Mylan-Risedronate Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Mylan-Risedronate (risedronate sodium hemi-pentahydrate) is indicated for:

• the treatment and prevention of osteoporosis in postmenopausal women
• the treatment of osteoporosis in men, to improve bone mineral density

Postmenopausal Osteoporosis: In the treatment of osteoporosis in postmenopausal women at risk of fracture, Mylan-Risedronate prevents vertebral and nonvertebral osteoporosis-related (fragility) 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 (e.g., at least 2 standard deviation [SD] below the premenopausal mean).

For the prevention of osteoporosis in postmenopausal women who are at risk of developing osteoporosis, Mylan-Risedronate preserves or increases BMD at sites of clinical importance.

Mylan-Risedronate 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), age, 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.

Important Limitations of Use: The optimal duration of use has not been determined. Patients should have the need for continued therapy re-evaluated on a periodic basis (see DOSAGE AND ADMINISTRATION).

Geriatrics: In risedronate sodium osteoporosis studies, 26-46% of patients were between 65 and 75 years of age and 10-23% were over 75 years of age. No overall differences in efficacy or safety were observed between these patients and younger patients (< 65 years) in the above osteoporosis studies. (see CLINICAL TRIALS).

Pediatrics: Safety and efficacy in children and growing adolescents have not been established.

CONTRAINDICATIONS

• Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.
• Hypocalcemia (see WARNINGS AND PRECAUTIONS, General).

WARNINGS AND PRECAUTIONS

General

Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting Mylan-Risedronate (risedronate sodium) therapy.

Adequate intake of calcium and vitamin D is important in all patients.

Mylan-Risedronate should be taken on an empty stomach at least 30 minutes before first food of the day. Detailed dosing instructions (see DOSAGE AND ADMINISTRATION) are provided to ensure correct dosing of each Mylan-Risedronate therapy.

Gastrointestinal

Bisphosphonates may cause upper gastrointestinal (GI) 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 Mylan-Risedronate 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).

Musculoskeletal

Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) has been reported post-market in patients treated with bisphosphonates as well as with other oral and intravenous bisphosphonates, including in, but not limited to, patients with cancer receiving treatment or patients that underwent invasive dental procedures such as root canal or dental extraction (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions).

Prior to treatment with Mylan-Risedronate a routine oral examination should be performed. Patients with possible risk factors (e.g., cancer, immunosuppression, chemotherapy, angiogenesis inhibitors, head and neck radiotherapy, corticosteroids, poor oral hygiene, and diabetes) should be referred to a dentist for examination and appropriate preventative dentistry should be performed prior to treatment with Mylan-Risedronate.

During treatment with risedronate sodium, patients should maintain good oral hygiene, undergo routine dental check-ups and immediately report any oral symptoms. While on treatment, these patients should avoid invasive dental procedures if possible but should continue with regular dental cleaning and oral hygiene. 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. ONJ. In patients who develop ONJ while on bisphosphonate therapy, surgery at the affected area may exacerbate the condition. Clinical judgment, of the treating physician should guide the management of patients undergoing dental procedures based on individual benefit/risk assessment.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures:

Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femur fractures most commonly occur with minimal or no impact trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. Poor healing of these fractures was also reported.

Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contra-lateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment. Although causality has not been established, the role of bisphosphonates cannot be ruled out.

Musculoskeletal Pain: In post-marketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates (see ADVERSE REACTIONS). The time-to-onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping the medication. A subset of patients had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.

Ophthalmologic:

Ocular disturbances including conjunctivitis, uveitis, episcleritis, iritis, and scleritis have been reported with risedronate sodium tablets therapy. Patients with ocular events other than uncomplicated conjunctivitis should be referred to an ophthalmologist for evaluation. If ocular inflammatory symptoms are observed, treatment may have to be discontinued.

Renal

Mylan-Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Special Populations

Pediatrics: The safety and efficacy of risedronate sodium in children and growing adolescents have not been established.

Pregnant Women: Mylan-Risedronate is not intended for use during pregnancy. There are no studies of risedronate sodium in pregnant women.

Nursing Women: Mylan-Risedronate 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.

Geriatrics: In risedronate sodium osteoporosis studies, 26-46% of patients were between 65 and 75 years of age and 10-23% were over 75 years of age. No overall differences in efficacy or safety were observed between these patients and younger patients (< 65 years of age) in the above osteoporosis studies (see CLINICAL TRIALS).

Monitoring and Laboratory Tests

Osteonecrosis of the jaw: Prior to treatment with Mylan-Risedronate routine oral examination should be performed. Patients with positive risk factors (e.g. cancer, chemotherapy, immunosuppression, angiogenesis inhibitors, head and neck radiotherapy, corticosteroids, poor oral hygiene, and diabetes) should be referred to a dentist for examination and appropriate preventative dentistry should be performed prior to treatment with Mylan-Risedronate. Patients should receive routine dental check-ups while taking Mylan-Risedronate.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

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 adverse event in patients who received risedronate sodium tablets for all indications and dosage forms.

In risedronate sodium tablets osteoporosis studies, the most commonly reported adverse reactions were abdominal pain, dyspepsia and nausea. In addition, diarrhea was the most commonly reported adverse reaction for the highest risedronate sodium tablets monthly dose.

Clinical Trial Adverse Drug Reactions

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.

Treatment and Prevention of Postmenopausal Osteoporosis: Risedronate sodium tablets 5 mg daily has been studied for up to 3 years in over 5000 women enrolled in Phase III clinical trials for treatment or prevention of postmenopausal osteoporosis. Most adverse events reported in these trials were either mild or moderate in severity, and did not lead to discontinuation from the study. The distribution of severe adverse events was similar across treatment groups. In addition, the overall incidence of adverse events (AEs) was found to be comparable amongst risedronate sodium tablets and placebo-treated patients.

