Actonel Plus Calcium 35mg/500mg

Interactions with herbs have not been studied.

Clinical benefits may be compromised by failure to take ACTONEL on an empty stomach. For dosing information see Dosage and Administration.

Bisphosphonates are known to interfere with the use of bone-imaging agents. Specific studies with ACTONEL have not been performed.

No specific drug-drug interaction studies were performed with ACTONEL. Animal studies have demonstrated that risedronate is highly concentrated in bone and is retained only minimally in soft tissue. No metabolites have been detected systemically or in bone. The binding of risedronate to plasma proteins in humans is low (24%), resulting in minimal potential for interference with the binding of other drugs. In an additional animal study, there was also no evidence of hepatic microsomal enzyme induction. In summary, ACTONEL is not systemically metabolized, does not induce cytochrome P450 enzymes and has low protein binding. ACTONEL PLUS CALCIUM is therefore not expected to interact with other drugs based on the effects of protein binding displacement, enzyme induction or metabolism of other drugs.

No dosage adjustment is necessary in elderly patients (see Indications and Clinical Use, Geriatrics).

Food and medications containing polyvalent cations (e.g., calcium, magnesium, aluminum, and iron) can interfere with the absorption of ACTONEL. Therefore, food and other medications should be administered at a different time of the day (see Recommended Dose and Dosage Adjustment and Drug Interactions, Drug-Drug Interactions).

The patient should be informed to pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions. Specifically, ACTONEL should be taken on an empty stomach at least 30 minutes before the first food or drink (other than plain water) and/or any other medication of the day. The ACTONEL tablet should be swallowed whole—do not chew.

The calcium tablet should be taken with food.

The recommended regimen is one 35 mg risedronate tablet, taken orally once a week (Day 1 of the 7-day treatment cycle) followed by one 1250 mg calcium carbonate (500 mg elemental calcium) tablet, taken orally daily on each of the remaining six days (Days 2 through 7) of the 7-day treatment cycle.

Absorption of calcium from calcium carbonate is poor in patients with achlorhydria unless taken with food.

No dosage adjustment is necessary in patients with a creatinine clearance ≥30 mL/min or in the elderly. Not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).

In case the ACTONEL tablet dose is missed, patients should be instructed that the ACTONEL tablet should be taken on the next day in the morning according to the dosing instructions. In this particular instance, patients should then take their calcium tablet on the following day. Patients should be instructed that the ACTONEL tablet and the calcium tablet should be taken on different days.

If the calcium tablet is missed, the patient should be instructed to take it as soon as she remembers. She should not take more than 1 tablet from the package on the same day. Any remaining calcium tablets at the end of the weekly cycle should be discarded.

The following adverse drug reactions were reported in ≤1% of patients who received ACTONEL for all indications.

Asymptomatic mild decreases in serum calcium and phosphorus levels have been observed in some patients (see Action and Clinical Pharmacology, Pharmacodynamics).

Rare cases of leukemia have been reported following therapy with bisphosphonates. Any causal relationship to either the treatment or to the patients' underlying disease has not been established.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and approximate rates of occurrence.

abnormal liver function tests, glossitis

In the 1-year, double-blind, multicentre study comparing ACTONEL 35 mg Once-a-Week (the same formulation as the risedronate in ACTONEL PLUS CALCIUM) to ACTONEL 5 mg daily for the treatment of osteoporosis in postmenopausal women, the overall safety and tolerability profiles of the 2 oral dosing regimens were similar.

Patients with active or a history of upper gastrointestinal disorders at baseline and those taking ASA, non-steroidal anti-inflammatory drugs (NSAIDs) or drugs traditionally used for the treatment of peptic ulcers were not specifically excluded from participating in the ACTONEL once-a-week dosing study. The proportion of patients who experienced an upper gastrointestinal adverse event and the pattern of those events were found to be similar between the ACTONEL 35 mg Once-a-Week and ACTONEL 5 mg daily-treated groups.

In the 1-year, double-blind, multicentre study comparing ACTONEL 35 mg Once-a-Week to placebo for the prevention of osteoporosis in postmenopausal women, the overall safety and tolerability profiles of the two groups were comparable with the exception of “arthralgia”. Specifically, 13.9% of patients taking ACTONEL 35 mg Once-a-Week experienced arthralgia compared to 7.8% of placebo patients. The overall safety profile observed in this study showed no substantive difference from that observed in the ACTONEL 5 mg daily versus ACTONEL 35 mg Once-a-Week treatment study.

duodenitis, iritis

ACTONEL 5 mg daily clinical studies enrolled over 5700 patients for the treatment and prevention of postmenopausal and glucocorticoid-induced osteoporosis, many with pre-existing gastrointestinal disease and concomitant use of NSAIDs or ASA. Investigators were encouraged to perform endoscopies in any patients with moderate-to-severe gastrointestinal complaints while maintaining the blind. These endoscopies were ultimately performed on equal numbers of patients between the treated and placebo groups (75 ACTONEL; 75 placebo).

