Actonel

Name: Actonel

What are the uses for risedronate?

  • Risedronate is used for the treatment of Paget's disease of bone (osteitis deformans), treatment and prevention of postmenopausal osteoporosis in women, and treatment of osteoporosis in men.
  • It also is used to prevent and treat osteoporosis caused by steroid medications (glucocorticoid-induced osteoporosis).

Cautions for Actonel

Contraindications

  • Abnormalities of the esophagus that delay esophageal emptying (e.g., stricture, achalasia).1

  • Inability to stand or sit upright for ≥30 minutes.1

  • Hypocalcemia.1

  • Known hypersensitivity to risedronate or any ingredient in the formulation.1

Warnings/Precautions

Upper GI Effects

Possible severe adverse esophageal effects (e.g., esophagitis, esophageal ulcers, erosions, strictures, perforation).1 (See Oral Administration under Dosage and Administration.) Monitor for any manifestations and discontinue if dysphagia, odynophagia, new or worsening heartburn, or retrosternal pain occurs.1

Risk of severe adverse esophageal effects greater in patients who do not drink 180–240 mL of water with risedronate, do not avoid lying down for ≥30 minutes following oral administration, and/or continue to take drug after developing symptoms suggesting esophageal irritation.1 Instruct patients carefully about proper administration and give copy of patient instructions provided by manufacturer.1

Use with caution in patients with history of upper GI disease (e.g., Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, ulcers).1 Gastric and duodenal ulcers (some severe and with complications) reported during postmarketing experience.1

Osteonecrosis of the Jaw

Osteonecrosis and osteomyelitis of the jaw reported, principally in cancer patients receiving bisphosphonates,28 29 30 31 32 33 usually when given IV.1 33 Known risk factors include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), cancer, concomitant therapies (e.g., chemotherapy, radiation therapy, corticosteroids), poor oral hygiene, and comorbid disorders (e.g., periodontal and/or other preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures).1

If osteonecrosis of the jaw develops, consult an oral surgeon for treatment.1 Dental surgery may exacerbate condition.1

In patients requiring dental procedures, no data are available to suggest whether discontinuance of therapy prior to procedure reduces the risk of osteonecrosis of the jaw.1 Base management of patients requiring dental treatment on an individual assessment of risks and benefits.1

Musculoskeletal Pain

Severe and occasionally incapacitating bone, joint, and/or muscle pain reported infrequently with bisphosphonate therapy.1 28 33 35 36 Time to onset varied from 1 day to years (mean onset about 3 months) after treatment initiation.1 28 33 35 36

If severe symptoms occur, discontinue drug.35 Such pain generally improves following discontinuance of the drug, but may recur upon subsequent rechallenge with the same drug or another bisphosphonate.1 28 33 36

Atypical Fracture of the Femur

Atypical (subtrochanteric or diaphyseal), low-energy or low-trauma femur fractures reported rarely with long-term use (>3 years) of bisphosphonates, mostly in patients receiving these drugs for osteoporosis.43 44 45 Often occurs with minimal or no trauma, and may be bilateral.41 42 43 45 Causality not established; atypical fractures also occur in osteoporotic patients not receiving bisphosphonates. 43 44 45 46 Risk may be increased with concomitant use of glucocorticoid, estrogen, and proton-pump inhibitor therapy.45 47 48 50

Evaluate patients who present with new thigh or groin pain for possibility of an atypical femoral fracture; include assessment of the contralateral limb.41 42 43 45 Consider interruption of bisphosphonate therapy in patients with manifestations of possible femoral fracture; weigh risks versus benefits of continued treatment.41 42 Discontinue if a femoral shaft fracture is confirmed.43 44 45

Potential Risk of Esophageal Cancer

Some evidence (from postmarketing experience and observational studies) suggests a possible association between use of oral bisphosphonates and an increased risk of esophageal cancer.40 51 52 However, because of conflicting data,52 53 54 additional study needed to confirm such findings.51

FDA states that benefits of oral bisphosphonates continue to outweigh their potential risks in patients with osteoporosis; it is important to consider that esophageal cancer is rare, especially in women.51 52

Avoidance of oral bisphosphonates in patients with Barrett’s esophagus, a known precursor to esophageal adenocarcinoma, has been recommended.40

Use of Combination Preparations

When risedronate is given concurrently with calcium carbonate, consider the cautions, precautions, and contraindications associated with calcium carbonate in addition to those associated with risedronate.1

Metabolic Effects

Possible asymptomatic decreases in serum calcium and phosphorus concentrations.1

Correct hypocalcemia and other disturbances of bone and mineral metabolism before initiating therapy.1 If daily dietary intake is inadequate, administer supplemental calcium and vitamin D.1