Table 1 lists adverse events considered possibly or probably drug-related, reported in ≥ 1% of risedronate sodium tablets 5 mg daily-treated patients, in Phase III postmenopausal osteoporosis trials. Discontinuation of therapy due to serious clinical adverse events occurred in 5.5% of risedronate sodium tablets 5 mg daily-treated patients and 6.0% of patients treated with placebo.

Weekly Dosing: In the 1-year, double-blind, multicentre study comparing risedronate sodium tablets 35 mg Once-a-Week to risedronate sodium tablets 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.

The proportion of patients who experienced an upper gastrointestinal adverse event and the pattern of those events were found to be similar between the risedronate sodium tablets 35 mg Once-a-Week and risedronate sodium tablets 5 mg daily-treated groups. In addition to the previously described adverse reactions reported in risedronate sodium tablets osteoporosis clinical trials, arthralgia (risedronate sodium tablets 35 mg, 2.1%; risedronate sodium tablets 5 mg, 1.3%) was reported in ≥ 1% of patients and in more risedronate sodium tablets 35 mg weekly treated patients than in risedronate sodium tablets 5 mg daily treated patients.

In the 1-year, double-blind, multicentre study comparing risedronate sodium tablets 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, 1.5% of patients taking risedronate sodium tablets 35 mg Once-a-Week experienced arthralgia compared to 0.7% of placebo patients. The overall safety profile observed in this study showed no substantive difference from that observed in the risedronate sodium tablets 5 mg daily versus risedronate sodium tablets 35 mg Once-a-Week treatment study.

Monthly Dosing: (Two Consecutive Days per Month) – In a 1-year, double-blind, multicentre study for the treatment of osteoporosis in postmenopausal women comparing risedronate sodium tablets 75 mg on two consecutive days per month to risedronate sodium tablets 5 mg daily, the overall safety profiles of the dosing regimens were similar. The proportion of patients who experienced an upper gastrointestinal adverse event and the pattern of those events were found to be similar between the risedronate sodium tablets 75 mg two consecutive days per month and the risedronate sodium tablets 5 mg daily treated groups. In addition to the previously described adverse reactions, arthralgia (risedronate sodium tablets 75 mg, 1.5%; risedronate sodium tablets 5 mg, 1.0%), vomiting (risedronate sodium tablets 75 mg, 1.1%; risedronate sodium tablets 5 mg, 1.0%) and gastritis erosive (risedronate sodium tablets 75 mg, 1.0%; risedronate sodium tablets 5 mg, 0.3%) was reported in ≥ 1% of patients and in more risedronate sodium tablets 75 mg treated patients than in risedronate sodium tablets 5 mg daily treated patients.

Symptoms consistent with acute phase reactions have been reported. Based on reporting of any 33 acute phase reaction-like symptoms (without regard to causality) within the first 5 days of first dose, the overall incidence of acute phase reaction was 7.6% of patients on risedronate sodium tablets 75 mg two consecutive days per month and 3.6% of patients on risedronate sodium tablets 5 mg daily. Fever or influenza-like illness (without regard to causality) occurring within the first 5 days of first dose were reported by 0.6% of patients in the risedronate sodium tablets 75 mg two consecutive days per month and 0.0% in the risedronate sodium tablets 5 mg daily groups.

(Once-a-Month) - In a 1-year, double-blind, multicentre study for the treatment of osteoporosis in postmenopausal women comparing risedronate sodium tablets 150 mg Once-a-Month to risedronate sodium tablets 5 mg daily, the overall safety profiles of the dosing regimens were similar. The proportion of patients who experienced an upper gastrointestinal adverse event and the pattern of those events were found to be similar between the risedronate sodium tablets 150 mg Once-a-Month and the risedronate sodium tablets 5 mg daily treated groups. In addition to the previously described adverse reactions, diarrhea (risedronate sodium tablets 150 mg, 3.1%; risedronate sodium tablets 5 mg, 0.5%), vomiting (risedronate sodium tablets 150 mg, 1.5%; risedronate sodium tablets 5 mg, 0.6%), arthralgia (risedronate sodium tablets 150 mg, 1.5%; risedronate sodium tablets 5 mg, 0.9%) and myalgia (risedronate sodium tablets 150 mg, 1.1%; risedronate sodium tablets 5 mg, 0.3%) were reported in ≥1% of patients and in more risedronate sodium tablets 150 mg treated patients than risedronate sodium tablets 5 mg daily treated patients.

Symptoms consistent with acute phase reactions have been reported. Based on reporting of any 33 acute phase reaction-like symptoms (without regard to causality) within the first 3 days of first dose and lasting less than 7 days, the overall incidence of acute phase reaction was 5.2 % of patients in the risedronate sodium tablets 150 mg once-a-month group and 1.1% in the risedronate sodium tablets 5 mg daily group. Fever or influenza-like illness (without regard to causality) occurring within the first 3 days of first dose and lasting less than 7 days was reported by 1.4% of patients in the risedronate sodium tablets 150 mg Once-a-Month group and 0.2% of patients in the risedronate sodium tablets 5 mg daily group.

Treatment of Osteoporosis in Men, to Improve Bone Mineral Density: In a 2-year, double- blind, multicentre study using risedronate sodium tablets 35 mg Once-a-Week (n=191) and placebo (n=93) in men with osteoporosis, the overall safety and tolerability profiles of the two treatment groups were similar.

The proportion of patients who experienced an upper gastrointestinal adverse event and the pattern of those events were higher in placebo (18%) than in risedronate sodium 35 mg tablets Once-a-Week treated patients (8%).

