Zoledronic Acid; Uses, Side Effects, Interactions, Pragnancy

Zoledronate (zoledronic acid, marketed by Novartis under the trade names Zometa and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases. An annual dose of Zoledronate may also prevent recurring fractures in patients with a previous hip fracture. Zoledronate is a single 5 mg infusion for the treatment of Paget’s disease of bone. In 2007, the FDA also approved Reclast for the treatment of postmenopausal osteoporosis.

Mechanism of Action of Zoledronic Acid

The action of zoledronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates such as zoledronate appear to act as analogs of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signaling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

Indications of Zoledronic Acid

• Hypercalcemia of Malignancy
• Osteoporosis
• Prevention of Osteoporosis
• Osteolytic Bone Lesions of Multiple Myeloma
• Osteolytic Bone Metastases of Solid Tumors
• Paget’s Disease
• Treatment to the inhibitor of osteoclastic bone resorption.
• Bone Metastases
• Hypercalcemia of Malignancy
• Used in the treatment of cancer chemotherapy to treat bone problems that may occur with multiple myeloma and other types of cancer (such as breast, lung)
• Bone destruction
• Polyarthralgia
• Muscles stiffness in nerve diseases
• Morning stiffness
• Multiple joint pain
• Steroid induce arthritis
• Osteoarthritis
• Rheumatoid arthritis
• Ankylosing spondylitis
• Gouty arthritis
• Pain due to especially musculoskeletal system
• Prevention of bone frequently fracture

Therapeutic Indications

• For the treatment of hypercalcemia of malignancy. Also for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. In May of 2007, the drug was approved for treatment of Paget’s Disease
• Treatment of osteoporosis in post-menopausal women in adult men at increased risk of fracture, including those with a recent low-trauma hip fracture.
• Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in post-menopausal women in adult me increased the risk of fracture.
• Treatment of Paget’s disease of the bone in adults.
• Prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia) in adult patients with advanced malignancies involving bone
• Treatment of adult patients with tumor-induced hypercalcemia (TIH).
• Prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia) in adult patients with advanced malignancies involving bone.
• Treatment of adult patients with tumor-induced hypercalcemia (TIH).Zoledronic Acid Hospira 4 mg/5 ml and 4 mg/100 ml:
• Prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia) in adult patients with advanced malignancies involving bone.
• Treatment of adult patients with tumor-induced hypercalcemia (TIH)Zoledronic Acid Hospira 5 mg/100 ml
• Treatment of Paget’s disease of the bone in adults.
• Prevention of skeletal-related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia) in adult patients with advanced malignancies involving bone.
• Treatment of adult patients with tumor-induced hypercalcemia (TIH).
• Treatment of osteoporosis in post-menopausal women in adult men at increased risk of fracture, including those with recent low-trauma hip fracture.
• Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in post-menopausal women in adult men at increased risk of fracture.
• Treatment of Paget’s disease of the bone in adults
• Treatment of osteoporosis in post-menopausal women in adult men at increased risk of fracture, including those with a recent low-trauma hip fracture
• Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy in post-menopausal women in adult men at increased risk of fracture.
• Treatment of Paget’s disease of the bone in adults.
• Treatment of glioma
• Treatment of complex regional pain syndrome

Contra-Indications of Zoledronic Acid

• Poor renal function (e.g. CrCl<30 mL/min)
• Abnormalities of the esophagus which delay oesophageal emptyings such as stricture or achalasia
• Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)
• Clinically manifest osteomalacia
• Certain malformations and malfunctions of the esophagus (strictures, achalasia)
• Inability to stand, walk, or sit for 30 minutes after oral administration
• Renal impairment with a creatinine clearance below 30ml/min
• Patients below 18 yrs. of age, as no clinical data exists
• Signs of colic, which is usually self-limiting, occurs in 30-45% of horses.
• Electrolyte disturbances – primarily calcium, magnesium, and potassium, which can last for several hours. Caution should be used in horses with disease processes that could be affected by electrolyte disturbances, such as hyperkalemic periodic paralysis or cardiac disease.
• Kidney damage – it is eliminated by the kidney and is not recommended for use in animals with impaired renal function.
• Less serious reactions include stiffness of the neck, decreased appetite, fever, and increased urination.
• Inability to stand, walk, or sit for 30 minutes after oral administration
• Renal impairment with a creatinine clearance below 30ml/min
• Hypocalcemia
• Pregnancy and breastfeeding
• Acute bronchospasm,
• asthma, phosphonate hypersensitivity
• diabetes mellitus,
• hypertension,
• Cardiac arrhythmias,
• Electrolyte imbalance,
• Hypocalcemia,
• Hypomagnesemia,
• Hypophosphatemia,

The dosage of Zoledronic Acid

Dosage Forms And Strengths

4 mg/100 mL single-use ready-to-use bottle

4 mg/5 mL single-use vial of concentrate

Hypercalcemia Of Malignancy

• The maximum recommended the dose of Zometa in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zometa should have serum creatinine assessed prior to each treatment.
• Dose adjustments of Zometa are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Hypercalcemia of Malignancy

• The maximum recommended the dose of Zometa in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zometa should have serum creatinine assessed prior to each treatment.
• Dose adjustments of Zometa are not necessary for treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Treatment of active Paget’s disease. 