Across treatment groups, the percentage of patients with normal esophageal, gastric, and duodenal mucosa on endoscopy was similar (21% ACTONEL; 20% placebo). Positive findings on endoscopy were also generally comparable across treatment groups. There were a higher number of reports of mild duodenitis in the ACTONEL group; however, there were more duodenal ulcers in the placebo group. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (39% ACTONEL; 51% placebo).

In the 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily in the treatment of postmenopausal osteoporosis, endoscopies performed during the study revealed no dose dependent pattern in the number of patients with positive endoscopic findings or in the anatomical location of abnormalities detected.

Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, esophageal ulcer, and gastric ulcer. It is therefore important to follow the recommended dosing instructions (see Dosage and Administration).

Musculoskeletal pain, rarely severe, has been reported as a common side effect in patients who received the ACTONEL component of ACTONEL PLUS CALCIUM.

In osteoporosis studies with ACTONEL, the most commonly reported adverse reactions were abdominal pain, dyspepsia and nausea.

Most adverse events (AEs) reported in the Phase III trials with ACTONEL were mild or moderate in severity and did not generally lead to discontinuation of ACTONEL.

Calcium carbonate may cause gastrointestinal adverse effects such as constipation, flatulence, nausea, abdominal pain, and bloating.

Very rare (<1 report per 10 000 new prescriptions): hypersensitivity and skin reaction, including angioedema, generalized rash, and bullous skin reactions, some severe; iritis and uveitis; osteonecrosis of the jaw (see Warnings and Precautions).

Of the patients receiving ACTONEL (risedronate) 5 mg daily in postmenopausal osteoporosis studies, 43% were between 65 and 75 years of age, and 20% were over 75. In the 1-year study comparing daily versus weekly oral dosing regimens of ACTONEL in postmenopausal women, 41% of patients receiving ACTONEL 35 mg Once-a-Week were between 65 and 75 years of age and 23% were over 75.

Based upon the above study populations, no overall differences in efficacy or safety were observed between these patients and younger patients (<65 years).

In postmenopausal patients at risk of developing osteoporosis, ACTONEL preserves or increases BMD at sites of clinical importance for osteoporosis.

ACTONEL may be considered in postmenopausal women who are at risk of developing osteoporosis and for whom the desired clinical outcome is to maintain bone mass and to reduce the risk of fracture.

Factors such as family history of osteoporosis (particularly maternal history), previous fracture, smoking, moderately low BMD, high bone turnover, thin body frame, Caucasian or Asian race, and early menopause are associated with an increased risk of developing osteoporosis and fractures.

The calcium component of ACTONEL PLUS CALCIUM contains calcium carbonate which is a calcium supplement to dietary intake of calcium.

In postmenopausal women with osteoporosis, ACTONEL prevents vertebral and nonvertebral osteoporosis-related fractures and increases bone mineral density (BMD) at all measured skeletal sites of clinical importance for osteoporotic fractures, including spine, hip, and wrist.

Osteoporosis may be confirmed by the presence or history of osteoporotic fracture, or by the finding of low bone mass (for example, at least 2 SD below the premenopausal mean).

Safety and efficacy of risedronate in children and growing adolescents have not been established.

Because of its limited intestinal absorption, overdosage with calcium carbonate is unlikely. However, prolonged use of very high doses can lead to hypercalcemia associated with milk alkali syndrome. Clinical manifestations of hypercalcemia may include anorexia, thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness, fatigue, mental disturbances, polydipsia, polyuria, bone pain, nephrocalcinosis, renal calculi and in severe cases, cardiac arrhythmias.

Calcium should be discontinued. Other therapies that may be contributing to the condition, such as thiazide diuretics, lithium, vitamin A, vitamin D and cardiac glycosides should also be discontinued. Gastric emptying of any residual calcium should be considered. Rehydration, and, according to severity, isolated or combined treatment with loop diuretics, bisphosphonates, calcitonin and corticosteroids should also be considered. Serum electrolytes, renal function and vital signs must be monitored. In severe cases, ECG and central venous pressure should be followed.

Decreases in serum calcium following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients.

Administration of milk or antacids containing calcium may be helpful to chelate ACTONEL and reduce absorption of the drug. In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug if performed within 30 minutes of ingestion. 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.

