Risedronate

Risedronate is an Bisphosphonate Derivative belonging to pharmacology class of Diphosphonate.

Risedronate can be used in the treatment of Postmenopausal Osteoporosis, Increase Bone Mass in Men with Osteoporosis, Glucocorticoid-Induced Osteoporosis and Paget Disease.

Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (Tmax) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 mg to 30 mg; multiple dose, from 2.5 mg to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution. The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting 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. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%).

Risedronate is available in the form of Tablets.

The molecule is available in India, Japan, Germany, China.

Risedronate treatment decreases the elevated rate of bone turnover that is typically seen in postmenopausal osteoporosis. In clinical trials, administration of Actonel to postmenopausal women resulted in decreases in biochemical markers of bone turnover, including urinary deoxypyridinoline/creatinine and urinary collagen cross-linked N-telopeptide (markers of bone resorption) and serum bone-specific alkaline phosphatase (a marker of bone formation).

Risedronate, a pyridinyl bisphosphonate analogue, binds to hydroxyapatite and inhibits bone resorption via actions on osteoclast or osteoclast precursors. It reduces the increased rate of bone turnover while osteoblast activity and bone mineralization are preserved.

Risedronate is approved for use in the following clinical indications

Postmenopausal Osteoporosis

• 5 mg orally daily
• 35 mg orally once-a-week
• 75 mg orally taken on two consecutive days for a total of two tablets each month
• 150 mg orally taken once-a-month

Prevention of Postmenopausal Osteoporosis

• 5 mg orally daily
• 35 mg Orally taken once-a-week
• Alternatively, 75 mg orally taken on two consecutive days for a total of two tablets each month may be considered
• Alternatively, 150 mg orally, taken once-a-month may be considered

Treatment to Increase Bone Mass in Men with Osteoporosis

• 35 mg orally once-a-week

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

• 5 mg orally daily

Treatment of Paget’s Disease

• 30 mg orally daily for 2 months.
• Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment.

Postmenopausal Osteoporosis

• 5 mg orally daily
• 35 mg orally once-a-week
• 75 mg orally taken on two consecutive days for a total of two tablets each month
• 150 mg orally taken once-a-month

Prevention of Postmenopausal Osteoporosis

• 5 mg orally daily
• 35 mg Orally taken once-a-week
• Alternatively, 75 mg orally taken on two consecutive days for a total of two tablets each month may be considered
• Alternatively, 150 mg orally, taken once-a-month may be considered

Treatment to Increase Bone Mass in Men with Osteoporosis

• 35 mg orally once-a-week

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

• 5 mg orally daily

Treatment of Paget’s Disease

• 30 mg orally daily for 2 months.
• Retreatment may be considered (following post-treatment observation of at least 2 months) if relapse occurs, or if treatment fails to normalize serum alkaline phosphatase. For retreatment, the dose and duration of therapy are the same as for initial treatment. No data are available on more than 1 course of retreatment.

Tablet

5mg, 30mg, 35mg, 150mg

Tablet

Multiple myeloma or metastatic bone lesions from solid tumors or Paget disease: Take adequate daily calcium and vitamin D supplement (if patient is not hypercalcemic).

Risedronate may be contraindicated in the following conditions:-

• Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia
• Inability to stand or sit upright for at least 30 minutes
• Hypocalcemia
• Known hypersensitivity to Risedronate or any of its excipients. Angioedema, generalized rash and bullous skin reactions

Drug Products with the Same Active Ingredient

• Risedronate contains the same active ingredient found in Atelvia®. A patient being treated with Atelvia should not receive Risedronate.

Upper Gastrointestinal Adverse Reactions

• Risedronate, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when Risedronate is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers).
• Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue Risedronate and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn.
• The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 ounces) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients who cannot comply with dosing instructions due to mental disability, therapy with Risedronate should be used under appropriate supervision.
• There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials.

Mineral Metabolism

• Hypocalcemia has been reported in patients taking Risedronate. Treat hypocalcemia and other disturbances of bone and mineral metabolism before starting Risedronate therapy. Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. Adequate intake of calcium and vitamin D is important in all patients, especially in patients with Paget’s disease in whom bone turnover is significantly elevated.

Jaw Osteonecrosis

• Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including Risedronate. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (for example, tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (for example, chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (for example, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates.
• For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment.
• Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment.

Musculoskeletal Pain

• In post-marketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates. 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 medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. Consider discontinuing use if severe symptoms develop.

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 traverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates.
• Atypical femur fractures most commonly occur with minimal or no 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. A number of reports note that patients were also receiving treatment with glucocorticoids (for example, prednisone) at the time of fracture.
• 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 contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Renal Impairment

• Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min).

Glucocorticoid-Induced Osteoporosis

• Before initiating Risedronate treatment for the treatment and prevention of glucocorticoid-induced osteoporosis, the sex steroid hormonal status of both men and women should be ascertained and appropriate replacement considered.

