What Is Zoledronate?

Zoledronic acid injection is indicated for the treatment of osteoporosis in postmenopausal women. Used to treat Paget's disease (deformative osteitis).

Drug Name: Zoledronic acid injection

Drug type: Prescription drugs, medicines for medical workers' injuries
Use classification: Antineoplastic adjuvant

Zoledronic acid injection ingredients

Active ingredient: Zoledronic acid Chemical name: 1-Hydroxy-2- (imidazole-1-yl) -ethylene-1,1-bisphosphate monohydrate Structural formula:

Molecular formula: C ₅ H ₁₀ N ₂ O ₇ P ₂ · H ₂ O
Molecular weight: 290.11
Excipients: sodium citrate, mannitol, water for injection.

Characteristics of Zoledronic Acid Injection

This product is a clear, colorless liquid.

Indications of zoledronic acid injection

Used to treat osteoporosis in postmenopausal women. Used to treat Paget's disease (deformative osteitis).

Zoledronic acid injection specifications

100ml: 5mg (based on zoledronic acid anhydrous).

Zoledronic acid injection dosage and dosage

For the treatment of osteoporosis, the recommended dose is 5 mg of Meguda, given once a year by intravenous drip.
There is not enough evidence to support continuous medication for more than 3 years.
For the treatment of Paget's disease, the recommended dose is 5 mg of meguda in a single intravenous infusion.
This product is infused at a constant rate through an infusion tube. The drip time should not be less than 15 minutes (see [Precautions]).
Patients must be properly hydrated before administration of this product, especially those who are receiving diuretics at the same time.
For women with osteoporosis, if the dietary intake is insufficient, it is necessary to supplement calcium and vitamin D appropriately.
In addition, for patients with Paget's disease, it is strongly recommended to ensure vitamin D and sufficient calcium supplementation within 10 days after receiving this product, and to ensure that at least 500 mg of elemental calcium and vitamin D are added each time, twice daily (see [Cautions] ). There are no data on the safety and efficacy of retreatment (after 1 year).
For special populations, see [Precautions] [Pharmacokinetics]

Adverse reactions of zoledronic acid injection

The following adverse reactions have been derived from different clinical trials of this product: a study of osteoporosis in postmenopausal women: a randomized double-blind, placebo-controlled, multicenter study involving a total of 7,736 women participating in the study; paget's disease Studies: Two double-blind, randomized, safety-effective, involving 357 patients; prevention of recurrent fractures in patients with recent low-trauma hip fractures; one randomized, double-blind, placebo-controlled, multicenter clinical study, total 2127 male and female patients participated in the study; treatment and prevention of osteoporosis caused by glucocorticoids; a randomized, multicenter, double-blind, multi-layer, active-controlled study involving 833 male and female patients; This product is used in male osteoporosis patients or patients with severe osteoporosis secondary to hypogonadism: a randomized, multicenter, double-blind, active-controlled study involving 302 male patients; this product is used to prevent concomitant Osteoporotic bone loss in menopausal women with reduced bone mass, a 2-year randomized, multicenter, double-blind, placebo-controlled study involving 581 menopausal bones Loose women.
Treatment of osteoporosis in men and postmenopausal women, prevention of recurrence of fractures after low-trauma hip fractures, prevention and treatment of osteoporosis caused by glucocorticoids, research on deformable osteitis confirmed that this product is positive with placebo or positive There was no significant difference in the overall incidence of serious adverse events compared to the control, with most adverse events being mild to moderate. This product was administered once a year in the above study.
As with intravenous bisphosphonates, the most common post-dose symptoms of this product include (incidence in studies treating osteoporosis in postmenopausal women): fever (18.1%), myalgia (9.4%), flu-like Symptoms (7.8%), arthralgia (6.8%), headache (6.5%), and most occurred within 3 days after medication. The majority of these symptoms are mild to moderate and resolve within 3 days of the occurrence of the adverse event. The incidence of these symptoms decreased significantly when the product was used later.
If acetaminophen or ibuprofen is administered within a short period of time after using this product, the incidence of symptoms after administration within 3 days after using this product can be reduced by about 50%.
Table 1 lists the adverse reactions suspected to be associated with the use of this product (investigator evaluation). These include studies on the treatment of osteoporosis in men and postmenopausal women, prevention of fractures after low-trauma hip fractures, prevention and treatment Osteoporosis and deformable osteitis caused by glucocorticoids: very common (1 / 10), common (1 / 100 and <1/10), uncommon (1 / 1000 and <1/100) , Rare (1 / 10,000 and <1 / 1,000) adverse drug reactions.
Table 1 Adverse reactions suspected to be associated with the use of this product

