zoledronic acid

General

Pronunciation:
zoe-led-dron-ic as-id


Trade Name(s)

  • Aclasta Canadian Tradename
  • Reclast
  • Zometa

Ther. Class.
bone resorption inhibitors
electrolyte modifiers
hypocalcemics

Pharm. Class.
biphosphonates

Indications

  • Hypercalcemia of malignancy (Zometa only).
  • Multiple myeloma and metastatic bone lesions from solid tumors (Zometa only).
  • Paget's disease (Reclast only).
  • Treatment of osteoporosis in men (Reclast only).
  • Treatment and prevention of osteoporosis in postmenopausal women (Reclast only).
  • Treatment and prevention of glucocorticoid-induced osteoporosis in patients expected to be on glucocorticoids for at least 12 mo (Reclast only).

Action

  • Inhibits bone resorption.
  • Inhibits increased osteoclast activity and skeletal calcium release induced by tumors.

Therapeutic Effect(s):

  • Decreased serum calcium.
  • Decreased serum alkaline phosphatase.
  • Decreased fractures, radiation/surgery to bone, or spinal cord compression in patients with multiple myeloma or metastatic bone lesions.
  • Decreased hip, vertebral, or non-vertebral osteoporosis-related fractures in postmenopausal women.
  • Increased bone mass in men, postmenopausal women, and patients on prolonged corticosteroid therapy.

Pharmacokinetics

Absorption: IV administration results in complete bioavailability.

Distribution: Unknown.

Metabolism and Excretion: Mostly excreted unchanged by the kidneys.

Half-life: 167 hr.

TIME/ACTION PROFILE (effect on serum calcium)

ROUTEONSETPEAKDURATION
IVwithin 4 days4–7 days30 days

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity to zoledronic acid or other bisphosphonates;
  • Severe renal impairment (CCr <35 mL/min) or acute renal failure;
  • Hypocalcemia (correct before administering); adequate supplemental calcium and vitamin D required;
  • OB:  Pregnancy (may cause fetal harm);

Use Cautiously in:

  • History of aspirin-induced asthma;
  • Chronic renal impairment;
  • Chronic renal impairment, concurrent use of diuretics or nephrotoxic drugs, or dehydration (↑ risk of renal impairment; correct deficits prior to use);
  • Concurrent use of nephrotoxic drugs;
  • Invasive dental procedures, cancer, receiving chemotherapy, corticosteroids, or angiogenesis inhibitors, undergoing radiation, poor oral hygiene, periodontal disease, dental disease, anemia, coagulopathy, infection, or poorly-fitting dentures (may ↑ risk of jaw osteonecrosis);
  • Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant.
  • Pedi:   Potential for long-term retention in bone in children; use only if potential benefit outweighs potential risk;
  • Geri:  ↑ risk of renal impairment in older adults.

Adverse Reactions/Side Effects

CV: hypotension, chest pain, leg edema

Derm: STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, pruritus, rash

EENT: conjunctivitis

F and E: hypophosphatemia, hypocalcemia, hypokalemia, hypomagnesemia

GI: abdominal pain, constipation, diarrhea, nausea, vomiting, dysphagia

GU: ↓ fertility (females), renal impairment/failure

Hemat: anemia

MS: musculoskeletal pain, femur fractures, osteonecrosis (primarily of jaw)

Neuro: agitation, anxiety, confusion, insomnia

Resp: asthma exacerbation

Misc: fever, flu-like syndrome

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  • Concurrent use of  loop diuretics,  calcitonin, or  aminoglycosides  ↑ risk of hypocalcemia.
  • Concurrent use of  NSAIDs  may ↑ risk of nephrotoxicity.

Route/Dosage

Reclast

IV (Adults): Paget's disease– 5 mg as a single dose (information regarding retreatment unknown);  Treatment of osteoporosis in men or postmenopausal women, treatment/prevention of glucocorticoid-induced osteoporosis– 5 mg once yearly;  Prevention of osteoporosis in postmenopausal women– 5 mg every 2 yr.

Zometa

IV (Adults): Hypercalcemia of malignancy– 4 mg; may be repeated after 7 days;  Multiple myeloma and bone metastases from solid tumors– 4 mg every 3–4 wk (has been used for up to 15 mo).

