Pfizer Corporation Hong Kong Limited 美國輝瑞科研製藥

Indications¹

Vfend™ is indicated for the treatment of invasive aspergillosis, candidemia in non-neutropenic patients, fluconazole-resistant serious invasive Candida infections (including Candida krusei), esophageal candidiasis, serious fungal infections caused by Scedosporium spp. and Fusarium spp.; it should be administered primarily to patients with progressive, possibly life threatening infections.

Clinical Evidence

Superior efficacy as initial therapy against invasive aspergillosis versus amphotericin B²
- Successful outcomes in 52.8% of patients in the voriconazole group compared with 31.6% in the amphotericin B group (21.2% absolute difference, 95% confidence interval [CI] 10.4–32.9)²
- Patients included those with acute leukemia, allogeneic bone marrow transplantation and other hematologic diseases²
- Improved survival rate in the voriconazole group (70.8%) versus that of the amphotericin B group (57.9%) at Week 12 (hazard ratio 0.59; 95% CI 0.40–0.88)²
- Voriconazole was more effective than amphotericin B at Week 12 irrespective of the site of infection or presence of neutropenia at baseline²
* Defined as complete or partial responses; 95% CI 10.4-32.9; stratified according to study Note: Results are based on a randomized, unblinded trial comparing the response and survival rates of patients receiving either intravenous (IV) Vfend™ (N=144; initial day 1 dosage of 6 mg/kg bid followed by 4 mg/kg bid for at least 7 days) or IV amphotericin B deoxycholate (1-1.5 mg/kg/d; n=133). The planned duration of initial randomized therapy in the Global Comparative Aspergillosis Study (GCAS) was 12 weeks with an additional 4-week follow-up period. Study cohorts evaluated in this trial were the intent-to-treat (ITT) and modified ITT (mITT) populations. The primary end point of this trial was to demonstrate non-inferiority of Vfend™ compared with amphotericin B at week 12 in the mITT population.

In non-neutropenic patients with candidemia (ie, C. albicans and non-albicans spp.), Vfend™ is as effective as sequential treatment with amphotericin B followed by fluconazole³
- Recommended as primary treatment of invasive aspergillosis by the Infectious Diseases Society of America (IDSA)⁴
- The only recommended drug supported by grade A1 level of evidence in the Third European Conference on Infections in Leukemia (ECIL-3) guidelines for the primary treatment of invasive pulmonary aspergillosis^5-7
- Active against fluconazole-resistant serious Candida spp.^1,8
*Sustained success as assessed by data-review committee at 12-week follow-up visit only; NS, not significant Note: Results are based on a multicenter, randomized trial comparing the efficacy of VfendTM (n=283) with a regimen of amphotericin B followed by fluconazole (n=139) for the treatment of candidemia in non-neutropenic patients [VfendTM (n=248) IV 6 mg/kg q12h on the first day, and then 3 mg/kg q12h]. After 3 days, patients could be switched to oral VfendTM 200 mg bid. In this randomized study, non-neutropenic patients were give amphotericin B (0.7-1.0 mg/kg/d) infused over 2 to 6 hours and then replaced by oral or IV fluconazole at 400 mg/d after a minimum of 3 days and a maximum of 7 days (n=122). Evaluation of efficacy was performed on the modified-intent-to-treat (mITT) population. The primary objective of the trial was to demonstrate the non-inferiority of VFENDTM to amphotericin B/fluconazole combination treatment in the mITT population.

Safety Profile¹

VERY COMMON AND COMMON ADVERSE REACTIONS: The most commonly reported adverse events were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema and abdominal pain. Other common adverse events included sinusitis, thrombocytopenia, anemia (ie, macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia, hypokalemia, hypoglycemia, hallucinations, confusion, depression, anxiety, agitation, dizziness, tremor, paresthesia, lung edema, hypotension, thrombophlebitis, phlebitis, respiratory distress syndrome, cheilitis, gastroenteritis, elevated liver function tests (including SGOT [AST], SGPT[ALT], alkaline phosphatase, GGT, LDH, bilirubin), jaundice, cholestatic jaundice, face edema, pruritus, maculopapular rash, photosensitivity skin reaction, alopecia, exfoliative dermatitis, purpura, back pain, increased creatinine, acute kidney failure, hematuria, chills, asthenia, chest pain, injection site reaction/inflammation, flu syndrome.

