FDA

Zoledronic Acid

Approved 5 Jun 2023IntravenousInjectable

The FDA lists this product in 50 strengths and forms.

Indications

Zoledronic Acid Injection is a bisphosphonate indicated for: Treatment of Paget's disease of bone in men and women ( 1.5 )

1.5Paget's Disease of Bone Zoledronic Acid

Injection is indicated for treatment of Paget's disease of bone in men and women. Treatment is indicated in patients with Paget's disease of bone with elevations in serum alkaline phosphatase of two times or higher than the upper limit of the age-specific normal reference range, or those who are symptomatic, or those at risk for complications from their disease [see Clinical Studies ( 14.5 )] .

Contraindications

Zoledronic acid is contraindicated in patients with the following conditions: Hypocalcemia [see Warnings and Precautions ( 5.2 )] Creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment due to an increased risk of renal failure [see Warnings and Precautions ( 5.3 )] . Known hypersensitivity to zoledronic acid or any components of zoledronic acid injection. Hypersensitivity reactions including urticaria, angioedema, and anaphylactic reaction/shock have been reported [see Adverse Reactions ( 6.2 )] .

Hypocalcemia ( 4 ) Patients with creatinine clearance less than 35 mL/min and in those with evidence of acute renal impairment ( 4 , 5.3 ) Hypersensitivity to any component of zoledronic acid ( 4 , 6.2 )

Warnings and precautions

Products Containing Same Active Ingredient : Patients receiving Zometa should not receive zoledronic acid injection ( 5.1 ) Hypocalcemia may worsen during treatment. Patients must be adequately supplemented with calcium and vitamin D ( 5.2 ) Renal Impairment : 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 ( 2.7 , 5.3 ) Osteonecrosis of the Jaw (ONJ) has been reported. All patients should have a routine oral exam by the prescriber prior to treatment ( 5.4 ) Atypical Femur Fractures have been reported. Patients with thigh or groin pain should be evaluated to rule out a femoral fracture ( 5.5 ) Severe Bone, Joint, and Muscle Pain may occur. Withhold future doses of zoledronic acid if severe symptoms occur ( 5.7 )

At a glance

Brand name: Zoledronic Acid
Route: Intravenous
Dosage form: Injectable
Applicant: Meitheal
Status: Prescription
FDA approval: 5 Jun 2023
Application: ANDA213371-001

Indications

Zoledronic Acid Injection is a bisphosphonate indicated for: Treatment of Paget's disease of bone in men and women ( 1.5 )

1.5Paget's Disease of Bone Zoledronic Acid

Contraindications

Warnings and precautions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Available data on the use of zoledronic acid in pregnant women are insufficient to inform a drug-associated risk of adverse maternal or fetal outcomes. Discontinue zoledronic acid when pregnancy is recognized. In animal reproduction studies, daily subcutaneous administration of zoledronic acid to pregnant rats during organogenesis resulted in increases in fetal skeletal, visceral, and external malformations, decreases in postimplantation survival, and decreases in viable fetuses and fetal weight starting at doses equivalent to 2 times the recommended human 5 mg intravenous dose (based on AUC).

Subcutaneous administration of zoledronic acid to rabbits during organogenesis did not cause adverse fetal effects at up to 0.4 times the human 5 mg intravenous dose (based on body surface area, mg/m 2 ), but resulted in maternal mortality and abortion associated with hypocalcemia starting at doses equivalent to 0.04 times the human 5 mg intravenous dose. Subcutaneous dosing of female rats from before mating through gestation and lactation and allowed to deliver caused maternal dystocia and periparturient mortality, increases in stillbirths and neonatal deaths, and reduced pup body weight starting at doses equivalent to 0.1 times the human 5 mg intravenous dose (based on AUC) ( see Data ).

Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and available for release into the systemic circulation is directly related to the dose and duration of bisphosphonate use. Consequently, based on the mechanism of action of bisphosphonates, there is a potential risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy.

The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15 to 20%, respectively. Data Animal Data In pregnant rats given daily subcutaneous doses of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg during organogenesis, fetal skeletal, visceral, and external malformations, increases in pre- and post-implantation loss, and decreases in viable fetuses and fetal weight were observed at 0.2 and 0.4 mg/kg/day (equivalent to 2 and 4 times the human 5 mg intravenous dose, based on AUC).

Adverse fetal skeletal effects at 0.4 mg/kg/day (4 times the human 5 mg dose) included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects at this dose included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were observed in all groups starting at 0.1 mg/kg/day (1.2 times the human 5 mg dose).

Signs of maternal toxicity including reduced body weight and food consumption were observed at 0.4 mg/kg/day (4 times the human 5 mg dose). In pregnant rabbits given daily subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg during gestation no adverse fetal effects were observed up to 0.1 mg/kg/day (0.4 times the human 5 mg intravenous dose, based on body surface area, mg/m 2 ). Maternal mortality and abortion were observed in all dose groups (starting at 0.04 times the human 5 mg dose).

Adverse maternal effects were associated with drug-induced hypocalcemia. In female rats given daily subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg, beginning 15 days before mating and continuing through gestation, parturition and lactation, dystocia and periparturient mortality were observed in pregnant rats allowed to deliver starting at 0.01 mg/kg/day (0.1 times the human 5 mg intravenous dose, based on AUC). Also, there was an increase in stillbirths and a decrease in neonate survival starting at 0.03 mg/kg/day (0.3 times the human 5 mg dose), while the number of viable newborns and pup body weight on postnatal Day 7 were decreased at 0.1 mg/kg/day (equivalent to the human 5 mg dose).

Maternal and neonatal deaths were considered related to drug-induced periparturient hypocalcemia.