* Adverse reactions in case studies: very common: myalgia, joint pain, fatigue, pain; common: lethargy, dyspnea, indigestion, esophagitis, abdominal pain, sweating, skeletal muscle (muscle) stiffness, arthritis, Chest bone pain, joint swelling, anorexia, thirst, acute reaction period; uncommon: uveitis is not included in the case study reported in Table 1 Other adverse reactions include (due to limited data, zoledronic acid group Incidence compared to placebo group): Eye congestion, increased C-reactive protein, hypocalcemia, taste disorders, toothache, gastritis, palpitations, injection site reactions.
In a 3-year trial (Horizon PFT) of postmenopausal women with osteoporosis, the overall incidence of all adverse events of AF was 2.5% in the treatment group (96 of 3862 patients), comfort The drug treatment group was 1.9% (75 of 3852 patients). The increased incidence observed in this trial did not appear in other zoledronic acid clinical trials.
The incidence of severe adverse events in patients with atrial fibrillation was 1.3% (51 of 3852 patients) and 0.6% (22 of 3852 patients) compared with patients receiving placebo. The mechanism for increasing the incidence of AF is unclear.
No inconsistency in adverse events between groups in this trial was observed in other zoledronic acid clinical trials.
Adverse effects of drugs in this category:
Renal dysfunction:
Intravenous administration of bisphosphonates (containing zoledronic acid) can cause renal impairment (increased plasma creatinine levels) or rare cases of acute renal failure. Existing patients may have renal impairment after receiving zoledronic acid treatment, especially those with previous renal impairment or other risk factors (for example, tumor patients receiving chemotherapy, concurrent use of drugs harmful to renal function, severe dehydration, etc. ) Is particularly serious, the treatment dose for most patients is 4 mg every 3-4 weeks, but some patients appear after a single dose.
In the HORIZON-PFT trial, after 3 years of treatment, changes in creatinine clearance (measured annually before dosing) and the incidence of kidney injury and renal failure were comparable between the Meguta and placebo groups. Transient elevations of plasma creatinine levels in the Meguta and placebo groups were 1.8% and 0.8% within 10 days after administration, respectively.
In the prevention of male and female hip fractures from re-fracture, treatment of osteoporosis in men, and prevention of osteoporosis caused by glucocorticoids, the creatinine clearance rate has changed over 3 years of treatment (measured before each year ), As well as the incidence of kidney injury and renal failure, were comparable between the Megida group, the placebo group, and the control group.
Laboratory research results:
In the HORIZON-PFT trial, approximately 0.2% of patients in the Meguta group experienced a decrease in blood calcium levels after administration (less than 1.87 mmol / L). No clinical symptoms of blood calcium reduction were observed.
In the HORIZON-RFT trial, patients treated with this product did not experience serum calcium levels below 1.87 mmol / L.
In the Paget's disease study, about 1% of patients developed symptoms of hypocalcemia.
Local reactions:
In the HORIZON-PET trial, 0.7% of patients experienced local reactions such as redness and / or pain at the injection site when zoledronic acid was administered.
In the HORIZON-RFT trial, adverse event rates were comparable between the zoledronic acid group and the placebo group.
Jaw Necrosis:
The earliest reports of osteonecrosis (mainly the jaw) appeared in cancer patients receiving bisphosphonate drugs including zoledronic acid (uncommon). Some patients have local infections, including osteomyelitis, and most are reported as tumor patients after tooth extraction or dental surgery. Many risk factors can cause jaw necrosis, including cancer diagnosis and treatment (chemotherapy, radiotherapy, corticosteroids), and other pathological conditions / disorders such as anemia, coagulopathy, infections, dental diseases. Although there is no direct causal relationship, dental surgery should be performed with caution during the recovery period of osteonecrosis (see [Precautions]).
In the HORIZON-PFT trial, a total of 7,736 patients were enrolled. One jaw necrosis occurred in the Meguta treatment group and one in the placebo group. Both patients were cured. No jaw necrosis has been reported in the HORIZON-RFT trial.
Post-Marketing Experience Following are reports of adverse reactions after zoledronic acid was approved for marketing. Because these reports are based on an uncertain number of people and are affected by some confounding factors, it is impossible to accurately assess their frequency or establish a cause related to drug exposure.
Allergic reactions including bronchoconstriction, urticaria, and angioedema are rarely reported, and allergic reactions / shock are very rarely reported.

