VORITEK Injection (Voriconazole)

Table of Content

For the use of a Registered Medical Practitioner or a Hospital or a Laboratory only

Qualitative and Quantitative Composition

Each Combipack contains:

  1.  Voriconazole Injection I.P. 200 mg

Each vial contains:

Voriconazole I.P. …………………200 mg

Excipients………………………………q.s.

Name of Excipients:

Hydroxypropyl betadex U.S.P.,

Sodium Hydroxide I.P..,

Hydrochloric Acid l.P.

  1. Sterile Water for Injections I.P. 20 mL in an FFS Plastic Ampoule

Each Ampoule contains:

Sterile Water for Injections I.P.

Dosage Form(s) and Strength(s)

Lyophilized powder for intravenous (IV) infusion containing 200 mg of voriconazole.

Clinical Particulars

Therapeutic Indications

Voriconazole for IV injection is indicated for the treatment of the following fungal infections:

  • Invasive aspergillosis.
  • Esophageal candidiasis
  • Fluconazole-resistant serious invasive Candida infections (including C. krusei).
  • Serious fungal infections caused by Scedosporium apiospermum and Fusarium spp., including Fusarium solani
  • Candidemia in non-neutropenic patients and the following Candida infections: disseminated infections in skin and infections in abdomen, kidney, bladder wall, and wounds

Posology and Method of Administration

Posology

Adults

INVASIVE ASPERGILLOSIS AND SERIOUS FUNGAL INFECTIONS DUE TO FUSARIUM SPP. AND SCEDOSPORIUM APIOSPERMUM

See Table 1. Therapy must be initiated with the specified loading dose regimen of IV voriconazole on day 1 followed by the recommended maintenance dose (RMD) regimen. IV treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV. Switching between the IV and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults.

CANDIDEMIA IN NON-NEUTROPENIC PATIENTS AND OTHER DEEP-TISSUE CANDIDA INFECTIONS

See Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.

ESOPHAGEAL CANDIDIASIS

See Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.

Table 1: Recommended Dosing Regimen

Infection

Loading Dose
 IV

Maintenance Dosea,b

IV

Oralc

Invasive aspergillosisd

6 mg/kg q12h for the first 24 hours

4 mg/kg q12h

200 mg q12h

Candidemia in non-neutropenic patients and other deep-tissue Candida infections

6 mg/kg q12h for the first 24 hours

3 to 4 mg/kg
q12h e

200 mg q12h

Esophageal candidiasis

f

f

200 mg q12h

Scedosporiosis and Fusariosis
 

6 mg/kg q12h for the first 24 hours

4 mg/kg q12h

200 mg q12h

h, hours

a Increase dose when voriconazole is co-administered with phenytoin or efavirenz; decrease dose in
   patients with hepatic impairment.

b In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ) similar to a 
3 mg/kg IV q12h dose; the 300 mg oral q12h dose provided an exposure (AUCτ) similar to a 4 mg/kg IV q12h dose.

c Adult patients who weigh <40 kg should receive half of the oral maintenance dose.

d In a clinical study of invasive aspergillosis, the median duration of IV voriconazole therapy was 10 days (range, 2 to 85 days). The median duration of oral voriconazole therapy was 76 days (range, 2 to 232 days).

e In clinical trials, patients with candidemia received 3 mg/kg IV q12h as primary therapy, while patients with other deep-tissue Candida infections received 4 mg/kg q12h as salvage therapy. Appropriate dose should be based on the severity and nature of the infection.

f Not evaluated in patients with esophageal candidiasis.

METHOD FOR ADJUSTING THE DOSING REGIMEN IN ADULTS

If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).

If patient is unable to tolerate 4 mg/kg IV q12h, reduce the IV maintenance dose to 3 mg/kg every 12 hours.

Special Populations

PEDIATRIC POPULATION

The safety and efficacy of voriconazole in children <2 years of age have not been established.

Clinical data to establish the safety of IV hydroxypropylbeta Cyclodextrin (HPBCD) administered in the pediatric population are limited.

CHILDREN (AGED 2 TO <12 YEARS) AND YOUNG ADOLESCENTS WITH LOW BODY WEIGHT (AGED 12 TO 14 YEARS AND <50 KG)

Voriconazole should be dosed as done for children as these young adolescents may metabolize voriconazole more similarly to children than to adults.

The recommended dosing regimen is as mentioned in Table 2:

Table 2: Dosing Regimen for Children (aged 2 to <12 years) and Young Adolescents (aged 12 to 14 years and <50 kg)

 

IV

Oral

Loading Dose Regimen (first 24 hours)

9 mg/kg every 12 hours

Not recommended

Maintenance Dose (after the first 24 hours)

8 mg/kg twice daily

9 mg/kg twice daily (a maximum dose of 350 mg twice daily)

Note: Based on a population pharmacokinetic analysis in 112 immunocompromised pediatric patients aged 2 to <12 years and 26 immunocompromised adolescents aged 12 to <17 years.

It is recommended to initiate the therapy with the IV regimen, and the oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg IV dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

DOSE ADJUSTMENT

If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps. If patient is unable to tolerate treatment, reduce the dose by 1 mg/kg steps.

Use in pediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied. 

ALL OTHER ADOLESCENTS (AGED 12 TO 14 YEARS AND ≥50 KG; 15 TO 17 YEARS, REGARDLESS OF AGE)

Voriconazole should be dosed as in adult patients.