Adverse reactions

The most common adverse reactions (greater than 10%) were pyrexia, myalgia, headache, arthralgia, pain in extremity ( 6.1 ). Other important adverse reactions were flu-like illness, nausea, vomiting, diarrhea ( 6.2 ), and eye inflammation ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Paget's Disease of Bone In the Paget's disease trials, two 6-month, double-blind, comparative, multinational studies of 349 men and women aged greater than 30 years with moderate to severe disease and with confirmed Paget's disease of bone, 177 patients were exposed to zoledronic acid and 172 patients exposed to risedronate.

Zoledronic acid was administered once as a single 5 mg dose in 100 mL solution infused over at least 15 minutes. Risedronate was given as an oral daily dose of 30 mg for 2 months. The incidence of serious adverse events was 5.1% in the zoledronic acid group and 6.4% in the risedronate group. The percentage of patients who withdrew from the study due to adverse events was 1.7% and 1.2% for the zoledronic acid and risedronate groups, respectively.

Adverse reactions occurring in at least 2% of the Paget's patients receiving zoledronic acid (single 5 mg intravenous infusion) or risedronate (30 mg oral daily dose for 2 months) over a 6-month study period are listed by system organ class in Table 4 . Table 4. Adverse Reactions Reported in at Least 2% of Paget's Patients Receiving Zoledronic Acid (Single 5 mg intravenous Infusion) or Risedronate (Oral 30 mg Daily for 2 Months) Over a 6-Month Follow-up Period System Organ Class 5 mg IV Zoledronic Acid % (N = 177) 30 mg/day x 2 Months risedronate % (N = 172) Infections and Infestations Influenza 7 5 Metabolism and Nutrition Disorders Hypocalcemia 3 1 Anorexia 2 2 Nervous System Disorders Headache 11 10 Dizziness 9 4 Lethargy 5 1 Paresthesia 2 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 5 1 Gastrointestinal Disorders Nausea 9 6 Diarrhea 6 6 Constipation 6 5 Dyspepsia 5 4 Abdominal Distension 2 1 Abdominal Pain 2 2 Vomiting 2 2 Abdominal Pain Upper 1 2 Skin and Subcutaneous Tissue Disorders Rash 3 2 Musculoskeletal, Connective Tissue and Bone Disorders Arthralgia 9 11 Bone Pain 9 5 Myalgia 7 4 Back Pain 4 7 Musculoskeletal Stiffness 2 1 General Disorders and Administrative Site Conditions Influenza-like Illness 11 6 Pyrexia 9 2 Fatigue 8 4 Rigors 8 1 Pain 5 4 Peripheral Edema 3 1 Asthenia 2 1 Laboratory Findings In the Paget's disease trials, early, transient decreases in serum calcium and phosphate levels were observed.

Approximately 21% of patients had serum calcium levels less than 8.4 mg/dL 9 to 11 days following zoledronic acid administration. Renal Impairment In clinical trials in Paget's disease there were no cases of renal deterioration following a single 5 mg 15-minute infusion [see Warnings and Precautions ( 5.3 )] . Acute Phase Reaction The signs and symptoms of acute phase reaction (influenza-like illness, pyrexia, myalgia, arthralgia, and bone pain) were reported in 25% of patients in the zoledronic acid-treated group compared to 8% in the risedronate-treated group.

Symptoms usually occur within the first 3 days following zoledronic acid administration. The majority of these symptoms resolved within 4 days of onset. Osteonecrosis of the Jaw Osteonecrosis of the jaw has been reported with zoledronic acid [see Warnings and Precautions ( 5.4 )] .

6.2Post-Marketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of zoledronic acid: Acute Phase Reactions Fever, headache, flu-like symptoms, nausea, vomiting, diarrhea, arthralgia, and myalgia. Symptoms may be significant and lead to dehydration.

Acute Renal Failure Acute renal failure requiring hospitalization and/or dialysis or with a fatal outcome have been rarely reported. Increased serum creatinine was reported in patients with 1) underlying renal disease, 2) dehydration secondary to fever, sepsis, gastrointestinal losses, or diuretic therapy, or 3) other risk factors such as advanced age, or concomitant nephrotoxic drugs in the post-infusion period. Transient rise in serum creatinine can be correctable with intravenous fluids.

Allergic Reactions Allergic reactions with intravenous zoledronic acid including anaphylactic reaction/shock, urticaria, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, and bronchoconstriction have been reported. Asthma Exacerbations Asthma exacerbations have been reported. Hypocalcemia Hypocalcemia has been reported. Hypophosphatemia Hypophosphatemia has been reported. Osteonecrosis of the Jaw Osteonecrosis of the jaw has been reported.

Osteonecrosis of other bones Cases of osteonecrosis of other bones (including femur, hip, knee, ankle, wrist and humerus) have been reported; causality has not been determined in the population treated with zoledronic acid. Ocular Adverse Events Cases of the following events have been reported: conjunctivitis, iritis, iridocyclitis, uveitis, episcleritis, scleritis and orbital inflammation/edema. Other Hypotension in patients with underlying risk factors has been reported.

Zoledronic Acid

Indications

1.5Paget's Disease of Bone Zoledronic Acid

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Zoledronic Acid

Indications

1.5Paget's Disease of Bone Zoledronic Acid

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.1Drug Products with Same Active Ingredient

5.2Hypocalcemia and Mineral Metabolism

5.3Renal Impairment

5.5Atypical Subtrochanteric and Diaphyseal Femoral Fractures

5.6Musculoskeletal Pain

5.7Patients with Asthma While

Interactions

7.1Aminoglycosides

7.2Loop Diuretics

7.3Nephrotoxic Drugs

7.4Drugs Primarily Excreted by the Kidney

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Post-Marketing Experience

Composition

Strengths and forms

Official product information