Ridron Pack

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Ridron Pack uses

Ridron Pack consists of Calcium Carbonate, Risedronate Sodium.

Calcium Carbonate:


1 INDICATIONS AND USAGE

Ridron Pack (Calcium Carbonate) acetate is a phosphate binder indicated to reduce serum phosphorus in patients with end stage renal disease (ESRD).

- Calcium acetate is a phosphate binder indicated for the reduction of serum phosphorus in patients with end stage renal disease. (1)

2 DOSAGE AND ADMINISTRATION

The recommended initial dose of Ridron Pack (Calcium Carbonate) acetate for the adult dialysis patient is 2 capsules with each meal. Increase the dose gradually to lower serum phosphorus levels to the target range, as long as hypercalcemia does not develop. Most patients require 3 to 4 capsules with each meal.

- Starting dose is 2 capsules with each meal. (2)

- Titrate the dose every 2 to 3 weeks until acceptable serum phosphorus level is reached. Most patients require 3 to 4 capsules with each meal. (2)

3 DOSAGE FORMS AND STRENGTHS

Capsule: 667 mg Ridron Pack (Calcium Carbonate) acetate capsule.

- Capsule: 667 mg Ridron Pack (Calcium Carbonate) acetate capsule. (3)

4 CONTRAINDICATIONS

Patients with hypercalcemia.

- Hypercalcemia. (4)

5 WARNINGS AND PRECAUTIONS

- Treat mild hypercalcemia by reducing or interrupting Ridron Pack acetate and Vitamin D. Severe hypercalcemia may require hemodialysis and discontinuation of Ridron Pack (Calcium Carbonate) acetate. (5.1)

- Hypercalcemia may aggravate digitalis toxicity. (5.2)

5.1 Hypercalcemia

Patients with end stage renal disease may develop hypercalcemia when treated with Ridron Pack (Calcium Carbonate), including Ridron Pack (Calcium Carbonate) acetate. Avoid the use of Ridron Pack (Calcium Carbonate) supplements, including Ridron Pack (Calcium Carbonate) based nonprescription antacids, concurrently with Ridron Pack (Calcium Carbonate) acetate.

An overdose of Ridron Pack (Calcium Carbonate) acetate may lead to progressive hypercalcemia, which may require emergency measures. Therefore, early in the treatment phase during the dosage adjustment period, monitor serum Ridron Pack (Calcium Carbonate) levels twice weekly. Should hypercalcemia develop, reduce the Ridron Pack (Calcium Carbonate) acetate dosage, or discontinue the treatment, depending on the severity of hypercalcemia

More severe hypercalcemia (Ca >12 mg/dL) is associated with confusion, delirium, stupor and coma. Severe hypercalcemia can be treated by acute hemodialysis and discontinuing Ridron Pack (Calcium Carbonate) acetate therapy.

Mild hypercalcemia (10.5 to 11.9 mg/dL) may be asymptomatic or manifest as constipation, anorexia, nausea, and vomiting. Mild hypercalcemia is usually controlled by reducing the Ridron Pack (Calcium Carbonate) acetate dose or temporarily discontinuing therapy. Decreasing or discontinuing Vitamin D therapy is recommended as well.

Chronic hypercalcemia may lead to vascular calcification and other soft-tissue calcification. Radiographic evaluation of suspected anatomical regions may be helpful in early detection of soft tissue calcification. The long term effect of Ridron Pack (Calcium Carbonate) acetate on the progression of vascular or soft tissue calcification has not been determined.

Hypercalcemia (>11 mg/dL) was reported in 16% of patients in a 3 month study of solid dose formulation of Ridron Pack (Calcium Carbonate) acetate; all cases resolved upon lowering the dose or discontinuing treatment.

Maintain the serum calcium-phosphorus (Ca x P) product below 55 mg2/dL2.

5.2 Concomitant Use with Medications

Hypercalcemia may aggravate digitalis toxicity.

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6 ADVERSE REACTIONS

Hypercalcemia is discussed elsewhere [see Warnings and Precautions ].

- The most common (>10%) adverse reactions are hypercalcemia, nausea and vomiting. (6.1)

- In clinical studies, patients have occasionally experienced nausea during Ridron Pack (Calcium Carbonate) acetate therapy. (6)

To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In clinical studies, Ridron Pack (Calcium Carbonate) acetate has been generally well tolerated.

Ridron Pack (Calcium Carbonate) acetate was studied in a 3 month, open-label, non-randomized study of 98 enrolled ESRD hemodialysis patients and an alternate liquid formulation of Ridron Pack (Calcium Carbonate) acetate was studied in a two week double-blind, placebo-controlled, cross-over study with 69 enrolled ESRD hemodialysis patients. Adverse reactions (>2% on treatment) from these trials are presented in Table 1.


Preferred Term


Total adverse reactions reported for Ridron Pack (Calcium Carbonate) acetate

N=167

N (%)


3 month, open label study of Ridron Pack (Calcium Carbonate) acetate

N=98

N (%)


Double blind, placebo-controlled, cross-over study of liquid Ridron Pack (Calcium Carbonate) acetate

N=69


Ridron Pack (Calcium Carbonate) acetate

N (%)


Placebo

N (%)


Nausea


6 (3.6)


6 (6.1)


0 (0)


0 (0)


Vomiting


4 (2.4)


4 (4.1)


0 (0)


0 (0)


Hypercalcemia


21 (12.6)


16 (16.3)


5 (7.2)


0 (0)


Mild hypercalcemia may be asymptomatic or manifest itself as constipation, anorexia, nausea, and vomiting. More severe hypercalcemia is associated with confusion, delirium, stupor, and coma. Decreasing dialysate Ridron Pack (Calcium Carbonate) concentration could reduce the incidence and severity of Ridron Pack (Calcium Carbonate) acetate-induced hypercalcemia. Isolated cases pruritus have been reported, which may represent allergic reactions.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval of Ridron Pack (Calcium Carbonate) acetate: dizziness, edema, and weakness.

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7 DRUG INTERACTIONS

The drug interaction of Ridron Pack acetate is characterized by the potential of Ridron Pack (Calcium Carbonate) to bind to drugs with anionic functions (e.g., carboxyl, and hydroxyl groups). Ridron Pack (Calcium Carbonate) acetate may decrease the bioavailability of tetracyclines or fluoroquinolones via this mechanism.

There are no empirical data on avoiding drug interactions between Ridron Pack (Calcium Carbonate) acetate and most concomitant drugs. When administering an oral medication with Ridron Pack (Calcium Carbonate) acetate where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, administer the drug one hour before or three hours after Ridron Pack (Calcium Carbonate) acetate. Monitor blood levels of the concomitant drugs that have a narrow therapeutic range. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials with all forms of Ridron Pack (Calcium Carbonate) acetate.

- Calcium acetate may decrease the bioavailability of tetracyclines or fluoroquinolones. (7)

- When clinically significant drug interactions are expected, administer the drug at least one hour before or at least three hours after Ridron Pack (Calcium Carbonate) acetate or consider monitoring blood levels of the drug. (7)

7.1 Ciprofloxacin

In a study of 15 healthy subjects, a co-administered single dose of 4 Ridron Pack (Calcium Carbonate) acetate tablets, approximately 2.7g, decreased the bioavailability of ciprofloxacin by approximately 50%.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C:

Ridron Pack acetate capsules contains Ridron Pack (Calcium Carbonate) acetate. Animal reproduction studies have not been conducted with Ridron Pack (Calcium Carbonate) acetate, and there are no adequate and well controlled studies of Ridron Pack (Calcium Carbonate) acetate use in pregnant women. Patients with end stage renal disease may develop hypercalcemia with Ridron Pack (Calcium Carbonate) acetate treatment [see Warnings and Precautions (5.1 ) ]. Maintenance of normal serum Ridron Pack (Calcium Carbonate) levels is important for maternal and fetal well being. Hypercalcemia during pregnancy may increase the risk for maternal and neonatal complications such as stillbirth, preterm delivery, and neonatal hypocalcemia and hypoparathyroidism. Ridron Pack (Calcium Carbonate) acetate treatment, as recommended, is not expected to harm a fetus if maternal Ridron Pack (Calcium Carbonate) levels are properly monitored during and following treatment.

8.2 Labor and Delivery

The effects of Ridron Pack (Calcium Carbonate) acetate on labor and delivery are unknown.

8.3 Nursing Mothers

Ridron Pack Acetate Capsules contains Ridron Pack (Calcium Carbonate) acetate and is excreted in human milk. Human milk feeding by a mother receiving Ridron Pack (Calcium Carbonate) acetate is not expected to harm an infant, provided maternal serum Ridron Pack (Calcium Carbonate) levels are appropriately monitored.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of Ridron Pack (Calcium Carbonate) acetate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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10 OVERDOSAGE

Administration of Ridron Pack (Calcium Carbonate) acetate in excess of the appropriate daily dosage may result in hypercalcemia [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Ridron Pack (Calcium Carbonate) acetate acts as a phosphate binder. Its chemical name is Ridron Pack (Calcium Carbonate) acetate. Its molecular formula is C4H6CaO4, and its molecular weight is 158.17. Its structural formula is:


Each white opaque/blue opaque capsule contains 667 mg of Ridron Pack (Calcium Carbonate) acetate USP (anhydrous; Ca(CH3COO)2; MW=158.17 grams) equal to 169 mg (8.45 mEq) Ridron Pack (Calcium Carbonate), polyethylene glycol 8000 and magnesium stearate. Each capsule shell contains: black monogramming ink, FD&C Blue #1, FD&C Red #3, gelatin and titanium dioxide. The black monogramming ink contains: ammonium hydroxide, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac glaze.