In addition to the previously described adverse events, the following adverse events were reported in ≥ 2% of patients and in more risedronate sodium tablets treated patients than placebo-treated patients in the male osteoporosis study (events are included without attribution of causality): hypoaesthesia (risedronate sodium tablets 35 mg, 2%; placebo, 1%), nephrolithiasis (risedronate sodium tablets 35 mg, 3%; placebo, 0%), benign prostatic hyperplasia (risedronate sodium tablets 35 mg, 5%; placebo, 3%) and arrhythmia (risedronate sodium tablets 35 mg, 2%; placebo, 0%).

Endoscopic Findings: Risedronate sodium tablets 5 mg daily clinical studies enrolled over 5700 patients for the treatment and prevention of postmenopausal 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 risedronate sodium tablets; 75 placebo).

Across treatment groups, the percentage of patients with normal esophageal, gastric and duodenal mucosa on endoscopy was similar (21% risedronate sodium tablets; 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 risedronate sodium tablets 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% risedronate sodium tablets; 51% placebo).

At the 1-year time point in studies, comparing risedronate sodium tablets 35 mg Once-a-Week to risedronate sodium tablets 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. Endoscopies were conducted only on consenting patients experiencing moderate to severe gastrointestinal complaints.

In two, 1-year studies for the treatment of osteoporosis in postmenopausal women comparing risedronate sodium tablets 75 mg on two consecutive days per month and risedronate sodium tablets 150 mg Once-a-Month respectively to risedronate sodium tablets 5 mg daily, a similar percentage of patients for each of the intermittent regimens had at least one abnormal endoscopic finding when compared to the daily regimen (risedronate sodium tablets 75 mg, 3.2%; risedronate sodium tablets 5 mg, 3.1% and risedronate sodium tablets 150 mg, 3.4%; risedronate sodium tablets 5 mg, 4.2%).

Less Common Clinical Trial Adverse Drug Reactions

The following adverse drug reactions were reported in ≤1% of patients who received risedronate sodium tablets for all indications:

• Uncommon (0.1-1.0%): duodenitis, iritis
• Rare (<0.1%): abnormal liver function tests, glossitis

Abnormal Hematologic and Clinical Chemistry Findings

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.

Post-Market Adverse Drug Reactions

Hypersensitivity and Skin Reactions: angioedema, generalized rash and bullous skin reactions, some severe.

Musculoskeletal and Connective tissue: low-energy femoral shaft fractures, osteonecrosis of the jaw (see WARNINGS AND PRECAUTIONS).

Ophthalmologic: conjunctivitis, episcleritis, iritis, scleritis and uveitis (see WARNINGS AND PRECAUTIONS).

DRUG INTERACTIONS

Overview

No specific drug-drug interaction studies were performed with risedronate sodium film-coated tablets. 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, risedronate sodium is not systemically metabolized, does not induce cytochrome P₄₅₀ enzymes and has low protein binding.

Risedronate sodium is therefore not expected to interact with other drugs based on the effects of protein binding displacement, enzyme induction or metabolism of other drugs.

Drug-Drug Interactions

Patients in the clinical trials were exposed to a wide variety of commonly used concomitant medications (including NSAIDs, H₂-blockers, proton pump inhibitors, antacids, calcium channel blockers, beta-blockers, thiazides, glucocorticoids, anticoagulants, anticonvulsants, cardiac glycosides). While there was no apparent evidence of clinically relevant interactions in the clinical trials, such interactions cannot be ruled out on the basis on these data.

The drugs listed in Table 2 are based on either drug interaction case reports or predicted interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Of over 5700 patients enrolled in the risedronate sodium tablets 5 mg daily Phase III osteoporosis studies, ASA use was reported by 31% of patients and NSAID use by 48%. Among these ASA or NSAID users, the incidence of upper gastrointestinal adverse events was similar between the risedronate sodium tablets-treated patients and placebo-treated patients.

In the 1-year study comparing risedronate sodium tablets 35 mg Once-a-Week to risedronate sodium tablets 5 mg daily, ASA use was reported by 56% and NSAID use by 41%. The incidence of upper gastrointestinal adverse events was similar between the risedronate sodium tablets weekly-and daily-treated groups.

In two, 1-year studies comparing risedronate sodium tablets 75 mg two consecutive days per month or risedronate sodium tablets 150 mg once-a-month to risedronate sodium tablets 5 mg daily in postmenopausal women, 55% (75 mg) and 46% (150 mg) of patients reported the use of ASA and/or NSAIDs. Among these ASA or NSAID users, the incidence of upper gastrointestinal adverse events was similar in the risedronate sodium tablets monthly-treated groups when compared to the daily-treated groups respectively.

Drug-Food Interactions

Clinical benefits may be compromised by failure to take risedronate sodium tablets on an empty stomach. For dosing information see DOSAGE AND ADMINISTRATION.

Drug-Herb Interactions

Interactions with herbs have not been studied.

Drug-Laboratory Interactions

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

DOSAGE AND ADMINISTRATION

Dosing Considerations

Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see WARNINGS AND PRECAUTIONS, General).