Endocrine Effects

Before initiating therapy in patients receiving long-term corticosteroid therapy, measure sex hormones and consider replacement therapy, if appropriate.1 4 11

Atrial Fibrillation

Although data are conflicting, possible increased risk of atrial fibrillation with use of bisphosphonates.37 38 39 FDA analysis of data from long-term (6 months to 3 years) controlled trials identified a higher rate of atrial fibrillation in patients receiving bisphosphonates (alendronate, ibandronate, risedronate, or zoledronic acid) versus placebo; however, only a few events reported in each study.39 FDA is continuing to monitor this safety concern.39

Specific Populations

Pregnancy

Category C.1

Lactation

Distributed into milk in rats.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established.1 Not indicated in pediatric patients.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Gender

Safety and efficacy of risedronate sodium copackaged with calcium carbonate not established in men for the treatment of primary osteoporosis.33

Hepatic Impairment

Safety and efficacy not established.1

Renal Impairment

Decreased clearance; use not recommended in patients with severe renal impairment (Clcr <30 mL/minute).1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Postmenopausal osteoporosis: Infection (unspecified),1 33 back pain,1 8 10 arthralgia,1 8 10 33 accidental injury,1 pain (unspecified), 1 33 constipation,1 33 abdominal pain,1 5 6 8 10 urinary tract infection,1 33 nausea,1 33 diarrhea,1 33 dyspepsia,1 33 flu syndrome,1 hypertension,1 bronchitis,1 33 headache,1 arthritis,1 33 traumatic bone fracture,1 33 sinusitis,1 33 rash,1 33 dizziness,1 joint disorder,1 depression,1 33 myalgia,1 33 cataract,1 rhinitis,1 pharyngitis,1 increased cough.1

Paget’s disease: Arthralgia,1 diarrhea,1 headache,1 abdominal pain,1 rash,1 flu syndrome,1 nausea,1 peripheral edema,1 chest pain,1 constipation,1 dizziness.1

Stability

Storage

Oral

Tablets

20–25 °C.1

Actions and Spectrum

  • Inhibits osteoclast-mediated bone resorption.1 2 4 5 6 8 9 12 13 14

  • Maintains or increases bone mineral density.1 5 6 7 8 10 18 19 20

Advice to Patients

  • Importance of providing a copy of the manufacturer’s patient information.1

  • Importance of proper administration (e.g., avoiding foods and beverages other than plain water, not lying down for 30 minutes following administration).1

  • Importance of swallowing tablets whole, without crushing, chewing, or sucking.1

  • Importance of discontinuing and informing clinician if symptoms of esophageal disease (e.g., difficulty or pain on swallowing; retrosternal, abdominal, or esophageal pain; severe or persistent heartburn) develop.1

  • Importance of adhering to recommended life-style modifications (e.g., weight-bearing exercise, calcium and vitamin D consumption, avoidance of excessive cigarette smoking and/or alcohol consumption).1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinicians of severe kidney disease.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Actonel Side Effects

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:

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:

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 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

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.

How is this medicine (Actonel) best taken?

Use Actonel as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Follow how to take this medicine as you have been told by your doctor. Do not use more than you were told to use.
  • Take with plain water only. Avoid taking with mineral water, milk, or other drinks.
  • Swallow whole. Do not chew, break, or crush.
  • Keep taking Actonel as you have been told by your doctor or other health care provider, even if you feel well.
  • To gain the most benefit, do not miss doses.
  • Take on an empty stomach before breakfast.
  • Take with a full glass of water.
  • Take at least 30 minutes before the first food, drink, or drugs of the day.
  • Do not lie down for at least 30 minutes after taking this medicine and until you eat your first food of the day.

What do I do if I miss a dose?

  • Do not take it later in the day.
  • Take the missed dose on the next morning after you think about it and then go back to your normal time.
  • Do not take 2 doses on the same day.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of low calcium levels like muscle cramps or spasms, numbness and tingling, or seizures.
  • Black, tarry, or bloody stools.
  • Chest pain.
  • Coughing up blood.
  • Very upset stomach or throwing up.
  • Throwing up blood or throw up that looks like coffee grounds.
  • Very bad belly pain.
  • Heartburn.
  • Trouble swallowing.
  • Very bad pain when swallowing.
  • Sore throat.
  • Very bad bone, joint, or muscle pain.
  • Any new or strange groin, hip, or thigh pain.
  • Very bad headache.
  • Very bad dizziness.
  • Change in eyesight, eye pain, or very bad eye irritation.
  • Trouble passing urine.
  • Pain when passing urine.
  • This medicine may cause jawbone problems. The chance may be higher the longer you take Actonel. The chance may be higher if you have cancer, dental problems, dentures that do not fit well, anemia, blood clotting problems, or an infection. The chance may also be higher if you are having dental work, getting chemo or radiation, or taking other drugs that may cause jawbone problems like some steroid drugs. There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure. Call your doctor right away if you have jaw swelling or pain.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

How do I store and/or throw out Actonel?

