Zoledronic Acid

>10%

Bone pain (55%)

Nausea (29-46%)

Fever (32-44%)

Fatigue (39%)

Anemia (22-33%)

Vomiting (14-32%)

Constipation (27-31%)

Dyspnea (22-27%)

Diarrhea (17-24%)

Anorexia (9-22%)

Arthralgia (5-21%)

Headache (5-19%)

Dizziness (18%)

Insomnia (15-16%)

Urinary tract infection (UTI; 12-14%)

Anxiety (11-14%)

Hypophosphatemia (5-14%)

Hypokalemia (12%)

Hypotension (11%)

Hypomagnesemia (11%)

Rash (11%)

Frequency Not Defined

Ocular inflammation (eg, uveitis, scleritis, episcleritis, conjunctivitis, iritis, orbital inflammation)

Postmarketing Reports

Ocular: Uveitis, scleritis, episcleritis, conjunctivitis, iritis, blurred vision, orbital inflammation (including orbital edema)

CNS: Taste disturbance, hyperesthesia, tremor

GI: Dry mouth

Skin: Increased sweating

Musculoskeletal: Muscle cramps, osteonecrosis of jaw, pain, atypical subtrochanteric and diaphyseal femoral fractures

Osteonecrosis of other bones including femur, hip, knee, ankle, wrist and humerus

Cardiovascular: Hypertension, bradycardia, hypotension (associated with syncope or circulatory collapse, primarily in patients with underlying risk factors)

Acute-phase reaction (≤3 days after administration) with symptoms including pyrexia, fatigue, bone pain or arthralgias, myalgias, chills, flulike illness, arthritis with subsequent joint swelling

Hypersensitivity: Bronchoconstriction or bronchospasm, interstitial lung disease, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis

Renal: Hematuria, proteinuria

General disorders and administration site: Weight increase, flulike illness (pyrexia, asthenia, fatigue or malaise) persisting for >30 days

Laboratory abnormalities: Hyperkalemia, hypernatremia

Acqured Fanconi syndrome

Mechanism of Action

Bisphosphonate; inhibits bone resorption via actions on osteoclast activity, leading to indirect increase in bone density

Absorption

Onset: Hypercalcemia of malignancy, 4-7 days; osteolytic bone metastases, 1 week

Duration: 32 days

Distribution

Protein bound: 28-53%

Metabolism

Not metabolized

Elimination

Half-life: 146 hr (terminal)

Renal clearance: 66 mL/min

Total body clearance: 5.6 L/hr

Excretion: Urine (39% as unchanged drug) within 24 hr, feces (<3%)

The most common adverse reactions of Reclast include:

• Fever
• Bone pain
• Muscle pain
• Headache
• Nausea
• Fatigue
• Constipation
• Anemia
• Pain in hands
• Pain in the feet

Other side effects include:

• Headache
• Joint pain
• Dizziness
• Insomnia
• Urinary tract infection
• Anxiety
• Low levels of phosphate
• Low levels of potassium
• Low blood pressure
• Low magnesium blood levels

Possible serious side effects include:

• Severe bone, joint, and muscle pain may occur.
• Low calcium levels may occur if calcium and vitamin D intake is not adequate.
• Reduced kidney function after administration of Reclast has occurred.
• Patients may experience jaw problems (osteonecrosis of the jaw) associated with delayed healing and infection after tooth extraction.
• Bone, joint, and muscle pain also occur and low-trauma femoral fractures have been reported.

Other important but rare side effects include cases of severe allergic reactions involving:

• Shock
• Swelling of tongue
• Throat
• Closure of airways

Zoledronic Acid may be found in some form under the following brand names:

• Reclast

• Zometa

Zoledronic acid is injected into the vein (intravenous) (IV) by a healthcare provider in a hospital or other medical facility.

• The infusion takes at least 15 minutes.
• Your doctor will monitor your kidney function before each dose.
• Your doctor may advise you to take oral calcium supplements and vitamin D daily.
• Drink plenty of water before receiving zoledronic acid injection.
• Administration of acetaminophen following zoledronic acid treatment may reduce the incidence of certain reactions such as chills, fever, joint pain, and bone pain.

Zometa (zoledronic acid):

• Zoledronic acid is given as a single dose in people with high blood calcium due to cancer (known medically as hypercalcemia of malignancy), although, sometimes a second dose is required. The second dose must be given at least 7 days after the first dose.
• Zoledronic acid is given every 3 to 4 weeks when used to prevent bone problems in people with cancer. Your doctor will make the decision as to how long you should continue zoledronic acid. It has been given to patients in studies for up to 24 months.
• If you have HCM, you should drink plenty of clear fluids before using zoledronic acid.

Reclast (zoledronic acid):

• Zoledronic acid is given once a year given for treating osteoporosis in postmenopausal women and treating osteoporosis in men.
• Zoledronic acid is given once every 2 years for preventing osteoporosis in postmenopausal women.
• Zoledronic acid is given once a year for treatment and prevention of glucocorticoid-induced osteoporosis.

The recommended zoledronic acid dose for treating high blood calcium due to cancer (known medically as hypercalcemia of malignancy) is 4 mg, taken as a single dose.

Zoledronic acid is also used to prevent bone problems (such as broken bones) in people with cancer. For this use, the recommended dose is zoledronic acid 4 mg every three to four weeks.

