Risedronate Sodium

ACTONEL (risedronate sodium) tablets is a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each ACTONEL tablet for oral administration contains the equivalent of 5, 30, 35, 75, or 150 mg of anhydrous risedronate sodium in the form of the hemipentahydrate with small amounts of monohydrate. The empirical formula for risedronate sodium hemipentahydrate is C7H10NO7P2Na •2.5 H2O. The chemical name of risedronate sodium is [1-hydroxy-2- (3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt. The chemical structure of risedronate sodium hemi-pentahydrate is the following:

Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and in aqueous solutions, and essentially insoluble in common organic solvents.

Inactive Ingredients

crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide.

5 mg - ferric oxide yellow, lactose monohydrate; 30 mg - lactose monohydrate; 35 mg - ferric oxide red, ferric oxide yellow, lactose monohydrate; 75 mg - ferric oxide red; 150 mg - FD&C blue #2 aluminum lake.

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].

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.

ACTONEL®
(AK-toh-nel)
(risedronate sodium) Tablets

Read the Medication Guide that comes with ACTONEL® before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your doctor about your medical condition or your treatment. Talk to your doctor if you have any questions about ACTONEL, there may be new information about it.

What is the most important information I should know about ACTONEL?

ACTONEL can cause serious side effects including:

1. Esophagus problems
2. Low calcium levels in your blood (hypocalcemia)
3. Severe jaw bone problems (osteonecrosis)
4. Bone, joint, or muscle pain
5. Unusual thigh bone fractures

1. Esophagus problems .

   Some people who take ACTONEL may develop problems in thees ophagus (the tube that connects the mouth and the stomach). These problems include irritation, inflammation, or ulcers of the esophagus which may sometimes bleed.

   • It is important that you take ACTONEL exactly as prescribed to help lower your chance of getting esophagus problems. (See the section “How should I take ACTONEL?”)
   • Stop taking ACTONEL and call your doctor right away if you get chest pain, new or worsening heartburn, or have trouble or pain when you swallow.
2. Low calcium levels in your blood (hypocalcemia).
   

   ACTONEL may lower the calcium levels in your blood. If you have low blood calcium before you start taking ACTONEL, it may get worse during treatment. Your low blood calcium must be treated before you take ACTONEL. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:

   • 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 (osteonecrosis).
   

   Severe jaw bone problems may happen when you take ACTONEL. Your doctor should examine your mouth before you start ACTONEL. Your doctor may tell you to see your dentist before you start ACTONEL. It is important for you to practice good mouth care during treatment with ACTONEL.

4. Bone, joint, or muscle pain.
   

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

5. Unusual thigh bone fractures .
   

   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.

What is ACTONEL?

ACTONEL is a prescription medicine used to:

• Treat or prevent osteoporosis in women after menopause. ACTONEL helps increase bone mass and
• helps reduce the chance of having a spinal or non-spinal fracture (break).
• Increase bone mass in men with osteoporosis.
• Treat or prevent osteoporosis in either men or women who are taking corticosteroid medicines.
• Treat certain men and women who have Paget’s disease of the bone.

It is not known how long ACTONEL works for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if ACTONEL is still right for you.

ACTONEL is not for use in children.

Who should not take ACTONEL?

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 or any of its ingredients. A list of ingredients is at the end of this leaflet.

What should I tell my doctor before taking ACTONEL?

Before you start ACTONEL, be sure to talk to your doctor if you:

• Have problems with swallowing
• Have stomach or digestive problems
• Have low blood calcium
• Plan to have dental surgery or teeth removed
• Have kidney problems
• Have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome)
• Are pregnant, or plan to become pregnant. It is not known if ACTONEL can harm your unborn baby.
• Are breastfeeding or plan to breastfeed. It is not known if ACTONEL passes into your milk and may harm your baby.

Especially tell your doctor if you take:

• antacids
• aspirin
• Nonsteroidal Anti-Inflammatory (NSAID) medicines

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Certain medicines may affect how ACTONEL works.

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist each time you get a new medicine.

How should I take ACTONEL?