Availability (generic available)

Premixed infusion (Reclast): 5 mg/100 mL

Premixed infusion (Zometa): 4 mg/100 mL

Solution for injection (Zometa): 0.8 mg/mL

Assessment

  • Monitor intake and output ratios. Initiate a vigorous saline hydration promptly and maintain a urine output of 2 L/day during therapy. Patients should be adequately hydrated, but avoid overhydration. Do not use diuretics prior to treatment of hypovolemia.
  • Assess for acute-phase reaction (fever, myalgia, flu-like symptoms, headache, arthralgia). Usually occur within 3 days of dose and resolve within 3 days of onset, but may take 7–14 days to resolve; incidence decreases with repeat dosing.
  • Perform a routine oral exam prior to initiation of therapy. Dental exam with appropriate preventative dentistry should be considered prior to therapy. Patients with history of tooth extraction, poor oral hygiene, gingival infections, diabetes, cancer, receiving radiation, anemia, coagulopathy, or use of a dental appliance or those taking immunosuppressive therapy, angiogenesis inhibitors, or systemic corticosteroids are at greater risk for osteonecrosis of the jaw.
  • Hypercalcemia: Monitor symptoms of hypercalcemia (nausea, vomiting, anorexia, weakness, constipation, thirst, cardiac arrhythmias).
  • Observe for evidence of hypocalcemia (paresthesia, muscle twitching, laryngospasm, Chvostek's or Trousseau's sign).
  • Paget's Disease: Assess for symptoms of Paget's disease (bone pain, headache, decreased visual and auditory acuity, increased skull size) periodically during therapy.
  • Osteoporosis: Assess patients via bone density study for low bone mass before and periodically during therapy.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.

Monitor serum creatinine, calculated based on actual body weight using the Cockcroft-Gault formula, prior to each treatment. Patients with a normal serum creatinine prior to treatment, who develop an increase of 0.5 mg/dL within 2 wk of next dose should have next dose withheld until serum creatinine is within 10% of baseline value. Patients with an abnormal serum creatinine prior to treatment who have an increase of 1.0 mg/dL within 2 wk of next dose should have next dose withheld until serum creatinine is within 10% of baseline value.

  • Assess serum calcium, phosphate, and magnesium before and periodically during therapy. If hypocalcemia, hypophosphatemia, or hypomagnesemia occur, temporary supplementation may be required. Hypocalcemia and vitamin D deficiency should be treated before initiating zoledronic acid therapy.
  • Monitor CBC with differential and hemoglobin and hematocrit closely during therapy.
  • Paget's Disease:  Monitor serum alkaline phosphatase prior to and periodically during therapy to monitor effectiveness.

Implementation

  • Vigorous saline hydration alone may be sufficient to treat mild, asymptomatic hypercalcemia. Adequate rehydration is required prior to administration.

    • Patients on long-term therapy should have 1200 mg of oral calcium and 800–1000 units of Vitamin D each day.
    • Patients treated for  Paget's disease  should receive 1500 mg elemental calcium and 800 IU of vitamin D daily, particularly during the 2 wk after dosing. Patients with osteoporosis should take 1200 mg of calcium and 800–1000 units of vitamin D daily. Patients with multiple myeloma and bone metastasis of solid tumors take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of vitamin D daily.
    • Administration of acetaminophen or ibuprofen following administration may reduce the incidence of acute-phase reaction symptoms.

