Zoledro-Denk (sometimes called zoledronate) is in a group of medicines called bisphosphonates (bis FOS fo nayts). Zoledro-Denk inhibits the release of calcium from bones.
Zoledro-Denk and Zoledro-Denk are two different brands of Zoledro-Denk.
The Zoledro-Denk brand of Zoledro-Denk is used to treat Paget’s disease, and to treat or prevent osteoporosis in postmenopausal women or people who take certain steroid medicines. Zoledro-Denk is also used to increase bone mass in men with osteoporosis.
The Zoledro-Denk brand of Zoledro-Denk is used to treat high blood levels of calcium caused by cancer (hypercalcemia of malignancy). Zoledro-Denk also treats multiple myeloma (a type of bone marrow cancer) or bone cancer that has spread from elsewhere in the body.
You should not be treated with Zoledro-Denk if you are already receiving Zoledro-Denk.
Treatment of Osteoporosis in Postmenopausal Women
Zoledro-Denk is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis, diagnosed by bone mineral density (BMD) or prevalent vertebral fracture, Zoledro-Denk reduces the incidence of fractures (hip, vertebral and non-vertebral osteoporosis-related fractures). In patients at high risk of fracture, defined as a recent low-trauma hip fracture, Zoledro-Denk reduces the incidence of new clinical fractures.
Prevention of Osteoporosis in Postmenopausal Women
Zoledro-Denk is indicated for the prevention of osteoporosis in postmenopausal women.
Osteoporosis in Men
Zoledro-Denk is indicated for treatment to increase bone mass in men with osteoporosis.
Zoledro-Denk is indicated for the treatment and prevention of glucocorticoid-induced osteoporosis in men and women who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who are expected to remain on glucocorticoids for at least 12 months.
Paget’s Disease of Bone
Zoledro-Denk is indicated for the 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.
Important Limitations of Use
The safety and effectiveness of Zoledro-Denk for the treatment of osteoporosis is based on clinical data of three years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.
HOW TO USE
Use Zoledro-Denk as directed by your doctor. Check the label on the medicine for exact dosing instructions.
- Zoledro-Denk comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Zoledro-Denk refilled.
- Zoledro-Denk is usually given as an injection at your doctor’s office, hospital, or clinic.
- Drink at least 2 full glasses (16 oz/480 mL) of fluid (eg, water) within a few hours before you receive Zoledro-Denk, as directed by your doctor.
- Use Zoledro-Denk as directed by your doctor. Check the label on the medicine for exact dosing instructions.
- Do not use Zoledro-Denk if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
- If you miss a dose of Zoledro-Denk, contact your doctor right away.
Ask your health care provider any questions you may have about how to use Zoledro-Denk.
- If you miss a dose of Zoledro-Denk, contact your doctor right away.
Ask your health care provider any questions you may have about how to use Zoledro-Denk.
Each vial contains Zoledronic Acid monohydrate equivalent to Zoledro-Denk 4 mg.
Zoledro-Denk belongs to the chemotherapy drug class of bisphosphonates. It is an inhibitor of osteoclastic bone resorption and is designated chemically as (1-Hydroxy-2-imidazole-1-yl-phosphonoethyl) phosphonic acid monohydrate. It is highly soluble in 0.1N sodium hydroxide solution, sparingly soluble in water and 0.1N hydrochloric acid and practically insoluble in organic solvents. 0.7% solution of Zoledro-Denk in water has a pH of approximately 2.0. The molecular formula and molecular weight of Zoledro-Denk are C5H10N2O7P2•H2O and 290.1 g/mol, respectively.
General: The incidence of post-dose symptoms occurring within the first 3 days after administration of Zoledro-Denk can be reduced with the administration of paracetamol or ibuprofen shortly following Zoledro-Denk administration.
Patients must be appropriately hydrated prior to administration of Zoledro-Denk. This is especially important in the elderly and for patients receiving diuretic therapy.
Treatment of Postmenopausal Osteoporosis: Recommended Dose: Single IV infusion of Zoledro-Denk 5 mg administered once a year.
Adequate supplemental calcium and vitamin D intake are important in women with osteoporosis if dietary intake is inadequate.
Prevention of Clinical Fractures After a Hip Fracture: Recommended Dose: Single IV infusion of Zoledro-Denk 5 mg administered once a year.
Supplemental calcium and vitamin D intake are recommended for patients treated to prevent clinical fractures after a low-trauma hip fracture.
Treatment of Osteoporosis in Men: Recommended Dose: Single IV infusion of Zoledro-Denk 5 mg administered once a year.
Adequate supplemental calcium and vitamin D intake are important in men with osteoporosis if dietary intake is inadequate.
Treatment and Prevention of Glucocorticoid-Induced Osteoporosis: Recommended Dose: Single IV infusion of Zoledro-Denk 5 mg administered once a year.
Adequate supplemental calcium and vitamin D intake are important in patients with osteoporosis if dietary intake is inadequate.