Contraindications of zoledronic acid injection

Those who are allergic to zoledronic acid or other bisphosphonates or any of the excipients of pharmaceutical ingredients are contraindicated.
Patients with hypocalcemia (see [Precautions]).
Pregnant and lactating women (see [Medication for pregnant and lactating women]).

Precautions for zoledronic acid injection

Overview This product is administered for at least 15 minutes.
Due to lack of adequate clinical use data, it is not recommended for patients with severe renal insufficiency (creatinine clearance is less than 35 mL / min). Before administration of this product, the serum creatinine level of the patient should be evaluated.
Patients must be properly hydrated before administration, especially for elderly patients and patients receiving diuretics.
Before giving this product, patients with hypocalcemia need to take enough calcium and vitamin D (see [Contraindications]). Effective treatment should also be given for other mineral metabolism abnormalities (eg, reduced parathyroid reserve: intestinal calcium malabsorption). Doctors should conduct clinical tests on such patients.
Renal failure Due to the lack of adequate clinical safety data for this population, this product is not recommended for patients with severe renal insufficiency (creatinine clearance <35mL / min). Patients should measure serum creatinine before administration.
No dose adjustment is necessary for patients with liver dysfunction (see [Pharmacokinetics]).
Calcium and Vitamin D
For women with osteoporosis who have inadequate daily intake of calcium and vitamin D, it is very important to take appropriate supplements.
Increased bone turnover is a major feature of deformable osteitis. Due to the rapid effect of zoledronic acid on bone turnover, transient, sometimes symptomatic hypocalcemia may occur after the administration of this product, which is usually most obvious in the first 10 days after administration (see [Adverse Reactions] ). It is recommended that this product be given at the same time as adequate vitamin D supplements. In addition, it is strongly recommended that patients with deformable osteitis receive at least 10 days of treatment with this product and receive a sufficient amount of calcium supplements to ensure at least 500 mg of elemental calcium twice daily. Patients should be informed of symptoms of hypocalcemia, and adequate clinical care should be given to patients at risk.
Skeletal muscle pain is rarely reported in patients using bisphosphonates (including this product) with severe and occasional disabling bone, joint and / or muscle pain.
Jaw osteonecrosis Jaw osteonecrosis mainly occurs in tumor patients treated with bisphosphonates (including this product). Many of these patients also received chemotherapy and corticosteroids. Osteonecrosis of the jaw in most patients appears to be related to some dental procedures, such as tooth extraction. Many patients have symptoms of local infection, including osteomyelitis. Before using bisphosphonates in patients with risk factors (such as tumors, chemotherapy, radiotherapy, corticosteroids, and poor oral hygiene), consider performing an oral examination and taking appropriate preventive measures. During treatment, these patients should try to avoid dental surgery. Patients with osteonecrosis of the jaw during treatment with bisphosphonates may exacerbate the disease. If a patient needs dental surgery, there is no data to suggest that discontinuing bisphosphonate treatment reduces the risk of jaw osteonecrosis. Clinicians should make clinical judgments for each patient based on their own benefit / risk assessment.
This product has the same active ingredients as Zetac® (zoledronic acid) for cancer patients. If the patient has already used Zetac®, do not use this product.
There is no data showing that this product will affect the ability to drive and operate equipment.
Compatibility Contraindications This product cannot be used simultaneously with other calcium preparations or other divalent ion injections.
Instructions for use This product cannot be mixed with any other drugs or administered intravenously. It must be infused at a constant and constant rate through a separate infusion tube. If this product is refrigerated, please use it at room temperature. It must be ensured that the preparation process before infusion is aseptic.
Please use this product alone. Any unused solution must be discarded. Only clear, particle-free and colorless solutions should be used.

