Vfend


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voriconazole

Vfend

Pharmacologic class: Triazole

Therapeutic class: Antifungal

Pregnancy risk category D

Action

Inhibits fungal cytochrome P450-mediated 14-alpha-lanosterol demethylation, preventing fungal biosynthesis and inactivating fungal cell

Availability

Lyophilized powder for injection: 200 mg

Powder for oral suspension: 40 mg/ml

Tablets: 50 mg, 200 mg

Indications and dosages

Invasive aspergillosis; serious fungal infections caused by Scedosporium apiospermum and Fusarium species

Adults and children ages 12 and older: Initially, 6 mg/kg I.V. q 12 hours for two doses (each dose infused over 1 to 2 hours), followed by a maintenance dose of 4 mg/kg I.V. q 12 hours given no faster than 3 mg/kg/hour. Change to oral dosing as described below when patient can tolerate it.

Adults and children ages 12 and older weighing more than 40 kg (88 lb): 200 mg P.O. q 12 hours 1 hour before or after a meal; may increase to 300 mg P.O. q 12 hours p.r.n.

Adults and children ages 12 and older weighing less than 40 kg (88 lb): 100 mg P.O. q 12 hours at least 1 hour before or after a meal; may increase to 150 mg P.O. q 12 hours p.r.n.

Esophageal candidiasis

Adults and children ages 12 and older weighing 40 kg (88 lb) or more: 200 mg P.O. q 12 hours for at least 14 days, and for at least 7 days after symptoms resolve

Adults and children ages 12 and older weighing less than 40 kg (88 lb): 100 mg P.O. q 12 hours for at least 14 days, and for at least 7 days after symptoms resolve

Candidemia (in nonneutropenic patients) and other deep-tissue Candida infections

Adults and children ages 12 and older: 6 mg/kg I.V. q 12 hours for first 24 hours, followed by maintenance dose of 3 mg/kg I.V. q 12 hours. Or 200 mg P.O. q 12 hours for candidemia and 4 mg/kg I.V. q 12 hours or 200 mg P.O. q 12 hours for other deep-tissue Candida infections. Patients should be treated for at least 14 days after resolution of symptoms or after last positive culture, whichever is longer.

Dosage adjustment

• Mild to moderate hepatic impairment
• Moderate to severe renal impairment (with I.V. use)
• Adult patients weighing less than 40 kg (88 lb)
• Concurrent use of phenytoin or efavirenz

Off-label uses

• Febrile neutropenia (as empiric therapy)

Contraindications

• Hypersensitivity to drug or its components
• Concurrent use of long-acting barbiturates, ergot alkaloids, rifabutin, rifampin, CYP450-3A4 substrates (such as astemizole, cisapride, pimozide, quinidine, terfenadine), sirolimus, high-dose ritonavir, St. John's wort, or carbamazepine

Precautions

Use cautiously in:
• hypersensitivity to other azoles
• renal disease, hepatic dysfunction, risk factors for pancreatitis (such as recent chemotherapy, hematopoietic stem cell transplant)
• hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption (avoid tablet use)
• concurrent use of low-dose ritonavir (avoid use unless benefit-risk to patient justifies use)
• pregnant or breastfeeding patients
• children younger than age 12 (safety and efficacy not established).

Administration

• Correct electrolyte disturbances before therapy starts.

Don't give concurrently with astemizole, cisapride, or terfenadine (no longer available in U.S.); carbamazepine; ergot alkaloids; long-acting barbiturates; pimozide; quinidine; rifabutin; rifampin; ritonavir; or sirolimus.

Don't give by I.V. bolus injection.
• Reconstitute powder with 19 ml of water for injection, to yield a volume of 20 ml. Shake vial until powder dissolves. Withdraw prescribed dose, then dilute further in compatible I.V. solution to a final concentration of 0.5 to 5 mg/ml. Give I.V. over 1 to 2 hours at a rate not exceeding 3 mg/kg/hour.
• Don't give through same I.V. line with other drugs, blood products, or electrolytes.
• To reconstitute powder for oral suspension, tap bottle to release powder. Add 46 ml of water, and shake vigorously for about 1 minute. Remove cap, push bottle adapter into neck of bottle, and replace cap. After reconstitution, suspension volume is 75 ml, providing usable volume of 70 ml (40 mg/ml). Shake bottle before each use. Use only 5-ml oral dispenser supplied. Don't mix with other drugs, and don't dilute further.
• Give oral suspension and tablets 1 hour before or after a meal.