Prevention of Postmenopausal Osteoporosis: Recommended Regimen: Single IV infusion of Zoledro-Denk 5 mg. An annual assessment of the patient’s risk of fracture and clinical response to treatment should guide the decision of when re-treatment should occur.
For the prevention of postmenopausal osteoporosis, it is important that patients be adequately supplemented with calcium and vitamin D if dietary intake is inadequate.
Treatment of Paget’s Disease of Bone: Zoledro-Denk should be prescribed only by physicians with experience in the treatment of Paget’s disease of the bone. The recommended dose is a single IV infusion of Zoledro-Denk 5 mg. Re-Treatment of Paget’s Disease: Specific re-treatment data are not available. After a single treatment with Zoledro-Denk in Paget’s disease, an extended remission period is observed in responding to patients. However, re-treatment with Zoledro-Denk may be considered in patients who have relapsed, based on increases in serum alkaline phosphatase, in patients who failed to achieve normalization of serum alkaline phosphatase or in patients with symptoms, as dictated by medical practice 12 months after the initial dose.
In patients with Paget’s disease, adequate vitamin D intake is recommended in association with Zoledro-Denk administration. In addition, it is strongly advised that adequate supplemental calcium corresponding to at least 500 mg elemental calcium twice daily is ensured in patients with Paget’s disease for at least 10 days following Zoledro-Denk administration.
Special Populations: Patients with Renal Impairment: The use of Zoledro-Denk in patients with CrCl <35 mL/min is not recommended due to limited clinical safety data in such patients.
No dose adjustment is necessary for patients with CrCl ≥35 mL/min.
Patients with Hepatic Impairment: No dose adjustment is required.
Elderly (≥65 years): No dose adjustment is necessary since bioavailability, distribution, and elimination were similar in elderly patients and younger subjects.
Administration: Zoledro-Denk (5 mg in 100 mL ready-to-infuse solution) is administered IV via a vented infusion line, given at a constant infusion rate. The infusion must not be <15 min.
For information on the infusion of Zoledro-Denk, see Instructions for Use & Handling under Cautions for Usage.
No in vivo drug interaction studies have been performed for Zoledro-Denk. In vitro and ex vivo studies showed a low affinity of Zoledro-Denk for the cellular components of human blood. In vitro mean Zoledro-Denk protein binding in human plasma ranged from 28% at 200 ng/mL to 53% at 50 ng/mL. In vivo studies showed that Zoledro-Denk is not metabolized, and is excreted into the urine as the intact drug.
Caution is advised when bisphosphonates, including Zoledro-Denk, are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zoledro-Denk clinical trials.
Caution should also be exercised when Zoledro-Denk is used in combination with loop diuretics due to an increased risk of hypocalcemia.
Caution is indicated when Zoledro-Denk is used with other potentially nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs.
Drugs Primarily Excreted By The Kidney
Renal impairment has been observed following the administration of Zoledro-Denk in patients with pre-existing renal compromise or other risk factors. In patients with renal impairment, exposure to concomitant medications that are primarily renally excreted (e.g., digoxin) may increase. Consider monitoring serum creatinine in patients at risk for renal impairment who are taking concomitant medications that are primarily excreted by the kidney.
Zoledro-Denk side effects
Postmenopausal Osteoporosis: In HORIZON-PFT, the Phase III randomized, double-blind, placebo-controlled, multinational study of 7736 women aged 65-89 years, there were no significant differences in the overall incidence of serious adverse events compared to placebo and most adverse events were mild to moderate. Zoledro-Denk was administered once yearly for 3 consecutive years for a total of 3 doses.
Consistent with the IV administration of bisphosphonates, Zoledro-Denk has been most commonly associated with the following post-dose symptoms: Fever (18.1%), myalgia (9.4%), flu-like symptoms (7.8%), arthralgia (6.8%) and headache (6.5%), the majority of which occur within the first 3 days following Zoledro-Denk administration. The majority of these symptoms were mild to moderate in nature and resolved within 3 days of the event onset. The incidence of these symptoms decreased markedly with subsequent doses of Zoledro-Denk.
The incidence of post-dose symptoms occurring within the first 3 days after administration of Zoledro-Denk, can be reduced by approximately 50% with the administration of paracetamol or ibuprofen shortly following Zoledro-Denk administration.
Very common (≥1/10), common (≥1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/1000, <1/10,000) adverse reactions suspected (investigator assessment) to be associated with Zoledro-Denk are shown as follows: Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse drug reactions suspected* (at least 1%) to be associated with Zoledro-Denk in postmenopausal osteoporosis in HORIZON-PFT study:
Nervous System Disorders: Common: Headache, dizziness. Uncommon: Lethargyb, paresthesia, somnolence, tremor, syncope, dysgeusia.
Eye Disorders: Uncommon: Conjunctivitis, eye pain, uveitis. Rare: Episcleritis, iritis.
Ear and Labyrinth Disorders: Uncommon: Vertigo.
Respiratory, Thoracic and Mediastinal Disorders: Common: Dyspnea.
Gastrointestinal Disorders: Common: Nausea, vomiting, diarrhea. Uncommon: Dyspepsia, abdominal pain, dry mouth, esophagitis.