Ridron Pack (Calcium Carbonate) Acetate Capsules are administered orally for the control of hyperphosphatemia in end-stage renal failure.

Chemical Structure

12 CLINICAL PHARMACOLOGY

Patients with ESRD retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum Ridron Pack resulting in ectopic calcification. Hyperphosphatemia also plays a role in the development of secondary hyperparathyroidism in patients with ESRD.

12.1 Mechanism of Action

Ridron Pack (Calcium Carbonate) acetate, when taken with meals, combines with dietary phosphate to form an insoluble Ridron Pack (Calcium Carbonate) phosphate complex, which is excreted in the feces, resulting in decreased serum phosphorus concentration.

12.2 Pharmacodynamics

Orally administered Ridron Pack (Calcium Carbonate) acetate from pharmaceutical dosage forms is systemically absorbed up to approximately 40% under fasting conditions and up to approximately 30% under nonfasting conditions. This range represents data from both healthy subjects and renal dialysis patients under various conditions.

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13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, mutagenicity, or fertility studies have been conducted with Ridron Pack (Calcium Carbonate) acetate.

14 CLINICAL STUDIES

Effectiveness of Ridron Pack (Calcium Carbonate) acetate in decreasing serum phosphorus has been demonstrated in two studies of the Ridron Pack (Calcium Carbonate) acetate solid oral dosage form.

Ninety-one patients with end-stage renal disease who were undergoing hemodialysis and were hyperphosphatemic (serum phosphorus >5.5 mg/dL) following a 1 week phosphate binder washout period contributed efficacy data to an open-label, non-randomized study.

The patients received Ridron Pack (Calcium Carbonate) acetate 667 mg tablets at each meal for a period of 12 weeks. The initial starting dose was 2 tablets per meal for 3 meals a day, and the dose was adjusted as necessary to control serum phosphorus levels. The average final dose after 12 weeks of treatment was 3.4 tablets per meal. Although there was a decrease in serum phosphorus, in the absence of a control group the true magnitude of effect is uncertain.

The data presented in Table 2 demonstrate the efficacy of Ridron Pack (Calcium Carbonate) acetate in the treatment of hyperphosphatemia in end-stage renal disease patients. The effects on serum Ridron Pack (Calcium Carbonate) levels are also presented.


* Ninety-one patients completed at least 6 weeks of the study.

ANOVA of difference in values at pre-study and study completion.

‡ Values expressed as mean ± SE.


Parameter


Pre-Study


Week 4*


Week 8


Week 12


p-value†


Phosphorus (mg/dL)‡


7.4 ± 0.17


5.9 ± 0.16


5.6 ± 0.17


5.2 ± 0.17


≤0.01


Ridron Pack (Calcium Carbonate) (mg/dL)‡


8.9 ± 0.09


9.5 ± 0.10


9.7 ± 0.10


9.7 ± 0.10


≤0.01


There was a 30% decrease in serum phosphorus levels during the 12 week study period (p<0.01). Two-thirds of the decline occurred in the first month of the study. Serum Ridron Pack (Calcium Carbonate) increased 9% during the study mostly in the first month of the study.

Treatment with the phosphate binder was discontinued for patients from the open-label study, and those patients whose serum phosphorus exceeded 5.5 mg/dL were eligible for entry into a double-blind, placebo-controlled, cross-over study. Patients were randomized to receive Ridron Pack (Calcium Carbonate) acetate or placebo, and each continued to receive the same number of tablets as had been individually established during the previous study. Following 2 weeks of treatment, patients switched to the alternative therapy for an additional 2 weeks.

The phosphate binding effect of Ridron Pack (Calcium Carbonate) acetate is shown in the Table 3.


* ANOVA of Ridron Pack (Calcium Carbonate) acetate vs. placebo after 2 weeks of treatment.

Values expressed as mean ± SEM.


Parameter


Pre-Study


Post-Treatment


p-value*


Ridron Pack (Calcium Carbonate) Acetate


Placebo


Phosphorus (mg/dL)


7.3 ± 0.18


5.9 ± 0.24


7.8 ± 0.22


<0.01


Ridron Pack (Calcium Carbonate) (mg/dL)


8.9 ± 0.11


9.5 ± 0.13


8.8 ± 0.12


<0.01


Overall, 2 weeks of treatment with Ridron Pack (Calcium Carbonate) acetate statistically significantly (p<0.01) decreased serum phosphorus by a mean of 19% and increased serum Ridron Pack (Calcium Carbonate) by a statistically significant (p<0.01) but clinically unimportant mean of 7%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Ridron Pack (Calcium Carbonate) Acetate Capsules

667 mg capsule is supplied as a white opaque/blue opaque capsule, imprinted with “54 215” on the cap and body.

NDC 0615-2303-39: Blistercards of 30 Capsules

NDC 0615-2303-30: Unit-dose Boxes of 30 Capsules

STORAGE

Store at 20° to 25°C (68° to 77°F).

17 PATIENT COUNSELING INFORMATION

Inform patients to take Ridron Pack (Calcium Carbonate) acetate capsules with meals, adhere to their prescribed diets, and avoid the use of Ridron Pack (Calcium Carbonate) supplements including nonprescription antacids. Inform the patients about the symptoms of hypercalcemia [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ].

Advise patients who are taking an oral medication where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy to take the drug one hour before or three hours after Ridron Pack (Calcium Carbonate) acetate capsules.

Distr. by: West-Ward

Pharmaceuticals Corp.

Eatontown, NJ 07724

10003705/05

Revised April 2016

Risedronate Sodium:


1 INDICATIONS AND USAGE

Ridron Pack tablets are a bisphosphonate indicated for:

  • Treatment and prevention of postmenopausal osteoporosis (1.1)
  • Treatment to increase bone mass in men with osteoporosis (1.2)
  • Treatment and prevention of glucocorticoid-induced osteoporosis (1.3)
  • Treatment of Paget’s disease (1.4)

Limitations of Use

Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use. (1.5)

1.1 Postmenopausal Osteoporosis

Ridron Pack (Risedronate Sodium) tablets are indicated for the treatment and prevention of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, risedronate reduces the incidence of vertebral fractures and a composite endpoint of nonvertebral osteoporosis-related fractures [see Clinical Studies (14.1, 14.2) ].

1.2 Osteoporosis in Men

Ridron Pack tablets are indicated for treatment to increase bone mass in men with osteoporosis.

1.3 Glucocorticoid-Induced Osteoporosis

Ridron Pack (Risedronate Sodium) tablets are indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoid treatment (daily dosage of greater than or equal to 7.5 mg of prednisone or equivalent) for chronic diseases. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D.

1.4 Paget’s Disease

Ridron Pack tablets are indicated for treatment of Paget’s disease of bone in men and women.

1.5 Important Limitations of Use

The optimal duration of use has not been determined. The safety and effectiveness of Ridron Pack (Risedronate Sodium) tablets for the treatment of osteoporosis are based on clinical data of 3 years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

2 DOSAGE AND ADMINISTRATION

Treatment of Postmenopausal Osteoporosis: 5 mg daily, 35 mg once-a-week, 150 mg once-a-month

Prevention of Postmenopausal Osteoporosis: 5 mg daily, 35 mg once-a-week (2.2)

Men with Osteoporosis: 35 mg once-a-week (2.3)

Glucocorticoid-Induced Osteoporosis: 5 mg daily (2.4)

Paget’s Disease: 30 mg daily for 2 months (2.5)

Instruct patients to:

  • Swallow tablet whole with 6 to 8 ounces of plain water, at least 30 minutes before the first food, beverage, or medication of the day
  • Avoid lying down for 30 minutes (2)
  • Take supplemental calcium and vitamin D if dietary intake is inadequate (2.7)

2.1 Treatment of Postmenopausal Osteoporosis

[See Indications and Usage (1.1).]

The recommended regimen is:

  • one 5 mg tablet orally, taken daily or
  • one 35 mg tablet orally, taken once-a-week or
  • one 150 mg tablet orally, taken once-a-month

2.2 Prevention of Postmenopausal Osteoporosis

[See Indications and Usage.]

The recommended regimen is:

  • one 5 mg tablet orally, taken daily or
  • one 35 mg tablet orally, taken once-a-week or
  • alternatively, one 150 mg tablet orally, taken once-a-month may be considered

2.3 Treatment to Increase Bone Mass in Men with Osteoporosis

[See Indications and Usage (1.2).]

The recommended regimen is:

  • one 35 mg tablet orally, taken once-a-week

2.4 Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

[See Indications and Usage.]

The recommended regimen is:

  • one 5 mg tablet orally, taken daily

2.5 Treatment of Paget’s Disease

[See Indications and Usage (1.4).]

The recommended treatment regimen is 30 mg orally once 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 one course of retreatment.