Laboratory Test Interactions

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

There is no sufficient scientific evidence traceable regarding use and safety of Risedronate in concurrent use with alcohol.

It is not known if Risedronate is present in breast milk.

Pregnancy Category (FDA): C

• Pregnancy Category C: There are no adequate and well-controlled studies of Risedronate in pregnant women. Risedronate should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
• Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.
• In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human dose of 30 mg/day. Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull from dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses approximately 5 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose. The relevance of this finding to human use of Risedronate is unclear.
• No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.
• Similar to other bisphosphonates, treatment during mating and gestation with doses of risedronate sodium approximately the same as the 30 mg/day human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.
• Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit.

The adverse reactions related to Risedronate can be categorized as

Common Adverse effects:

Atypical subtrochanteric and diaphyseal femoral fractures (prolonged use); severe bone, joint or muscle pain

Less Common Adverse effects:

Upper gastrointestinal mucosa irritation (e.g. dysphagia, esophagitis, esophageal or gastric ulcers, esophageal erosions or stricture), ocular effects (e.g. iritis, uveitis)

Rare Adverse effects:

Hypocalcemia, osteonecrosis of the jaw and external auditory canal.

• The clinically relevant drug interactions of Risedronate is briefly summarized here

Calcium Supplements/Antacids

• Co-administration of Risedronate and calcium, antacids, or oral medications containing divalent cations will interfere with the absorption of Risedronate.

Hormone Replacement Therapy

• One study of about 500 early postmenopausal women has been conducted to date in which treatment with Risedronate 5 mg daily plus estrogen replacement therapy was compared to estrogen replacement therapy alone. Exposure to study drugs was approximately 12 to 18 months and the primary endpoint was change in BMD. If considered appropriate, Risedronate may be used concomitantly with hormone replacement therapy.

Aspirin/Nonsteroidal Anti-Inflammatory Drugs

• Of over 5700 patients enrolled in the Risedronate Phase 3 osteoporosis studies, aspirin use was reported by 31% of patients, 24% of whom were regular users (3 or more days per week). Forty-eight percent of patients reported NSAID use, 21% of whom were regular users. Among regular aspirin or NSAID users, the incidence of upper gastrointestinal adverse experiences in placebo-treated patients (24.8%) was similar to that in Risedronate-treated patients (24.5%).

H2 Blockers and Proton Pump Inhibitors (PPIs)

• Of over 5700 patients enrolled in the Risedronate Phase 3 osteoporosis studies, 21% used H2 blockers and/or PPIs. Among these patients, the incidence of upper gastrointestinal adverse experiences in the placebo-treated patients was similar to that in Risedronate-treated patients.

The most common side effects of Risedronate includes: Atypical subtrochanteric and diaphyseal femoral fractures (prolonged use); severe bone, joint or muscle pain.

Pregnancy Category (FDA): C

• Pregnancy Category C: There are no adequate and well-controlled studies of Risedronate in pregnant women. Risedronate should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus.
• Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been studied.
• In animal studies, pregnant rats received risedronate sodium during organogenesis at doses 1 to 26 times the human dose of 30 mg/day. Survival of neonates was decreased in rats treated during gestation with oral doses approximately 5 times the human dose and body weight was decreased in neonates from dams treated with approximately 26 times the human dose. The number of fetuses exhibiting incomplete ossification of sternebrae or skull from dams treated with approximately 2.5 times the human dose was significantly increased compared to controls. Both incomplete ossification and unossified sternebrae were increased in rats treated with oral doses approximately 5 times the human dose. A low incidence of cleft palate was observed in fetuses from female rats treated with oral doses approximately equal to the human dose. The relevance of this finding to human use of Risedronate is unclear.
• No significant fetal ossification effects were seen in rabbits treated with oral doses approximately 7 times the human dose (the highest dose tested). However, 1 of 14 litters were aborted and 1 of 14 litters were delivered prematurely.
• Similar to other bisphosphonates, treatment during mating and gestation with doses of risedronate sodium approximately the same as the 30 mg/day human dose resulted in periparturient hypocalcemia and mortality in pregnant rats allowed to deliver.
• Dosing multiples provided above are based on the recommended human dose of 30 mg/day and normalized using body surface area (mg/m2). Actual animal doses were 3.2, 7.1 and 16 mg/kg/day in the rat and 10 mg/kg/day in the rabbit.

Labor and Delivery

• There is no FDA guidance on use of Risedronate during labor and delivery.

