Actonel (Tablets) Instructions for Use

ATC Code

M05BA07 (Risedronic acid)

Active Substance

Risedronic acid (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Bone resorption inhibitor for osteoporosis

Pharmacotherapeutic Group

Bone resorption inhibitor – bisphosphonate

Pharmacological Action

Risedronic acid is a pyridinyl bisphosphonate that binds to hydroxyapatite crystals in bone tissue.

The effect of risedronic acid on bone metabolism is associated with the inhibition of osteoclasts and a reduction in the bone resorption mediated by them.

At the same time, the activity of osteoblasts and the process of bone formation and mineralization are preserved.

When using risedronic acid, bone mineral density increases in a dose-dependent manner and its biomechanical properties improve.

The inhibition of bone resorption by risedronic acid is reversible and ceases after discontinuation of the drug.

After just one month of taking risedronic acid, a decrease in the level of biochemical markers of bone metabolism is observed, which reaches a maximum level after 3-6 months of treatment.

Risedronic acid reduces the risk of developing compression fractures of vertebral bodies and the proximal femur in osteoporosis in postmenopausal women and in women and men who are taking systemic glucocorticosteroid drugs for a long time.

In addition, it slows the rate of height loss in women with postmenopausal osteoporosis.

Bone formed during 2-3 years of treatment with risedronic acid has a normal lamellar structure and a normal degree of mineralization.

Pharmacokinetics

Absorption

After oral administration, Risedronic acid is absorbed in the upper part of the small intestine; its absorption occurs relatively quickly (time to reach C_max is approximately 1 h) and is independent of dose (when used in doses from 2.5 to 30 mg).

The bioavailability of risedronic acid from the tablet after oral administration averages 0.63% and decreases when the drug is taken with food.

Bioavailability is the same in men and women.

Distribution

The V_d of risedronic acid at steady-state concentration is 6.3 L/kg, and its binding to plasma proteins is about 24%.

Metabolism

There are no signs of systemic metabolism of risedronic acid.

Excretion

After IV administration of risedronic acid, its concentration-time curve has three elimination phases with a terminal half-life of about 480 h.

Approximately half of the absorbed dose is excreted by the kidneys within 24 h.

Renal clearance averages 105 mL/min, and total clearance is 122 mL/min.

The difference between them probably reflects the clearance of risedronic acid due to its absorption by bone tissue.

Renal clearance is independent of the plasma concentration of the drug; however, a linear relationship is observed between the renal clearance of risedronic acid and creatinine clearance.

The unabsorbed drug is excreted unchanged in the feces.

Indications

• Treatment of postmenopausal osteoporosis (to reduce the risk of hip fractures and vertebral fractures);
• Prevention of postmenopausal osteoporosis;
• Prevention and treatment of osteoporosis in postmenopausal women undergoing systematic and prolonged treatment with glucocorticosteroid drugs.

ICD codes

Dosage Regimen

Tablets

The recommended dose of Actonel for adults is 5 mg/day (1 tablet).

The drug is taken orally; the tablet should be taken whole, not sucked or chewed, while in an upright position, and washed down with a glass of drinking water (≥120 mL).

Do not lie down for 30 minutes after taking the tablet (see “Special Precautions”).

The absorption of the drug is significantly affected by food, therefore, to ensure optimal conditions for drug absorption, it is recommended

• To take the drug before breakfast, at least 30 minutes before the first meal, other medications, or drinks (except plain drinking water) of the day.

In individual cases, when taking the drug before breakfast is not possible, Actonel can be taken at the same time or between meals, or in the evening, following the recommendations below, which ensure the drug is taken on an empty stomach

• Between meals – at least 2 hours before and 2 hours after any food, medications, or drinks (except drinking water),
• In the evening – Actonel should be taken at least 2 hours after the last intake of food, medications, or drinks (except drinking water) and at least 30 minutes before going to bed.

If a dose is accidentally missed, the drug can be taken before breakfast, or between meals, or in the evening in accordance with the above recommendations.

In case of insufficient dietary intake of calcium and vitamin D, their additional intake should be ensured.

Elderly age

No dose adjustment is required, as the bioavailability and distribution of the drug in elderly patients (over 60 years) and younger individuals are the same.