2.6 Important Administration Instructions

Instruct patients to do the following:

  • Take Ridron Pack tablets at least 30 minutes before the first food or drink of the day other than water, and before taking any oral medication or supplementation, including calcium, antacids, or vitamins to maximize absorption and clinical benefit, [see Drug Interactions (7.1) ]. Avoid the use of water with supplements, including mineral water, because they may have a higher concentration of calcium.
  • Swallow Ridron Pack (Risedronate Sodium) tablets whole with a full glass of plain water (6 to 8 ounces). Avoid lying down for 30 minutes after taking the medication [see Warnings and Precautions (5.1) ]. Do not chew or suck the tablet because of a potential for oropharyngeal ulceration.
  • Do not eat or drink anything except plain water, or take other medications for at least 30 minutes after taking Ridron Pack (Risedronate Sodium) tablets.

2.7 Recommendations for Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate; and to take calcium supplements, antacids, magnesium-based supplements or laxatives, and iron preparations at a different time of the day as they interfere with the absorption of Ridron Pack (Risedronate Sodium) tablets.

2.8 Administration Instructions for Missed Doses

Instruct patients about missing Ridron Pack (Risedronate Sodium) tablet doses as follows:

  • If a dose of Ridron Pack (Risedronate Sodium) 35 mg once-a-week is missed:
    • Take 1 tablet on the morning after they remember and return to taking 1 tablet once-a-week, as originally scheduled on their chosen day.
    • Do not take 2 tablets on the same day.
  • If the dose of Ridron Pack (Risedronate Sodium) 150 mg once-a-month is missed, and the next month’s scheduled dose is more than 7 days away:
    • Take the missed tablet in the morning after the day it is remembered and then return to taking their Ridron Pack (Risedronate Sodium) 150 mg tablet once-a-month as originally scheduled.
    • Do not take more than one 150 mg tablet within 7 days.
  • If the dose of Ridron Pack (Risedronate Sodium) 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days:
    • Wait until their next month’s scheduled dose and then continue taking Ridron Pack (Risedronate Sodium) 150 mg tablet once-a-month as originally scheduled.

3 DOSAGE FORMS AND STRENGTHS

  • 5 mg tablets are light beige, film-coated, round, unscored tablets debossed with M on one side of that tablet and 44 on the other side.
  • 30 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and 114 on the other side.
  • 35 mg tablets are light orange, film-coated, round, unscored tablets debossed with M on one side of the tablet and 714 on the other side.
  • 150 mg tablets are light blue, film-coated, round, tablets debossed with M over RE on one side of the tablet and 150 on the other side.

Tablets: 5 mg, 30 mg, 35 mg and 150 mg (3)

4 CONTRAINDICATIONS

Ridron Pack (Risedronate Sodium) tablets are contraindicated in patients with the following conditions:

  • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia [see Warnings and Precautions (5.1) ]
  • Inability to stand or sit upright for at least 30 minutes [see Dosage and Administration (2), Warnings and Precautions (5.1) ]
  • Hypocalcemia [see Warnings and Precautions (5.2) ]
  • Known hypersensitivity to Ridron Pack (Risedronate Sodium) tablets or any of its excipients. Angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported [see Adverse Reactions (6.2) ]
  • Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia (4, 5.1)
  • Inability to stand or sit upright for at least 30 minutes (4, 5.1)
  • Hypocalcemia (4, 5.2)
  • Known hypersensitivity to any component of this product (4, 6.2)

5 WARNINGS AND PRECAUTIONS

  • Products Containing Same Active Ingredient: Patients receiving Atelvia® should not be treated with Ridron Pack tablets (5.1)
  • Upper Gastrointestinal Adverse Reactions can occur. Instruct patients to follow dosing instructions. Discontinue use if new or worsening symptoms occur (5.2)
  • Hypocalcemia may worsen and must be corrected prior to use (5.3)
  • Osteonecrosis of the Jaw has been reported (5.4)
  • Severe Bone, Joint, Muscle Pain may occur. Discontinue use if severe symptoms develop (5.5, 6.2)
  • Atypical Femur Fractures have been reported. Patients with new thigh or groin pain should be evaluated to rule out a femoral fracture (5.6)

5.1 Drug Products with the Same Active Ingredient

Ridron Pack (Risedronate Sodium) tablets contain the same active ingredient found in Atelvia®. A patient being treated with Atelvia® should not receive Ridron Pack (Risedronate Sodium) tablets.

5.2 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 [see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17.1) ].

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 [see Dosage and Administration (2) ]. In patients who cannot comply with dosing instructions due to mental disability, therapy with risedronate should be used under appropriate supervision.

There have been postmarketing 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.

5.3 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 [see Contraindications (4), Adverse Reactions (6.1), Information for Patients (17.1) ].

5.4 Jaw Osteonecrosis

Osteonecrosis of the jaw, 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, angiogenesis inhibitors), 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 [see Adverse Reactions (6.2) ].

5.5 Musculoskeletal Pain

In postmarketing experience, there have been reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates [see Adverse Reactions (6.2) ]. 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.

5.6 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 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.

5.7 Renal Impairment

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

5.8 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.

5.9 Laboratory Test Interactions

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

6 ADVERSE REACTIONS

Most common adverse reactions reported in greater than 10% of patients treated with risedronate and with a higher frequency than placebo are: back pain, arthralgia, abdominal pain, and dyspepsia

Hypersensitivity reactions (angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome, and toxic epidermal necrolysis), and eye inflammation (iritis, uveitis) have been reported rarely (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals, Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Treatment of Postmenopausal Osteoporosis

Daily Dosing

The safety of Ridron Pack 5 mg once daily in the treatment of postmenopausal osteoporosis was assessed in four randomized, double-blind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis. The duration of the trials was up to 3 years, with 1619 patients exposed to placebo and 1613 patients exposed to Ridron Pack (Risedronate Sodium) 5 mg. Patients with pre-existing gastrointestinal disease and concomitant use of nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at baseline.

The incidence of all-cause mortality was 2% in the placebo group and 1.7% in the Ridron Pack (Risedronate Sodium) 5 mg daily group. The incidence of serious adverse events was 24.6% in the placebo group and 27.2% in the Ridron Pack (Risedronate Sodium) 5 mg group. The percentage of patients who withdrew from the study due to adverse events was 15.6% in the placebo group and 14.8% in the Ridron Pack (Risedronate Sodium) 5 mg group. The most common adverse reactions reported in greater than 10 percent of subjects were: back pain, arthralgia, abdominal pain and dyspepsia. Table 1 lists adverse events from the Phase 3 postmenopausal osteoporosis trials reported in greater than or equal to 5% of patients. Adverse events are shown without attribution of causality.


Body System


Placebo

N = 1,619

%


5 mg Ridron Pack (Risedronate Sodium)

N = 1,613

%


Body as a Whole

Infection

Back Pain

Accidental Injury

Pain

Abdominal Pain

Flu Syndrome

Headache

Asthenia

Neck Pain

Chest Pain

Allergic Reaction



29.9

26.1

16.8

14

9.9

11.6

10.8

4.5

4.7

5.1

5.9



31.1

28

16.9

14.1

12.2

10.5

9.9

5.4

5.4

5

3.8


Cardiovascular System

Hypertension



9.8



10.5


Digestive System

Constipation

Diarrhea

Dyspepsia

Nausea



12.6

10

10.6

11.2



12.9

10.8

10.8

10.5


Metabolic & Nutritional Disorders

Peripheral Edema



8.8



7.7


Musculoskeletal System

Arthralgia

Arthritis

Traumatic Bone Fracture

Joint Disorder

Myalgia

Bone Pain



22.1

10.1

12.3

5.3

6.2

4.8



23.7

9.6

9.3

7

6.7

5.3


Nervous System

Dizziness

Depression

Insomnia



5.7

6.1

4.6



7.1

6.8

5


Respiratory System

Bronchitis

Sinusitis

Rhinitis

Pharyngitis

Increase Cough



10.4

9.1

5.1

5

6.3



10

8.7

6.2

6

5.9


Skin and Appendages

Rash



7.1



7.9


Special Senses

Cataract



5.7



6.5


Urogenital System

Urinary Tract Infection



10.4



11.1

Gastrointestinal Adverse Events

The incidence of adverse events in the placebo and Ridron Pack (Risedronate Sodium) 5 mg daily groups were: abdominal pain (9.9% versus 12.2%), diarrhea (10% versus 10.8%), dyspepsia (10.6% versus 10.8%) and gastritis (2.3% versus 2.7%). Duodenitis and glossitis have been reported uncommonly in the Ridron Pack (Risedronate Sodium) 5 mg daily group (0.1% to 1%). In patients with active upper gastrointestinal disease at baseline, the incidence of upper gastrointestinal adverse events was similar between the placebo and Ridron Pack (Risedronate Sodium) 5 mg daily groups.

Musculoskeletal Adverse Events

The incidence of adverse events in the placebo and Ridron Pack 5 mg daily groups were: back pain (26.1% versus 28%), arthralgia (22.1% versus 23.7%), myalgia (6.2% versus 6.7%) and bone pain (4.8% versus 5.3%).

Laboratory Test Findings

Throughout the Phase 3 studies, transient decreases from baseline in serum calcium (less than 1%) and serum phosphate (less than 3%) and compensatory increases in serum PTH levels (less than 30%) were observed within 6 months in patients in osteoporosis clinical trials treated with Ridron Pack (Risedronate Sodium) 5 mg once daily. There were no significant differences in serum calcium, phosphate, or PTH levels between placebo and Ridron Pack (Risedronate Sodium) 5 mg once daily at 3 years. Serum calcium levels below 8 mg/dL were observed in 18 patients, nine (0.5%) in each treatment arm (placebo and Ridron Pack (Risedronate Sodium) 5 mg once daily). Serum phosphorus levels below 2 mg/dL were observed in 14 patients, three (0.2%) treated with placebo and 11 (0.6%) treated with Ridron Pack (Risedronate Sodium) 5 mg once daily. There have been rare reports (less than 0.1%) of abnormal liver function tests.