Each film-coated, oval, blue tablet with “NE 2” engraved on both faces, contains: 500 mg elemental calcium as 1250 mg calcium carbonate. Nonmedicinal ingredients: hypromellose, hydroxypropyl cellulose, indigo carmine, magnesium stearate, polyethylene glycol, polysorbate, pregelatinized starch, sodium starch glycolate and titanium dioxide.

Each film-coated, oval, light orange tablet with “RSN” on one face and “35 mg” on the other, contains: the equivalent of 35 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate. Nonmedicinal ingredients: crospovidone, ferric oxide, hypromellose, hydroxypropyl cellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, silicon dioxide and titanium dioxide.

The ACTONEL component of ACTONEL PLUS CALCIUM is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min).

Administration of calcium has been associated with a slight increase in the 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 should be needed in these patients, urinary calcium excretion and other appropriate testing should be monitored periodically.

Bisphosphonates may cause upper gastrointestinal disorders such as dysphagia, esophagitis, esophageal ulcer, and gastric ulcer (see Adverse Reactions). Since some bisphosphonates have been associated with esophagitis and esophageal ulcerations, to facilitate delivery to the stomach and minimize the risk of these events, patients should take the ACTONEL tablet while in an upright position (i.e., sitting or standing) and with sufficient plain water (>120 mL). Patients should not lie down for at least 30 minutes after taking the drug. Health professionals should be particularly careful to emphasize the importance of the dosing instructions to patients with a history of esophageal disorders (e.g., inflammation, stricture, ulcer, or disorders of motility).

Patients with achlorhydria may have decreased absorption of calcium that may be attenuated by taking calcium with food. Taking calcium with food enhances absorption. See Dosage and Administration.

Before commencing ACTONEL PLUS CALCIUM, patients' calcium requirements should be assessed. It is recommended that patients receive at least 1200-1500 mg per day of calcium from all sources, as well as a daily vitamin D intake of at least 400-800 IU. The calcium carbonate tablet in ACTONEL PLUS CALCIUM provides 500 mg elemental calcium per day and does not contain vitamin D.

Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ACTONEL PLUS CALCIUM combination pack therapy.

In post-marketing reporting, osteonecrosis of the jaw has been reported in patients treated with bisphosphonates. The majority of reports occurred following dental procedures such as tooth extractions; and have involved cancer patients treated with intravenous bisphosphonates, but some occurred in patients receiving oral treatment for postmenopausal osteoporosis and other diagnoses. Many had signs of local infection, including osteomyelitis. Osteonecrosis has other well documented multiple risk factors. It is not possible to determine if these events are related to bisphosphonates, to concomitant drugs or other therapies, to the patient's underlying disease or to other co-morbid risk factors (e.g. anemia, infection, pre-existing oral disease). A dental examination with appropriate preventative dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors (e.g. cancer, immune suppression, head and neck radiotherapy or poor oral hygiene). While on treatment, these patients should avoid invasive dental procedures if possible. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment prior to the procedure reduces the risk of osteonecrosis of the jaw. Clinical judgment, based on individual risk assessment, should guide the management of patients undergoing dental procedures.

Concomitant use of calcium-containing antacids should be monitored to avoid excessive intake of calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits, however daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones.

The safety and efficacy of ACTONEL in children and growing adolescents have not been established.

ACTONEL PLUS CALCIUM is not intended for use during pregnancy. There are no studies of ACTONEL PLUS CALCIUM in pregnant women.

Calcium crosses the placenta, reaching higher levels in fetal blood than in maternal blood.

ACTONEL PLUS CALCIUM is not intended for use with nursing mothers. It is not known whether risedronate is excreted in human milk. Risedronate was detected in feeding pups exposed to lactating rats for a 24-hour period post-dosing, indicating a small degree of lacteal transfer. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bisphosphonates, 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.

Calcium is excreted in breast milk.

Approximately 50% of calcium in the plasma is in the physiologically active ionized form; about 10% is complexed to phosphate, citrate or other anions, while the remaining 40% is bound to proteins, primarily albumin.

Calcium is released from calcium complexes during digestion in a soluble, ionized form, for absorption from the small intestine. Absorption can be by both passive and active mechanisms. As calcium intake increases, the active transfer mechanism becomes saturated and an increasing proportion of calcium is absorbed via passive diffusion. Absorption of calcium carbonate is dose-dependent, with fractional absorption being highest when taken at doses up to 500 mg and when taken with food.

Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an intravenous dose is recovered in the urine over 28 days. Mean renal clearance is 105 mL/min (CV=34%) and mean total clearance is 122 mL/min (CV=19%), with the difference primarily reflecting non-renal 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. Once risedronate is absorbed, the serum concentration-time profile is multi-phasic with an initial half-life of about 1.5 hours and a terminal exponential half-life of 480 hours. Although the elimination rate of bisphosphonates from human bone is unknown, the 480 hour half-life is hypothesized to represent the dissociation of risedronate from the surface of bone.

Bioavailability and disposition following oral administration of risedronate are similar in men and women.

Unabsorbed calcium from the small intestine is excreted in the feces. Renal excretion depends largely on glomerular filtration and calcium tubular reabsorption with more than 98% of calcium reabsorbed from the glomerular filtrate.

There is no evidence that risedronate is systemically metabolized.

No data are available.

Osteoporosis is a degenerative and debilitating bone disease characterized by decreased bone mass and increased fracture risk at the spine, hip, and wrist. The diagnosis can be confirmed by the finding of low bone mass, evidence of fracture on x-ray, a history of osteoporotic fracture, or height loss or kyphosis indicative of vertebral fracture. Osteoporosis occurs in both men and women but is more common among women following menopause.

In healthy humans, bone formation and resorption are closely linked; old bone is resorbed and replaced by newly-formed bone. In postmenopausal osteoporosis, bone resorption exceeds bone formation, leading to bone loss and increased risk of bone fracture. After menopause, the risk of fractures of the spine and hip increases dramatically; approximately 40% of 50-year-old women will experience an osteoporosis-related fracture of the spine, hip, or wrist during their remaining lifetimes. After experiencing one osteoporosis-related fracture, the risk of future fracture increases 5-fold compared to the risk among a non-fractured population.

ACTONEL treatment decreases the elevated rate of bone turnover and corrects the imbalance of bone resorption relative to bone formation that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of ACTONEL to postmenopausal women resulted in dose-dependent decreases in biochemical markers of bone turnover, including urinary markers of bone resorption and serum markers of bone formation, at doses as low as 2.5 mg daily. At the 5 mg daily dose, decreases in resorption markers 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 formation and bone resorption; decreases in bone formation 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.

These data demonstrate that ACTONEL 5 mg administered daily to postmenopausal women produces a rapid reduction in bone resorption without over-suppression of bone formation. Bone turnover is decreased as early as 2 weeks and maximally within about 6 months of treatment, with achievement of a new steady-state which more nearly approximates the rate of bone turnover seen in premenopausal women.

In a 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily for the treatment of osteoporosis in postmenopausal women, similar decreases in bone resorption (about 60%) and formation markers (about 40%) were observed for both dosage regimens.

As a result of the inhibition of bone resorption, asymptomatic and usually transient decreases from baseline in serum calcium (about 2%) and serum phosphate levels (about 5%) and compensatory increases in serum PTH levels were observed within 6 months in ACTONEL 5 mg daily-treated patients in postmenopausal osteoporosis trials. No further decreases in serum calcium or phosphate, or increases in PTH were observed in postmenopausal women treated for up to 3 years. In the 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily for the treatment of osteoporosis in postmenopausal women, similar mean changes from baseline in serum calcium, phosphate and PTH were found for both dosage regimes.

Consistent with the effects of ACTONEL on biochemical markers of bone turnover, daily oral doses as low as 2.5 mg produced dose dependent, significant increases in lumbar spine bone mineral density (BMD) (2.5 mg, 3% to 3.7%; 5 mg, 4% to 4.5%) after 12 months of treatment in large-scale postmenopausal osteoporosis trials. A dose-dependent response to treatment was also observed in the BMD of the femoral neck over the same time (2.5 mg, 0.7% to 0.9%; 5 mg, 1.5% to 2%). In the 1-year study comparing ACTONEL 35 mg Once-a-Week to ACTONEL 5 mg daily for the treatment of osteoporosis in postmenopausal women, similar mean changes from baseline in BMD of the lumbar spine, total proximal femur, femoral neck and femoral trochanter were found for both dosage regimens.

Risedronate pharmacokinetics have not been studied in patients <18 years of age.

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 (<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.

Bioavailability and disposition of risedronate are similar in elderly (>65 years of age) and younger subjects. No dosage adjustment is necessary.

Pharmacokinetic differences of risedronate due to race have not been studied.

Risedronate is excreted intact primarily via the kidney. Patients with mild-to-moderate renal impairment (creatinine clearance >30 mL/min) do not require a dosage adjustment. Exposure to risedronate was estimated to increase by 44% in patients with creatinine clearance of 20 mL/min. ACTONEL is not recommended for use in patients with severe renal impairment (creatinine clearance <30 mL/min) because of a lack of clinical experience.

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

Hypocalcemia (see Warnings and Precautions, General).