• 5 mg as a single intravenous infusion over no less than 15 minutes. After a single treatment, an extended remission period is observed.
• During clinical trials, most patients showed a therapeutic response within 60 days of treatment, with the maintenance of effect at 24 months.
• Specific retreatment data are not available. However, retreatment may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, or in those patients who failed to achieve normalization of their serum alkaline phosphatase, or in those patients with symptoms, as dictated by medical practice.

Treatment of osteoporosis.

In postmenopausal women.Intravenous dosage (Reclast)Postmenopausal females

• 5 mg intravenously infused once yearly. Administer the infusion over no less than 15 minutes at a constant rate of infusion. To reduce the risk of hypocalcemia and maintain proper bone health, postmenopausal women require an average of 1,200 mg calcium orally and 800 to 1,000 International Units vitamin D orally each day. Supplement calcium and vitamin D if dietary intake is inadequate.
• The optimal duration of bisphosphonate therapy for osteoporosis has not been determined. Periodically re-evaluate the need for continued therapy in all patients on bisphosphonate therapy. For those patients determined to be at low-risk for fracture, consider stopping treatment after 3 to 5 years.
• After discontinuation of therapy, continue to periodically re-evaluate the fracture risk. According to the North American Menopause Society (NAMS), bisphosphonates are considered to be first-line therapy for the treatment of postmenopausal osteoporosis.
• The HORIZON Pivotal Fracture study indicates that the annual 5 mg IV regimen, as compared to placebo, is associated with a 70% reduction in fracture of the spine, a 40% reduction in fracture of the hip, and a 25% reduction in other non-vertebral fractures after 3 years (p less than 0.001 for all comparisons). In a second phase III trial, patients taking alendronate (70 mg orally once weekly for 1 year) were able to switch to a single 5 mg intravenous infusion of zoledronic acid and maintain similar BMD for at least 12 months.

Prevention of glucocorticoid-induced osteoporosis

In the clinical studies, Zometa treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zometa should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and multiple vitamins containing 400 international units of vitamin D daily.

Side Effects of Zoledronic Acid

• Heartburn
• The most commonrn (a burning feeling in the chest, behind the breastbone or gullet)
• Abdominal or stomach pain
• pain, warmth and/or swelling in a leg or in the pelvis
• sudden tingling or coldness in an arm or leg
• Burning, itching, stinging, redness, or other sign of irritation at the application site, rash
• Indigestion
• Constipation
• High blood pressure
• Nausea, vomiting,
• painful or swollen gums
• numbness or heavy feeling in the jaw
• dull, aching pain in the hip, groin, or thigh
• liver problems,
• stomach pain,
• Dizziness
• a headache,
• reversible hair loss or thinning, and
• fever.

Common

• chills or fever
• a headache, severe and throbbing
• joint or back pain
• muscle aching or cramping
• muscle pains or stiffness
• chest pressure or squeezing pain in the chest
• excessive sweating
• sudden drowsiness or need to sleep
• sharp pain when taking a deep breath
• coughing up blood
• rust colored urine
• liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
• decreased amount of urine

Rare

• Anxiety
• change in vision
• chest pain or tightness
• confusion
• a cough
• Agitation
• arm, back, or jaw pain
• blurred vision
• chest pain or discomfort
• convulsions
• extra heartbeats
• hallucinations
• a headache
• irritability
• lightheadedness
• muscle pain or cramps
• muscle spasm or jerking of all extremities
• severe pain in your upper stomach spreading to your back, nausea, and vomiting;

Drug Interactions of Zoledronic Acid

Zoledronic acid may interact with following drugs, supplements & may change the efficacy of drugs

• NSAIDs (nonsteroidal anti-inflammatory drugs) such as ibuprofen, naproxen 
• aspirin
• antacids
• proton pump inhibitors such as esomeprazole, lansoprazole, omeprazole, pantoprazole,
• H2 blockers such as cimetidine, famotidine, nizatidine, ranitidine 
• hormone therapy such as estrogens and estrogen agonist/blockers
• cancer chemotherapy treatments
• steroids such as dexamethasone, methylprednisolone, and prednisone 
• calcium supplements
• aluminum supplements
• magnesium supplements
• The additional beneficial effect of HRT (hormone replacement therapy) with estrogens/progestins or raloxifene in postmenopausal women remains to be elucidated, but no interactions have been seen.
• iron supplements
• Milk, diet, and drugs containing high amounts of calcium, magnesium or aluminum (antacids): the absorption of clodronic acid is decreased. At least half an hour should pass after intake of clodronic acid before taking the supplement or drug.
• The combination of NSAIDs and clodronic acid may increase the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastrointestinal mucosa.

Pregnancy & Lactation of  Zoledronic acid

FDA Pregnancy  Category D

Zoledronic acid is classified as FDA pregnancy risk category D; use should be avoided during pregnancy due to the bone resorptive effects. Zoledronic acid may cause fetal harm when administered to a pregnant woman. The drug should be avoided during pregnancy whenever possible. In reproductive studies in the pregnant rat, doses 2.4—4.8 times the human systemic exposure resulted in pre-and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no formal studies of zoledronic acid therapy in pregnant women. A single case of zoledronic acid during the second and third trimesters of pregnancy has been reported.

Lactation

According to the manufacturers, zoledronic acid is not recommended for use during lactation (breastfeeding) and a decision should be made to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother. It is not known if zoledronic acid is excreted into breast milk. Reports describing use in breastfeeding women are not available. Bisphosphonates bind to bone long-term, may be released over weeks to years, and can present a potentially serious risk to an exposed infant. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Safe and effective use of zoledronic acid in neonates, infants, children, and adolescents has not been established.

References

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