Adverse reactions

CNS: dizziness, headache, hallucinations

CV: hypotension, hypertension, tachycardia, chest pain, vasodilation, peripheral edema

EENT: photophobia, blurred vision, visual disturbances, eye hemorrhage, chromatopsia

GI: nausea, vomiting, diarrhea, abdominal pain, dry mouth, pancreatitis

GU: renal dysfunction, acute renal failure

Hematologic: anemia, pancytopenia, leukopenia, thrombocytopenia

Hepatic: cholestatic jaundice, hepatic failure

Metabolic: hypomagnesemia, hypokalemia

Musculoskeletal: fluorosis, periostitis (with long-term use)

Respiratory: respiratory disorders

Skin: pruritus, maculopapular rash, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome

Other: chills, fever, sepsis, infusion-related reactions including anaphylaxis

Interactions

Drug-drug.Barbiturates (long-acting), carbamazepine, phenytoin, rifampin: decreased voriconazole blood level

Benzodiazepines: sedation

Calcium channel blockers, HMG-CoA reductase inhibitors: increased blood levels of these drugs

Cyclosporine, sirolimus, tacrolimus: increased blood levels of these drugs, greater risk of nephrotoxicity

CYP450-3A4 substrates: increased blood levels of these drugs, causing prolonged QT interval and risk of torsades de pointes

Ergot alkaloids: increased blood levels of these drugs, resulting in ergotism

Non-nucleoside reverse transcriptase inhibitors, protease inhibitors: inhibited voriconazole metabolism

Rifabutin: decreased voriconazole blood level, increased rifabutin blood level

Sulfonylureas: increased sulfonylurea blood level, greater risk of hypoglycemia

Vinca alkaloids: increased risk of neurotoxicity

Warfarin, other coumarin derivatives: increased partial thromboplastin time

Drug-diagnostic tests.Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, creatinine: increased levels

Drug-herbs.Gossypol: increased risk of nephrotoxicity

St. John's wort: significantly reduced voriconazole plasma exposure

Patient monitoring

• Monitor kidney and liver function tests. Watch for signs and symptoms of organ toxicity.
• Assess electrolyte levels and CBC, including platelet count.

Monitor ECG. Stay alert for prolonged QT interval.

During infusion, monitor patient for anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, and rash; consider stopping infusion should these reactions occur.

Be aware of postmarketing reports of pancreatitis, especially in children, and monitor appropriately.

Monitor patient receiving longterm therapy for skeletal pain. Discontinue drug if radiologic findings indicate fluorosis or periostitis.
• Check for vision problems in therapy exceeding 28 days.

Patient teaching

• Explain therapy to patient. Stress importance of follow-up laboratory tests.
• Tell patient using oral form to take doses 1 hour before or after a meal.
• Emphasize importance of taking drug exactly as directed for entire duration prescribed.
• Instruct patient to promptly report adverse reactions.
• Tell female of childbearing age to immediately report pregnancy.
• Caution patient to avoid driving and other hazardous activities, because drug may cause visual disturbances.
• Advise patient to minimize GI upset by eating small, frequent servings of food and drinking plenty of fluids.
• Advise patient not to use St. John's wort without consulting prescriber.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and herbs mentioned above.

voriconazole

(vor-i-kon-a-zole) ,

VFEND

(trade name)

Classification

Therapeutic: antifungals
Pregnancy Category: D

Indications

Serious systemic fungal infections including candidemia, esophageal candidiasis, candidal deep tissue and skin infections, abdominal, kidney, bladder wall and wound infections, and aspergillosis.

Action

Inhibits fungal ergosterol synthesis leading to production of abnormal fungal plasma membrane.

Therapeutic effects

Antifungal activity.

Pharmacokinetics

Absorption: Well absorbed following oral administration (96%); IV administration results in complete bioavailability.
Distribution: Extensive tissue distribution.
Protein Binding: 58%.
Metabolism and Excretion: Highly metabolized by the hepatic P450 enzymes (CYP2C19, CYP2C9, CYP3A4); <2% excreted unchanged in urine. Much individual variation in metabolism; metabolites are inactive. genetic implication The CYP2C19 enzyme system exhibits genetic polymorphism; 15–20% of Asian patients and 3–5% of Caucasian and Black patients may be poor metabolizers and may have significantly ↑ voriconazole concentrations and an ↑ risk of adverse effects.
Half-life: Dose-dependent (adults 6–9 hrs); ↑ in hepatic impairment.