GERIATRIC USE
No dose adjustment is necessary for elderly patients.

DOSAGE MODIFICATIONS IN PATIENTS WITH HEPATIC IMPAIRMENT

ADULTS

The maintenance dose of voriconazole should be reduced in patients with mild-to-moderate hepatic impairment, Child-Pugh Class A and B. There are no pharmacokinetic data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C).

Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and clinical response.

In the clinical program, patients were included who had baseline liver function tests up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended.

It is advised that the recommended voriconazole loading dose regimens be used, but that the maintenance dose be halved in adult patients with mild-to-moderate hepatic cirrhosis (Child-Pugh Classes A and B).

Voriconazole has not been studied in adult patients with severe hepatic cirrhosis (Child- Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Voriconazole has been associated with elevations in liver function tests and with clinical signs of liver damage, such as jaundice. Voriconazole should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.

PEDIATRIC PATIENTS

Dosage adjustment of voriconazole in pediatric patients with hepatic impairment has not been established.

DOSAGE MODIFICATIONS IN PATIENTS WITH RENAL IMPAIRMENT

ADULTS

The pharmacokinetics of orally administered voriconazole is not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild-to-severe renal impairment.

In patients with moderate or severe renal impairment (creatinine clearance <50 mL/min) who are receiving an IV infusion of voriconazole for IV injection, accumulation of the IV vehicle, HPBCD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of IV voriconazole for IV injection. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy.  Use in patients who are not undergoing hemodialysis is not recommended.

Voriconazole is hemodialyzed with clearance of 121 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

The IV vehicle, HPBCD, is hemodialyzed with a clearance of 37.5 ± 24 mL/min.

PEDIATRIC PATIENTS

Dosage adjustment of voriconazole in pediatric patients with renal impairment has not been established.

DOSE ADJUSTMENTS IN CASE OF CO-ADMINISTRATION

Rifabutin or phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to IV 5 mg/kg twice daily.

Efavirenz may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e., to 300 mg once daily. When treatment with voriconazole is stopped, the initial dose of efavirenz should be restored.

Method of Preparation and Administration

Important Administration Instructions for Use in All Patients

Voriconazole for IV injection requires reconstitution to 10 mg/mL and subsequent dilution to 5 mg/mL or less prior to administration as an infusion, at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.

Administer diluted voriconazole for IV injection by IV infusion over 1 to 3 hours only. Do not administer as an IV bolus injection.

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy.

Use of Voriconazole for IV Injection with Other Parenteral Drug Products

Blood Products and Concentrated Electrolytes

Voriconazole for IV injection must not be infused concomitantly with any blood product or short-term infusion of concentrated electrolytes, even if the two infusions are running in separate IV lines (or cannulas). Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole for IV injection therapy.

IV Solutions Containing (Non-Concentrated) Electrolytes

Voriconazole for IV injection can be infused at the same time as other IV solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.

Total Parenteral Nutrition (TPN)

Voriconazole for IV injection can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole for IV injection.

Preparation and IV Administration of Voriconazole for IV Injection

Reconstitution

The powder is reconstituted with 19 mL of Sterile Water for Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19.0 mL) of Sterile Water for Injection is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial. Shake the vial until all the powder is dissolved.

Dilution

Voriconazole for IV injection must be infused over 1 to 3 hours, at a concentration of 5 mg/mL or less. Therefore, the required volume of the 10 mg/mL voriconazole for IV injection concentrate should be further diluted as follows (appropriate diluents listed below):

1. Calculate the volume of 10 mg/mL voriconazole for IV injection concentrate required based on the patient’s weight (see Table 3).

2. In order to allow the required volume of voriconazole for IV injection concentrate to be added, withdraw and discard at least an equal volume of diluent from the infusion bag or bottle to be used. The volume of diluent remaining in the bag or bottle should be such that when the 10 mg/mL voriconazole for IV injection concentrate is added, the final concentration is not less than 0.5 mg/mL nor greater than 5 mg/mL.

3. Using a syringe of suitable size and aseptic technique, withdraw the required volume of voriconazole for IV injection concentrate from the appropriate number of vials and add to the infusion bag or bottle. Discard partially used vials.

The final voriconazole for IV injection solution must be infused over 1 to 3 hours at a maximum rate of 3 mg/kg per hour.

Table 3: Required Volumes of 10 mg/mL Voriconazole for Injection Concentrate

Body Weight (kg)

Volume of Voriconazole for Injection Concentrate (10 mg/mL) Required for:

3 mg/kg Dose (number of vials)

4 mg/kg Dose (number of vials)

6 mg/kg Dose (number of vials)

30

9.0 mL (1)

12.0 mL (1)

18.0 mL (1)

 

35

10.5 mL (1)

14.0 mL (1)

21.0 mL (2)

 

40

12.0 mL (1)

16.0 mL (1)

24.0 mL (2)

 

45

13.5 mL (1)

18.0 mL (1)

27.0 mL (2)

 

50

15.0 mL (1)

20.0 mL (1)

30.0 mL (2)

 

55

16.5 mL (1)

22.0 mL (2)

33.0 mL (2)

 

60

18.0 mL (1)

24.0 mL (2)

36.0 mL (2)

 

65

19.5 mL (1)

26.0 mL (2)

39.0 mL (2)

 

70

21.0 mL (2)

28.0 mL (2)

42.0 mL (3)

 

75

22.5 mL (2)

30.0 mL (2)

45.0 mL (3)

 

80

24.0 mL (2)

32.0 mL (2)

48.0 mL (3)

 

85

25.5 mL (2)

34.0 mL (2)

51.0 mL (3)

 

90

27.0 mL (2)

36.0 mL (2)

54.0 mL (3)

 

95

28.5 mL (2)

38.0 mL (2)

57.0 mL (3)

 

100

30.0 mL (2)

40.0 mL (2)

60.0 mL (3)

 

Voriconazole is a single-dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2° to 8°C (36° to 46°F). This medicinal product is for single use only and any unused solution should be discarded. Only clear solutions without particles should be used.