Risedronate sodium tablets

• Mylan-Risedronate should be taken on an empty stomach at least 30 minutes before consuming the first food, drink (other than plain water) and/or any other medication of the day. Food, medication or drink (other than plain water) can interfere with the absorption of risedronate sodium. (see Recommended Dose and Dosage Adjustment and DRUG INTERACTIONS).
• Each Mylan-Risedronate tablet should be swallowed whole while the patient is in an upright position and with sufficient plain water (≥ 120 mL) to facilitate delivery to the stomach.
• Patients taking Mylan-Risedronate should not lie down for at least 30 minutes after taking the medication (see WARNINGS AND PRECAUTIONS, General).
• Mylan-Risedronate should not be chewed, cut, or crushed (see WARNINGS AND PRECAUTIONS, General).
• Medications containing polyvalent cations (e.g., calcium, magnesium, aluminium and iron) can interfere with the absorption of risedronate sodium tablets. These medications should be administered at a different time of the day (see Recommended Dose and Dosage Adjustment).
• The optimal duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of risedronate on an individual patient basis.

Recommended Dose and Dosage Adjustment

For all indications and doses: 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.

Treatment of Postmenopausal Osteoporosis: The recommended regimen is weekly (35 mg Once-a-Week tablets) or monthly (1 tablet of 150 mg once-a-month on the same calendar day of each month), taken orally.

Prevention of Postmenopausal Osteoporosis: The recommended regimen is weekly (35 mg Once-a-Week tablets), taken orally.

Treatment of Osteoporosis in Men, to Improve Bone Mineral Density: The recommended regimen is 35 mg Once-a-Week tablets, taken orally.

Renal Impairment: 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).

Geriatrics: No dosage adjustment is necessary in elderly patients (see INDICATIONS AND CLINICAL USE, Geriatrics).

Missed Dose

Weekly: Patients should be instructed that if they miss a dose of risedronate sodium tablets 35 mg Once-a-Week on their regularly scheduled day, they should take 1 tablet on the day they first remember missing their dose. Patients should then return to taking 1 tablet once a week as originally scheduled on their chosen day. Patients should not take 2 tablets on the same day.

Once-a-Month: Patients should be instructed that if they miss a 150 mg dose of risedronate sodium tablets (1 tablet of 150 mg), and the next month’s scheduled dose is more than 7 days away, they should take the missed tablet in the morning after the day it is remembered. Patients should then return to taking their risedronate sodium tablets 150 mg as originally scheduled.

If a dose of risedronate sodium tablets 150 mg is missed, and the next month’s scheduled dose is within 7 days, patients should be instructed to wait until their next month’s scheduled dose and then continue taking risedronate sodium tablets 150 mg. Patients should not take more than 150 mg of risedronate sodium tablets within 7 days.

OVERDOSAGE

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.

Milk or antacids containing calcium, magnesium, and aluminum may be given to bind risedronate sodium film-coated tablets 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Risedronate sodium, a pyridinyl-bisphosphonate in the form of hemi-pentahydrate with small amounts of monohydrate, inhibits osteoclast bone resorption and modulates bone metabolism. Risedronate has a high affinity for hydroxyapatite crystals in bone and is a potent antiresorptive agent. At the cellular level, risedronate inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (e.g., lack of ruffled border). Histomorphometry in rats, dogs, minipigs and humans showed that risedronate treatment reduces bone turnover (i.e., activation frequency, the rate at which bone remodelling sites are activated) and bone resorption at remodelling sites.

Pharmacodynamics

Treatment and Prevention of Osteoporosis in Postmenopausal Women: 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. One in five men older than 50 years will have an osteoporotic fracture, most commonly at the spine, hip and wrist.

Risedronate sodium 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 risedronate sodium tablets 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 (BTMs) 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 risedronate sodium tablets 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 weekly and monthly risedronate sodium tablets postmenopausal osteoporosis dosing studies, consistent decreases in bone resorption (50-60%) and bone formation (30-40%) markers were observed at Month 12.

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 parathyroid hormone (PTH) levels were observed within 6 months in risedronate sodium tablets 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 two 1-year studies for the treatment of osteoporosis in postmenopausal women comparing risedronate sodium tablets 35 mg Once-a-Week and risedronate sodium tablets 150 mg Once-a-Month respectively to risedronate sodium tablets 5 mg daily, similar mean changes from baseline in serum calcium, phosphate and PTH were found for each of the intermittent regimens when compared to the daily dosage regimen. In the 1-year study comparing risedronate sodium tablets 75 mg on two consecutive days per month to risedronate sodium tablets 5 mg daily, the mean percent changes from baseline were for serum calcium (0.8% and 0.2%), phosphate (-1.1% and -1.9%) and PTH (-11.7% and -3.0%), respectively.

Consistent with the effects of risedronate sodium tablets 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) (risedronate sodium tablets 2.5 mg, 3% to 3.7%; risedronate sodium tablets 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 (risedronate sodium tablets 2.5 mg, 0.7% to 0.9%; risedronate sodium tablets 5 mg, 1.5% to 2%). In three 1-year weekly and monthly dosing studies for the treatment of osteoporosis in postmenopausal women, comparing risedronate sodium tablets 35 mg Once-a-Week, risedronate sodium tablets 75 mg on two consecutive days per month and risedronate sodium tablets 150 mg Once-a-Month respectively to risedronate sodium tablets 5 mg daily, similar mean changes from baseline in BMD of the lumbar spine, total proximal femur, femoral neck and femoral trochanter were found for each of the intermittent regimens when compared to the daily regimen (see CLINICAL TRIALS, Treatment of Osteoporosis in Postmenopausal Women).

Treatment of Osteoporosis in Men, to Improve Bone Mineral Density: In a 2-year clinical trial in the treatment of osteoporosis in men, risedronate sodium tablets 35 mg Once-a-Week decreased urinary collagen cross-linked N-telopeptide (NTX) (a marker of bone resorption), and serum bone specific alkaline phosphatase (BAP) (a marker of bone formation) by approximately 40% and 30%, below baseline values, respectively, within 12 months. The BTMs all had statistically significant decreases in bone turnover from baseline compared to placebo at all time points. The decreases in bone turnover were observed within 3 months after initiation of therapy and maintained throughout the 2-year study.