Time/action profile (blood levels)

ROUTEONSETPEAKDURATION
POrapid1–2 hr12 hr
IVrapidend of infusion12 hr

Contraindications/Precautions

Contraindicated in: Concurrent use of ritonavir, rifampin, rifabutin, St. John's wort, carbamazepine, and phenobarbital (↓ antifungal activity);Concurrent use of sirolimus, pimozide, quinidine, ergotamine, and dihydroergotamine (↑ risk of toxicity of these agents);Tablets contain lactose and should be avoided in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
Use Cautiously in: Mild to moderate liver disease (Child-Pugh Class A and B); maintenance dose reduction recommended;Renal impairment (CCr <50 mL/min); use only if justified by risk/benefit assessment (IV form should be avoided, use oral form only); Obstetric / Lactation: Use only if benefits justify risk; Pediatric: Children <12 yr (limited dosing information); suspension contains benzyl alcohol which may cause potentially fatal "gasping syndrome" in neonates.

Adverse Reactions/Side Effects

Central nervous system

  • dizziness
  • hallucinations
  • headache

Ear, Eye, Nose, Throat

  • visual disturbances (most frequent)
  • eye hemorrhage

Cardiovascular

  • changes in BP
  • peripheral edema
  • tachycardia
  • QT interval prolongation

Gastrointestinal

  • hepatotoxicity (life-threatening)
  • abdominal pain
  • diarrhea
  • nausea
  • pancreatitis
  • vomiting

Dermatologic

  • melanoma (life-threatening)
  • squamous cell carcinoma (life-threatening)
  • stevens-johnson syndrome (life-threatening)
  • photosensitivity
  • rash

Fluid and Electrolyte

  • hypokalemia
  • hypomagnesemia
  • hyperglycemia

Musculoskeletal

  • fluorosis
  • periostitis

Miscellaneous

  • chills
  • fever
  • infusion reactions

Interactions

Drug-Drug interaction

Voriconazole is a substrate and inhibitor of the CYP3A4, CYP2C9, and CYP2C19 enzyme systems.Carbamazepine, ritonavir, phenobarbital, St. John's wort, rifabutin, and rifampin ↑ metabolism and ↓ antifungal activity of voriconazole; concurrent use is contraindicated.Efavirenz ↑ metabolism and ↓ antifungal activity of voriconazole; voriconazole also ↓ metabolism and ↑ risk of toxicity of efavirenz ; if used together, ↑ dose of voriconazole to 400 mg q 12 hr and ↓ dose of efavirenz to 300 mg daily.↓ metabolism and ↑ risk of toxicity from dihydroergotamine, ergotamine, pimozide, rifabutin, quinidine, and sirolimus ; concurrent use is contraindicated.Fluconazole ↑ levels and toxicity of voriconazole; avoid concurrent use.↓ metabolism and ↑ risk of toxicity from cyclosporine, HMG-CoA reductase inhibitors, some benzodiazepines (alprazolam, midazolam, triazolam ), fentanyl, hydrocodone, NSAIDs (ibuprofen, diclofenac ), some calcium channel blockers, sulfonylureas (glipizide, glyburide, tolbutamide ), alfentanil, tacrolimus, warfarin, and vinca alkaloids (vincristine, vinblastine ); careful monitoring required during concurrent use.May ↑ methadone levels; may ↑ risk of QT interval prolongation.Oral contraceptives containing ethinyl estadiol and norethindone may ↑ voriconazole levels.Phenytoin ↑ metabolism and ↓ antifungal activity of voriconazole; voriconazole ↑ phenytoin levels and may cause toxicity; careful monitoring required during concurrent use.↑ blood levels of omeprazole ; ↓ omeprazole dose by 50% during concurrent use. Similar effects may occur with other proton-pump inhibitors.May ↓ metabolism and ↑ blood levels and effects of protease-inhibitor antiretrovirals and non-nucleoside reverse transcriptase inhibitor antiretrovirals ; frequent monitoring recommended.Non-nucleoside reverse transcriptase inhibitor antiretrovirals ; may induce or inhibit the metabolism of voriconazole; frequent monitoring recommended.