The reconstituted solution can be diluted with any of the following diluents:

  • 9 mg/mL (0.9%) Sodium Chloride Injection IP
  • Lactated Ringer’s Injection USP
  • 5% Dextrose and Lactated Ringer’s Injection USP
  • 5% Dextrose and 0.45% Sodium Chloride Injection IP
  • 5% Dextrose IP
  • 5% Dextrose and 20 mEq Potassium Chloride Injection USP
  • 0.45% Sodium Chloride Injection IP

The compatibility of voriconazole with diluents other than those described above and those mentioned under INCOMPATIBILITY is unknown.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Contraindications

  • Voriconazole is contraindicated in patients with known hypersensitivity to voriconazole or its excipients. There is no information regarding cross-sensitivity between voriconazole and other azole antifungal agents. Caution should be used when prescribing voriconazole to patients with hypersensitivity to other azoles.
  • Co-administration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine with voriconazole is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsades de pointes.
  • Co-administration of voriconazole with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations.
  • Co-administration of voriconazole with rifampicin, carbamazepine and long-acting barbiturates is contraindicated since these drugs are likely to decrease plasma voriconazole concentrations significantly.
  • Co-administration of standard doses of voriconazole with efavirenz doses of 400 mg q24h or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations.
  • Co-administration of voriconazole for IV injection with high-dose ritonavir (400 mg every 12 hours) is contraindicated because ritonavir (400 mg every 12 hours) significantly decreases plasma voriconazole concentrations. Co-administration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
  • Co-administration of voriconazole with rifabutin is contraindicated since voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases voriconazole plasma concentrations.
  • Co-administration of voriconazole with ergot alkaloids (ergotamine and dihydroergotamine), is contraindicated because voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism.
  • Co-administration of voriconazole with St. John’s wort is contraindicated because this herbal supplement may decrease voriconazole plasma concentration.
  • Co-administration of voriconazole for IV injection with naloxegol is contraindicated because voriconazole for IV injection may increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms.
  • Co-administration of voriconazole for IV injection with tolvaptan is contraindicated because voriconazole for IV injection may increase tolvaptan plasma concentrations and increase risk of adverse reactions.
  • Co-administration of voriconazole for IV injection with venetoclax at initiation and during the ramp-up phase is contraindicated in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for increased risk of tumor lysis syndrome.

Special Warnings and Precautions for Use

Hypersensitivity

Caution should be used in prescribing VORITEK IV to patients with a hypersensitivity to other azoles.

Duration of IV Treatment

The duration of treatment with the IV formulation should be no longer than 6 months. 

Hepatic Toxicity

In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy.

A higher frequency of liver enzyme elevations was observed in the pediatric population. Hepatic function should be monitored in both adult and pediatric patients.

Measure serum transaminase levels and bilirubin at the initiation of voriconazole therapy and monitor at least weekly for the first month of treatment. Monitoring frequency can be reduced to monthly during continued use if no clinically significant changes are noted. If liver function tests become markedly elevated compared with baseline, voriconazole should be discontinued unless the medical judgment of the benefit/risk of the treatment for the patient justifies continued use.

Visual Disturbances

The effect of voriconazole on visual function is not known if treatment continues beyond 28 days. There have been postmarketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function (including visual acuity, visual field and color perception) should be monitored.

Arrhythmias and QT Prolongation

Some azoles, including voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and postmarketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsades de pointes), cardiac arrests and sudden deaths in patients taking voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.

Voriconazole should be administered with caution to patients with potentially pro-arrhythmic conditions, such as the following:

  • Congenital or acquired QT prolongation.
  • Cardiomyopathy, in particular when heart failure is present.
  • Sinus bradycardia.
  • Existing symptomatic arrhythmias.
  • Concomitant medicinal product that is known to prolong the QT interval.

Rigorous attempts to correct potassium, magnesium and calcium should be made before starting and during voriconazole therapy.

Infusion-related Reactions

During infusion of the IV formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus and rash, have occurred uncommonly. Symptoms appeared immediately upon initiating the infusion. Consideration should be given to stopping the infusion should these reactions occur.

Laboratory Tests

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of and during voriconazole therapy.

Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).

Renal Toxicity

Acute renal failure has been observed in patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Pancreatitis

Pancreatitis has been observed in patients undergoing treatment with voriconazole for IV injection. Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation ) should be monitored for the development of pancreatitis during voriconazole for IV injection treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Severe Cutaneous Adverse Reactions

Serious cutaneous reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported during treatment with voriconazole for IV injection. If a patient develops an exfoliative cutaneous reaction, voriconazole should be discontinued.