Endoscopic Findings

In the risedronate clinical trials, endoscopic evaluation was encouraged in any patient with moderate-to-severe gastrointestinal complaints, while maintaining the blind. Endoscopies were performed on equal numbers of patients between the placebo and treated groups [75 placebo; 75 (11.9%) risedronate]. Clinically important findings (perforations, ulcers, or bleeding) among this symptomatic population were similar between groups (51% placebo; 39% risedronate).

Once-a-Week Dosing

The safety of Ridron Pack (Risedronate Sodium) 35 mg once-a-week in the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing Ridron Pack (Risedronate Sodium) 5 mg daily and Ridron Pack (Risedronate Sodium) 35 mg once-a-week in postmenopausal women aged 50 to 95 years. The duration of the trials was one year, with 480 patients exposed to Ridron Pack (Risedronate Sodium) 5 mg daily and 485 exposed to Ridron Pack (Risedronate Sodium) 35 mg once-a-week. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in these clinical trials. All women received 1000 mg of elemental calcium plus vitamin D supplementation up to 500 international units per day if their 25-hydroxyvitamin D3 level was below normal at baseline.

The incidence of all-cause mortality was 0.4% in the Ridron Pack (Risedronate Sodium) 5 mg daily group and 1% in the Ridron Pack (Risedronate Sodium) 35 mg once-a-week group. The incidence of serious adverse events was 7.1% in the Ridron Pack (Risedronate Sodium) 5 mg daily group and 8.2% in the Ridron Pack (Risedronate Sodium) 35 mg once-a-week group. The percentage of patients who withdrew from the study due to adverse events was 11.9% in the Ridron Pack (Risedronate Sodium) 5 mg daily group and 11.5% in the Ridron Pack (Risedronate Sodium) 35 mg once-a-week group. The overall safety and tolerability profiles of the two dosing regimens were similar.

Gastrointestinal Adverse Events

The incidence of gastrointestinal adverse events was similar between the Ridron Pack 5 mg daily group and the Ridron Pack (Risedronate Sodium) 35 mg once-a-week group: dyspepsia (6.9% versus 7.6%), diarrhea (6.3% versus 4.9%) and abdominal pain (7.3% versus 7.6%).

Musculoskeletal Adverse Events

Arthralgia was reported in 11.5% of patients in the Ridron Pack (Risedronate Sodium) 5 mg daily group and 14.2% of patients in the Ridron Pack (Risedronate Sodium) 35 mg once-a-week group. Myalgia was reported by 4.6% of patients in the Ridron Pack (Risedronate Sodium) 5 mg daily group and 6.2% of patients in the Ridron Pack (Risedronate Sodium) 35 mg once-a-week group.

Laboratory Test Findings

The mean percent changes from baseline at 12 months were similar between the Ridron Pack 5 mg daily and Ridron Pack (Risedronate Sodium) 35 mg once-a-week groups, respectively, for serum calcium (0.4% versus 0.7%), phosphate (-3.8% versus -2.6%) and PTH (6.4% versus 4.2%).

Once-a-Month

The safety of Ridron Pack (Risedronate Sodium) 150 mg administered once-a-month for the treatment of postmenopausal osteoporosis was assessed in a double-blind, multicenter study in postmenopausal women aged 50 to 88 years. The duration of the trial was one year, with 642 patients exposed to Ridron Pack (Risedronate Sodium) 5 mg daily and 650 exposed to Ridron Pack (Risedronate Sodium) 150 mg once-a-month. Patients with pre-existing gastrointestinal disease and concomitant use of nonsteroidal anti-inflammatory drugs, proton pump inhibitors, and H2 antagonists were included in this clinical trial. All women received 1000 mg of elemental calcium plus up to 1000 international units of vitamin D supplementation per day.

The incidence of all-cause mortality was 0.5% for the Ridron Pack (Risedronate Sodium) 5 mg daily group and 0% for the Ridron Pack (Risedronate Sodium) 150 mg once-a-month group. The incidence of serious adverse events was 4.2% in the Ridron Pack (Risedronate Sodium) 5 mg daily group and 6.2% in the Ridron Pack (Risedronate Sodium) 150 mg once-a-month group. The percentage of patients who withdrew from treatment due to adverse events was 9.5% in the Ridron Pack (Risedronate Sodium) 5 mg daily group and 8.6% in the Ridron Pack (Risedronate Sodium) 150 mg once-a-month group. The overall safety and tolerability profiles of the two dosing regimens were similar.

Acute Phase Reactions

Symptoms consistent with acute phase reaction have been reported with bisphosphonate use. The overall incidence of acute phase reaction was 1.1% in the Ridron Pack 5 mg daily group and 5.2% in the Ridron Pack (Risedronate Sodium) 150 mg once-a-month group. These incidence rates are based on reporting of any of 33 acute phase reaction-like symptoms within 3 days of the first dose and for a duration of 7 days or less. Fever or influenza-like illness with onset within the same period were reported by 0.2% of patients on Ridron Pack (Risedronate Sodium) 5 mg daily and 1.4% of patients on Ridron Pack (Risedronate Sodium) 150 mg once-a-month.

Gastrointestinal Adverse Events

A greater percentage of patients experienced diarrhea with Ridron Pack (Risedronate Sodium) 150 mg once-a-month compared to 5 mg daily (8.2% versus 4.7%, respectively). The Ridron Pack (Risedronate Sodium) 150 mg once-a-month group resulted in a higher incidence of discontinuation due to abdominal pain upper (2.5% versus 1.4%) and diarrhea (0.8% versus 0%) compared to the Ridron Pack (Risedronate Sodium) 5 mg daily regimen. All of these events occurred within a few days of the first dose. The incidence of vomiting that led to discontinuation was the same in both groups (0.3% versus 0.3%).

Ocular Adverse Events

None of the patients treated with Ridron Pack 150 mg once-a-month reported ocular inflammation such as uveitis, scleritis, or iritis; two patients treated with Ridron Pack (Risedronate Sodium) 5 mg daily reported iritis.

Laboratory Test Findings

When Ridron Pack (Risedronate Sodium) 5 mg daily and Ridron Pack (Risedronate Sodium) 150 mg once-a-month were compared in postmenopausal women with osteoporosis, the mean percent changes from baseline at 12 months were 0.1% and 0.3% for serum calcium, -2.3% and -2.3% for phosphate, and 8.3% and 4.8% for PTH, respectively. Compared to the Ridron Pack (Risedronate Sodium) 5 mg daily regimen, Ridron Pack (Risedronate Sodium) 150 mg once-a-month resulted in a slightly higher incidence of hypocalcemia at the end of the first month of treatment (0.2% versus 2.2%). Thereafter, the incidence of hypocalcemia with these regimens was similar at approximately 2%.

Prevention of Postmenopausal Osteoporosis

Daily Dosing

The safety of Ridron Pack 5 mg daily in the prevention of postmenopausal osteoporosis was assessed in two randomized, double-blind, placebo-controlled trials. In one study of postmenopausal women aged 37 to 82 years without osteoporosis, the use of estrogen replacement therapy in both placebo- and risedronate-treated patients was included. The duration of the trial was one year, with 259 exposed to placebo and 261 patients exposed to Ridron Pack (Risedronate Sodium) 5 mg. The second study included postmenopausal women aged 44 to 63 years without osteoporosis. The duration of the trial was one year, with 125 exposed to placebo and 129 patients exposed to Ridron Pack (Risedronate Sodium) 5 mg. All women received 1000 mg of elemental calcium per day.

In the trial with estrogen replacement therapy, the incidence of all-cause mortality was 1.5% for the placebo group and 0.4% for the Ridron Pack (Risedronate Sodium) 5 mg group. The incidence of serious adverse events was 8.9% in the placebo group and 5.4% in the Ridron Pack (Risedronate Sodium) 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 18.9% in the placebo group and 10.3% in the Ridron Pack (Risedronate Sodium) 5 mg group. Constipation was reported by 1.9% of the placebo group and 6.5% of Ridron Pack (Risedronate Sodium) 5 mg group.

In the second trial, the incidence of all-cause mortality was 0% for both groups. The incidence of serious adverse events was 17.6% in the placebo group and 9.3% in the Ridron Pack (Risedronate Sodium) 5 mg group. The percentage of patients who withdrew from treatment due to adverse events was 6.4% in the placebo group and 5.4% in the Ridron Pack (Risedronate Sodium) 5 mg group. Nausea was reported by 6.4% of patients in the placebo group and 13.2% of patients in the Ridron Pack (Risedronate Sodium) 5 mg group.

Once-a-Week Dosing

There were no deaths in a one-year, double-blind, placebo-controlled study of Ridron Pack (Risedronate Sodium) 35 mg once-a-week for prevention of bone loss in 278 postmenopausal women without osteoporosis. More treated subjects on risedronate reported arthralgia (placebo 7.8%; risedronate 13.9%), myalgia (placebo 2.1%; risedronate 5.1%) and nausea (placebo 4.3%; risedronate 7.3%) than subjects on placebo.

