Zoledronic Acid

When ATH:
M05BA08

Characteristic.

The white crystalline powder. Very soluble in 0,1N NaOH solution, poorly soluble in water (pH 0,7% zoledronic acid solution in water of about 2,0) и 0,1N HCl, practically insoluble in organic solvents.

Pharmacological action.
Inhibiting bone resorption.

Application.

According to Physicians Desk Reference (2003), zoledronic acid is used for the following indications: hypercalcemia of malignancy; mnozhestvennaya myeloma; confirmed bone metastases tumor sólidnoy (in addition to the standard anti-cancer therapy).

Contraindications.

Hypersensitivity (clinically significant), incl. other bisphosphonates.

Restrictions apply.

Renal failure

From clinical research at SRC were excluded patients with serum creatinine rates >4,5 mg / dL (>400 mmol / l). From clinical trials for bone metastases were excluded patients with serum creatinine rates >3,0 mg / dL (>265 mmol / l). Patients with bone metastases not recommended for use in severe renal insufficiency.

No clinical and pharmacokinetic data to support dosing regimen or a choice of tactics of safe use of zoledronic acid in severe renal insufficiency. At SRC in patients with severe renal insufficiency use is possible only if the expected benefit of therapy prevails over the risk of renal failure, after considering other available therapeutic approaches. In patients with hypercalcemia with initial mild to moderate renal impairment (serum creatinine <400 mmol / l or <4,5 mg / dL) dose adjustment is not required. If signs of worsening renal function in patients with SRC is necessary to conduct an appropriate examination to address the prevalence of the potential benefits of further treatment of possible risk. Patients, treated for bone metastases, If signs of renal impairment, treatment should be suspended until recovery of kidney function to baseline.

Hepatic failure

Experience in the use of zoledronic acid in the treatment of SRC patients with hepatic impairment is limited, and the data do not allow us to recommend a specific dosage regimen or the tactics of safe use in these patients.

Application for asthma

In patients with aspirin-sensitive asthma bronchial been cases when other bisphosphonates. Despite the lack of data about these manifestations during treatment with zoledronic acid, caution should be exercised when administered to patients with aspirin-sensitive asthma.

Pregnancy and breast-feeding.

Contraindicated in pregnancy. When applied in pregnant women is possible deleterious effects on the fetus. In animal studies, pregnant rats n / a dosage, in 2.4-4.8 times the systemic exposure in humans when in/in a dose of 4 mg (сравнение по AUC) It led to previous- and post-implantation loss, reduce fetal survival, skeletal malformations, internal organs and external malformations. Studies in pregnant women have not been conducted. If pregnancy occurs during treatment, the patient should be informed about the possible negative effects on the fetus; women of childbearing age is recommended to protect themselves from pregnancy.

Unknown, whether zoledronic acid gets into breast milk in humans. Because many drugs penetrate the breast milk, and zoledronic acid for a long time is deposited in bone, not recommended for use in nursing women. At the time of treatment must stop breastfeeding.

Side effects.

Hypercalcemia of malignancy

Side effects of zoledronic acid are usually mild and transient and similar to the side effects, marked by the use of other bisphosphonates. In / in the introduction often accompanied by fever. Sometimes patients develop flu-like symptoms, include fever, chills, pain in the bones and / or arthralgia, mialgiyu. The reactions from the gastrointestinal tract, such as nausea and vomiting, marked after / in the. Local injection site reactions, such as redness and swelling, observed infrequently. In most cases, non-specific treatment, and symptoms subside within 24-48 h. It was reported about rare cases of rash, pruritus or chest pain after administration of zoledronic acid. As well as the use of other bisphosphonates, reported cases of conjunctivitis and hypomagnesemia.

In two clinical trials with the SRC noted the following laboratory abnormalities in patients, treated with zoledronic acid dose 4 mg: increase in serum creatinine of more than 3 fold in 2,3% patients; hypocalcemia (<7 mg / dL) in 1,2%; gipofosfatemiя <2 mg/dl at 51,4% and <1 mg/dl — 1,4%.