Photosensitivity

Voriconazole has been associated with photosensitivity skin reaction. Patients, including children, should avoid exposure to direct sunlight during voriconazole treatment and should use measures such as protective clothing and sunscreen with high sun protection factor (SPF). If phototoxic reactions occur, the patient should be referred to a dermatologist and voriconazole discontinuation should be considered. If voriconazole is continued despite the occurrence of phototoxicity-related lesions, dermatologic evaluation should be performed on a systematic and regular basis to allow early detection and management of premalignant lesions. Squamous cell carcinoma of the skin and melanoma has been reported during long-term voriconazole therapy in patients with photosensitivity skin reactions. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole should be discontinued. In addition, voriconazole for IV injection has been associated with photosensitivity-related skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus. Patients should avoid strong, direct sunlight during voriconazole for IV injection therapy.

The frequency of phototoxicity reactions is higher in the pediatric population. Because squamous cell carcinoma has been reported in patients who experience photosensitivity reactions, stringent measures for photoprotection are warranted in children. In children experiencing photo-aging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Skeletal Adverse Reactions

Fluorosis and periostitis have been reported during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, voriconazole should be discontinued.

Sodium Content

Each vial of VORITEK IV contains sodium. Voriconazole is considered high in sodium. This should be taken into account for those on a low-salt diet.

HPBCD (Hydroxypropylbeta Cyclodextrin)

In children less than 2 years, the lower glomerular function may protect against renal toxicity, but can lead to higher blood levels of cyclodextrins. In patients with moderate–to-severe renal dysfunction accumulation of cyclodextrins may occur.

Adrenal Dysfunction

Reversible cases of azole-induced adrenal insufficiency have been reported in patients receiving azoles, including voriconazole for IV injection. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression. Cushing’s syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole for IV injection concomitantly with corticosteroids.

Patients receiving voriconazole for IV injection and corticosteroids (via all routes of administration) should be carefully monitored for adrenal dysfunction both during and after voriconazole for IV injection treatment. Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency.

Embryo-Fetal Toxicity

Voriconazole can cause fetal harm when administered to a pregnant woman.

In animals, voriconazole administration was associated with fetal malformations, embryotoxicity, increased gestational length, dystocia and embryomortality.

If voriconazole for IV injection is used during pregnancy, or if the patient becomes pregnant while taking voriconazole for IV injection, inform the patient of the potential hazard to the fetus. Advise females of reproductive potential to use effective contraception during treatment with voriconazole for IV injection.

Long-Term Treatment

Long-term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessment of the benefit/risk balance and physicians should, therefore, consider the need to limit the exposure to voriconazole.

Squamous cell carcinoma of the skin has been reported in relation with long-term voriconazole treatment.

Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis, voriconazole discontinuation should be considered after multidisciplinary advice.

Clinically Significant Drug Interactions

See Table 4 for a listing of drugs that may significantly alter voriconazole concentrations. Also, see Table 5 for a listing of drugs that may interact with voriconazole, resulting in altered pharmacokinetics or pharmacodynamics of the other drug.

Drug Interactions

Voriconazole is metabolized by, and inhibits the activity of, CYP450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolized by these CYP450 isoenzymes, in particular for substances metabolised by CYP3A4 since voriconazole is a strong CYP3A4 inhibitor though the increase in the area under the curve (AUC) is substrate-dependent.

Unless otherwise specified, interaction studies with other medicinal products have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID). These results are relevant to other populations and routes of administration.

Voriconazole should be administered with caution in patients with concomitant medicinal product that is known to prolong QTc interval. When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide), co-administration is contraindicated.

Tables 4 and 5 provide the clinically significant interactions between voriconazole and other medical products.

Table 4: Effect of Other Drugs on Voriconazole Pharmacokinetics

Drug/Drug Class (Mechanism of Interaction by the Drug)

Voriconazole Plasma Exposure (Cmax and AUCτafter 200 mg every 12 hours)

Recommendations for Voriconazole Dosage Adjustment/Comments

Rifampin* and Rifabutin* (CYP450 Induction)

Significantly reduced

Contraindicated

Efavirenz (400 mg every 24 hours)** (CYP450 Induction)

 

Efavirenz (300 mg every 24 hours)** (CYP450 Induction)

Significantly reduced

 

 

Slight decrease in AUCτ

Contraindicated

 

 

When voriconazole is co-administered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.

High-Dose Ritonavir (400 mg every 12 hours)** (CYP450 Induction)

 

Low-Dose Ritonavir (100 mg every 12 hours)** (CYP450 Induction)

Significantly reduced

 

 

 

Reduced

Contraindicated

 

 

 

Co-administration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Carbamazepine (CYP450 Induction)

Not studied in vivo or in vitro, but likely to result in significant reduction

Contraindicated

Long-acting Barbiturates (e.g., phenobarbital, mephobarbital) (CYP450 Induction)

Not studied in vivo or in vitro, but likely to result in significant reduction

Contraindicated

Phenytoin* (CYP450 Induction)

Significantly reduced

Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hours or from 200 mg to 400 mg orally every 12 hours (100 mg to 200 mg orally every 12 hours in patients weighing less than 40 kg).

Letermovir (CYP2C9/2C19 Induction)

Reduced

If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for reduced effectiveness of voriconazole.

St. John’s wort (CYP450 inducer; P-gp inducer)

Significantly reduced

Contraindicated

Oral Contraceptives** Containing Ethinyl Estradiol and Norethindrone (CYP2C19 Inhibition)

Increased

Monitoring for adverse events and toxicity related to voriconazole is recommended when co-administered with oral contraceptives.

Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)

Significantly increased

Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole.

