Zoledronic Acid; Uses, Side Effects, Interactions, Pragnancy

Zoledronic acid
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Zoledronic acid anhydrous is a Bisphosphonate. The chemical classification of zoledronic acid anhydrous is Diphosphonates. Anhydrous form of a synthetic imidazole third-generation bisphosphonate analog of pyrophosphate with antiresorptive activity. Zoledronate binds to hydroxyapatite crystals in the bone matrix and inhibits farnesyl pyrophosphate (diphosphate) synthase, thereby preventing protein prenylation within the mevalonate pathway. This leads to the loss of downstream metabolites essential for osteoclast function, leading to the induction of apoptosis and eventually, osteoclast-cell death. By preventing osteoclast-mediated bone resorption, zoledronate decreases bone turnover and stabilizes the bone matrix.

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

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
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Contra-Indications of Zoledronic Acid

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.

Treat men with osteoporosis

Intravenous dosage (Reclast)
  • 5 mg infused intravenously once yearly. Administer infusion over no less than 15 minutes at a constant rate of infusion. If dietary intake is not sufficient, supplement calcium and vitamin D daily. Men require at least 1,200 mg calcium and 800 to 1,000 International Units of vitamin D daily.
  • In a 2-year study of men with osteoporosis, including osteoporosis secondary to hypogonadism, 2 once-yearly infusions of zoledronic acid were found to be non-inferior to an oral bisphosphonate administered weekly as demonstrated by changes in bone mineral density at 24 months (increase in 6.2% relative to baseline in zoledronic acid group vs. 6.1% in control group).
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For secondary fracture prophylaxis in high-risk patients

Intravenous dosage (Reclast)
  • 5 mg infused intravenously once yearly. Administer infusion over no less than 15 minutes at a constant rate of infusion. If dietary intake is not sufficient, supplement calcium and vitamin D daily.
  • Zoledronic acid was initiated within 90 days of surgical repair in one study. Patients were randomized to receive a 15-minute intravenous infusion of zoledronic acid 5 mg (n = 1,065) or placebo (n = 1,062) once yearly for up to 5 years; the trial was stopped after a median follow-up of 1.9 years as the boundaries for efficacy in favor of zoledronic acid had been met.
  • Zoledronic acid was initiated within 90 days of surgical repair. The rate of any new clinical fracture (minus digital or facial fractures or fractures in abnormal bone) was reduced significantly in patients receiving zoledronic acid (8.6% vs. 13.9% for placebo, RR 0.65, 95% CI 0.5 to 0.84, p = 0.001).
  • In addition, vertebral and non-vertebral fractures, but not hip fractures, were decreased (p = 0.02 for vertebral fractures, and p = 0.03 for non-vertebral fractures). The bone mineral density of the total hip and the femoral neck increased in patients taking zoledronic acid at 12, 24, and 36 months as compared to placebo (p less than 0.001).

Treatment of glucocorticoid-induced osteoporosis in men and women taking systemic glucocorticoids

(i.e., oral prednisone 7.5 mg/day or more, or equivalent) and expected to continue glucocorticoid therapy for 12 months or longer.
Intravenous dosage (Reclast)
  • 5 mg infused intravenously once yearly. Administer infusion over no less than 15 minutes at a constant rate of infusion. If dietary intake is not sufficient, supplement calcium and vitamin D daily.
  • If dietary intake is not sufficient, patients should also take at least 1,200 mg calcium orally and 800 to 1,000 International Units of vitamin D orally each day. In a randomized, controlled trial of 833 patients, zoledronic acid was compared to an oral bisphosphonate for 1 year for the prevention and treatment of glucocorticoid-induced osteoporosis.
  • All groups also received 1,000 mg of elemental calcium and 400 to 1,000 International Units of vitamin D daily. The mean increase in lumbar spine bone mineral density was higher at 1 year with the use of zoledronic acid compared to the active control in the osteoporosis treatment group (4.1% vs. 2.7%, p less than 0.001).

Prevention of glucocorticoid-induced osteoporosis

In men and women taking systemic glucocorticoids (i.e., oral prednisone 7.5 mg/day or more, or equivalent) and expected to continue glucocorticoid therapy for 12 months or longer.
Intravenous dosage (Reclast)
  • 5 mg infused IV once every year. Administer over no less than 15 minutes at a constant rate of infusion. Supplement with calcium and vitamin D daily if dietary intake is not sufficient.
  • If dietary intake is not sufficient, patients should also take at least 1,200 mg calcium and 800 to 1,000 International Units of vitamin D daily. In a randomized, controlled trial of 833 patients, zoledronic acid was compared to an oral bisphosphonate for 1 year for the prevention and treatment of glucocorticoid-induced osteoporosis. All groups also received supplements of calcium and vitamin D daily.
  • The mean increase in lumbar spine bone mineral density was higher at 1 year with the use of zoledronic acid compared to the active control in the osteoporosis prevention group (2.6% vs. 0.6%, p less than 0.001).

In patients that have undergone a liver transplantation

  • Limited data suggest 4 mg IV infused within 7 days of transplantation and at months 1, 3, 6, and 9 after transplantation is effective in increasing BMD at the lumbar spine, femoral neck, and total hip. Calcium and vitamin D are supplemented if dietary intake is inadequate. In 62 post-liver transplant patients, after 6 months and as compared to placebo, zoledronic acid significantly increased the BMD of the lumbar spine by 4.2% (95% CI 0.9 to 7.7%, p = 0.015), the femoral neck by 4.6% (95% CI 1.8 to 7.4, p = 0.002), and the total hip by 3.8% (95% CI 1.7 to 6, p less than 0.001).
  • At 12 months, the improvement in BMD was significant only at the total hip. All patients were receiving calcium carbonate, vitamin D, tacrolimus or cyclosporine, azathioprine or mycophenolate, and methylprednisolone. Hypocalcemia was reported more often in patients taking zoledronic acid.

In men with prostate cancer receiving androgen deprivation therapy

(e.g., gonadotropin releasing hormone agonist with or without antiandrogen therapy)†.
Intravenous dosage
  • Studies suggest 4 mg IV infused every 3 months is effective in increasing BMD; a dose of 4 mg IV once yearly has also been shown to be effective. Patients receive calcium and vitamin D supplementation if dietary intake is inadequate.
  • In patients with nonmetastatic and metastatic prostate cancer (with or without bony metastases), zoledronic acid every 3 months for 4 doses significantly increased lumbar spine BMD (increases of approximately 7% compared to placebo); BMD also increased significantly at the femoral neck by 3.3 to 4.2% compared to placebo and at the total hip by 3.8 to 3.9% compared to placebo.
  • Additionally, a small study of 40 men with nonmetastatic breast carcinoma found that a single 4 mg IV dose increased lumbar spine BMD by 4% in patients taking zoledronic acid (between-group difference compared to placebo of 7.1%, p less than 0.001) at 1 year. In all 4 studies, all patients also took calcium and vitamin D daily. None of the studies were powered to assess the effects of zoledronic acid on fracture rate.
  • For patients with normal baseline creatinine, the increase of 0.5 mg/dL
  • For patients with abnormal baseline creatinine, the increase of 1.0 mg/dL
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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

Common

Rare

www.rxharun.com/zolendroic acid side effects

Drug Interactions of Zoledronic Acid

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

Pregnancy & Lactation of  Zoledronic acid

FDA Pregnancy  Category D

Pregnancy

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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