  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Check with your pharmacist about how to throw out unused drugs.

Use in specific populations

Pregnancy

Pregnancy Category C: There are no adequate and well-controlled studies of Actonel in pregnant women. Actonel should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.

In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human dose of 30 mg/day. Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull from dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses approximately 5 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose. The relevance of this finding to human use of Actonel is unclear.

No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.

Similar to other bisphosphonates, treatment during mating and gestation with doses of risedronate sodium approximately the same as the 30 mg/day human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit.

Nursing Mothers

Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. It is not known whether Actonel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Actonel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Actonel is not indicated for use in pediatric patients.

The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In Actonel-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12.

The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in greater than or equal to 10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%).

Geriatric Use

Of the patients receiving Actonel in postmenopausal osteoporosis studies [see Clinical Studies (14)], 47% were between 65 and 75 years of age, and 17% were over 75. The corresponding proportions were 26% and 11% in glucocorticoid-induced osteoporosis trials, and 40% and 26% in Paget’s disease trials. No overall differences in efficacy between geriatric and younger patients were observed in these studies. In the male osteoporosis trial, 28% of patients receiving Actonel were between 65 and 75 years of age and 9% were over 75. The lumbar spine BMD response for Actonel compared to placebo was 5.6% for subjects less than 65 years and 2.9% for subjects greater than or equal to 65 years. No overall differences in safety between geriatric and younger patients were observed in the Actonel trials, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment

Actonel 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 human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment.

Overdose

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 ).

Clinical pharmacology

Mechanism Of Action

ACTONEL has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, ACTONEL 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 ACTONEL treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

Pharmacodynamics

ACTONEL treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of ACTONEL 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 ACTONEL for the treatment of osteoporosis in postmenopausal women, ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week decreased urinary collagen cross-linked Ntelopeptide by 60% and 61%, respectively. In addition, serum bone-specific alkaline phosphatase was also reduced by 42% and 41% in the ACTONEL 5 mg daily and ACTONEL 35 mg once-a-week groups, respectively. When postmenopausal women with osteoporosis were treated for 1 year with ACTONEL 5 mg daily or ACTONEL 75 mg two consecutive days per month, urinary collagen crosslinked 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 ACTONEL 5 mg daily versus ACTONEL 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 bonespecific alkaline phosphatase was reduced by 31% and 32%, respectively.

Osteoporosis In Men

In a 2-year study of men with osteoporosis, treatment with ACTONEL 35 mg once-a-week resulted in a mean decrease from baseline compared to placebo of 16% (placebo 20%; ACTONEL 35 mg 37%) for the bone resorption marker urinary collagen cross-linked N-telopeptide, 45% (placebo -6%; ACTONEL 35 mg 39%) for the bone resorption marker serum C-telopeptide, and 27% (placebo -2%; ACTONEL 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. ACTONEL decreases bone resorption without directly inhibiting bone formation.

In two 1-year clinical trials in the treatment and prevention of glucocorticoid-induced osteoporosis, ACTONEL 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 ACTONEL 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 (T ) 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. ACTONEL 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

ACTONEL is not indicated for use in pediatric patients [see Pediatric Use].

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. ACTONEL 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].

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  
VERT NA Placebo
N = 678
ACTONEL 5 mg
N = 696
Absolute Risk Reduction (%) Relative Risk Reduction (%)
New and Worsening
  01 Year 7.2 3.9 3.3 49
  02 Years 12.8 8.0 4.8 42
  03 Years 18.5 13.9 4.6 33
New
  01 Year 6.4 2.4 4.0 65
  02 Years 11.7 5.8 5.9 55
  03 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
  01 Year 15.3 8.2 7.1 50
  02 Years 28.3 13.9 14.4 56
  03 Years 34.0 21.8 12.2 46
New
  01 Year 13.3 5.6 7.7 61
  02 Years 24.7 11.6 13.1 59
  03 Years 29.0 18.1 10.9 49
aCalculated by Kaplan-Meier methodology.

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
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
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

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

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%; estrogenalone, -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
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
*Values shown are mean ± SEM; ULN = upper limit of normal.

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.