Renal impairment

No dose adjustment is required in patients with creatinine clearance ≥30 mL/min.

There are limited clinical data on the use of Actonel in patients with severe renal impairment (creatinine clearance < 30 mL/min), so it is not possible to provide any recommendations regarding the drug dose in this category of patients.

Children

The safety and efficacy of Actonel in children and adolescents have not been studied.

Adverse Reactions

Data on adverse effects were obtained from Phase III clinical studies in women with postmenopausal osteoporosis who received treatment with risedronate at a dose of 5 mg/day for up to 36 months (5020 patients) or placebo (5048 patients).

The undesirable effects listed below are given by system organ class according to the following frequency gradations

Very common: (≥10%);

Common: (≥1%-<10%);

Uncommon: (≥0.1%-<1%);

Rare: (≥0.01% – <0.1%);

Very rare:(<0.01%)

The frequency of adverse effects when taking risedronic acid compared to placebo is indicated in parentheses, and the symbol “*” marks the absence of relevant data from Phase III studies (for osteoporosis) on the frequency of adverse effects, which are indicated based on data from earlier clinical studies.

Most adverse effects were mild to moderate in severity and usually did not require discontinuation of treatment.

Nervous system disorders

Common: headache (1.8% vs. 1.4%), dizziness, asthenia, depression, insomnia.

Eye disorders

Uncommon: acute iritis *.

Gastrointestinal disorders

Common: constipation (5.0% vs. 4.8%), dyspepsia (4.5% vs. 4.1%), nausea (4.3% vs. 4.0%), abdominal pain (3.5% vs. 3.3%), diarrhea (3.0% vs. 2.7%).

Uncommon: gastritis (0.9% vs. 0.7%), esophagitis (0.9% vs. 0.9%), dysphagia (0.4% vs. 0.2%), duodenitis (0.2% vs. 0.1%), esophageal ulcer (0.2% vs. 0.2%).

Rare: glossitis (<0.1% vs. 0.1%), esophageal stricture (<0.1% vs. 0.0%)

Musculoskeletal and connective tissue disorders

Common: musculoskeletal pain (2.1% vs. 1.9%).

Liver function tests

Rare: abnormalities in liver function tests*.

Laboratory findings

Some patients experienced an early, transient, asymptomatic, and slight decrease in serum calcium and phosphate concentrations.

During post-marketing use, the following additional adverse reactions have been observed.

Eye disorders

Uveitis (inflammation of the uvea of the eyeball).

Musculoskeletal and connective tissue disorders

Osteonecrosis of the jaw.

Cases of osteonecrosis of the jaw have been described mainly in cancer patients undergoing anticancer treatment that includes bisphosphonates.

Risk factors for the development of osteonecrosis are cancer, chemotherapy, radiation therapy, treatment with corticosteroid drugs, poor oral hygiene, local infectious-inflammatory process, including osteomyelitis.

In most described cases, tooth extraction was performed in patients while being treated with bisphosphonates.

The causal relationship between osteonecrosis of the jaw and the use of bisphosphonates remains unclear.

Skin reactions

Very rare: allergic and skin reactions, including angioedema, generalized rash, and bullous skin reactions, sometimes severe.

Other

Infections (including urinary tract infections), increased blood pressure.

Contraindications

• Hypersensitivity to risedronic acid or to any other component of the drug;
• Severe disorders of mineral metabolism, including hypocalcemia;
• Severe renal impairment (creatinine clearance < 30 mL/min);
• Pregnancy and breastfeeding;
• Age under 18 years (efficacy and safety have not been established);
• Hereditary lactose intolerance, lactase deficiency, or glucose-galactose malabsorption (due to the presence of lactose in the drug as an excipient).

With caution in erosive and ulcerative lesions of the esophagus and stomach (including history); in narrowing or achalasia of the esophagus (insufficient experience with the drug); in inability to stand or sit for at least 30 minutes (insufficient experience with the drug).

Use in Pregnancy and Lactation

The use of the drug during pregnancy is prohibited.

The use of the drug during lactation is prohibited.

Use in Renal Impairment

Contraindication: severe renal impairment (creatinine clearance < 30 mL/min).

Pediatric Use

Contraindication: age under 18 years (efficacy and safety have not been established).