Route/Dosage

Intravenous (Adults and children >12 yr) Loading dose—6 mg/kg every 12 hour for 2 doses, followed by maintenance dosing—3–4 mg/kg every 12 hours. IV then switched to oral dosing when possible. If intolerance occurs, dose may be ↓ to 3 mg/kg every 12 hr. If phenytoin is coadministered, ↑ maintenance dose to 5 mg/kg every 12 hr.
Intravenous (Children 2–11 yrs) Loading dose—6–8 mg/kg (maximum: 400 mg/dose) every 12 hour for 2 doses, followed by Maintenance dosing—7 mg/kg (maximum: 200 mg/dose) every 12 hours. Invasive aspergillosis—5–7 mg/kg every 12 hr.
Oral (Adults and children >12 yr and >40 k g) Most infections—(following IV loading dose) 200 mg every 12 hr; may be increased to 300 mg every 12 hr if response if inadequate. If phenytoin is coadministered, ↑ maintenance dose to 400 mg every 12 hr; Esophageal candidiasis—200 mg every 12 hr for 14 days or 7 days following symptom resolution.
Oral (Adults and children >12 yr and <40 kg) Most infections—(following IV loading dose) 100 mg every 12 hr; may be increased to 150 mg every 12 hr if response is inadequate. If phenytoin is coadministered, ↑ maintenance dose to 200 mg every 12 hr; Esophageal candidiasis—100 mg every 12 hr for 14 days or 7 days following symptom resolution.
Oral (Children <12 yrs or <25 kg) Invasive aspergillosis—8 mg/kg/dose (maximum: 400 mg/dose) q 12 hr x 2 doses then Maintenance dosing—7 mg/kg (maximum: 200 mg/dose) every 12 hrs.

Hepatic Impairment

Intravenous (Adults and Children >12 yr) Child-Pugh Class A and B—Use standard loading dose, ↓ maintenance dose by 50%; Child-Pugh Class C—Not recommended.

Availability (generic available)

Tablets: 50 mg, 200 mg
Oral suspensionorange: 40 mg/mL
Powder for injection (requires reconstitution): 200 mg/vial

Nursing implications

Nursing assessment

  • Monitor for signs and symptoms of fungal infections prior to and during therapy.
  • Obtain specimens for culture and histopathology prior to therapy to isolate and identify organism. Therapy may be started before results are received.
  • Monitor visual function including visual acuity, visual field, and color perception in patients receiving more than 28 days of therapy. Vision usually returns to normal within 14 days after discontinuation of therapy.
  • Monitor for allergic reactions during infusion of voriconazole (flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, rash). Symptoms occur immediately upon start of infusion. May require discontinuation.
  • Monitor patients with risk factors for acute pancreatitis (recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) for the signs of pancreatitis (abdominal pain, ↑ serum amylase and lipase).
  • Assess for rash periodically during therapy. May cause Stevens-Johnson syndrome. Discontinue therapy if severe or if accompanied with fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis and/or eosinophilia.
  • Lab Test Considerations: Monitor liver function tests prior to and during therapy. If abnormal liver function tests occur, monitor for development of severe hepatic injury. Discontinue therapy if clinical signs and symptoms of liver disease develop.
    • Monitor renal function (serum creatinine) during therapy.

Potential Nursing Diagnoses

Risk for infection (Indications)