Actonel Precautions

1. Actonel can cause esophagus (tube connecting the throat to the stomach) problems. It is important that you take Actonel exactly as prescribed to help lower your chance of getting esophagus problems including:

  • irritation
  • inflammation
  • ulcers of the esophagus which may sometimes bleed

Stop taking Actonel and call your doctor right away if you have painful or difficult swallowing, chest pain, or new or worsening heartburn.

2. Actonel can cause low calcium levels in your blood (hypocalcemia), which can worsen already low blood calcium conditions. If you have low blood calcium before taking Actonel it must be treated before you take Actonel. You may not know you have low blood calcium, but some people may have the following symptoms:

  • Spasms, twitches, or cramps in your muscles
  • Numbness or tingling in your fingers, toes, or around your mouth

Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take Actonel. Take calcium and vitamin D as your doctor tells you to.

3. Severe jaw bone problems may happen when you take Actonel. Your doctor and dentist may examine your mouth before you start Actonel. 

4. Some people who take Actonel develop severe bone, joint, or muscle pain.

5. Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh.

Call your doctor right away if you have any of these side effects.

Do not take Actonel if you:

  • have certain problems with your esophagus, the tube that connects your mouth with your stomach
  • cannot stand or sit upright for at least 30 minutes
  • have low levels of calcium in your blood
  • are allergic to Actonel any of its ingredients

Actonel Food Interactions

Foods and some vitamin supplements and medicines can stop your body from absorbing (using) Actonel. Therefore, do not take anything other than plain water at or near the time you take Actonel and for 30 minutes after.

Actonel and Lactation

Tell your doctor before using Actonel if you are breastfeeding or plan to breastfeed. It is not known if Actonel is excreted in human breast milk or if it can harm your baby.

Warnings

Contraindications

Hypersensitivity; angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported

Hypocalcemia

Hypercalcemia from any cause including, but not limited to, hyperparathyroidism, hypercalcemia of malignancy, or sarcoidosis

Inability to stand or sit upright for at least 30 minutes

Esophagus abnormalities (eg, stricture, achalasia) that delay esophageal emptying

Cautions

Ensure adequate intake of calcium and vitamin D; correct hypocalcemia, if present, before initiating therapy

Avoid concomitant polyvalent cation-containing medications

May cause upper GI disorders (eg, dysphagia, esophagitis, esophageal or gastric ulcer); instruct patients to follow dosing instructions; discontinue use if new or worsening symptoms occur

Severe irritation of upper GI mucosa; discontinue if new or worsening symptoms occur in patients with active upper GI disease

Osteonecrosis of the jaw, can occur spontaneously and is generally associated with tooth extraction and/or local infection with delayed healing; known risk factors include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders; risk of osteonecrosis of jaw may increase with duration of exposure to bisphosphonates

Food decreases bioavailability

Not recommended in severe renal impairment (CrCl <30 mL/min)

Risk of severe joint, muscle, or bone pain

Possible increased risk of atypical subtrochanteric and diaphyseal femur fractures; consider periodic reevaluation of need for continued bisphosphonate therapy, particularly if treatment lasts >5 years; patients with new thigh or groin pain should be evaluated to rule out a femoral fracture

Consider appropriate hormone replacement therapy if necessary

Administration of calcium has been associated with a slight increase in risk of kidney stones; in patients with a history of kidney stones or hypercalciuria, metabolic assessment to seek treatable causes of these conditions is warranted; if administration of calcium tablets necessary, monitor urinary calcium excretion periodically; patients with achlorhydria may have decreased absorption of calcium; taking calcium with food enhances absorption; concomitant use of calcium-containing antacids should be monitored to avoid excessive intake of calcium

Esophageal cancer risk (July 21, 2011, FDA safety communication)

  • Conflicting findings exist from studies evaluating the risk of esophageal cancer with oral bisphosphonates
  • Esophagitis and other esophageal events have been reported, particularly in patients who do not follow specific directions for use of oral bisphosphonates (eg, sitting up or standing after administration, taking with full glass of water)
  • Ongoing review of data from published studies to evaluate whether use of oral bisphosphonates is associated with increased risk of cancer of esophagus is currently being conducted by FDA
  • FDA has not concluded that taking oral bisphosphonates increases risk of esophageal cancer
  • Data are insufficient to recommend endoscopic screening of asymptomatic patients
  • FDA will continue to evaluate all available data supporting safety and effectiveness of bisphosphonates and will update public when more information becomes available
  • Instruct patients to contact their healthcare provider if they develop symptoms of esophagitis (eg, swallowing difficulties, chest pain, new or worsening heartburn, trouble or pain when swallowing)

Where can i get more information?

Your pharmacist can provide more information about risedronate.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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What other drugs will affect Actonel?

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.

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