Other HIV Protease Inhibitors (CYP3A4 Inhibition)

In vivo studies showed no significant effects of indinavir on voriconazole exposure

 

 

 

In vitro studies demonstrated potential for inhibition of voriconazole metabolism (increased plasma exposure)

No dosage adjustment in the voriconazole dosage needed when co-administered with indinavir.

 

Frequent monitoring for adverse events and toxicity related to voriconazole when co-administered with other HIV protease inhibitors.

Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)

In vitro studies demonstrated potential for inhibition of voriconazole metabolism by delavirdine and other NNRTIS (increased plasma exposure)

 

A voriconazole-efavirenz drug interaction study demonstrated the potential for the metabolism of voriconazole to be induced by efavirenz and other NNRTIS (decreased plasma exposure)

Frequent monitoring for adverse events and toxicity related to voriconazole.

 

 

Careful assessment of voriconazole effectiveness.

* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12 hours voriconazole to healthy subjects

** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects

*** Non-nucleoside reverse transcriptase inhibitors

Table 5: Effect of Voriconazole on Pharmacokinetics of Other Drugs

Drug/Drug Class (Mechanism of Interaction by Voriconazole)

Drug Plasma Exposure (Cmax and AUCτ)

Recommendations for Drug Dosage Adjustment/Comments

Sirolimus* (CYP3A4 Inhibition)

Significantly increased

Contraindicated

Rifabutin* (CYP3A4 Inhibition)

Significantly increased

Contraindicated

Efavirenz (400 mg every 24 hours)** (CYP3A4 Inhibition)

 

Efavirenz (300 mg every 24 hours)** (CYP3A4 Inhibition)

Significantly increased

 

 

Slight Increase in AUCτ

Contraindicated

 

When voriconazole is co-administered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12 hours and efavirenz should be decreased to 300 mg every 24 hours.

High-Dose Ritonavir (400 mg every 12 hours)**(CYP3A4 Inhibition) Low-Dose Ritonavir (100 mg every 12 hours)**

No significant effect of voriconazole on ritonavir Cmax or AUCτ slight decrease in ritonavir Cmax and AUCτ

Contraindicated because of significant reduction of voriconazole Cmax and AUCτ. Co-administration of voriconazole and low-dose ritonavir (100 mg every 12 hours) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Cisapride, Pimozide, Quinidine, Ivabradine (CYP3A4 Inhibition)

Not studied in vivo or in vitro, but drug plasma exposure likely to be increased

Contraindicated because of potential for QT prolongation and rare occurrence of torsades de pointes.

Ergot Alkaloids (CYP450 Inhibition)

Not studied in vivo or in vitro, but drug plasma exposure likely to be increased

Contraindicated

Naloxegol (CYP3A4 Inhibition)

Not studied in vivo or in vitro, but drug plasma exposure likely to be increased which may increase the risk of adverse reactions

Contraindicated

Tolvaptan (CYP3A4 Inhibition)

Although not studied clinically, voriconazole is likely to significantly increase the plasma concentrations of tolvaptan

Contraindicated

Venetoclax (CYP3A4 Inhibition)

Not studied in vivo or in vitro, but venetoclax plasma exposure likely to be significantly increased

Co-administration of voriconazole is contraindicated at initiation and during the ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Refer to the venetoclax labeling for safety monitoring and dose reduction in the steady daily dosing phase in CLL/SLL patients.

 

For patients with acute myeloid leukemia, dose reduction and safety monitoring are recommended across all dosing phases when co-administering voriconazole with venetoclax. Refer to the venetoclax prescribing information for dosing instructions.

Cyclosporine* (CYP3A4 Inhibition)

AUCτ significantly increased; no significant effect on Cmax

When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.

Methadone*** (CYP3A4 Inhibition)

Increased

Increased plasma concentrations of methadone have been associated with toxicity, including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during co-administration. Dose reduction of methadone may be needed.

Fentanyl (CYP3A4 Inhibition)

Increased

Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when co-administered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary.

Alfentanil (CYP3A4 Inhibition)

Significantly increased

An increase in the incidence of delayed and persistent alfentanil-associated nausea and vomiting were observed when co-administered with voriconazole. Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when co-administered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary.

Oxycodone (CYP3A4 Inhibition)

Significantly increased

Increased visual effects (heterophoria and miosis) of oxycodone were observed when co-administered with voriconazole. Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when co-administered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary.

NSAIDs****, including ibuprofen and diclofenac (CYP2C9 Inhibition)

Increased

Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed.

Tacrolimus* (CYP3A4 Inhibition)

Significantly increased

When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.

Phenytoin* (CYP2C9 Inhibition)

Significantly increased

Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.

Oral Contraceptives Containing Ethinyl Estradiol and Norethindrone (CYP3A4 Inhibition)**

Increased

Monitoring for adverse events related to oral contraceptives is recommended during co-administration.

Prednisolone and Other Corticosteroids (CYP3A4 Inhibition)

In vivo studies showed no significant effects of voriconazole on prednisolone exposure not studied in vitro or in vivo for other corticosteroids, but drug exposure likely to be increased

No dosage adjustment for prednisolone when co-administered with voriconazole. Monitor for potential adrenal dysfunction when voriconazole is administered with other corticosteroids .

Warfarin* (CYP2C9 Inhibition) Other Oral Coumarin Anticoagulants (CYP2C9/3A4 Inhibition)

Prothrombin time significantly increased not studied in vivo or in vitro for other oral coumarin anticoagulants, but drug plasma exposure likely to be increased

If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time or other suitable anticoagulation tests should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.