Zoledronic acid injection for pregnant and lactating women

There are insufficient clinical data on the use of zoledronic acid in pregnant women. Animal studies suggest that this product has reproductive toxicity. The potential dangers to humans are unclear. This product is contraindicated in pregnant and lactating women (see [Contraindications]).

Zoledronic acid injection for children

Due to lack of safety and effectiveness data, the use of this product in children and adolescents under 18 years is not recommended.

Zoledronic acid injection for the elderly

Elderly patients (65 years of age) have similar bioavailability, drug distribution and clearance as younger people, so no need to adjust the dosage However, as renal function is more commonly weakened in older patients, special attention should be paid to renal function testing in older patients.

Zoledronic acid injection drug interactions

No clear studies have been conducted on the interaction of zoledronic acid with other drugs. Zoledronic acid is not systematically metabolized, and in vitro tests have shown no effect on the human cytochrome P450 enzyme system (see [Pharmacokinetics]). Zoledronic acid has a low plasma protein binding rate (approximately 43-55%) and therefore does not compete competitively with drugs with high plasma protein binding rates.
Zoledronic acid is excreted by the kidneys. Therefore, special attention should be paid when combined with drugs that significantly affect renal function.

Zoledronate injection overdose

There are currently no reports of overdose of this product. If overdose occurs that leads to significant symptoms of hypocalcemia, treatment with oral calcium and / or intravenous infusion of calcium gluconate can reverse the overdose.

