Osteoporosis related agents (treatment)

Dosing (Adults):
Osteoporosis in postmenopausal females: Oral: Prophylaxis: 5 mg once daily or 35 mg once weekly.  Treatment: 10 mg once daily or 70 mg once weekly.
Osteoporosis in males: Oral: 10 mg once daily or 70 mg once weekly.

Osteoporosis secondary to glucocorticoids in males and females: Oral: Treatment: 5 mg once daily; a dose of 10 mg once daily should be used in postmenopausal females who are not receiving estrogen.

Paget's disease of bone in males and females: Oral: 40 mg once daily for 6 months.
Retreatment: Relapses during the 12 months following therapy occurred in 9% of patients who responded to treatment. Specific retreatment data are not available. Following a 6-month post-treatment evaluation period, treatment with alendronate may be considered in patients who have relapsed based on increases in serum alkaline phosphatase, which should be measured periodically. Retreatment may also be considered in those who failed to normalize their serum alkaline phosphatase.

Renal Dosing:
CrCl <35 ml/minute: Alendronate is not recommended due to lack of experience.

May cause esophagitis. Alendronate should be taken in the morning with a full glass (eg, 6 to 8 ounces) of plain water at least one-half hour before food, beverages, or other medications.

Supplied:
Oral Solution:  70 mg/75 ml.  Tablet: 5 mg, 10 mg, 35 mg, 40 mg, 70 mg.

Dosing (Adults): 
Oral formulation should be taken on an empty stomach 2 hours before any meal.
Paget's disease: Oral:   Initial: 5-10 mg/kg/day (not to exceed 6 months) or 11-20 mg/kg/day (not to exceed 3 months). Doses >10 mg/kg/day are not recommended.  Retreatment: Initiate only after etidronate-free period ≥ 90 days. Monitor patients every 3-6 months. Retreatment regimens are the same as for initial treatment.

Heterotopic ossification: Oral:  Caused by spinal cord injury: 20 mg/kg/day for 2 weeks, then 10 mg/kg/day for 10 weeks; total treatment period: 12 weeks

Complicating total hip replacement: 20 mg/kg/day for 1 month preoperatively then 20 mg/kg/day for 3 months postoperatively; total treatment period is 4 months

Hypercalcemia associated with malignancy:  I.V. (dilute dose in at least 250 mL NS): 7.5 mg/kg/day for 3 days; there should be at least 7 days between courses of treatment.  Oral: Start 20 mg/kg/day on the last day of infusion and continue for 30-90 days

Dosing adjustment in renal impairment:
Scr 2.5-5 mg/dL: Use with caution
Scr >5 mg/dL: Not recommended

Supplied:
Injection, solution: 50 mg/mL (6 mL)
Tablet: 200 mg, 400 mg

Bisphosphonate.

Dosing (Adults): (usual):
Treatment of postmenopausal osteoporosis: 2.5 mg orally once day or 150 mg once a month.
Prevention of postmenopausal osteoporosis: 2.5 mg orally once daily. 150 mg once a month may be considered.

Supplied: 2.5 mg tablet (once-daily formulation), 150 mg tablet - (once-monthly formulation).

Dosing (Adults):
Drug must be diluted properly before administration and infused intravenously slowly. Due to risk of nephrotoxicity, doses should not exceed 90 mg.

Hypercalcemia of malignancy:
Moderate cancer-related hypercalcemia (corrected serum calcium: 12-13.5 mg/dL): 60-90 mg, as a single dose, given as a slow infusion over 2-24 hours; dose should be diluted in 1000 mL 0.45% NaCl, 0.9% NaCl, or D5W.    
Severe cancer-related hypercalcemia (corrected serum calcium: >13.5 mg/dL): 90 mg, as a single dose, as a slow infusion over 2-24 hours; dose should be diluted in 1000 mL 0.45% NaCl, 0.9% NaCl, or D5W.

A period of 7 days should elapse before the use of second course; repeat infusions every 2-3 weeks have been suggested, however, could be administered every 2-3 months according to the degree and of severity of hypercalcemia and/or the type of malignancy.

Note: Some investigators have suggested a lack of a dose-response relationship. Courses of pamidronate for hypercalcemia may be repeated at varying intervals, depending on the duration of normocalcemia (median 2-3 weeks), but the manufacturer recommends a minimum interval between courses of 7 days. Oral etidronate at a dose of 20 mg/kg/day has been used to maintain the calcium lowering effect following I.V. bisphosphonates, although it is of limited effectiveness.