Nursing Mothers

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

Pediatric Use

• Risedronate is not indicated for use in pediatric patients.
• The safety and effectiveness of risedronate was assessed in a one-year, randomized, double-blind, placebo controlled study of 143 pediatric patients (94 received risedronate) with osteogenesis imperfecta (OI). The enrolled population was predominantly patients with mild osteogenesis imperfecta (85% Type-I), aged 4 to less than 16 years, 50% male and 82% Caucasian, with a mean lumbar spine BMD Z-score of -2.08 (2.08 standard deviations below the mean for age-matched controls). Patients received either a 2.5 mg (less than or equal to 30 kg body weight) or 5 mg (greater than 30 kg body weight) daily oral dose. After one year, an increase in lumbar spine BMD in the risedronate group compared to the placebo group was observed. However, treatment with risedronate did not result in a reduction in the risk of fracture in pediatric patients with osteogenesis imperfecta. In Risedronate-treated subjects, no mineralization defects were noted in paired bone biopsy specimens obtained at baseline and month 12.
• The overall safety profile of risedronate in OI patients treated for up to 12 months was generally similar to that of adults with osteoporosis. However, there was an increased incidence of vomiting compared to placebo. In this study, vomiting was observed in 15% of children treated with risedronate and 6% of patients treated with placebo. Other adverse events reported in greater than or equal to 10% of patients treated with risedronate and with a higher frequency than placebo were: pain in the extremity (21% with risedronate versus 16% with placebo), headache (20% versus 8%), back pain (17% versus 10%), pain (15% versus 10%), upper abdominal pain (11% versus 8%), and bone pain (10% versus 4%).

· Geriatic Use

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

Gender

There is no FDA guidance on the use of Risedronate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Risedronate with respect to specific racial populations.

Renal Impairment

• Risedronate is not recommended for use in patients with severe renal impairment (creatinine clearance less than 30 mL/min) because of lack of clinical experience. No dosage adjustment is necessary in patients with a creatinine clearance greater than or equal to 30 mL/min.

Hepatic Impairment

• No studies have been performed to assess risedronate’s safety or efficacy in patients with hepatic impairment. Risedronate is not metabolized in human liver preparations. Dosage adjustment is unlikely to be needed in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Risedronate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Risedronate in patients who are immunocompromised.

Decreases in serum calcium and phosphorus following substantial overdose may be expected in some patients. Signs and symptoms of hypocalcemia may also occur in some of these patients. Milk or antacids containing calcium should be given to bind Risedronate and reduce absorption of the drug.

In cases of substantial overdose, gastric lavage may be considered to remove unabsorbed drug. Standard procedures that are effective for treating hypocalcemia, including the administration of calcium intravenously, would be expected to restore physiologic amounts of ionized calcium and to relieve signs and symptoms of hypocalcemia.

Lethality after single oral doses was seen in female rats at 903 mg/kg and male rats at 1703 mg/kg. The minimum lethal dose in mice and rabbits was 4000 mg/kg and 1000 mg/kg, respectively. These values represent 320 to 620 times the 30 mg human dose based on surface area (mg/m2).

Pharmacodynamics:

Risedronate has an affinity for hydroxyapatite crystals in bone and acts as an antiresorptive agent. At the cellular level, Risedronate inhibits osteoclasts. The osteoclasts adhere normally to the bone surface, but show evidence of reduced active resorption (for example, lack of ruffled border). Histomorphometry in rats, dogs, and minipigs showed that Risedronate treatment reduces bone turnover (activation frequency, that is, the rate at which bone remodeling sites are activated) and bone resorption at remodeling sites.

Pharmacokinetics:

Absorption

Based on simultaneous modeling of serum and urine data, peak absorption after an oral dose is achieved at approximately 1 hour (Tmax) and occurs throughout the upper gastrointestinal tract. The fraction of the dose absorbed is independent of dose over the range studied (single dose, from 2.5 mg to 30 mg; multiple dose, from 2.5 mg to 5 mg). Steady-state conditions in the serum are observed within 57 days of daily dosing. Mean absolute oral bioavailability of the 30 mg tablet is 0.63% (90% CI: 0.54% to 0.75%) and is comparable to a solution.

Distribution

The mean steady-state volume of distribution for risedronate is 13.8 L/kg in humans. Human plasma protein binding of drug is about 24%. Preclinical studies in rats and dogs dosed intravenously with single doses of [14C] risedronate indicate that approximately 60% of the dose is distributed to bone. The remainder of the dose is excreted in the urine. After multiple oral dosing in rats, the uptake of risedronate in soft tissues was in the range of 0.001% to 0.01%.

Metabolism

There is no evidence of systemic metabolism of risedronate.

Excretion

In young healthy subjects, approximately half of the absorbed dose of risedronate was excreted in urine within 24 hours, and 85% of an intravenous dose was recovered in the urine over 28 days. Based on simultaneous modeling of serum and urine data, mean renal clearance was 105 mL/min (CV = 34%) and mean total clearance was 122 mL/min (CV = 19%), with the difference primarily reflecting 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. In osteopenic postmenopausal women, the terminal exponential half-life was 561 hours, mean renal clearance was 52 mL/min (CV = 25%), and mean total clearance was 73 mL/min (CV = 15%).

1. https://www.uptodate.com/contents/ Risedronate -drug-information?search= Risedronate &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/ Risedronate _2015-1215.pdf
4. https://www.mims.com/india/drug/info/ Risedronate ?type=full&mtype=generic#mechanism-of-action