Below are the side effects, registered with a frequency ≥10% among 86 patients in two controlled, multicenter studies with SRC, treated with zoledronic acid dose 4 mg. The overall incidence of side effects in these patients was 94,2%.

From the nervous system and sensory organs: insomnia (15,1%), alarm (14,0%), excitation (12,8%), confusion (12,8%).

Cardio-vascular system and blood: anemia (22,1%), gipotenziya (10,5%).

From the respiratory system: breathlessness (22,1%), cough (11,6%).

From the digestive tract: nausea (29,1%), constipation (26,7%), diarrhea (17,4%), abdominal pain (16,3%), vomiting (14,0%), anorexia (9,3%).

Metabolism: gipofosfatemiя (12,8%), kaliopenia (11,6%), gipomagniemiya (10,5%).

With the genitourinary system: urinary tract infection (14,0%).

On the part of the musculoskeletal system: bone pain (11,6%).

Other: fever (44,2%), tumor progression (16,3%), kandidomikoz (11,6%).

Multiple myeloma and bone metastases tumors sólidnyh

In four controlled multicentre studies in 1099 patients with bone metastases overall incidence of adverse events was 98%, The following side effects were observed at a frequency of ≥10% (the percentage in brackets in the placebo group — 445 patients):

From the nervous system and sensory organs: headache - 18% (10%), dizziness (excluding vertigo) - 14% (11%), insomnia — 14% (15%), parestesia- 12% (6%), Depression - 12% (9%), hypoesthesia- 10% (8%), alarm - 9% (8%).

Cardio-vascular system and blood (hematopoiesis, hemostasis): anemia — 29% (26%), neutropenia- 11% (8%).

From the respiratory system: shortness of breath is 24% (20%), cough- 19% (13%), infection of the upper respiratory tract is 8% (6%).

From the digestive tract: nausea - 43% (35%), vomiting - 30% (25%), constipation - 28% (35%), diarrhea is 22% (17%), abdominalьnaя fitting - 12% (10%), the decline of appetite — 11% (9%), anorexia - 20% (22%).

On the part of the musculoskeletal system: bone pain is 53% (60%), myalgia - 21% (15%), arthralgia - 18% (13%), backache - 10% (6%).

For the skin: alopecia is 11% (7%), Dermatitis- 10% (8%).

Other: fatigue is 36% (28%), heat — 30% (18%), weakness is 21% (23%), edema of the lower limbs is 19% (17%), chills — 10% (5%), the progression of malignant novoobrazovaniya15% (16%), reduce body weight — 13% (13%), dehydration — 12% (12%), urinary tract infection- 11% (9%).

In four controlled multicenter study in patients with bone metastases, treated with zoledronic acid dose 4 mg, noted the following Laboratory Abnormalities (in brackets the percentage placebo):

increase in serum creatinine of more than 3 fold in 1,3% (0,8%) more than 4 fold in 0,4% (0%) patients; hypocalcemia <7 mg/dl at 0,7% (0%) and <6 mg/dl at 0,6% (0,2%); gipofosfatemiя <2 mg/dl at 9,2% (3,1%) and <1 mg/dl — 0,6% (0,2%); gipermagniemiya >3 mjekv/l- 1,8% (1,9%); gipomagniemiya <0,7 mjekv/l- 0,2% (0%) patients.

Nephrotoxicity

In a study with bone metastases the deterioration of renal function was defined as increased creatinine in the serum 0,5 mg/dl in patients with initially normal levels of creatinine (<1,4 mg / dL) and on and 1,0 mg/dl in patients with initially elevated values (≥ 1.4 mg/dl).

In these studies, the frequency of renal impairment in patients, treated with zoledronovuju acid 4 mg in the form of 15-minute infusions amounted for multiple myeloma and breast cancer 8,8% (in patients with normal and elevated creatinine, respectively 9,3% and 3,8%); with sólidnyh tumors — 10,9% (11% and 9,1% respectively); When prostate cancer is 15,2% (12,2% and 40% respectively).

Cooperation.