Geriatric Use

No dose adjustment is required, as the bioavailability and distribution of the drug in elderly patients (over 60 years) and younger individuals are the same.

Special Precautions

The efficacy of bisphosphonates in postmenopausal osteoporosis has been established for low bone mineral density (BMD) (BMD T-score in the proximal femur or lumbar spine ≤-2.5 SD) and/or a history of fractures.

Old age or clinical risk factors for fractures are not sufficient grounds for initiating osteoporosis treatment with bisphosphonates.

The efficacy of bisphosphonates (including risedronic acid) in preventing fractures in osteoporosis in very elderly women (over 80 years) is less than in younger women, which may be explained by the increasing importance of other (besides osteoporosis) factors for fracture occurrence due to aging.

Foods, beverages (except plain drinking water), and medications containing polyvalent cations (such as calcium, magnesium, iron, and aluminum) should not be taken simultaneously with Actonel, as this may affect the absorption of sodium risedronate.

Some bisphosphonates are associated with esophagitis and esophageal ulcers.

Therefore, patients must strictly follow the instructions regarding the dosage regimen and method of administration (see the “Dosage Regimen” section).

The recommendations for taking the drug are particularly important for patients with esophageal diseases that impair esophageal patency, such as esophageal stricture and esophageal achalasia.

Particular caution should be exercised when taking the drug by patients who are unable to remain in an upright position for at least 30 minutes after taking the drug (lack of sufficient experience with the drug in such patients).

Before starting treatment with Actonel 5 mg tablets, hypocalcemia, as well as other pathologies affecting bone and mineral metabolism (e.g., parathyroid disorders, vitamin D deficiency), should be corrected.

In case of insufficient dietary intake of calcium and vitamin D, their additional intake is necessary.

Osteonecrosis of the jaw has been observed in cancer patients whose treatment included bisphosphonates (mainly administered IV), usually following tooth extraction and/or in the presence of local infection (including osteomyelitis).

Many of these patients received chemotherapy and glucocorticosteroid drugs.

In patients with risk factors for the development of jaw osteonecrosis, such as cancer, chemotherapy and/or radiation therapy, use of glucocorticosteroids, poor oral hygiene, a dental consultation is recommended before prescribing bisphosphonates.

Furthermore, jaw surgery should be avoided in such patients if possible.

If osteonecrosis develops in patients receiving bisphosphonate treatment, jaw surgery may worsen the condition.

There is no information that discontinuing bisphosphonate treatment in patients requiring jaw surgery reduces the risk of developing jaw osteonecrosis.

Overdose

Symptoms of overdose

A significant decrease in plasma calcium levels can be expected in a number of patients after a significant overdose.

Some of these patients may also show signs and symptoms of hypocalcemia.

Treatment of overdose

There is no specific information on the treatment of acute overdose with Actonel 5 mg tablets.

In case of significant overdose, gastric lavage is recommended to remove the unabsorbed drug.

Milk or antacids containing magnesium, calcium, or aluminum can be given to bind risedronic acid and reduce its absorption.

Drug Interactions

No formal interaction studies have been conducted, but no clinically significant interactions with other medicinal products were observed during clinical studies, namely, non-steroidal anti-inflammatory drugs (NSAIDs), H₂-histamine blockers, proton pump inhibitors, antacids, slow calcium channel blockers, beta-blockers, thiazide diuretics, glucocorticosteroids, anticoagulants, anticonvulsants, cardiac glycosides.

When risedronic acid and acetylsalicylic acid or NSAIDs (3 or more days per week) were taken concomitantly, the frequency of gastrointestinal adverse effects did not increase.

If necessary, risedronic acid can be used in combination with estrogen hormone replacement therapy.

Medicinal products containing polyvalent cations, such as calcium, magnesium, iron, and aluminum, may reduce the absorption of risedronic acid (see “Special Precautions”).

Risedronic acid does not undergo systemic metabolism, does not induce cytochrome P450 isoenzymes, and is weakly bound to proteins, so it is unlikely to have pharmacokinetic interactions at the level of metabolism or protein binding.

Storage Conditions

The drug should be stored at a temperature not exceeding 25°C (77°F) in a place inaccessible to children!

Shelf Life

The shelf life is 5 years. Do not use the drug after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.