Treatment of Osteoporosis in Postmenopausal Women: The recommended regimen is a 5 mg infusion injected into the vein (intravenously) once a year.

Treatment and Prevention of Glucocorticoid-Induced Osteoporosis: The recommended regimen is a 5 mg infusion injected into the vein (intravenously) once a year.

• Reclast
• Zometa

Note: Acetaminophen administration after the infusion may reduce symptoms of acute-phase reactions. Patients treated for bone metastases from solid tumors, multiple myeloma, and Paget disease should receive a daily calcium and vitamin D supplement, and patients with osteoporosis should receive calcium and vitamin D supplementation if dietary intake is inadequate.

Bone metastases from solid tumors (Zometa): IV: 4 mg once every 3 to 4 weeks

Bone metastases due to breast cancer or prostate cancer (off-label dosing): IV: 4 mg once every 12 weeks; dosing once every 12 weeks (compared to once every 4 weeks) did not result in an increased risk of skeletal events within 2 years in patients with at least 1 site of bone involvement (Himmelstein 2017).

Hypercalcemia of malignancy (albumin-corrected serum calcium ≥12 mg/dL) (Zometa): IV: 4 mg (maximum) given as a single dose. Wait at least 7 days before considering re-treatment.

Multiple myeloma osteolytic lesions (Zometa): IV: 4 mg once every 3 to 4 weeks

Multiple myeloma (off-label dosing): IV: 4 mg once every 12 weeks; dosing once every 12 weeks (compared to once every 4 weeks) did not result in an increased risk of skeletal events within 2 years in patients with at least 1 site of bone involvement (Himmelstein 2017).

Osteoporosis, glucocorticoid-induced, treatment and prevention (Reclast, Aclasta [Canadian product]): IV: 5 mg once a year

Osteoporosis, prevention (Reclast): IV: 5 mg once every 2 years

Canadian labeling (Aclasta): 5 mg as a single (one-time) dose

Osteoporosis, treatment (Reclast, Aclasta [Canadian product]): IV: 5 mg once a year; consider discontinuing after 3 to 5 years of use in patients at low risk for fracture

Paget disease (Reclast, Aclasta [Canadian product]): IV: 5 mg as a single dose.

Re-treatment: Data concerning retreatment is not available; retreatment may be considered for relapse (increase in alkaline phosphatase) if appropriate, for inadequate response, or in patients who are symptomatic.

Canadian labeling (Aclasta): Data concerning retreatment is limited; retreatment with 5 mg (single dose) may be considered for relapse after an interval of at least 1 year from initial treatment.

The Endocrine Society guidelines suggest re-treatment is seldom required within 5 years (Singer 2014).

Postrenal transplant bone loss (prevention) (off-label use): IV: 4 mg at week 2 and month 3 after engraftment (Haas 2003; Schwarz 2004). Additional data may be necessary to further define the role of zoledronic acid in this condition.

Bone loss associated with androgen deprivation therapy in prostate cancer, prevention (off-label use): IV: 4 mg once every 3 months for 1 year (Smith, 2003) or 4 mg every 12 months (Michaelson 2007)

Bone loss associated with aromatase inhibitor therapy in women with breast cancer, prevention (off-label use): IV: 4 mg once every 6 months for 5 years (Brufsky 2012)

If refrigerated, allow solution to reach room temperature before administration. Infuse over at least 15 minutes. Flush IV line with 10 mL NS flush following infusion. Infuse in a line separate from other medications. Patients must be appropriately hydrated prior to treatment. Acetaminophen after administration may reduce the incidence of acute reaction (eg, arthralgia, fever, flu-like symptoms, myalgia).

Multiple myeloma: If treatment is withheld for unexplained albuminuria, consider increasing the infusion time to at least 30 minutes upon reinitiation (Kyle 2007).

Aminoglycosides: May enhance the hypocalcemic effect of Bisphosphonate Derivatives. Monitor therapy

Calcitonin: May enhance the hypocalcemic effect of Zoledronic Acid. Monitor therapy

Deferasirox: Bisphosphonate Derivatives may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Monitor therapy

Proton Pump Inhibitors: May diminish the therapeutic effect of Bisphosphonate Derivatives. Monitor therapy

Systemic Angiogenesis Inhibitors: May enhance the adverse/toxic effect of Bisphosphonate Derivatives. Specifically, the risk for osteonecrosis of the jaw may be increased. Monitor therapy

Thalidomide: May enhance the adverse/toxic effect of Zoledronic Acid. Monitor therapy

Zometa(R):
-Maximum dose: Single dose of 4 mg IV infusion over no less than 15 minutes

Comments: If serum calcium does not return to normal, retreatment should be considered after a minimum of 7 elapsed days.

Use: Treatment of hypercalcemia of malignancy (albumin-corrected calcium equal 12 mg/dL or grater)

Reclast(R):
5 mg IV infusion, at a constant infusion rate, over no less than 15 minutes

Calcium and vitamin D supplementation:
-Calcium: 750 mg elemental calcium orally twice a day, or 500 mg orally three times a day
-Vitamin D: 800 international units orally daily, especially in the 2 weeks following drug administration

Comments: Retreatment may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase or failure to achieve normalization of serum alkaline phosphatase.

Uses: Paget's disease of bone with elevations in serum alkaline phosphatase of two times or higher than upper limit of age- specific normal reference range