Studies in vitro found, The binding to plasma proteins is 56% and an inhibitory effect on the microsomal enzymes CYP450 missing. Studies live shows, that zoledronic acid is not metabolised and excreted in the urine as unchanged. Studies of drug interactions live not performed.

Aminoglycosides may additively enhance hypocalcemic effect of bisphosphonates for a long period, therefore, while the application is recommended to be careful (in clinical trials of zoledronic acid with respect to such phenomena were observed).

Be wary appointed in combination with loop diuretics (increased risk of hypocalcemia), other potentially nephrotoxic drugs.

In patients with multiple myeloma may increase the risk of renal dysfunction, while the use of thalidomide.

There is evidence of a pharmaceutical incompatibility with calcium-containing solutions (Ringer).

Overdose.

No cases of acute overdose of zoledronic acid. Two patients received a dose of 32 mg in the form of 5-minute infusion; no clinical or laboratory manifestations of toxic action not observed.

Symptoms: clinically significant hypocalcemia, gipofosfatemiя, gipomagniemiya.

Treatment: symptomatic-in/with the introduction of Calcium Gluconate, sodium / potassium phosphate, Magnesium sulfate.

Dosing and Administration.

Hypercalcemia of malignancy at zlokachesktvennyh: usefulness of zoledronic acid must be determined taking into account both the severity, and displays SRC. For the treatment of soft, asymptomatic hypercalcemia may be enough only enhanced by the introduction of hydration salt solutions (with or without the use of loop diuretics). The maximum recommended dose for SRC (KSK ≥ 12.0 mg/dl or 3,0 mmol / l) is 4 mg, in a single I / infusion for at least, than 15 m. For a repeat possible, If the calcium level returns to normal or deteriorates after a clear clinical effect. The interval before re-introduction should be at least 7 d, are necessary to achieve full clinical effect initial dose.

Throughout the course of treatment is necessary to ensure adequate hydration (salt solutions), but should avoid excessive hydration, especially in patients with congestive heart failure. It is recommended to maintain a urine output of about 2 l / day throughout the treatment period. Diuretics can be used only after correction of hypovolemia.

Multiple myeloma and bone metastases tumors sólidnyh: the recommended dose - 4 mg in/in infusion during 15 min every 3-4 weeks, treatment duration in clinical studies was 12 month for multiple myeloma and breast cancer, 15 mo for prostate cancer and 9 sólidnyh months for other tumors. Patients should also receive inside drugs calcium dose 500 mg/day and multivitamins, contain vitamin D based 400 IU / day.

Precautions.

Due to the possibility of clinically significant impairment of renal function until renal failure, single dose not exceed 4 mg and the duration of the infusion should be no less than 15 m.

Bifosfonatы, incl. zoledronic acid, may have nephrotoxicity, manifest deterioration of renal function and, perhaps, renal failure. In clinical studies, the risk of renal dysfunction (defined as an increase in serum creatinine) It was significantly higher in patients, receiving infusion for 5 min compared to patients, that the same dose administered during 15 m. Besides, the risk of deterioration of renal function and renal failure was significantly higher in patients, dosed 8 mg, even if the duration of infusion was 15 m. Although the level of risk is reduced with the introduction of dose 4 mg for 15 m, Renal function impairment is likely. Risk factors such violations are initially elevated levels of serum creatinine and repeated cycles of treatment with bisphosphonates.

Patients, receiving zoledronic acid, you must determine the level of serum creatinine prior to each dose. With the deterioration of kidney function in patients with bone metastases is necessary to cancel the introduction of the next dose. If any signs of deterioration in renal function in patients with SRC must be a thorough examination to decide on the prevalence of the potential benefits of the use of zoledronic acid over the possible risk.

After initiation of therapy requires careful monitoring of calcium, Phosphorus, magnesium and creatinine in blood serum, Hematocrit and Hemoglobin. The development of hypocalcemia, hypophosphatemia or hypomagnesemia require short-term corrective therapy. Before each dose is necessary to determine the level of serum creatinine.

Patients with SRC before treatment should receive adequate rehydration. Loop diuretics combined with zoledronic acid with caution (may develop hypocalcaemia) and only after reaching a sufficient hydration.

Cooperation