Pharmacokinetics

Absorption: Absorption after an oral dose is relatively rapid (t_max ~ 1 hour) for the film-coated tablet and occurs throughout the upper gastrointestinal tract. Absorption is independent of dose up to 75 mg two consecutive days per month; systemic exposure increases disproportionally at 150 mg (about 2 fold greater than expected based on dose). Steady-state conditions in the serum are observed within 57 days of daily dosing. The mean oral bioavailability of the 30 mg film-coated tablet is 0.63% and is bioequivalent to a solution. Extent of absorption when administered 30 minutes before breakfast is reduced by 55% compared to dosing in the fasting state (i.e., no food or drink for 10 hours prior to or 4 hours after dosing). Dosing 1 hour prior to breakfast reduces extent of absorption by 30% compared to dosing in the fasting state. Dosing either 30 minutes prior to breakfast or 2 hours after a meal results in a similar extent of absorption.

Distribution: The mean steady-state volume of distribution is 6.3 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 found to be minimal (in the range of 0.001% to 0.01%), with drug levels quickly decreasing after the final dose.

Metabolism: There is no evidence that risedronate is systemically metabolized.

Excretion: 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. The 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.

Special Populations and Conditions

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

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

Gender: Bioavailability and disposition following oral administration are similar in men and women.

Race: Pharmacokinetic differences due to race have not been studied.

Hepatic Insufficiency: 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.

Renal Insufficiency: 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. Risedronate sodium tablets are not recommended for use in patients with severe renal impairment (creatinine clearance < 30 mL/min) because of a lack of clinical experience.

Genetic Polymorphism: No data are available.

STORAGE AND STABILITY

Store in tightly closed containers between 15^oC and 30^oC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Medicinal Ingredients:

35 mg

Each film-coated Mylan-Risedronate (risedronate sodium tablet) 35 mg for oral administration contains 35 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate.

150 mg

Each film-coated Mylan-Risedronate (risedronate sodium tablet) 150 mg for oral administration contains 150 mg of anhydrous risedronate sodium in the form of the hemi-pentahydrate with small amounts of monohydrate.

Nonmedicinal Ingredients

35 mg: Colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, and microcrystalline cellulose.

Coating: hydroxypropylmethylcellulose, iron oxide yellow, iron oxide red, polydextrose, polyethylene glycol, titanium dioxide, and triacetin.

150 mg: colloidal silicon dioxide, crospovidone, magnesium stearate, mannitol, and microcrystalline cellulose.

Coating: FD&C blue #2/indigo carmine aluminum lake, FD&C yellow#6/sunset yellow FCF aluminum lake, hypromellose, polydextrose, polyethylene glycol, and titanium dioxide.

Description

35 mg: A light orange film-coated, oval, biconvex tablet debossed with R35 on one side of the tablet and blank on the other side.

150 mg: A blue, oval, biconvex film-coated tablet debossed with “RR2” on one side of the tablet and “M” on the other side.

Packaging

35 mg: Bottles of 30’s and unit dose blisters of 4.

150 mg: Bottles of 30’s and unit dose blister of 1.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: risedronate sodium hemi-pentahydrate

Chemical Name: Risedronate sodium tablets contain risedronate sodium in the form of hemi-pentahydrate with small amounts of monohydrate. The chemical name of risedronate sodium is [1-hydroxy-2-(3 -pyridinyl)ethylidene]bis [phosphonic acid] monosodium salt.

Molecular Formula: C₇H₁₀NO₇P₂Na.2.5H₂O

Structural Formula:

P OH O OH OH P O Na HO O N .2.5 H2O

Molecular Weight: Anhydrous: 305.10; Hemi-pentahydrate: 350.13

Solubility:

Quantitative aqueous pH solubility profile at 25°C ± 2°C:

Quantitative aqueous pH solubility profile at 37°C:

pH (1.0% aqueous suspension): 4.14

pKa values: 6.7

Description: Risedronate sodium is a white to off-white powder.

CLINICAL TRIALS

Comparative Bioavailability

35 mg tablets

A Single-Dose Fasting Bioequivalence Study of Risedronate Sodium Tablets (35 mg; Mylan Pharmaceuticals ULC) versus the Canadian reference product, Actonel^® Tablets (35 mg; Procter & Gamble) in 117 Healthy Male and Female (not of childbearing potential) Volunteers was performed. A summary of the comparative bioavailability data is presented below.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Risedronate sodium 35 mg tablets, Mylan Pharmaceuticals ULC

^{† ®} 35 mg tablets, Sanofi-aventis Canada Inc.

^§ arithmetic mean (CV%) is presented

150 mg tablets

A pivotal, double-blind, randomized, two-treatment, two-period, two-sequence, single oral dose, two way crossover bioequivalence study comparing 1 x 150 mg Mylan-Risedronate (Risedronate sodium tablets, USP) (Mylan Pharmaceuticals ULC) with 1 x 150 mg ^PrActonel^® (Risedronate sodium tablets) (Warner Chilcott Canada Co.) was performed in 51 healthy, adult male volunteers and (not of child bearing potential) female volunteers under fasting conditions.