Treatment to Increase Bone Mass in Men with Osteoporosis

In a 2-year, double-blind, multicenter study, 284 men with osteoporosis were treated with placebo or Ridron Pack (Risedronate Sodium) 35 mg once-a-week (N = 191). The overall safety and tolerability profile of risedronate in men with osteoporosis was similar to the adverse events reported in the risedronate postmenopausal osteoporosis clinical trials, with the addition of benign prostatic hyperplasia (placebo 3%; Ridron Pack (Risedronate Sodium) 35 mg 5%), nephrolithiasis (placebo 0%; Ridron Pack (Risedronate Sodium) 35 mg 3%) and arrhythmia (placebo 0%; Ridron Pack (Risedronate Sodium) 35 mg 2%).

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

The safety of Ridron Pack (Risedronate Sodium) 5 mg daily in the treatment and prevention of glucocorticoid-induced osteoporosis was assessed in two randomized, double-blind, placebo-controlled multinational trials of 344 patients [male (123) and female (221)] aged 18 to 85 years who had recently initiated oral glucocorticoid therapy (less than or equal to 3 months, prevention study) or were on long-term oral glucocorticoid therapy (greater than or equal to 6 months, treatment study). The duration of the trials was one year, with 170 patients exposed to placebo and 174 patients exposed to Ridron Pack (Risedronate Sodium) 5 mg daily. Patients in one study received 1000 mg elemental calcium plus 400 international units of vitamin D supplementation per day; patients in the other study received 500 mg calcium supplementation per day.

The incidence of all-cause mortality was 2.9% in the placebo group and 1.1% in the Ridron Pack (Risedronate Sodium) 5 mg daily group. The incidence of serious adverse events was 33.5% in the placebo group and 30.5% in the Ridron Pack (Risedronate Sodium) 5 mg daily group. The percentage of patients who withdrew from the study due to adverse events was 8.8% in the placebo group and 7.5% in the Ridron Pack (Risedronate Sodium) 5 mg daily group. Back pain was reported in 8.8% of patients in the placebo group and 17.8% of patients in the Ridron Pack (Risedronate Sodium) 5 mg daily group. Arthralgia was reported in 14.7% of patients in the placebo group and 24.7% of patients in the Ridron Pack (Risedronate Sodium) 5 mg daily group.

Treatment of Paget’s Disease

Risedronate has been studied in 392 patients with Paget’s disease of bone. As in trials of risedronate for other indications, the adverse experiences reported in the Paget’s disease trials have generally been mild or moderate, have not required discontinuation of treatment and have not appeared to be related to patient age, gender, or race.

The safety of risedronate was assessed in a randomized, double-blind, active-controlled study of 122 patients aged 34 to 85 years. The duration of the trial was 540 days, with 61 patients exposed to risedronate and 61 patients exposed to Didronel®. The adverse event profile was similar for risedronate and Didronel®: 6.6% of patients treated with Ridron Pack (Risedronate Sodium) 30 mg daily for 2 months discontinued treatment due to adverse events, compared to 8.2% (5/61) of patients treated with Didronel® 400 mg daily for 6 months. Table 2 lists adverse events reported in greater than or equal to 5% of risedronate-treated patients in Phase 3 Paget's disease trials. Adverse events shown are considered to be possibly or probably causally related in at least one patient.


Body System


30 mg/day

x 2 months

Ridron Pack (Risedronate Sodium)

%

(N = 61)


400 mg/day

x 6 months

DIDRONEL®

%

(N = 61)


Body as a Whole

Flu Syndrome

Chest Pain



9.8

6.6



1.6

3.3


Gastrointestinal

Diarrhea

Abdominal Pain

Nausea

Constipation



19.7

11.5

9.8

6.6



14.8

8.2

9.8

8.2


Metabolic and Nutritional Disorders

Peripheral Edema



8.2



6.6


Musculoskeletal

Arthralgia



32.8



29.5


Nervous

Headache

Dizziness



18

6.6



16.4

4.9


Skin and Appendages

Rash



11.5



8.2

Gastrointestinal Adverse Events

During the first year of the study (treatment and nontreatment follow-up), the proportion of patients who reported upper gastrointestinal adverse events was similar between the treatment groups; no patients reported severe upper gastrointestinal adverse events. The incidence of diarrhea was 19.7% in the risedronate group and 14.8% in the Didronel® group; none were serious or resulted in withdrawal.

Ocular Adverse Events

Three patients who received Ridron Pack 30 mg daily experienced acute iritis in one supportive study. All three patients recovered from their events; however, in one of these patients, the event recurred during risedronate treatment and again during treatment with pamidronate. All patients were effectively treated with topical steroids.

6.2 Postmarketing Experience

Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions

Hypersensitivity and skin reactions have been reported, including angioedema, generalized rash, bullous skin reactions, Stevens-Johnson syndrome and toxic epidermal necrolysis.

Gastrointestinal Adverse Events

Events involving upper gastrointestinal irritation, such as esophagitis and esophageal or gastric ulcers, have been reported [see Warnings and Precautions ].

Musculoskeletal Pain

Bone, joint, or muscle pain, described as severe or incapacitating, have been reported rarely [see Warnings and Precautions (5.4) ].

Eye Inflammation

Reactions of eye inflammation including iritis and uveitis have been reported rarely.

Jaw Osteonecrosis

Osteonecrosis of the jaw has been reported rarely [see Warnings and Precautions ].

Pulmonary

Asthma exacerbations.

7 DRUG INTERACTIONS

No specific drug-drug interaction studies were performed. Risedronate is not metabolized and does not induce or inhibit hepatic microsomal drug-metabolizing enzymes.

Calcium, antacids, or oral medications containing divalent cations interfere with the absorption of risedronate (7.1)

7.1 Calcium Supplements/Antacids

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

7.2 Hormone Replacement Therapy

One study of about 500 early postmenopausal women has been conducted to date in which treatment with Ridron Pack 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.

7.3 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%).

7.4 H2 Blockers and Proton Pump Inhibitors

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.

8 USE IN SPECIFIC POPULATIONS

Risedronate is not recommended for use in patients with severe renal impairment (5.6, 8.6, 12.3)

Risedronate is not indicated for use in pediatric patients (8.4)

8.1 Pregnancy

Terotogenic Effects. 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 on this risk has not been studied.

In animal studies, pregnant rats received Ridron Pack (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 Ridron Pack (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.

8.3 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.

8.4 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 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%).

8.5 Geriatric Use

Of the patients receiving risedronate in postmenopausal osteoporosis studies [see Clinical Studies (14) ], 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.

8.6 Renal Impairment

Risedronate is not recommended for use in patients with severe renal impairment 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.

8.7 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.

10 OVERDOSAGE

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).

11 DESCRIPTION

Ridron Pack tablets, USP are a pyridinyl bisphosphonate that inhibits osteoclast-mediated bone resorption and modulates bone metabolism. Each Ridron Pack (Risedronate Sodium) tablet for oral administration contains the equivalent of 5 mg, 30 mg, 35 mg or 150 mg of anhydrous Ridron Pack (Risedronate Sodium) in the form of the hemi-pentahydrate. The molecular formula for Ridron Pack (Risedronate Sodium) hemi-pentahydrate is C7H10NO7P2Na - 2.5 H2O. The chemical name of Ridron Pack (Risedronate Sodium) is Sodium trihydrogen [1-hydroxy-2-(3-pyridyl)ethylidene] diphosphonate. The chemical structure of Ridron Pack (Risedronate Sodium) hemi-pentahydrate is the following:

Figure 1 Nonvertebral Osteoporosis-Related Fractures Cumulative Incidence Over 3 Years Combined VERT MN and VERT NA

Effect on Bone Mineral Density

The results of four randomized, placebo-controlled trials in women with postmenopausal osteoporosis (VERT MN, VERT NA, BMD MN, BMD NA) demonstrate that Ridron Pack (Risedronate Sodium) 5 mg daily increases BMD at the spine, hip, and wrist compared to the effects seen with placebo. Table 4 displays the significant increases in BMD seen at the lumbar spine, femoral neck, femoral trochanter, and midshaft radius in these trials compared to placebo. In both VERT studies (VERT MN and VERT NA), Ridron Pack (Risedronate Sodium) 5 mg daily produced increases in lumbar spine BMD that 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.

ND = analysis not done

VERT MN The duration of the studies was 3 years.


VERT NA


BMD MN The duration of the studies was 1.5 to 2 years.


BMD NA


Placebo


5 mg


Placebo


5 mg


Placebo


5 mg


Placebo


5 mg


N = 323


N = 323


N = 599


N = 606


N = 161


N = 148


N = 191


N = 193


Lumbar Spine


1


6.6


0.8


5


0


4


0.2


4.8


Femoral Neck


-1.4


1.6


-1


1.4


-1.1


1.3


0.1


2.4


Femoral Trochanter


-1.9


3.9


-0.5


3


-0.6


2.5


1.3


4


Midshaft Radius


-1.5BMD of the midshaft radius was measured in a subset of centers in VERT MN (placebo, N = 222; 5 mg, N = 214) and VERT NA (placebo, N = 310; 5 mg, N = 306).