Osteolytic bone lesions with multiple myeloma: 90 mg in 500 mL D5W, 0.45% NaCl or 0.9% NaCl administered over 4 hours on a monthly basis.

Osteolytic bone lesions with metastatic breast cancer: 90 mg in 250 mL D5W, 0.45% NaCl or 0.9% NaCl administered over 2 hours, repeated every 3-4 weeks

Paget's disease: 30 mg in 500 mL 0.45% NaCl, 0.9% NaCl or D5W administered over 4 hours for 3 consecutive days

Dosing adjustment in renal impairment: Not recommended in severe renal impairment (patients with bone metastases).      Dosing adjustment in renal toxicity: In patients with bone metastases, treatment should be withheld in patients who experience deterioration in renal function (increase of serum creatinine ≥ 0.5 mg/dL in patients with normal baseline or ≥ 1.0 mg/dL in patients with abnormal baseline). Resumption of therapy may be considered when serum creatinine returns to within 10% of baseline.

Supplied:
Injection, powder for reconstitution, as disodium (Aredia®): 30 mg, 90 mg
Injection, solution: 3 mg/mL (10 mL); 6 mg/mL (10 mL); 9 mg/mL (10 mL)

Dosing (Adults):
Risedronate should be taken at least 30 minutes before the first food or drink of the day other than water. Oral:  Adults (patients should receive supplemental calcium and vitamin D if dietary intake is inadequate):
Paget's disease of bone: 30 mg 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.

Osteoporosis (postmenopausal) prevention and treatment: 5 mg once daily; efficacy for use longer than 1 year has not been established; alternatively, a dose of 35 mg once weekly has been demonstrated to be effective

Osteoporosis (glucocorticoid-induced) prevention and treatment: 5 mg once daily

Elderly: Dosage adjustment is not necessary in patients with Clcr ≥ 30 mL/minute.

Renal dosing:
Dosage adjustment in renal impairment: Clcr<30 mL/minute: Not recommended for use

Should be taken on an empty stomach in an upright position with at least 6 ounces of plain water. The upright position and empty stomach should be maintained for at least 30 minutes to minimize gastrointestinal adverse events and increase absorption.

[Supplied: 5 mg, 30 mg, 35 mg tablet]

Dosing (Adults):
Tiludronate should be taken with 6-8 oz of plain water and not taken within 2 hours of food.

Treatment of Paget's disease of the bone in patients who have a level of serum alkaline phosphatase (SAP) at least twice the upper limit of normal, or who are symptomatic, or who are at risk for future complications of their disease:    Oral: 400 mg (2 tablets of tiludronic acid) daily for a period of 3 months; allow an interval of 3 months to assess response

Dosing adjustment in renal impairment: Clcr<30 mL/minute: Not recommended

Supplied:
200 mg tablet[equivalent to 240 mg tiludronate disodium]

Mechanism of Action
Reclast is a bisphosphonate and acts primarily on bone. It is an inhibitor of osteoclast-mediated bone resorption.

The selective action of bisphosphonates on bone is based on their high affinity for mineralized bone. Intravenously administered zoledronic acid rapidly partitions to bone and localizes preferentially at sites of high bone turnover. The main molecular target of zoledronic acid in the osteoclast is the enzyme farnesyl pyrophosphate synthase. The relatively long duration of action of zoledronic acid is attributable to its high binding affinity to bone mineral.

INDICATIONS AND USAGE:
Reclast is a bisphosphonate indicated for:
Treatment and prevention of postmenopausal osteoporosis.

Treatment to increase bone mass in men with osteoporosis.

Treatment and prevention of glucocorticoid-induced osteoporosis.

Treatment of Paget’s disease of bone in men and women.
The optimal duration of use has not been determined. Patients should have the need for continued therapy re-evaluated on a periodic basis.