INTERACTIONS: Inhibitors or inducers of CYP450 isoenzymes (CYP2C19, CYP2C9 and CYP3A4 inhibitors and/or inducers (IMPORTANT: Please refer to Section 4.5 in the full prescribing information1)

Dosage and Administration¹

For adults^a
Dosing	IV	Oral
Dosing	IV	Patients ≥40 kg	Patients <40 kg
Loading dose (first 24 h)^b,#	6 mg/kg q12h	400 mg q12h	200 mg q12h
Maintenance dose (after 24 h)	4 mg/kg q12h^b,c	200 mg q12h^d	100 mg q12h^d
If inadequate response, maintenance dose may be increased to:		300 mg q12h^e	150 mg q12h^e
For children aged 2 to <12 years
	IV	Oral
Loading dosing regimen	No oral or IV loading dose is recommended
Maintenance dose^f	7mg/kg twice daily ^g	200 mg twice daily

#The loading dose of VfendTM allows steady state to be reached by the end of day 1
^a Adolescents (≥ 12 years) should be dosed as adults; ^b Not evaluated in patients with esophageal candidiasis; ^c if patients are unable to tolerate treatment, reduce to a minimum of 3mg/kg q12h; ^dFor esophageal candidiasis, patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms; ^e If patients are unable to tolerate treatment at these higher doses, reduce the dose by 50 mg steps to original maintenance dose; ^f No recommended maintenance dosing regimen in pediatric patients aged 2 to <12 years for the indication of esophageal candidiasis; ^g If pediatric patients are unable to tolerate IV treatment, a dose reduction to 4 mg/kg twice daily may be considered; this provides equivalent exposure to 3 mg/kg twice daily in adults

Strengths¹

Film-coated tablet: 50 mg, 200 mg
Vial: 200 mg voriconazole (equivalent to a 10 mg/mL solution)

Packing¹

Film-coated tablets: 50 mg x 14’s, 200 mg x 14’s
Vial: 200 mg x 1’s

Important Safety Information¹

CONTRAINDICATIONS: Hypersensitivity to voriconazole and its excipients. Coadministration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine, sirolimus, rifampicin, carbamazepine and long-acting barbiturates, high-dose ritonavir (400mg and above b.i.d), ergot alkaloids or St. John’s Wort is contraindicated.

SPECIAL PRECAUTIONS: Hypersensitivity; cardiac, visual, renal, pancreatic and dermatological adverse events; Infusion-related reaction; Hepatic toxicity; Pediatric use.

VERY COMMON AND COMMON ADVERSE REACTIONS: The most commonly reported adverse events were visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, peripheral edema and abdominal pain. Other common adverse events included sinusitis, thrombocytopenia, anemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia, hypokalemia, hypoglycemia, hallucinations, confusion, depression, anxiety, agitation, dizziness, tremor, paresthesia, lung edema, hypotension, thrombophlebitis, phlebitis, respiratory distress syndrome, cheilitis, gastroenteritis, elevated liver function tests (including SGOT [AST], SGPT[ALT], alkaline phosphatase, GGT, LDH, bilirubin), jaundice, cholestatic jaundice, face edema, pruritus, maculopapular rash, photosensitivity skin reaction, alopecia, exfoliative dermatitis, purpura, back pain, creatinine increased, acute kidney failure, hematuria, chills, asthenia, chest pain, injection site reaction/inflammation, flu syndrome.

POST-MARKETING ADVERSE REACTIONS: Higher occurrence of skin reactions among the pediatric population compared with adults; pancreatitis in pediatric patients; prolonged visual adverse events.

PREGNANCY and LACTATION: No adequate information is available. Animal studies have shown reproductive toxicity at high doses. It must not be used during pregnancy unless benefits to the mother clearly outweigh the potential risk to the fetus. Women with child-bearing potential must always use effective contraception during treatment. Breastfeeding must be stopped on initiation of treatment with Vfend™.

Please refer to the full prescribing information for more safety information.

Please review the full product information or package insert before prescribing.

References

1. Vfend™ (voriconazole) Prescribing Information. Pfizer Corporation Hong Kong Ltd.: 17 April 2010.

2. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. Aug 8 2002;347(6):408-415.

3. Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet. Oct 22-28 2005;366(9495):1435-1442.

4. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. Feb 1 2008;46(3):327-360.

5. Herbrecht R, Fluckiger U, Gachot B, et al. Antifungal therapy in leukemia patients 2009 update of the ECIL1 and ECIL2 guidelines. Presented at: The Third European Conference on Infections in Leukemia; 25-26 September, 2009; Juan-les-Pins, France.

6. Herbrecht R, Flückiger U, Gachot B et al. Treatment of invasive candida and invasive aspergillus infections in adult haematological patients. Eur. J. Cancer 2007; supp 5:49–59.

7. Maertens J, Marchetti O, Herbrecht R et al.European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL3 – 2009 update. Bone Marrow Transplant. 2011; 46: 709–718.

8. Maschmeyer G & Haas A. Voriconazole: a broad spectrum triazole for the treatment of serious and invasive fungal infections. Future Microbiol 2006;1:365-385.

Please review the full product information or package insert before prescribing.

VFE11004P