0.2


-1.2


0.1


ND


ND


Ridron Pack (Risedronate Sodium) 35 mg once-a-week (N = 485) was shown to be non-inferior to Ridron Pack (Risedronate Sodium) 5 mg daily (N = 480) in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 4% (3.7, 4.3; 95% confidence interval [CI]) in the 5 mg daily group (N = 391) and 3.9% (3.6, 4.3; 95% CI) in the 35 mg once-a-week group (N = 387) and the mean difference between 5 mg daily and 35 mg once-a-week was 0.1% (-0.4, 0.6; 95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The two treatment groups were also similar with regard to BMD increases at other skeletal sites.

In a double-blind, multicenter study of postmenopausal women with osteoporosis, treatment with Ridron Pack (Risedronate Sodium) 75 mg two consecutive days per month (N = 616) was shown to be non-inferior to Ridron Pack (Risedronate Sodium) 5 mg daily (N = 613). In the primary efficacy analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 3.6% (3.3, 3.9; 95% CI) in the 5 mg daily group (N = 527) and 3.4% (3.1, 3.7; 95% CI) in the 75 mg two days per month group (N = 524) with a mean difference between groups being 0.2% (-0.2, 0.6; 95% CI). The results of the intent-to-treat analysis with the last observation carried forward were consistent with the primary efficacy analysis of completers. The two treatment groups were also similar with regard to BMD increases at other skeletal sites.

Ridron Pack (Risedronate Sodium) 150 mg once-a-month (N = 650) was shown to be non-inferior to Ridron Pack (Risedronate Sodium) 5 mg daily (N = 642) in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. The primary efficacy analysis was conducted in all randomized patients with baseline and post-baseline lumbar spine BMD values (modified intent-to-treat population) using last observation carried forward. The mean increases from baseline in lumbar spine BMD at one year were 3.4% (3, 3.8; 95% CI) in the 5 mg daily group (N = 561), and 3.5% (3.1, 3.9; 95% CI) in the 150 mg once-a-month group (N = 578) with a mean difference between groups being -0.1% (-0.5, 0.3; 95% CI). The results of the completers analysis were consistent with the primary efficacy analysis. The two treatment groups were also similar with regard to BMD increases at other skeletal sites.

Histology/Histomorphometry

Bone biopsies from 110 postmenopausal women were obtained at endpoint. Patients had received placebo or daily Ridron Pack (2.5 mg or 5 mg) for 2 to 3 years. Histologic evaluation (N = 103) showed no osteomalacia, impaired bone mineralization, or other adverse effects on bone in risedronate-treated women. These findings demonstrate that bone formed during risedronate administration is of normal quality. The histomorphometric parameter mineralizing surface, an index of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 21 treated with placebo and 23 patients treated with Ridron Pack (Risedronate Sodium) 5 mg. Mineralizing surface decreased moderately in risedronate-treated patients (median percent change: placebo, -21%; Ridron Pack (Risedronate Sodium) 5 mg, -74%), consistent with the known effects of treatment on bone turnover.

Effect on Height

In the two 3-year osteoporosis treatment studies, standing height was measured yearly by stadiometer. Both risedronate and placebo-treated groups lost height during the studies. Patients who received risedronate had a statistically significantly smaller loss of height than those who received placebo. In VERT MN, the median annual height change was -2.4 mm/yr in the placebo group compared to -1.3 mm/yr in the Ridron Pack (Risedronate Sodium) 5 mg daily group. In VERT NA, the median annual height change was -1.1 mm/yr in the placebo group compared to -0.7 mm/yr in the Ridron Pack (Risedronate Sodium) 5 mg daily group.

14.2 Prevention of Osteoporosis in Postmenopausal Women

The safety and effectiveness of Ridron Pack 5 mg daily for the prevention of postmenopausal osteoporosis were demonstrated in a 2-year, double-blind, placebo-controlled study of 383 postmenopausal women (age range 42 to 63 years) within 3 years of menopause (risedronate sodium 5 mg, N = 129). All patients in this study received supplemental calcium 1000 mg/day. Increases in BMD were observed as early as 3 months following initiation of risedronate treatment. Ridron Pack (Risedronate Sodium) 5 mg daily produced significant mean increases in BMD at the lumbar spine, femoral neck, and trochanter compared to placebo at the end of the study (Figure 2). Ridron Pack (Risedronate Sodium) 5 mg daily was also effective in patients with lower baseline lumbar spine BMD (more than one SD below the premenopausal mean) and in those with normal baseline lumbar spine BMD. Bone mineral density at the distal radius decreased in both risedronate and placebo-treated women following one year of treatment.

The safety and effectiveness of Ridron Pack (Risedronate Sodium) 35 mg once-a-week for the prevention postmenopausal osteoporosis were demonstrated in a one-year, double-blind, placebo-controlled study of 278 patients (risedronate sodium 35 mg, N = 136). All patients were supplemented with 1000 mg elemental calcium and 400 international units vitamin D per day. The primary efficacy measure was the percent change in lumbar spine BMD from baseline after one year of treatment using LOCF (last observation carried forward). Ridron Pack (Risedronate Sodium) 35 mg once-a-week resulted in a statistically significant mean difference from placebo in lumbar spine BMD of + 2.9% (least square mean for placebo - 1.05%; risedronate + 1.83%). Ridron Pack (Risedronate Sodium) 35 mg once-a-week also showed a statistically significant mean difference from placebo in BMD at the total proximal femur of + 1.5% (placebo - 0.53%; risedronate + 1.01%), femoral neck of + 1.2% (placebo - 1%; risedronate + 0.22%) and trochanter of + 1.8% (placebo - 0.74%; risedronate + 1.07%).

Combined Administration with Hormone Replacement Therapy

The effects of combining Ridron Pack (Risedronate Sodium) 5 mg daily with conjugated estrogen 0.625 mg daily (N = 263) were compared to the effects of conjugated estrogen alone (N = 261) in a one-year, randomized, double-blind study of women ages 37 to 82 years, who were on average 14 years postmenopausal. The BMD results for this study are presented in Table 5.

Values shown are mean (± SEM) percent change from baseline.

Estrogen 0.625 mg

N = 261


Ridron Pack (Risedronate Sodium) 5 mg + Estrogen 0.625 mg

N = 263


Lumbar Spine

Femoral Neck

Femoral Trochanter

Midshaft Radius

Distal Radius


4.6 ± 0.20

1.8 ± 0.25

3.2 ± 0.28

0.4 ± 0.14

1.7 ± 0.24


5.2 ± 0.23

2.7 ± 0.25

3.7 ± 0.25

0.7 ± 0.17

1.6 ± 0.28

Histology/Histomorphometry

Bone biopsies from 53 postmenopausal women were obtained at endpoint. Patients had received Ridron Pack 5 mg plus estrogen or estrogen-alone once daily for one year. Histologic evaluation (N = 47) demonstrated that the bone of patients treated with risedronate plus estrogen was of normal lamellar structure and normal mineralization. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 12 patients treated with risedronate plus estrogen and 12 treated with estrogen-alone. Mineralizing surface decreased in both treatment groups (median percent change: risedronate plus estrogen, -79%; estrogen-alone, -50%), consistent with the known effects of these agents on bone turnover.

Figure 2 Change in BMD from Baseline 2-Year Prevention Study

14.3 Men with Osteoporosis

The effects of Ridron Pack (Risedronate Sodium) 35 mg once-a-week on BMD were examined in a 2-year, double-blind, placebo-controlled, multinational study in 285 men with osteoporosis (risedronate, N = 192). The patients had a mean age of 61 years (range 36 to 84 years) and 95% were Caucasian. At baseline, mean lumbar spine T-score was -3.2 and mean femoral neck T-score was -2.4. All patients in the study had either, 1) a BMD T-score less than or equal to -2 at the femoral neck and less than or equal to -1 at the lumbar spine, or 2) a BMD T-score less than or equal to -1 at the femoral neck and less than or equal to -2.5 at the lumbar spine. All patients were supplemented with calcium 1000 mg/day and vitamin D 400 to 500 international units/day. Ridron Pack (Risedronate Sodium) 35 mg once-a-week produced significant mean increases in BMD at the lumbar spine, femoral neck, trochanter, and total hip compared to placebo after 2 years of treatment (treatment difference: lumbar spine, 4.5%; femoral neck, 1.1%; trochanter, 2.2%; total proximal femur, 1.5%).

14.4 Glucocorticoid-Induced Osteoporosis

Bone Mineral Density

Two one-year, double-blind, placebo-controlled trials in patients who were taking greater than or equal to 7.5 mg/day of prednisone or equivalent demonstrated that Ridron Pack 5 mg daily was effective in the prevention and treatment of glucocorticoid-induced osteoporosis in men and women who were either initiating or continuing glucocorticoid therapy. The efficacy of risedronate therapy for glucocorticoid-induced osteoporosis beyond one year has not been studied.