DOSAGE AND ADMINISTRATION:
Infusion given intravenously over no less than 15 minutes:

Treatment of postmenopausal osteoporosis; treatment to increase bone mass in men with osteoporosis: treatment and prevention of glucocorticoid-induced osteoporosis: 5 mg once a year

Prevention of postmenopausal osteoporosis: 5 mg once every 2 years

Treatment of Paget’s disease of bone: a single 5 mg infusion. Patients should receive 1500 mg elemental calcium and 800 IU vitamin D daily

DOSAGE FORMS AND STRENGTHS:
5 mg in a 100 mL ready-to-infuse solution

CONTRAINDICATIONS:
-Hypocalcemia.
-Patients with creatinine clearance < 35 mL/min and in those with evidence of acute renal impairment.
-Hypersensitivity to any component of Reclast.

WARNINGS AND PRECAUTIONS

• Patients receiving Zometa should not receive Reclast
• Patients must be adequately supplemented with calcium and vitamin D
• A single dose should not exceed 5 mg and the duration of infusion should be no less than 15 minutes. Renal toxicity may be greater in patients with underlying renal impairment or with other risk factors, including advanced age or dehydration. Monitor creatinine clearance before each dose
• Osteonecrosis of the jaw has been reported. All patients should have a routine oral exam by the prescriber prior to treatment
• Atypical femur fractures have been reported. Patients with thigh or groin pain should be evaluated to rule out a femoral fracture
• Reclast can cause fetal harm. Women of childbearing potential should be advised
• Severe incapacitating bone, joint, and/or muscle pain may occur. Withhold future doses of Reclast if severe symptoms occur

ADVERSE REACTIONS
The most common adverse reactions (>10%) were pyrexia, myalgia, headache, arthralgia, pain in extremity. Other important adverse reactions were flu-like illness, nausea, vomiting, diarrhea, and eye inflammation.

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Aminoglycosides: May lower serum calcium for prolonged periods

Loop diuretics: May increase risk of hypocalcemia

Nephrotoxic drugs: Use with caution

Drugs primarily excreted by the kidney: Exposure may be increased with renal impairment. Monitor serum creatinine in patients at risk

USE IN SPECIFIC POPULATIONS
Nursing Mothers: Reclast should not be given to nursing women

Pediatric Use: Not indicated for use in pediatric patients

Geriatric Use: Special care to monitor renal function

Zometa® (zoledronic acid) Injection
INDICATIONS AND USAGE
Zometa is a bisphosphonate indicated for the treatment of:

>> Hypercalcemia of malignancy.

>> Patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

Important limitation of use: The safety and efficacy of Zometa has not been established for use in hyperparathyroidism or nontumor-related hypercalcemia.

DOSAGE AND ADMINISTRATION
Hypercalcemia of malignancy

• 4 mg as a single-use intravenous infusion over no less than 15 minutes.
• 4 mg as retreatment after a minimum of 7 days.

Multiple myeloma and bone metastasis from solid tumors.

• 4 mg as a single-use intravenous infusion over no less than 15 minutes every 3-4 weeks for patients with creatinine clearance of greater than 60 mL/min.
• Reduce the dose for patients with renal impairment.
• Coadminister oral calcium supplements of 500 mg and a multiple vitamin containing 400 IU of Vitamin D daily.

Administer through a separate vented infusion line and do not allow to come in contact with any calcium or divalent cation-containing solutions.

DOSAGE FORMS AND STRENGTHS
4 mg/100 mL single-use ready-to-use bottle

4 mg/5 mL single-use vial of concentrate

CONTRAINDICATIONS
Hypersensitivity to any component of Zometa

WARNINGS AND PRECAUTIONS
Patients being treated with Zometa should not be treated with Reclast®.

Adequately rehydrate patients with hypercalcemia of malignancy prior to administration of Zometa and monitor electrolytes during treatment.

Renal toxicity may be greater in patients with renal impairment. Do not use doses greater than 4 mg. Treatment in patients with severe renal impairment is not recommended. Monitor serum creatinine before each dose.

Osteonecrosis of the jaw has been reported. Preventive dental exams should be performed before starting Zometa. Avoid invasive dental procedures.

Severe incapacitating bone, joint, muscle pain may occur. Discontinue Zometa if severe symptoms occur.

Zometa can cause fetal harm. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant.

Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy. These fractures may occur after minimal or no trauma. Evaluate patients with thigh or groin pain to rule out a femoral fracture. Consider drug discontinuation in patients suspected to have an atypical femur fracture.

ADVERSE REACTIONS
The most common adverse events (greater than 25%) were nausea, fatigue, anemia, bone pain, constipation, fever, vomiting, and dyspnea

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS
Aminoglycosides: May have an additive effect to lower serum calcium for prolonged periods. (7.1)

Loop diuretics: Concomitant use with Zometa may increase risk of hypocalcemia. (7.2)

Nephrotoxic drugs: Use with caution.