Implementation

  • Once patient can tolerate oral medication, PO voriconazole may be used.
  • Correct electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia) prior to initiation therapy.
  • Oral: Administer 1 hr before or 1 hr after a meal.
    • Shake suspension well (approximately 10 seconds) before measuring suspension. Do not mix suspension with other medicine, flavored liquid, or syrup.
  • Intravenous Administration
  • pH: 6.0–7.0.
  • Intermittent Infusion: Reconstitute each 200-mg vial with 19 mL of sterile water for injection to achieve concentration of 10 mg/mL. Calculate volume of 10 mg/mL solution required for patient dose. Diluent: Withdraw and discard equal volume of diluent from infusion bag or bottle to be used. Withdraw required volume of voriconazole solution from vial(s) and add to appropriate volume of 0.9% NaCl, LR, D5/LR, D5/0.45% NaCl, D5W, 0.45% NaCl, or D5/0.9% NaCl. Reconstituted solution stable for 24 hr if refrigerated. Discard partially used vials.Concentration: Final concentration of infusion should be 0.5–5 mg/mL.
  • Rate: Infuse over 1–2 hr at a rate not to exceed 3 mg/kg/hr.
  • Y-Site Compatibility: acyclovir, alemtuzumab, alfentanil, allopurinol, amifostine, amikacin, aminophylline, amiodarone, amphotericin B liposome, ampicillin, ampicillin/sulbactam, anidulafungin, argatroban, azithromycin, aztreonam, bivalirudin, bleomycin, buprenorphine, butorphanol, bumetanide, buprenorphine, butorphanol, calcium acetate, calcium chloride, calcium gluconate, carboplatin, carmustine, caspofungin, cefazolin, cefotaxime, cefotetan, cefoxitin, ceftaroline, ceftazidime, ceftriaxone, chloramphenicol, chlorpromazine, ciprofloxacin, cisatracurium, cisplatin, clindamycin, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daptomycin, daunorubicin, dexamethasone, dexmedetomidine, dexrazoxane, digoxin, diltiazem, diphenhydramine, dobutamine, docetaxel, dolasetron, dopamine, doripenem, doxacurium, doxycycline, droperidol, enalaprilat, ephedrine, epinephrine, epirubicin, ertapenem, erythromycin, esmolol, etoposide, etoposide phosphate, famotidine, fenoldopam, fentanyl, fluconazole, fludarabine, fluorouracil, foscarnet, fosphenytoin, furosemide, ganciclovir, gemcitabine, gentamicin, glycopyrrolate, granisetron, haloperidol, heparin, hydralazine, hydrocortisone, ifosfamide, imipenem/cilastatin, insulin, irinotecan, isoproterenol, ketorolac, labetalol, leucovorin, levofloxacin, lidocaine, linezolid, lorazepam, magnesium sulfate, mannitol, mechlorethamine, melphalan, meperidine, meropenem, mesna, metaraminol, methohexital, methotrexate, methyldopate, methylprednisolone, metioclopramide, metoprolol, metronidazole, midazolam, milrinone, mitomycin, morphine, mycophenolate, nafcillin, nalbuphine, naloxone, nicardipine, nitroglycerin, norepinephrine, octreotide, ondansetron, oxaliplatin, oxytocin, paclitaxel, pamidronate, pancuronium, pentamidine, pentazocine, pentobarbital, phenobarbital, phentolamine, phenylephrine, piperacillin/tazobactam, potassium acetate, potassium chloride, potassium phosphates, procainamide, promethazine, propranolol, quinupristin/dalfopristin, remifentanil, rocuronium, sodium acetate, sodium bicarbonate, sodium phosphates, streptozocin, succinylcholine, sufentanil, tacrolimus, teniposide, theophylline, thiotepa, ticarcillin/clavulanate, tirofiban, tobramycin, topotecan, trimethoprim/sulfamethoxazole, vancomycin, vasopressin, vecuronium, verapamil, vinblastine, vincristine, vinorelbine, zidovudine, zoledronic acid
  • Y-Site Incompatibility: amphotericin B colloidal, amphotericin B lipid complex, busulfan, cefepime, cyclosporine, dantrolene, diazepam, doxorubicin, idarubicin, mitoxantrone, moxifloxacin, nitroprusside, pantoprazole, phenytoin, thiopental

Patient/Family Teaching

  • Advise patient to take voriconazole as directed, on an empty stomach.
  • May cause blurred vision, photophobia, and dizziness. Caution patient to avoid driving and other activities requiring alertness until response to medication is known. Also advise patient to avoid driving at night during voriconazole therapy.
  • Advise patient to avoid direct sunlight, sunlamps and tanning beds during voriconazole therapy. Use sunscreen and protective clothing to prevent severe sunburn.
  • Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications.
  • Advise patient to notify health care professional if rash or signs and symptoms of allergic reaction occur.
  • Advise women of childbearing age to use contraception and notify health care professional if pregnancy is planned or suspected or if breast feeding. If pregnancy is detected, discontinue medication as soon as possible.

Evaluation/Desired Outcomes

  • Resolution of fungal infections.

Vfend

A brand name for VORICONAZOLE.
References in periodicals archive ?
Vfend was initially approved in the US for the primary treatment of acute invasive aspergillosis and salvage therapy for rare but serious infections caused by the pathogens Scedosporium apiospermum and Flusarium spp.
Astellas Pharma s Cresemba (isavuconazonium) treatment, a once-daily drug for Aspergillosis, is found to be more useful and safer in comparison with the Vfend of Pfizer.
percent); infectious and respiratory diseases (Zyvox up 33 percent, Vfend up
34 percent), Geodon (up 32 percent), and Vfend (up 28 percent).
NYSE:PFE) today reported the top-line results of an international Phase III clinical trial which compared the combination of VFEND([R]) (voriconazole) and ERAXIS(TM) (anidulafungin) to VFEND monotherapy for primary therapy of invasive aspergillosis (IA), a life-threatening invasive fungal infection that can develop as a complication in patients with compromised immune systems.
Diflucan followed by the launch of Vfend, another important antifungal, in
including Geodon (+56 percent), Relpax (+77 percent), Vfend (+38 percent), and
s (NYSE: MRK-Free Report) Cancidas (intravenous) followed by Vfend (oral) for the treatment of candidemia and other invasive candida infections.
Rebif, for the treatment of multiple sclerosis; Vfend, with a new
percent), Relpax (up 99 percent), Vfend (up 44 percent), and other key
The basis for the approval of VFEND to treat candidemia in nonneutropenic