The results of the bioequivalence study are tabulated below.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

^* Mylan-Risedronate (Risedronate sodium tablets) 150 mg (Mylan Pharmaceuticals ULC)

^{† Pr}Actonel^® (Risedronate sodium tablets) 150 mg (Warner Chilcott Canada Co.) were purchased in Canada

^{^}n=49

^§Expressed as the arithmetic mean (CV %) only

Treatment of Osteoporosis in Postmenopausal Women

Study Demographics and Trial Design

In Studies 1 and 2, patients were selected on the basis of radiographic evidence of previous vertebral fracture, and had established disease. The average number of prevalent vertebral fractures per patient at study entry was 4 in Study 1, and 2.5 in Study 2, with a broad range of baseline BMD levels. All fractures (symptomatic/painful/clinical vertebral fractures and asymptomatic/nonpainful/silent vertebral fractures) were systematically captured and measured by annual radiographs.

In Studies 3 to 5 postmenopausal women were recruited on the basis of low lumbar spine bone mass (i.e., more than 2 SD below the premenopausal mean) rather than a history of vertebral fracture.

In Studies 5 to 7, patients had either lumbar spine bone mass more than 2.5 SD below the premenopausal mean, or lumbar spine bone mass more than 2.0 SD below, and a prevalent vertebral fracture.

Patients with active or a history of upper gastrointestinal disorders at baseline and those taking ASA, NSAIDs or drugs usually used for the treatment of peptic ulcers were not specifically excluded from participating in the risedronate sodium tablets daily, weekly or monthly dosing osteoporosis studies.

Study Results

Results of Studies 1 and 2:

The pivotal studies of risedronate sodium tablets in the treatment of postmenopausal osteoporosis clearly demonstrate that risedronate sodium tablets 5 mg daily reduces vertebral fracture incidence in patients with low bone mass and vertebral fractures, regardless of age, years since menopause or disease severity at baseline. Risedronate sodium tablets 5 mg daily significantly reduced the risk of new vertebral fractures in each of the two large treatment studies. When measured by annual radiographs, the effect of risedronate sodium tablets 5 mg daily on vertebral fracture incidence was seen at the first year of treatment in each study. In the North American study, treatment with risedronate sodium tablets 5 mg daily for 1 year significantly reduced the risk of new vertebral fractures by 65% compared to treatment with placebo (p < 0.001). In the Multinational study, a similar significant reduction of 61% was seen (p = 0.001). Treatment with risedronate sodium tablets 5 mg daily also significantly reduced the proportion of patients experiencing new and worsening vertebral fractures in each of the studies. Figures 1 and 2 below display the cumulative incidence of vertebral and nonvertebral fractures (i.e., hip, wrist, humerus, clavicle, pelvis and leg). In both figures, the cumulative incidence of these types of fractures is lower with risedronate sodium tablets compared with placebo at all time points, consistent with the positive effect of risedronate sodium on bone strength.

Figure 1 Cumulative New Vertebral Fracture Incidence in Postmenopausal Women with Osteoporosis

Placebo Risedronate sodium tablets 5 mg

Figure 2 Cumulative Incidence of Osteoporosis-Related Non-vertebral Fractures Studies 1 and 2 Combined

Placebo Risedronate sodium tablets 5 mg

Risedronate sodium tablets 5 mg daily were associated with a significant reduction of about 50% in the annual rate of height loss compared to treatment with placebo.

Risedronate sodium tablets 5 mg daily produced increases in lumbar spine BMD which 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 (12, 18, 24 and 36 months).

Results of Studies 3 and 4:

In Studies 3 and 4, risedronate sodium tablets 5 mg daily produced significant mean increases in BMD of the lumbar spine compared to placebo at 6 months in women with low bone mass. Compared to placebo after 1.5 to 2 years, further significant mean increases in BMD were seen at the lumbar spine, femoral neck and trochanter.

The results of four large, randomized, placebo-controlled trials (Studies 1 to 4) in women with postmenopausal osteoporosis separately and together demonstrate that risedronate sodium tablets 5 mg daily reverses the progression of disease, increasing BMD at the spine, hip and wrist compared to the effects seen with placebo.

Results of Study 5:

The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. There were also no statistically significant differences between the two treatment groups at 1 year in regards to BMD increases from baseline at other skeletal sites (total proximal femur, femoral neck and femoral trochanter). Based on these BMD outcomes, risedronate sodium tablets 35 mg Once-a-Week was concluded to be non-inferior to risedronate sodium tablets 5 mg daily.

In trials with risedronate sodium tablets 5 mg daily, changes in BMD of this magnitude were associated with a significant decrease in fracture incidence relative to placebo (see Table 5). This is further supported by the fact that within the 1-year study comparing risedronate sodium tablets 35 mg Once-a-Week to risedronate sodium tablets 5 mg daily, no statistically significant differences amongst these treatment groups were seen with respect to the number of patients with at least 1 new fractured vertebra at 1 year. Risedronate sodium tablets 35 mg taken once a week is similar in safety and efficacy to risedronate sodium tablets 5 mg daily for the treatment of postmenopausal osteoporosis.

Results of Study 6:

In the first year of a 2-year, double-blind, multicentre study of postmenopausal women with osteoporosis, risedronate sodium tablets 75 mg monthly duet, given on two consecutive days per month was shown to be non-inferior to risedronate sodium tablets 5 mg daily.

Risedronate sodium tablets 75 mg on two consecutive days per month was statistically shown to be non-inferior to the risedronate sodium tablets 5 mg daily regimen for the primary efficacy variable of percent change from baseline to 1 year in lumbar spine BMD. The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The incidences of vertebral and non-vertebral fractures, reported as adverse events, were similar in the two treatment groups. Risedronate sodium tablets 75 mg taken on two consecutive days per month is similar in safety and efficacy to risedronate sodium tablets 5 mg daily for the treatment of postmenopausal osteoporosis. The safety and efficacy of risedronate sodium tablets 75 mg, on two consecutive days per month, has not yet been assessed beyond one year of treatment.