Clinical trial of zoledronic acid injection

Postmenopausal osteoporosis In a randomized, double-blind, placebo-controlled trial, aged 65 to 89 years, femoral neck BMDT score -1.5 and currently associated with at least two mild or one moderate Vertebral fractures, or femoral neck BMDT score -2.5 7736 female patients with or without evidence of vertebral fractures were enrolled in the trial and given 5mg Migudad once a year for 3 consecutive years. All patients were supplemented with 1000 to 1500 mg of elemental calcium and 400 to 1200 IU of vitamin D daily. Tier I patients (3045 in the Miguida group and 3039 in the placebo group) must not receive other osteoporosis medications; Tier II patients (830 in the Miguda group and 822 in the placebo group) can receive double Treatment of osteoporosis other than phosphonates. The two main efficacy variables were: the incidence of vertebral morphological fractures in patients with layer after 3 years, and the incidence of hip fractures in the entire population during a median treatment period of 3 years.
Among Tier I patients, 5561 were evaluable patients and could be evaluated for vertebral fractures. Megida significantly reduced the risk of one or more new vertebral fractures within 3 years. Fracture events in the Meguda group were 3.9% compared to 12.8% in the placebo group (p <0.0001, RR0.30 [Cl0 .24, 0.38]).
Hip fractures occurred in 1.45% of the Meguta group compared to 2.5% of the placebo group (p = 0.0032). Tier I patients had a 40% reduction in risk and Tier II patients had a 42% reduction in risk.
During the treatment period, the incidence of clinical fractures in the Meguta group and the placebo group was 8.4% and 12.9% (p <0.0001), and the incidences of clinical vertebral fractures were O.6% and 2.6% (p <0.0001). The incidence of peripheral fractures was 7.9% and 10.7% (<0.001), respectively.
At all time points (6, 12, 24, and 36 months), Megida significantly increased BMD in the lumbar spine, hip, and distal radius over placebo. Compared with placebo, 3 years of Megdar treatment increased BMD in the lumbar spine, whole bone, femoral neck, and distal radius by 6.90%, 6.0%, 5.0%, and 3.2%, respectively.
Histomorphology analysis was performed in a subgroup of patients in this trial (n = 89). The results of the Meguta group were significantly better than those of the placebo group.
After 3 years, the height of the patients in the Meguta group decreased less than the placebo group (4.2mmvs, 6.7mm, p <0.0001).
Compared with placebo. Miguida reduced the number of days of restricted mobility due to back pain and fractures, as well as the number of days of bed rest (all p <0.01).
Deformed osteitis: confirmed by x-ray examination in patients with mild and moderate deformed osteitis over 30 years of age (baseline average serum alkaline phosphatase level is 2.6-3 times the upper limit of normal age) Research of this product is in progress.
Two 6-month clinical controlled trials compared the efficacy of daily oral risedronate sodium 30 mg for two months with a single dose of 5 mg zoledronic acid. Therapeutic efficacy was defined as the return of serum alkaline phosphatase (SAP) to normal or at the end of the 6-month trial period when the SAP excess decreased by at least 75% from baseline levels. The SAP excess is the difference between the measured level and the normal median.
In the above two tests, biochemical markers of bone formation (SAP, serum type I collagen amino terminal peptide (PINP)) and bone resorption biochemical markers (serum CTx1 (type I collagen crosslinked carboxy terminus) Peptide) and urine.-CTx) methods have confirmed that this product is more effective and faster than risedronate sodium.
Comprehensive data from two trials showed that after 2 months, zoledronic acid injection showed a significantly better treatment effect than risedronate sodium, and 158 of 176 patients reached the standard of treatment effectiveness (90%). The normalization rate of SAP was 63% (111/176), compared with 47% (81/171) and 26% (45/171) in the risedronate group, with p values [0.001. After 6 months, Of the 176 patients in the zoledronic acid injection group, 169 met the treatment effectiveness standard (96%), and 89% (156/176) of the patients recovered SAP levels, which was normal, compared with 171 in the risedronate sodium group. Only 127 patients (74%) met the treatment effectiveness standard, and only 56% (99/171) patients returned to normal (two indicators, P <0.001).
Comprehensive research results show that compared with baseline values, pain levels and pain scores decreased by the same degree after 6 months of application of zoledronic acid injection and risedronate sodium.
Subgroup treatment results are shown in Table 2
Table 2 Percentage of patients who responded significantly at 6 months (various factors)

SAP = serum alkaline phosphatase; ULN = upper limit of normal value. Therapeutic effect means that the SAP returns to normal or the SAP excess decreases by at least 75% compared to the baseline level. N = Number of patients measured at baseline and at least once after baseline. n = number of patients who responded effectively.
At the end of the 6-month core study, patients who were classified as having a therapeutic effect entered an extended follow-up trial. A total of 143 patients treated with zoledronic acid and 107 patients treated with risedronate entered the expanded observational study. Data from an average of 18 months from the start of dosing showed that 141 patients treated with zoledronic acid maintained the treatment effect, while only 71 patients treated with risedronate sodium maintained the treatment effect.
The time-treatment effect curve during the extended trial is shown in Figure 1.
Figure 1 Time-treatment effect maintenance curve

* Time to start to lose treatment effect: SAP level no longer meets the effective treatment standard (SAP excess decreases by less than 75% / or SAP value is above the upper limit of the normal range).
Seven patients with Paget's disease treated with 5 mg zoledronic acid for 6 months. Bone tissue biopsy results showed normal bones, no bone tissue reconstruction and calcification damage. This conclusion is consistent with the results of normal bone turnover indicated by bone biochemical indicators.