INDICATIONS AND USAGE:
Prolia is a RANK ligand (RANKL) inhibitor indicated for:

-Treatment of postmenopausal women with osteoporosis at high risk for fracture.
-Treatment to increase bone mass in men with osteoporosis at high risk for fracture.
-Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer.
-Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

USE IN SPECIFIC POPULATIONS
Nursing mothers: Discontinue drug or nursing taking into consideration importance of drug to mother.
Pediatric patients: Safety and efficacy not established.

Renal impairment: No dose adjustment is necessary in patients with renal impairment. Patients with creatinine clearance < 30 mL/min or receiving dialysis are at risk for hypocalcemia. Supplement with calcium and vitamin D, and consider monitoring serum calcium

DOSAGE AND ADMINISTRATION:
Prolia should be administered by a healthcare professional
Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen.
Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily .

DOSAGE FORMS AND STRENGTHS:
Single-use prefilled syringe containing 60 mg in a 1 mL solution
Single-use vial containing 60 mg in a 1 mL solution

CONTRAINDICATIONS:
Hypocalcemia
Pregnancy
Known hypersensitivity to Prolia

WARNINGS AND PRECAUTIONS
Same Active Ingredient: Patients receiving Prolia should not receive XGEVA®
Hypocalcemia: Must be corrected before initiating Prolia. May worsen, especially in patients with renal impairment. Adequately supplement patients with calcium and vitamin D

Serious infections including skin infections: May occur, including those leading to hospitalization. Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis

Dermatologic reactions: Dermatitis, rashes, and eczema have been reported. Consider discontinuing Prolia if severe symptoms develop.

Osteonecrosis of the jaw: Has been reported with Prolia. Monitor for symptoms
Atypical femoral fractures: Have been reported. Evaluate patients with thigh or groin pain to rule out a femoral fracture.

Suppression of bone turnover: Significant suppression has been demonstrated. Monitor for consequences of bone oversuppression.

ADVERSE REACTIONS
Postmenopausal osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials.

Male Osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis.

Bone loss due to hormone ablation for cancer: Most common adverse reactions (>/=10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials .

To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dosing (Adults): (usual):
Osteoporosis prevention: 60 mg orally qd.
Osteoporosis treatment: 60 mg orally qd.

INDICATIONS
Treatment and Prevention of Osteoporosis in Postmenopausal Women: EVISTA is indicated for the treatment and prevention of osteoporosis in postmenopausal women.

Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis: EVISTA is indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis.

Reduction in the Risk of Invasive Breast Cancer in Postmenopausal Women at High Risk of Invasive Breast Cancer: EVISTA is indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer. The effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years [see Clinical Studies]. Twenty-seven percent of the participants received drug for 5 years. The long-term effects and the recommended length of treatment are not known.

High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer ≥ 1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Healthcare professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-545-5979. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty.

After an assessment of the risk of developing breast cancer, the decision regarding therapy with EVISTA should be based upon an individual assessment of the benefits and risks.

EVISTA does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting EVISTA and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with EVISTA.

Important Limitations of Use for Breast Cancer Risk Reduction

* There are no data available regarding the effect of EVISTA on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of EVISTA.
* EVISTA is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence.
* EVISTA is not indicated for the reduction in the risk of noninvasive breast cancer.

Dosing (Adults): (usual):
The recommended dosage is one 60 mg EVISTA tablet daily, which may be administered any time of day without regard to meals.

Supplied: 60 mg tablet

Mechanism of Action
Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high-affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues.

The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of teriparatide manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton because bone resorption may be stimulated more than bone formation.

Dosing (Adults):
Treatment of osteoporosis in postmenopausal women at high risk of fracture; treatment of primary or hypogonadal osteoporosis in men at high risk of fracture:  20 mcg  SubQ once daily; Note: Initial administration should occur under circumstances in which the patient may sit or lie down, in the event of orthostasis.

Dosage adjustment in renal impairment: No dosage adjustment required. Bioavailability and half-life increase with Clcr<30 mL/minute.

SUPPLIED:
Injection, solution: 250 mcg/mL (3 mL) [prefilled syringe, delivers teriparatide 20 mcg/dose]