The prevention study enrolled 228 patients (risedronate sodium 5 mg, N = 76) (18 to 85 years of age), each of whom had initiated glucocorticoid therapy (mean daily dose of prednisone 21 mg) within the previous 3 months (mean duration of use prior to study 1.8 months) for rheumatic, skin, and pulmonary diseases. The mean lumbar spine BMD was normal at baseline (average T-score 0.7). All patients in this study received supplemental calcium 500 mg/day. By the third month of treatment, and continuing through the year-long treatment, the placebo group experienced losses in BMD at the lumbar spine, femoral neck, and trochanter, while BMD was maintained or increased in the Ridron Pack (Risedronate Sodium) 5 mg group. At each skeletal site there were statistically significant differences between the placebo group and the Ridron Pack (Risedronate Sodium) 5 mg group at all timepoints (Months 3, 6, 9, and 12). The treatment differences increased with continued treatment. Although BMD increased at the distal radius in the Ridron Pack (Risedronate Sodium) 5 mg group compared to the placebo group, the difference was not statistically significant. The differences between placebo and Ridron Pack (Risedronate Sodium) 5 mg after one year were 3.8% at the lumbar spine, 4.1% at the femoral neck, and 4.6% at the trochanter, as shown in Figure 3. The results at these skeletal sites were similar to the overall results when the subgroups of men and postmenopausal women, but not premenopausal women, were analyzed separately. Risedronate was effective at the lumbar spine, femoral neck, and trochanter regardless of age (less than 65 vs. greater than or equal to 65), gender, prior and concomitant glucocorticoid dose, or baseline BMD. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

The treatment study of similar design enrolled 290 patients (risedronate sodium 5 mg, N = 100) (19 to 85 years of age) with continuing, long-term (greater than or equal to 6 months) use of glucocorticoids (mean duration of use prior to study 60 months; mean daily dose of prednisone 15 mg) for rheumatic, skin, and pulmonary diseases. The baseline mean lumbar spine BMD was low (1.63 SD below the young healthy population mean), with 28% of the patients more than 2.5 SD below the mean. All patients in this study received supplemental calcium 1000 mg/day and vitamin D 400 international units/day.

After one year of treatment, the BMD of the placebo group was within 1% of baseline levels at the lumbar spine, femoral neck, and trochanter. Ridron Pack (Risedronate Sodium) 5 mg increased BMD at the lumbar spine (2.9%), femoral neck (1.8%), and trochanter (2.4%). The differences between risedronate and placebo were 2.7% at the lumbar spine, 1.9% at the femoral neck, and 1.6% at the trochanter as shown in Figure 4. The differences were statistically significant for the lumbar spine and femoral neck, but not at the femoral trochanter. Risedronate was similarly effective on lumbar spine BMD regardless of age (less than 65 vs. greater than or equal to 65), gender, or pre-study glucocorticoid dose. Positive treatment effects were also observed in patients taking glucocorticoids for a broad range of rheumatologic disorders, the most common of which were rheumatoid arthritis, temporal arteritis, and polymyalgia rheumatica.

Figure 3 Change in BMD from Baseline Patients Recently Initiating Glucocorticoid Therapy Figure 4 Change in BMD from Baseline Patients on Long-Term Glucocorticoid Therapy

Vertebral Fractures

In the prevention study of patients initiating glucocorticoids, the incidence of vertebral fractures at one year was reduced from 17% in the placebo group to 6% in the risedronate group. In the treatment study of patients continuing glucocorticoids, the incidence of vertebral fractures was reduced from 15% in the placebo group to 5% in the risedronate group (Figure 5). The statistically significant reduction in vertebral fracture incidence in the analysis of the combined studies corresponded to an absolute risk reduction of 11% and a relative risk reduction of 70%. All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (that is, clinical fractures).

Figure 5 Incidence of Vertebral Fractures in Patients Initiating or Continuing Glucocorticoid Therapy

Histology/Histomorphometry

Bone biopsies from 40 patients on glucocorticoid therapy were obtained at endpoint. Patients had received placebo or daily Ridron Pack (2.5 mg or 5 mg) for one year. Histologic evaluation (N = 33) showed that bone formed during treatment with risedronate was of normal lamellar structure and normal mineralization, with no bone or marrow abnormalities observed. The histomorphometric parameter mineralizing surface, a measure of bone turnover, was assessed based upon baseline and post-treatment biopsy samples from 10 patients treated with Ridron Pack (Risedronate Sodium) 5 mg. Mineralizing surface decreased 24% (median percent change) in these patients. Only a small number of placebo-treated patients had both baseline and post-treatment biopsy samples, precluding a meaningful quantitative assessment.

14.5 Treatment of Paget’s Disease

The efficacy of risedronate was demonstrated in two clinical studies involving 120 men and 65 women. In a double-blind, active-controlled study of patients with moderate-to-severe Paget’s disease (serum alkaline phosphatase levels of at least 2 times the upper limit of normal), patients were treated with Ridron Pack (Risedronate Sodium) 30 mg daily for 2 months or Didronel® (etidronate disodium) 400 mg daily for 6 months. At Day 180, 77% (43/56) of risedronate-treated patients achieved normalization of serum alkaline phosphatase levels, compared to 10.5% (6/57) of patients treated with Didronel® (p less than 0.001). At Day 540, 16 months after discontinuation of therapy, 53% (17/32) of risedronate-treated patients and 14% (4/29) of Didronel®-treated patients with available data remained in biochemical remission.

During the first 180 days of the active-controlled study, 85% (51/60) of risedronate-treated patients demonstrated a greater than or equal to 75% reduction from baseline in serum alkaline phosphatase excess (difference between measured level and midpoint of the normal range) with 2 months of treatment compared to 20% (12/60) in the Didronel®-treated group with 6 months of treatment (p less than 0.001). Changes in serum alkaline phosphatase excess over time (shown in Figure 6) were significant following only 30 days of treatment, with a 36% reduction in serum alkaline phosphatase excess at that time compared to only a 6% reduction seen with Didronel® treatment at the same time point (p less than 0.01).

Response to risedronate therapy was similar in patients with mild to very severe Paget’s disease. Table 6 shows the mean percent reduction from baseline at Day 180 in excess serum alkaline phosphatase in patients with mild, moderate, or severe disease.


Ridron Pack (Risedronate Sodium) 30 mg


Didronel® 400 mg


Subgroup: Baseline Disease Severity (AP)


n


Baseline Serum AP (U/L) Values shown are mean ± SEM; ULN = upper limit of normal.


Mean % Reduction


n


Baseline Serum AP (U/L)


Mean % Reduction


greater than 2, less than 3x ULN

greater than or equal to 3, less than 7x ULN

greater than or equal to 7x ULN


32

14


271.6 ± 5.3


-88.1


22


277.9 ± 7.45


-44.6


475.3 ± 28.8


-87.5


25


480.5 ± 26.44


-35


8


1336.5 ± 134.19


-81.8


6


1331.5 ± 167.58


-47.2


Response to risedronate therapy was similar between patients who had previously received anti-pagetic therapy and those who had not. In the active-controlled study, four patients previously non-responsive to one or more courses of anti-pagetic therapy (calcitonin, Didronel®) responded to treatment with Ridron Pack (Risedronate Sodium) 30 mg daily (defined by at least a 30% change from baseline). Each of these patients achieved at least 90% reduction from baseline in serum alkaline phosphatase excess, with three patients achieving normalization of serum alkaline phosphatase levels.

Histomorphometry of the bone was studied in 14 patients with bone biopsies: nine patients had biopsies from pagetic bone lesions and five patients from non-pagetic bone. Bone biopsy results in non-pagetic bone did not reveal osteomalacia, impairment of bone remodeling, or induction of a significant decline in bone turnover in patients treated with risedronate.

Figure 6 Mean Percent Change from Baseline in Serum Alkaline Phosphatase Excess by Visit

16 HOW SUPPLIED/STORAGE AND HANDLING

Ridron Pack (Risedronate Sodium) Tablets, USP are available containing 5 mg, 30 mg, 35 mg or 150 mg Ridron Pack (Risedronate Sodium), USP.

The 5 mg tablets are light beige, film-coated, round, unscored tablets debossed with M on one side of the tablet and 44 on the other side. They are available as follows:

NDC 0378-4044-93

bottles of 30 tablets

NDC 0378-4044-05

bottles of 500 tablets

The 30 mg tablets are white, film-coated, round, unscored tablets debossed with M on one side of the tablet and 114 on the other side. They are available as follows:

NDC 0378-4114-93

bottles of 30 tablets

NDC 0378-4114-05

bottles of 500 tablets

The 35 mg tablets are light orange, film-coated, round, unscored tablets debossed with M on one side of the tablet and 714 on the other side. They are available as follows:

NDC 0378-4714-99

unit of use blister card containing 4 tablets

NDC 0378-4714-92

carton of 10 cards each containing 4 tablets

NDC 0378-4714-96

unit of use blister card containing 12 tablets

NDC 0378-4714-78

carton of 10 cards each containing 12 tablets

The 150 mg tablets are light blue, film-coated, round, unscored tablets debossed with M over RE on one side of the tablet and 150 on the other side. They are available as follows:

NDC 0378-4150-32

unit of use blister card containing 1 tablet

NDC 0378-4150-97

carton of 10 cards each containing 1 tablet

NDC 0378-4150-53

unit of use blister card containing 3 tablets

NDC 0378-4150-93

carton of 10 cards each containing 3 tablets

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

17 PATIENT COUNSELING INFORMATION

Instruct patients to read the Medication Guide before starting therapy with Ridron Pack (Risedronate Sodium) tablets and to re-read it each time the prescription is renewed.

Instruct patients that Atelvia® and Ridron Pack (Risedronate Sodium) tablets contain the same active ingredient and if they are taking Atelvia®, they should not take Ridron Pack (Risedronate Sodium) tablets [see Warnings and Precautions (5.1) ].

Instruct patients to pay particular attention to the dosing instructions as clinical benefits may be compromised by failure to take the drug according to instructions. Specifically, Ridron Pack (Risedronate Sodium) tablets should be taken at least 30 minutes before the first food or drink of the day other than water.