Ivacaftor (CYP3A4 Inhibition)

Not studied in vivo or in vitro, but drug plasma exposure likely to be increased which may increase the risk of adverse reactions

Dose reduction of ivacaftor is recommended. Refer to the prescribing information for ivacaftor.

Omeprazole* (CYP2C19/3A4 Inhibition)

Significantly increased

When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton-pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton-pump inhibitors.

Other HIV Protease Inhibitors (CYP3A4 Inhibition)

In vivo studies showed no significant effects on indinavir exposure in vitro studies demonstrated potential for voriconazole to inhibit metabolism (increased plasma exposure)

No dosage adjustment for indinavir when co-administered with voriconazole. Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors.

Other NNRTIs***** (CYP3A4 Inhibition)

A voriconazole-efavirenz drug interaction study demonstrated the potential for voriconazole to inhibit metabolism of other nnrtis (increased plasma exposure)

Frequent monitoring for adverse events and toxicity related to NNRTIs.

Benzodiazepines (CYP3A4 Inhibition)

In vitro studies demonstrated potential for voriconazole to inhibit metabolism (increased plasma exposure)

Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.

HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)

In vitro studies demonstrated potential for voriconazole to inhibit metabolism (increased plasma exposure)

Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.

Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)

In vitro studies demonstrated potential for voriconazole to inhibit metabolism (increased plasma exposure)

Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.

Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)

Not studied in vivo or in vitro, but drug plasma exposure likely to be increased

Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.

Vinca Alkaloids (CYP3A4 Inhibition)

Not studied in vivo or in vitro, but drug plasma exposure likely to be increased

Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.

Everolimus (CYP3A4 Inhibition)

Not studied in vivo or in vitro, but drug plasma exposure likely to be increased

Concomitant administration of voriconazole and everolimus is not recommended.

* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects

** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for at least 2 days voriconazole to healthy subjects

*** Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg every 24 hours)

**** Non-steroidal anti-inflammatory drug

***** Non-nucleoside reverse transcriptase inhibitors

Drug Interaction Studies

Effects of Other Drugs on Voriconazole

Voriconazole is metabolized by the human hepatic cytochrome (CY) P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Results of in vitro metabolism studies indicate that the affinity of voriconazole is highest for CYP2C19, followed by CYP2C9, and is appreciably lower for CYP3A4. Inhibitors or inducers of these three enzymes may increase or decrease voriconazole systemic exposure (plasma concentrations), respectively.

The systemic exposure to voriconazole is significantly reduced by the concomitant administration of the following agents and their use is contraindicated:

• Rifampin (potent CYP450 inducer): Rifampin (600 mg once daily) decreased the steady state Cmax and AUCτ of voriconazole (200 mg every 12 hours x 7 days) by an average of 93% and 96%, respectively, in healthy subjects. Doubling the dose of voriconazole to 400 mg every 12 hours does not restore adequate exposure to voriconazole during co-administration with rifampin.

• Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the co-administration of voriconazole and ritonavir (400 mg and 100 mg) was investigated in two separate studies. High-dose ritonavir (400 mg every 12 hours for 9 days) decreased the steady state Cmax and AUCτ of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 66% and 82%, respectively, in healthy subjects. Low-dose ritonavir (100 mg every 12 hours for 9 days) decreased the steady state Cmax and AUCτ of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) by an average of 24% and 39%, respectively, in healthy subjects. Although repeat oral administration of voriconazole did not have a significant effect on steady state Cmax and AUCτ of high-dose ritonavir in healthy subjects, steady-state Cmax and AUCτ of low-dose ritonavir decreased slightly by 24% and 14%, respectively, when administered concomitantly with oral voriconazole in healthy subjects.

• St. John’s wort (CYP450 inducer; P-gp inducer): In an independent published study in healthy volunteers who were given multiple oral doses of St. John’s wort (300 mg LI 160 extract three times daily for 15 days) followed by a single 400 mg oral dose of voriconazole, a 59% decrease in mean voriconazole AUC0-inf was observed. In contrast, co-administration of single oral doses of St. John’s wort and voriconazole had no appreciable effect on voriconazole AUC0-inf. Long-term use of St. John’s wort could lead to reduced voriconazole exposure.

Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole-related adverse events/toxicity:

• Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Concurrent administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 2.5 days) and oral fluconazole (400 mg on day 1, then 200 mg every 24 hours for 4 days) to 6 healthy male subjects resulted in an increase in Cmax and AUCτ of voriconazole by an average of 57% (90% CI: 20%, 107%) and 79% (90% CI: 40%, 128%), respectively. In a follow-on clinical study involving 8 healthy male subjects, reduced dosing and/or frequency of voriconazole and fluconazole did not eliminate or diminish this effect.

• Letermovir (CYP2C9/2C19 inducer): Co-administration of oral letermovir with oral voriconazole decreased the steady state Cmax and AUC0-12 of voriconazole by an average of 39% and 44%, respectively.

Minor or no significant pharmacokinetic interactions that do not require dosage adjustment:

• Cimetidine (non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg every 12 hours x 8 days) increased voriconazole steady state Cmax and AUCτ by an average of 18% (90% CI: 6%, 32%) and 23% (90% CI: 13%, 33%), respectively, following oral doses of 200 mg every 12 hours x 7 days to healthy subjects.

