomach pain (severe)
  • belching
  • bone pain
  • cramping of the stomach
  • trouble swallowing
Rare
  • Red, sore eyes
Incidence not known
  • 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 while taking risedronate:

Symptoms of overdose
  • 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 of risedronate 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:

More common
  • Back pain
  • cough or hoarseness
  • diarrhea
  • fever or chills
  • headache
  • joint pain
  • lower back or side pain
  • painful or difficult urination
Less common
  • 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
Rare
  • 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
Incidence not known
  • 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

Bottom Line

Actonel helps to reduce the risk of fracture in people with osteoporosis and some other bone conditions. Dosage instructions, including remaining upright for at least 30 minutes and taking with a full glass of water, must be strictly followed. The optimal length of therapy remains unknown.

Response and Effectiveness

Actonel 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 Actonel by up to 55%.

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