Instruct patients to take Ridron Pack (Risedronate Sodium) tablets while in an upright position (sitting or standing) with a full glass of plain water (6 to 8 ounces) to facilitate delivery to the stomach, and thus reduce the potential for esophageal irritation.

Instruct patients not to lie down for 30 minutes after taking the medication [see Warnings and Precautions (5.1) ].

Instruct patients not to chew or suck on the tablet because of a potential for oropharyngeal irritation.

Instruct patients that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or severe persistent or worsening heartburn) they should consult their physician before continuing Ridron Pack (Risedronate Sodium) tablets.

Instruct patients about missing Ridron Pack (Risedronate Sodium) tablet doses as follows:

  • If a dose of Ridron Pack (Risedronate Sodium) 35 mg once-a-week is missed, they should take one tablet on the morning after they remember and return to taking one tablet once-a-week, as originally scheduled on their chosen day. Patients should not take two tablets on the same day.
  • If the dose of Ridron Pack (Risedronate Sodium) 150 mg once-a-month is missed, and the next month’s scheduled dose is more than 7 days away, the patient should be instructed to take the missed tablet in the morning after the day it is remembered. Patients should then return to taking their Ridron Pack (Risedronate Sodium) 150 mg tablet once-a-month as originally scheduled. Patients should not take more than one 150 mg tablet within 7 days.
  • If the dose of Ridron Pack (Risedronate Sodium) 150 mg once-a-month is missed, and the next month's scheduled dose is within 7 days, patients should wait until their next month’s scheduled dose and then continue taking Ridron Pack (Risedronate Sodium) 150 mg tablet once-a-month as originally scheduled.

Instruct patients to take supplemental calcium and vitamin D if dietary intake is inadequate [see Warnings and Precautions (5.3) ]. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as excessive cigarette smoking, and/or alcohol consumption, if these factors exist.

Instruct patients to take calcium supplements or calcium-, aluminum-, and magnesium-containing medications at a different time of the day than Ridron Pack (Risedronate Sodium) tablets as these medications may interfere with the absorption of Ridron Pack (Risedronate Sodium) tablets.

Remind patients to give all of their healthcare providers an accurate medication history. Instruct patients to tell all of their healthcare providers that they are taking Ridron Pack (Risedronate Sodium) tablets. Patients should be instructed that any time they have a medical problem they think may be from Ridron Pack (Risedronate Sodium) tablets, they should talk to their doctor.

MEDICATION GUIDE

Ridron Pack (Risedronate Sodium) TABLETS, USP

(ris″ e droe′ nate soe′ dee um)

5 mg, 30 mg, 35 mg and 150 mg

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

What is the most important information I should know about Ridron Pack (Risedronate Sodium) tablets?

Ridron Pack (Risedronate Sodium) tablets can cause serious side effects including:

  • Esophagus problems
  • Low calcium levels in your blood (hypocalcemia)
  • Severe jaw bone problems (osteonecrosis)
  • Bone, joint, or muscle pain
  • Unusual thigh bone fractures
  • Esophagus problems. Some people who take Ridron Pack (Risedronate Sodium) tablets may develop problems in the esophagus (the tube that connects the mouth and the stomach). These problems include irritation, inflammation, or ulcers of the esophagus which may sometimes bleed.
    • It is important that you take Ridron Pack (Risedronate Sodium) tablets exactly as prescribed to help lower your chance of getting esophagus problems. tablets?”)
    • Stop taking Ridron Pack (Risedronate Sodium) tablets and call your doctor right away if you get chest pain, new or worsening heartburn, or have trouble or pain when you swallow.
  • Low calcium levels in your blood (hypocalcemia).
  • Ridron Pack (Risedronate Sodium) tablets may lower the calcium levels in your blood. If you have low blood calcium before you start taking Ridron Pack (Risedronate Sodium) tablets, it may get worse during treatment. Your low blood calcium must be treated before you take Ridron Pack (Risedronate Sodium) tablets. Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:
    • Spasms, twitches, or cramps in your muscles
    • Numbness or tingling in your fingers, toes, or around your mouth
  • Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood, while you take Ridron Pack (Risedronate Sodium) tablets. Take calcium and vitamin D as your doctor tells you to.
  • Severe jaw bone problems (osteonecrosis).
  • Severe jaw bone problems may happen when you take Ridron Pack (Risedronate Sodium) tablets. Your doctor should examine your mouth before you start Ridron Pack (Risedronate Sodium) tablets. Your doctor may tell you to see your dentist before you start Ridron Pack (Risedronate Sodium) tablets. It is important for you to practice good mouth care during treatment with Ridron Pack (Risedronate Sodium) tablets.
  • Bone, joint, or muscle pain.
  • Some people who take Ridron Pack (Risedronate Sodium) tablets develop severe bone, joint, or muscle pain.
  • Unusual thigh bone fractures.
  • Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture may include new or unusual pain in your hip, groin, or thigh.

Call your doctor right away if you have any of these side effects.

What are Ridron Pack (Risedronate Sodium) tablets?

Ridron Pack (Risedronate Sodium) tablets are a prescription medicine used to:

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

It is not known how long Ridron Pack (Risedronate Sodium) tablets work for the treatment and prevention of osteoporosis. You should see your doctor regularly to determine if Ridron Pack (Risedronate Sodium) tablets are still right for you.

Ridron Pack (Risedronate Sodium) tablets are not for use in children.

Who should not take Ridron Pack (Risedronate Sodium) tablets?

Do not take Ridron Pack (Risedronate Sodium) tablets if you:

  • Have certain problems with your esophagus, the tube that connects your mouth with your stomach
  • Cannot stand or sit upright for at least 30 minutes
  • Have low levels of calcium in your blood
  • Are allergic to Ridron Pack (Risedronate Sodium) tablets or any of its ingredients. A list of ingredients is at the end of this leaflet.

What should I tell my doctor before taking Ridron Pack (Risedronate Sodium) tablets?

Before you start Ridron Pack (Risedronate Sodium) tablets, be sure to talk to your doctor if you:

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

Especially tell your doctor if you take:

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

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Certain medicines may affect how Ridron Pack (Risedronate Sodium) tablets work.

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

How should I take Ridron Pack (Risedronate Sodium) tablets?

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

After swallowing the Ridron Pack (Risedronate Sodium) tablet, wait at least 30 minutes:

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

Do not lie down for at least 30 minutes after you take Ridron Pack (Risedronate Sodium) tablets and after you eat your first food of the day.

If you miss a dose of Ridron Pack (Risedronate Sodium) tablets, do not take it later in the day. Take your missed dose the next morning and then return to your normal schedule. Do not take two doses at the same time.

If you miss more than two doses of Ridron Pack (Risedronate Sodium) tablets in a month, call your doctor for instructions.

If you take too many Ridron Pack (Risedronate Sodium) tablets, call your doctor. Do not try to vomit. Do not lie down.

What are the possible side effects of Ridron Pack (Risedronate Sodium) tablets?

Ridron Pack (Risedronate Sodium) tablets may cause serious side effects:

  • See “What is the most important information I should know about Ridron Pack (Risedronate Sodium) tablets?”

The most common side effects of Ridron Pack (Risedronate Sodium) tablets are:

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

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

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

These are not all the possible side effects of Ridron Pack (Risedronate Sodium) tablets. For more information, ask your doctor or pharmacist.

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

How should I store Ridron Pack (Risedronate Sodium) tablets?

  • Store Ridron Pack (Risedronate Sodium) tablets at 20° to 25°C (68° to 77°F).

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

Keep Ridron Pack (Risedronate Sodium) tablets and all medicines out of the reach of children.

General information about the safe and effective use of Ridron Pack (Risedronate Sodium) tablets.

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

This Medication Guide summarizes the most important information about Ridron Pack (Risedronate Sodium) tablets. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Ridron Pack (Risedronate Sodium) tablets that is written for health professionals.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in Ridron Pack (Risedronate Sodium) tablets, USP?

Active ingredient: Ridron Pack (Risedronate Sodium), USP

Inactive ingredients in all dose strengths: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polydextrose, polyethylene glycol and titanium dioxide

Inactive ingredients specific to a dose strength: 5 mg-FD&C Blue No. 2 Aluminum Lake, FD&C Yellow No. 6 Aluminum Lake and triacetin; 30 mg-triacetin; 35 mg-red iron oxide, triacetin and yellow iron oxide; 150 mg-FD&C Blue No. 2 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake.

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

The brands listed are trademarks of their respective owners.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

REVISED DECEMBER 2015

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Ridron Pack pharmaceutical active ingredients containing related brand and generic drugs:


Ridron Pack available forms, composition, doses:


Ridron Pack destination | category:


Ridron Pack Anatomical Therapeutic Chemical codes:


Ridron Pack pharmaceutical companies:


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References

  1. Dailymed."RISEDRONATE SODIUM TABLET, FILM COATED [MYLAN PHARMACEUTICALS INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. Dailymed."D-CAL (CALCIUM CARBONATE) TABLET, CHEWABLE [A&Z PHARMACEUTICAL INC.]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  3. Dailymed."RISEDRONATE SODIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Ridron Pack?

Depending on the reaction of the Ridron Pack after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Ridron Pack not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Ridron Pack addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Ridron Pack, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Ridron Pack consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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