Pharmacology and toxicology of zoledronic acid injection

Pharmacodynamic characteristics Zoledronic acid is a nitrogen-containing bisphosphonic acid compound, which mainly acts on human bones and inhibits bone resorption by inhibiting osteoclasts.
Bisphosphonic compounds have a high affinity for mineralized bone and can selectively act on bone. Zoledronic acid can be quickly distributed in the bone after intravenous injection, and like other bisphosphonic compounds, it preferentially gathers at high bone transformation sites. The main molecular target of zoledronic acid is farnesyl pyrophosphate synthase in osteoclasts, but other mechanisms of action are not excluded. Long-term tests in estrogen-deficient animals have shown that zoledronic acid can inhibit resorption of bone cells and increase bone density in the range of 0.03-8 times the human dose. Studies have shown dose-dependent increases in bone strength and other bone mechanical properties. When the administered dose is equivalent to 0.8 to 8 times of the human dose, compared with the unresected animals (control group), zoledronic acid can significantly improve the skeletal mechanical properties of the ovariectomized animals. Histomorphological analysis showed that the typical response of bone anti-bone resorption drugs was dose-dependent inhibition of osteoclast activity, and the frequency of activation of trabecular bone and Harvard system reconstruction sites. Sustained skeletal reconstruction was observed in bone samples from animals treated with clinically relevant doses of zoledronic acid. No calcification defects, abnormal osteoid accumulation, and woven bone formation were found in the treated animals.
Preclinical safety data No zoledronic acid was found to be mutagenic in genotoxicity tests.
Reproductive toxicity was subcutaneously administered and teratogenicity studies were performed on two animals. When the dosage was 0.2mg / kg, zoledronic acid caused teratogenic effects in rats, mainly in appearance. Deformity of internal organs and bones. Rats given low doses of zoledronic acid (0.01 mg / kg body weight) will experience dystocia. Although when the dosage reached 0.1 mg / kg, rabbits could have obvious maternal toxicity due to the decrease of blood calcium level, but no teratogenic effect and no effect on embryos or fetuses were observed.
Carcinogenicity Carcinogenicity tests have not found that zoledronic acid is potentially carcinogenic.

Pharmacokinetics of Zoledronic Acid Injection

Absorption After the start of zoledronic acid infusion, the plasma concentration of the active ingredient rises rapidly. It peaks at the end of the infusion.
Distributed in the first 24 hours, 39 ± 16% of the administered dose appeared in the urine in its original form. The remaining drugs are mainly combined with bone tissue. The active ingredients are released very slowly from bone tissue into the systemic circulatory system and eliminated by the kidneys. Only about 43-55% of zoledronic acid binds to plasma proteins, and the protein binding rate is independent of concentration.
Metabolism Zoledronic acid cannot be metabolized by the body. The total body clearance was 5.04 ± 2.5L / h, which was independent of the dose, and was not affected by the patient's gender, age, race or weight.
Elimination of zoledronic acid excreted in the kidneys. Intravenous administration of zoledronic acid is eliminated by a three-phase process: rapid two-phase elimination from systemic circulation, half-life t1 / 2 = 0.24 hours and t1 / 2 = 1.87 hours, followed by a long elimination period, and finally elimination half-life It's 146 hours. After multiple administrations every 28 days, no accumulation of pharmaceutically active ingredients was found in the plasma.
Zoledronic acid renal clearance is related to creatinine clearance in special populations. In a trial of 64 patients, the mean zoledronic acid clearance was 84 ± 29mL / min (range 22-143mL / min). ), Which is 75 ± 33% of creatinine clearance. Compared with patients with normal renal function, the AUC value of patients with mild to moderate renal impairment increased from 0 to 24 hours, an increase of about 30-40%, but multiple doses did not produce drug accumulation. This shows that patients with mild (CI = 50-80mL / min) and moderate (CI = 30-50mL / min) renal impairment do not need to adjust the dosage when using zoledronic acid. Due to limited clinical safety data for patients with severe renal impairment (creatinine clearance of less than 35 mL / min), no recommended dose of zoledronic acid has been given for this population. This product is not recommended for patients with creatinine clearance <35mL / min (see [Precautions]). No dose adjustment is required for patients with creatinine clearance 35mL / min.

Zoledronic acid injection storage

Store below 30 ° C, and avoid children.

Zoledronic acid injection packaging

100ml per bottle, 1 bottle per box.

The effective period of zoledronic acid injection

36 months. After opening, store at 2-8 for 24 hours.

Zoledronic acid injection standard

Import drug registration standard JX20060152 ^[1]