• Take ACTONEL exactly as your doctor tells you. Your doctor may change your dose of ACTONEL if needed.
• ACTONEL works only if taken on an empty stomach.
• Take 1 ACTONEL tablet, after you get up for the day and before taking your first food, drink, or other medicine.
• Take ACTONEL while you are sitting or standing.
• Do not chew or suck on a tablet of ACTONEL.
• Swallow ACTONEL tablet with a full glass (6 to 8 ounces) of plain water only.
• Do not take ACTONEL with mineral water, coffee, tea, soda, or juice.

After swallowing ACTONEL tablet, wait at least 30 minutes:

• Before you lie down. You may sit, stand or walk, and do normal activities like reading.
• Before you take your first food or drink except for plain water.
• Before you take other medicines, including antacids, calcium, and other supplements and vitamins.

Do not lie down for at least 30 minutes after you take ACTONEL and after you eat your first food of the day.

If you miss a dose of ACTONEL, do not take it later in the day. Take your missed dose the next morning and then return to your normal schedule. Do not take 2 doses at the same time.

If you miss more than 2 doses of ACTONEL in a month, call your doctor for instructions.

If you take too much ACTONEL, call your doctor. Do not try to vomit. Do not lie down.

What are the possible side effects of ACTONEL?

ACTONEL may cause serious side effects:

• See “What is the most important information I should know about ACTONEL?”

The most common side effects of ACTONEL are:

• pain, including back and joint pain
• stomach area (abdominal) pain
• heartburn

You may get allergic reactions, such as hives, swelling of your face, lips, tongue, or throat.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of ACTONEL. For more information, ask your doctor or pharmacist.

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

How should I store ACTONEL?

• Store ACTONEL at room temperature, 68° F to 77° F (20° C to 25° C).

Safely throw away medicine that is out of date or no longer needed.

Keep ACTONEL and all medicines out of the reach of children.

General information about the safe and effective use of ACTONEL.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ACTONEL for a condition for which it was not prescribed. Do not give ACTONEL to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about ACTONEL. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about ACTONEL that is written for health professionals.

For more information, go to www.ACTONEL.com or call 1-800-521-8813.

What are the ingredients in ACTONEL?

Active ingredient: risedronate sodium

Inactive ingredients in all dose strengths: crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide, titanium dioxide.

Inactive ingredients specific to a dose strength: 5 mg—ferric oxide yellow, lactose monohydrate; 30 mg—lactose monohydrate; 35 mg—ferric oxide red, ferric oxide yellow, lactose monohydrate; 75 mg—ferric oxide red; 150 mg—FD&C blue #2 aluminum lake.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Do not take a risedronate tablet if you cannot sit upright or stand for at least 30 minutes. Risedronate can cause serious problems in the stomach or esophagus (the tube that connects your mouth and stomach). You will need to stay upright for at least 30 minutes after taking this medication.

You should not take this medication if you are allergic to risedronate, or if you have low levels of calcium in your blood (hypocalcemia), or a problem with the movement of muscles in your esophagus.

To make sure you can safely take risedronate, tell your doctor if you have any of these other conditions:

• low blood calcium (hypocalcemia);
• a vitamin D deficiency;
• kidney disease; or
• an ulcer in your stomach or esophagus.

Some people using medicines similar to risedronate have developed bone loss in the jaw, also called osteonecrosis of the jaw. Symptoms of this condition may include jaw pain, swelling, numbness, loose teeth, gum infection, or slow healing after injury or surgery involving the gums.

You may be more likely to develop osteonecrosis of the jaw if you have cancer or have been treated with chemotherapy, radiation, or steroids. Other conditions associated with osteonecrosis of the jaw include blood clotting disorders, anemia (low red blood cells), and dental surgery or pre-existing dental problems.

Talk with your doctor about the risks and benefits of using this medication.

FDA pregnancy category C. It is not known whether risedronate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether risedronate passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are taking risedronate.

Synthetic bisphosphonate; bone resorption inhibitor.1 2 4 5 6 8 9 12 13 14

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

Category C.1

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

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

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

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

Safety and efficacy not established.1

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

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.