IV Administration

  • Intermittent Infusion:   Diluent:  Dilute 4-mg dose further with 100 mL of 0.9% NaCl or D5W. If not used immediately, may be refrigerated for up to 24 hr.  Reclast comes ready to use 5 mg in 100-mL solution. If refrigerated, allow solution to reach room temperature prior to administration. Do not administer solution that is discolored or contains particulate matter.
  • Rate: Administer as a single infusion over at least 15 min. Rapid infusions increase risk of renal deterioration and renal failure.
  • Y-Site Compatibility:
    • acyclovir
    • alfentanil
    • allopurinol
    • MORE...
      • amifostine
      • amikacin
      • aminocaproic acid
      • aminophylline
      • amiodarone
      • amphotericin B lipid complex
      • amphotericin B liposome
      • ampicillin
      • ampicillin/sulbactam
      • anidulafungin
      • argatroban
      • arsenic trioxide
      • azithromycin
      • aztreonam
      • bivalirudin
      • bleomycin
      • bumetanide
      • buprenorphine
      • busulfan
      • butorphanol
      • carboplatin
      • carmustine
      • caspofungin
      • cefazolin
      • cefepime
      • cefotaxime
      • cefotetan
      • cefoxitin
      • ceftazidime
      • ceftriaxone
      • cefuroxime
      • chloramphenicol
      • chlorpromazine
      • ciprofloxacin
      • cisatracurium
      • cisplatin
      • clindamycin
      • cyclophosphamide
      • cyclosporine
      • cytarabine
      • dacarbazine
      • dactinomycin
      • daptomycin
      • daunorubicin hydrochloride
      • dexamethasone
      • dexmedetomidine
      • dexrazoxane
      • digoxin
      • diltiazem
      • diphenhydramine
      • dobutamine
      • docetaxel
      • dopamine
      • doxorubicin hydrochloride
      • doxorubicin liposomal
      • doxycycline
      • droperidol
      • enalaprilat
      • ephedrine
      • epinephrine
      • epirubicin
      • eptifibatide
      • ertapenem
      • erythromycin
      • esmolol
      • etoposide
      • etoposide phosphate
      • famotidine
      • fenoldopam
      • fentanyl
      • fluconazole
      • fludarabine
      • fluorouracil
      • foscarnet
      • fosphenytoin
      • furosemide
      • ganciclovir
      • gemcitabine
      • gentamicin
      • glycopyrrolate
      • granisetron
      • haloperidol
      • heparin
      • hydralazine
      • hydrocortisone
      • hydromorphone
      • idarubicin
      • ifosfamide
      • imipenem/cilastatin
      • insulin, regular
      • irinotecan
      • isoproterenol
      • ketorolac
      • labetalol
      • levofloxacin
      • lidocaine
      • linezolid
      • lorazepam
      • magnesium sulfate
      • mannitol
      • melphalan
      • meperidine
      • meropenem
      • mesna
      • methadone
      • methotrexate
      • methylprednisolone
      • metoclopramide
      • metoprolol
      • metronidazole
      • midazolam
      • milrinone
      • mitomycin
      • mitoxantrone
      • morphine
      • moxifloxacin
      • mycophenolate
      • nafcillin
      • nalbuphine
      • naloxone
      • nicardipine
      • nitroglycerin
      • nitroprusside
      • norepinephrine
      • octreotide
      • ondansetron
      • oxaliplatin
      • oxytocin
      • paclitaxel
      • pancuronium
      • pantoprazole
      • pemetrexed
      • pentamidine
      • pentobarbital
      • phenobarbital
      • phenylephrine
      • piperacillin/tazobactam
      • potassium acetate
      • potassium chloride
      • potassium phosphates
      • procainamide
      • prochlorperazine
      • promethazine
      • propranolol
      • quinupristin/dalfopristin
      • remifentanil
      • rocuronium
      • sodium acetate
      • sodium bicarbonate
      • sodium phosphates
      • streptozocin
      • succinylcholine
      • sufentanil
      • tacrolimus
      • theophylline
      • thiopental
      • thiotepa
      • tigecycline
      • tirofiban
      • tobramycin
      • topotecan
      • trimethoprim/sulfamethoxazole
      • vancomycin
      • vecuronium
      • verapamil
      • vinblastine
      • vincristine
      • vinorelbine
      • voriconazole
      • zidovudine
  • Y-Site Incompatibility:
    • alemtuzumab
    • calcium-containing solutions
    • dantrolene
    • MORE...
      • diazepam
      • gemtuzumab ozogamicin
      • phenytoin.
    Manufacturer recommends administration as a single infusion in a line separate from all other drugs.
  • Additive Incompatibility: Do not mix with solutions containing calcium, such as Lactated Ringer's solution.

Patient/Family Teaching

  • Explain the purpose of zoledronic acid to patient. Advise patient to read  Medication Guide  prior to each administration in case of changes.
  • Advise patients of the importance of adequate hydration. Patient should be instructed to drink at least two glasses of water prior to receiving dose.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Advise patient to eat a balanced diet and consult health care professional about the need for supplemental calcium and vitamin D.
  • Inform patient that severe musculoskeletal pain may occur within days, mo, or yr after starting zoledronic acid. Symptoms may resolve completely after discontinuation or slow or incomplete resolution may occur. Notify health care professional if severe pain occurs.
  • Encourage patient to participate in regular exercise and to modify behaviors that increase the risk of osteoporosis (stop smoking, reduce alcohol consumption).
  • Advise patient to notify health care professional if signs and symptoms if osteonecrosis of the jaw (pain, numbness, swelling of or drainage from the jaw, mouth, or teeth) or hypocalcemia (spasms, twitches, or cramps in muscles; numbness or tingling in fingers, toes, or around mouth) or thigh, hip, or groin pain occur.
  • Advise patient to inform health care professional of zoledronic acid therapy prior to dental surgery.
  • Rep:  May cause fetal harm. Advise females of reproductive potential use effective contraception and avoid breastfeeding during and after therapy. May impair fertility in females.
  • Emphasize the importance of lab tests to monitor progress.

Evaluation/Desired Outcomes

  • Decrease in serum calcium.
  • Decrease in serum alkaline phosphatase and the progression of Paget's disease.
  • Reversal of the progression of osteoporosis with decreased fractures and other sequelae. Discontinuation after 3–5 yr should be considered for postmenopausal women with low risk for fractures.
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