Skin and Subcutaneous Tissue Disorders: Uncommon: Rash.
Musculoskeletal Disorders: Common: Myalgia, arthralgia, bone pain, back pain, pain in extremity. Uncommon: Joint swelling.
Renal and Urinary Disorders: Uncommon: Increase blood creatinine.
General Disorders and Administration Site Conditions: Very common: Fever. Common: Hypocalcemiaa, flu-like symptoms, chills, fatigue, asthenia, pain, malaise, rigors. Uncommon: Anorexia, peripheral edema, thirst.
*Incidence based on investigator assessment of causality and includes those events with a greater frequency than placebo.
Key deviations in the adverse events in the Paget’s disease clinical trials compared to the postmenopausal HORIZON-PFT trial are summarized as follows:
a Common in Paget’s disease only.
b Common in Paget’s disease.
c Very common in Paget’s disease.
In one 3-year trial in postmenopausal osteoporosis women (HORIZON-PFT), the overall incidence of atrial fibrillation was low, reported in 2.5% of patients (96 out of 3862) in the Zoledro-Denk group versus 1.9% of patients (75 out of 3852) in the placebo group. The increased incidence observed in this trial has not been observed in other clinical trials with Zoledro-Denk.
Class Effects: Renal Dysfunction: Treatment with IV bisphosphonates, including Zoledro-Denk, has been associated with renal dysfunction manifested as deterioration in renal function (ie, increased serum creatinine) and in rare cases, acute renal failure. Renal dysfunction has been observed following the administration of Zoledro-Denk, especially in patients with preexisting renal compromise or additional risk factors (eg, oncology patients with chemotherapy, concomitant nephrotoxic medications, severe dehydration), the majority of whom received a 4-mg dose every 3-4 weeks, but it has been observed in patients after a single administration.
In the HORIZON-PFT trial, the change in creatinine clearance (measured annually prior to dosing), and the incidence of renal failure and impairment was comparable for both the Zoledro-Denk and placebo treatment groups over 3 years. There was a transient increase in serum creatinine observed within 10 days in 1.8% of Zoledro-Denk-treated patients versus 0.8% of placebo-treated patients.
Laboratory Findings: In the HORIZON-PFT trial, approximately 0.2% of patients had notable declines of serum calcium levels (<1.87 mmol/L) following Zoledro-Denk administration. No symptomatic cases of hypocalcemia were observed.
In the Paget’s disease trials, symptomatic hypocalcemia was observed in approximately 1% of patients, all of which resolved.
Local Reactions: Local reactions at the infusion site eg, redness, swelling and/or pain were reported (0.7%) following the administration of Zoledro-Denk.
Osteonecrosis of the Jaw: Cases of osteonecrosis (primarily of the jaw) have been reported predominantly in cancer patients treated with bisphosphonates, including Zoledro-Denk (uncommon). Many of these patients had signs of local infection including osteomyelitis, and the majority of the reports refer to cancer patients following tooth extractions or other dental surgeries. Osteonecrosis of the jaw has multiple well-documented risk factors including a diagnosis of cancer, concomitant therapies (eg, chemotherapy, radiotherapy, corticosteroids) and co-morbid conditions (eg, anemia, coagulopathies, infection, preexisting dental disease). Although causality has not been determined, it is prudent to avoid dental surgery as recovery may be prolonged. In the HORIZON-PFT trial in 7736 patients, ONJ has been reported in 1 patient treated with Zoledro-Denk and 2 patients treated with a placebo. All 3 cases resolved.
Zoledro-Denk can harm your kidneys. This effect is increased when you also use other medicines harmful to the kidneys, such as chemotherapy, antiviral medication, pain or arthritis medicine, injected antibiotics, or medicines to treat a bowel disorder or prevent organ transplant rejection. You may need dose adjustments or special tests if you use any of these medications.
Do not receive Zoledro-Denk without telling your doctor if you have had an allergic reaction to Zoledro-Denk or similar medicine such as alendronate (Fosamax), etidronate (Didronel), ibandronate (Boniva), pamidronate (Aredia), risedronate (Actonel), or tiludronate (Skelid).
Do not use Zoledro-Denk if you are pregnant. It could harm the unborn baby.
Your doctor may recommend you have a dental exam for preventive tooth and gum care before you start your treatment with Zoledro-Denk. This is especially important if you have cancer, if you are undergoing chemotherapy or using steroids, or if you have poor dental health.
Some people using medicines similar to Zoledro-Denk have developed bone loss in the jaw, also called osteonecrosis of the jaw. Symptoms of this condition may include jaw pain, swelling, numbness, loose teeth, gum infection, or slow healing after injury or surgery involving the gums. You may be more likely to develop osteonecrosis of the jaw if you have cancer or have been treated with chemotherapy, radiation, or steroids. Other conditions associated with osteonecrosis of the jaw include blood clotting disorders, anemia (low red blood cells), and pre-existing dental problems.
Avoid having any type of dental surgery while you are being treated with Zoledro-Denk. It may take longer than normal for you to recover.