Results of Study 7:

In the first year of a 2-year, double-blind, multicentre study of postmenopausal women with osteoporosis, risedronate sodium tablets 150 mg Once-a-Month was shown to be non-inferior to risedronate sodium tablets 5 mg daily. Risedronate sodium tablets 150 mg Once-a-Month was statistically shown to be non-inferior to the risedronate sodium tablets 5 mg daily regimen for the primary efficacy variable of percent change from baseline to 1 year in increasing lumbar spine BMD. The two treatment groups were similar with regard to BMD increases at the lumbar spine, total proximal femur, femoral neck and femoral trochanter. The incidence of vertebral and non-vertebral fractures, reported as adverse events, was similar in the two treatment groups. risedronate sodium tablets 150 mg Once-a-Month is similar in safety and efficacy to risedronate sodium tablets 5 mg daily for the treatment of postmenopausal osteoporosis. The safety and efficacy of risedronate sodium tablets 150 mg Once-a-Month is currently being assessed beyond one year of treatment.

Histology/Histomorphometry: Histomorphometric evaluation of 278 bone biopsy samples from 204 postmenopausal women who received risedronate sodium tablets 5 mg or placebo once daily for 2 to 3 years (including 74 pairs of biopsies, 43 from risedronate sodium tablets -treated patients) showed a moderate and expected decrease in bone turnover in risedronate sodium tablets -treated women.

Histologic assessment showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in risedronate sodium tablets -treated women. These findings demonstrate that the bone formed during risedronate sodium tablets administration is of normal quality.

Prevention of Osteoporosis in Postmenopausal Women

Study Demographics and Trial Design

Women in Study 8 were within 3 years of menopause and all patients in this study received supplemental calcium 1000 mg/day. Study 9 included women who were 0.5 to 5 years postmenopausal without osteoporosis. All patients were supplemented with 1000 mg elemental calcium and 400 IU vitamin D per day.

Results of Study 8:

Increases in BMD were observed as early as 3 months following initiation of risedronate sodium tablets treatment. Prevention of spinal bone loss was observed in the vast majority of women who received risedronate sodium tablets treatment. In contrast, most placebo-treated women experienced significant and progressive bone loss, despite receiving supplemental calcium 1000 mg/day. Risedronate sodium tablets 5 mg daily was similarly effective in patients with lower baseline BMD (i.e., more than 1 SD below the premenopausal mean) and in those with higher BMD.

Results of Study 9:

Combined Administration with Hormone Replacement Therapy

Study Demographics and Trial Design

For inclusion in Study 10 women had a mean lumbar spine BMD 1.3 SD below the pre-menopausal mean and had recently initiated conjugated estrogen treatment (i.e., not taken estrogen for more than 1 month in the past year).

Results of Study 10:

Consistent with the changes in BMD, the reduction in bone turnover, as measured by urinary deoxypyridinoline/creatinine, was significantly greater in the combined risedronate sodium tablets 5 mg daily plus estrogen group compared to the estrogen alone group (45-50% vs. 40%) and remained within the premenopausal range.

Histomorphometric evaluation of 93 bone biopsy samples from 61 women on estrogen therapy who received either placebo or risedronate sodium tablets 5 mg daily for 1 year (including 32 pairs of biopsies, 16 from risedronate sodium tablets-treated patients) found decreases in bone turnover in the risedronate sodium tablets-treated patients that were consistent with the changes in BTMs. Bone histology demonstrated that the bone of patients treated with risedronate sodium tablets plus estrogen was of normal lamellar structure and normal mineralization.

Treatment of Osteoporosis in Men, to Improve Bone Mineral Density

Study Demographics and Trial Design

Patients with active or a history of upper gastrointestinal disorders at baseline and those taking ASA, NSAIDs, or drugs traditionally used for the treatment of peptic ulcers were not specifically excluded from participating in the 2-year male osteoporosis study.

Results of Study 11:

Risedronate sodium tablets 35-mg Once-a-Week demonstrated efficacy in men with osteoporosis, as measured by change in BMD. All patients in this study received supplemental calcium 1000 mg/day and vitamin D 400-500 IU/day. Risedronate sodium tablets 35 mg produced significant mean increases in BMD at the lumbar spine, femoral neck, trochanter and total hip compared to placebo in a 2 year study (lumbar spine, 4.5%; femoral neck, 1.1%; trochanter, 2.2%; total hip, 1.5%). Statistically significant increases in lumbar spine BMD were observed within 6 months following initiation of risedronate sodium tablets treatment. Lumbar spine BMD percent change from baseline at Months 6, 12 and 24 showed that the risedronate sodium tablets 35 mg Once-a-Week group had a statistically significant increase in mean percent change from baseline versus placebo at all time points (see Figure 3).

Figure 3

Mean Percent Change from Baseline in Lumbar Spine BMD at all Time Points (Intent-to-Treat Population)

DETAILED PHARMACOLOGY

There are extensive preclinical data to support that bone produced during risedronate sodium tablets treatment at therapeutic doses is of normal quality, consistent with clinical experience. Risedronate demonstrated potent anti-osteoclast, antiresorptive activity in ovariectomized animals, increasing bone mass and biomechanical strength dose-dependently. Risedronate treatment maintained the positive correlation between BMD and bone strength. In intact dogs, risedronate induced positive bone balance at the level of the basic multicellular unit.

Long-term oral administration of risedronate to ovariectomized rats (up to 2.5 mg/kg/day for 12 months) and ovariectomized minipigs (up to 2.5 mg/kg/day for 18 months) did not impair bone structure, mineralization, or biomechanical strength. These doses were 5 times the optimal antiresorptive dose for these species. Normal lamellar bone was formed in these animals. Risedronate treatment did not impair the normal healing of radial fractures in adult dogs. 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 (5 mg/kg/day, subcutaneously), which was > 3000 times the lowest antiresorptive dose (1.5 µg/kg/day).