• Ranitidine (increases gastric pH): Ranitidine (150 mg every 12 hours) had no significant effect on voriconazole Cmax and AUCτ following oral doses of 200 mg every 12 hours x 7 days to healthy subjects.

• Macrolide Antibiotics: Co-administration of erythromycin (CYP3A4 inhibitor; 1 gram every 12 hours for 7 days) or azithromycin (500 mg every 24 hours for 3 days) with voriconazole 200 mg every 12 hours for 14 days had no significant effect on voriconazole steady state Cmax and AUCτ in healthy subjects. The effects of voriconazole on the pharmacokinetics of either erythromycin or azithromycin are not known.

Effects of Voriconazole on Other Drugs

In vitro studies with human hepatic microsomes show that voriconazole inhibits the metabolic activity of the CYP450 enzymes CYP2C19, CYP2C9, and CYP3A4. In these studies, the inhibition potency of voriconazole for CYP3A4 metabolic activity was significantly less than that of two other azoles, ketoconazole and itraconazole. In vitro studies also show that the major metabolite of voriconazole, voriconazole N-oxide, inhibits the metabolic activity of CYP2C9 and CYP3A4 to a greater extent than that of CYP2C19. Therefore, there is potential for voriconazole and its major metabolite to increase the systemic exposure (plasma concentrations) of other drugs metabolized by these CYP450 enzymes.

The systemic exposure of the following drug is significantly increased by co-administration of voriconazole and their use is contraindicated:

• Sirolimus (CYP3A4 substrate): Repeat-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 7-fold (90% CI: 5.7, 7.5) and 11-fold (90% CI: 9.9, 12.6), respectively, in healthy male subjects .

Co-administration of voriconazole with the following agents results in increased exposure to these drugs. Therefore, careful monitoring and/or dosage adjustment of these drugs is needed:

• Alfentanil (CYP3A4 substrate): Co-administration of multiple doses of oral voriconazole (400 mg every 12 hours on day 1, 200 mg every 12 hours on day 2) with a single 20 mcg/kg IV dose of alfentanil with concomitant naloxone resulted in a 6-fold increase in mean alfentanil AUC0-inf and a 4-fold prolongation of mean alfentanil elimination half-life, compared to when alfentanil was given alone.

• Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of voriconazole (400 mg every 12 hours on day 1, then 200 mg every 12 hours on day 2) with a single IV dose of fentanyl (5 μg/kg) resulted in an increase in the mean AUC0-inf of fentanyl by 1.4-fold (range, 0.81- to 2.04-fold).

• Oxycodone (CYP3A4 substrate): In an independent published study, co-administration of multiple doses of oral voriconazole (400 mg every 12 hours, on day 1 followed by five doses of 200 mg every 12 hours on days 2 to 4) with a single 10 mg oral dose of oxycodone on day 3 resulted in an increase in the mean Cmax and AUC0-inf of oxycodone by 1.7-fold (range, 1.4- to 2.2-fold) and 3.6-fold (range, 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2.0-fold (range, 1.4- to 2.5-fold).

• Cyclosporine (CYP3A4 substrate): In stable renal transplant recipients receiving chronic cyclosporine therapy, concomitant administration of oral voriconazole (200 mg every 12 hours for 8 days) increased cyclosporine Cmax and AUCτ an average of 1.1 times (90% CI: 0.9, 1.41) and 1.7 times (90% CI: 1.5, 2.0), respectively, compared with when cyclosporine was administered without voriconazole.

• Methadone (CYP3A4, CYP2C19, CYP2C9 substrate): Repeat-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the Cmax and AUCτ of pharmacologically active R-methadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%), respectively, in subjects receiving a methadone maintenance dose (30 to100 mg every 24 hours). The Cmax and AUC of (S)-methadone increased by 65% (90% CI: 53%, 79%) and 103% (90% CI: 85%, 124%), respectively.

• Tacrolimus (CYP3A4 substrate): Repeat oral dose administration of voriconazole (400 mg every 12 hours x 1 day, then 200 mg every 12 hours x 6 days) increased tacrolimus (0.1 mg/kg single dose) Cmax and AUCτ in healthy subjects by an average of 2-fold (90% CI: 1.9, 2.5) and 3-fold (90% CI: 2.7, 3.8), respectively.

• Warfarin (CYP2C9 substrate): Co-administration of voriconazole (300 mg every 12 hours x 12 days) with warfarin (30 mg single dose) significantly increased maximum prothrombin time by approximately 2 times that of placebo in healthy subjects.

• Non-Steroidal Anti-Inflammatory Drugs (; CYP2C9 substrates): In two independent published studies, single doses of ibuprofen (400 mg) and diclofenac (50 mg) were co-administered with the last dose of voriconazole (400 mg every 12 hours on day 1, followed by 200 mg every 12 hours on day 2). Voriconazole increased the mean Cmax and AUC of the pharmacologically active isomer, S (+)-ibuprofen by 20% and 100%, respectively. Voriconazole increased the mean Cmax and AUC of diclofenac by 114% and 78%, respectively.

No significant pharmacokinetic interactions were observed when voriconazole was co-administered with the following agents. Therefore, no dosage adjustment for these agents is recommended:

• Prednisolone (CYP3A4 substrate): Voriconazole (200 mg every 12 hours x 30 days) increased Cmax and AUC of prednisolone (60 mg single dose) by an average of 11% and 34%, respectively, in healthy subjects.