TOXICOLOGY

Acute Toxicity: Lethality after single oral doses was seen in female rats at 903 mg/kg (5826 mg/m²) and male rats at 1703 mg/kg (10967 mg/m²). The minimum lethal dose in mice, rabbits, and dogs was 4000 mg/kg (10909 mg/m²), 1000 mg/kg (10870 mg/m²), and 128 mg/kg (2560 mg/m²), respectively. These values represent 140 to 620 times the human 30 mg dose based on surface area, mg/m².

Chronic Toxicity: In a 1-year daily repeat dose toxicity study in dogs, the limiting toxicity of risedronate was observed at 8 mg/kg/day (160 mg/m²) and consisted of liver, testicular, renal, and gastrointestinal changes. Gastrointestinal effects at 16 mg/kg (111 mg/m²) were the first limiting toxicity in rats in a 26-week study. These doses are equivalent to approximately 6.25 to 9 times the human 30 mg dose based on surface area, mg/m². In 6 month and 1-year monthly repeat dose toxicity studies in dogs, the limiting systemic toxicity of risedronate was observed at 32 mg/kg (640 mg/m²) and consisted of liver, testicular, and renal toxicities. Gastric lesions were observed at 16 mg/kg (320 mg/m²). These doses are equivalent to approximately 3.5 and 7 times the human 150 mg dose based on surface area, mg/m².

A 13-week oral dog study was performed to evaluate the gastric and lower gastrointestinal toxicity and toxicokinetics of risedronate (8 and 16 mg/kg) when dosed with or without EDTA (2.5 and 12.5 mg/kg) following 14 once-weekly oral doses. No additional GI toxicity was observed with the addition of either dose of EDTA to either dose of risedronate. No new organs of toxicity were identified when dogs were treated with risedronate in combination with EDTA (vs risedronate alone). Treatment with EDTA alone was not associated with any treatment-related changes.

Co-administration of EDTA with 8 and/or 16 mg/kg risedronate was associated with potentiation of risedronate-mediated histologic alterations in the liver, kidneys, and testes (incidence and/or severity). Potentiation of toxicity was more evident at 12.5 mg/kg EDTA when compared with 2.5 mg/kg EDTA. With respect to expected pharmacological effects (e.g. increased bone), 12.5 mg/kg EDTA potentiated the severity of rib hypertrophy and the incidence of increased bone in nasal turbinates when administered in combination with 8 and 16 mg/kg risedronate (vs risedronate alone). These findings may be related to the observed increase in exposure noted when risedronate was administered in combination with EDTA.

Carcinogenicity: Three carcinogenicity studies in two species (mouse and rat) have been completed. All studies clearly showed dose-dependent bone pharmacologic effects. Risedronate was not carcinogenic in male or female rats dosed daily by gavage for 104 weeks at doses up to 24 mg/kg/day (12 times the human 30 mg dose based on surface area, mg/m²). Similarly, there was no evidence of a carcinogenic potential in male or female mice dosed daily by gavage for 80 weeks at doses up to 32 mg/kg/day (5 times the human 30 mg dose based on surface area, mg/m²).

Mutagenesis: In a series of seven in vitro and in vivo mutagenicity assays, risedronate was not genotoxic. An in vitro chromosomal aberration assay in Chinese hamster ovary cells was weakly positive at highly cytotoxic doses (> 675 µg/mL). However, when the assay was repeated at doses exhibiting increased cell survival (300 µg/mL), risedronate was negative.

Reproduction: In female rats, ovulation was inhibited at an oral dose of 16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m²). Decreased implantation was noted in female rats treated with doses ≥7 mg/kg/day (approximately 2.3 times the 30 mg/day human dose based on surface area, mg/m²). In male rats, testicular and epididymal atrophy and inflammation were noted at 40 mg/kg/day (approximately 13 times the 30 mg/day human dose based on surface area, mg/m²). Testicular atrophy was also noted in male rats after 13 weeks of treatment at oral doses of 16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m²). There was moderate-to-severe spermatid maturation block after 13 weeks in male dogs at an oral dose of 8 mg/kg/day (approximately 8 times the 30 mg/day human dose based on surface area, mg/m²). These findings tended to increase in severity with increased dose and exposure time.

Survival of neonates was decreased in rats treated during gestation with oral doses ≥16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m²). Body weight was decreased in neonates from dams treated with 80 mg/kg (approximately 26 times the 30 mg/day human dose based on surface area, mg/m²). In rats treated during gestation, the number of fetuses exhibiting incomplete ossification of sternebrae or skull was statistically significantly increased at 7.1 mg/kg/day (approximately 2.3 times the 30 mg/day human dose based on surface area, mg/m²). Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses ≥16 mg/kg/day (approximately 5.2 times the 30 mg/day human dose based on surface area, mg/m²). A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses ≥3.2 mg/kg/day (approximately 1 time the 30 mg/day human dose based on surface area, mg/m²). The relevance of this finding to human use of risedronate sodium tablets is unclear. No significant fetal ossification effects were seen in rabbits treated with oral doses up to 10 mg/kg/day during gestation (approximately 6.7 times the 30 mg/day human dose based on surface area, mg/m²). However, in rabbits treated with 10 mg/kg/day, 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 as low as 3.2 mg/kg/day (approximately 1 time the 30 mg/day human dose based on surface area, mg/m²) has resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.

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.

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Actonel^® Product Monograph, Control Number: 188707, date of revision: February 29, 2016.