• Digoxin (P-glycoprotein-mediated transport): Voriconazole (200 mg every 12 hours x 12 days) had no significant effect on steady-state Cmax and AUCτ of digoxin (0.25 mg once daily for 10 days) in healthy subjects.

• Mycophenolic Acid (UDP-glucuronyl transferase substrate): Voriconazole (200 mg every 12 hours x 5 days) had no significant effect on the Cmax and AUCτ of mycophenolic acid and its major metabolite, mycophenolic acid glucuronide after administration of a 1 gram single oral dose of mycophenolate mofetil.

Two-Way Interactions

Concomitant use of the following agents with voriconazole is contraindicated:

• Rifabutin (potent CYP450 inducer): Rifabutin (300 mg once daily) decreased the Cmax and AUCτ of voriconazole at 200 mg twice daily by an average of 67% (90% CI: 58%, 73%) and 79% (90% CI: 71%, 84%), respectively, in healthy subjects. During co-administration with rifabutin (300 mg once daily), the steady-state Cmax and AUCτ of voriconazole following an increased dose of 400 mg twice daily were on average approximately 2 times higher, compared with voriconazole alone at 200 mg twice daily. Co-administration of voriconazole at 400 mg twice daily with rifabutin 300 mg twice daily increased the Cmax and AUCτ of rifabutin by an average of 3-times (90% CI: 2.2, 4.0) and 4 times (90% CI: 3.5, 5.4), respectively, compared with rifabutin given alone.

Significant drug interactions that may require dosage adjustment, frequent monitoring of drug levels and/or frequent monitoring of drug-related adverse events/toxicity:

• Efavirenz (a non-nucleoside reverse transcriptase inhibitor; CYP450 inducer; CYP3A4 inhibitor and substrate): Standard doses of voriconazole and efavirenz (400 mg every 24 hours or higher) must not be co-administered . Steady-state efavirenz (400 mg PO every 24 hours) decreased the steady-state Cmax and AUCτ of voriconazole (400 mg PO every 12 hours for 1 day, then 200 mg PO every 12 hours for 8 days) by an average of 61% and 77%, respectively, in healthy male subjects. Voriconazole at steady state (400 mg PO every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) increased the steady-state Cmax and AUCτ of efavirenz (400 mg PO every 24 hours for 9 days) by an average of 38% and 44%, respectively, in healthy subjects.

The pharmacokinetics of adjusted doses of voriconazole and efavirenz were studied in healthy male subjects following administration of voriconazole (400 mg PO every 12 hours on days 2 to 7) with efavirenz (300 mg PO every 24 hours on days 1 to 7), relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg PO every 12 hours for 2 days) or efavirenz (600 mg every 24 hours for 9 days). Co-administration of voriconazole 400 mg every 12 hours with efavirenz 300 mg every 24 hours, decreased voriconazole AUCτ by 7% (90% CI: -23%, 13%) and increased Cmax by 23% (90% CI: -1%, 53%); efavirenz AUCτ was increased by 17% (90% CI: 6%, 29%) and Cmax was equivalent.

• Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Repeat-dose administration of phenytoin (300 mg once daily) decreased the steady-state Cmax and AUCτ of orally administered voriconazole (200 mg every 12 hours x 14 days) by an average of 50% and 70%, respectively, in healthy subjects. Administration of a higher voriconazole dose (400 mg every 12 hours x 7 days) with phenytoin (300 mg once daily) resulted in comparable steady-state voriconazole Cmax and AUCτ estimates as compared to when voriconazole was given at 200 mg every 12 hours without phenytoin.

Repeat-dose administration of voriconazole (400 mg every 12 hours x 10 days) increased the steady state Cmax and AUCτ of phenytoin (300 mg once daily) by an average of 70% and 80%, respectively, in healthy subjects. The increase in phenytoin Cmax and AUC when co-administered with voriconazole may be expected to be as high as 2 times the Cmax and AUC estimates when phenytoin is given without voriconazole.

• Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate): Co-administration of omeprazole (40 mg once daily x 10 days) with oral voriconazole (400 mg every 12 hours x 1 day, then 200 mg every 12 hours x 9 days) increased the steady-state Cmax and AUCτ of voriconazole by an average of 15% (90% CI: 5%, 25%) and 40% (90% CI: 29%, 55%), respectively, in healthy subjects. No dosage adjustment of voriconazole is recommended.

Co-administration of voriconazole (400 mg every 12 hours x 1 day, then 200 mg x 6 days) with omeprazole (40 mg once daily x 7 days) to healthy subjects significantly increased the steady-state Cmax and AUCτ of omeprazole an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4), respectively, compared with when omeprazole is given without voriconazole.

• Oral Contraceptives (CYP3A4 substrate; CYP2C19 inhibitor): Co-administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 3 days) and oral contraceptive (Ortho-Novum1/35® consisting of 35 mcg ethinyl estradiol and 1 mg norethindrone, every 24 hours) to healthy female subjects at steady state increased the Cmax and AUCτ of ethinyl estradiol by an average of 36% (90% CI: 28%, 45%) and 61% (90% CI: 50%, 72%), respectively, and that of norethindrone by 15% (90% CI: 3%, 28%) and 53% (90% CI: 44%, 63%), respectively in healthy subjects. Voriconazole Cmax and AUCτ increased by an average of 14% (90% CI: 3%, 27%) and 46% (90% CI: 32%, 61%), respectively.

No significant pharmacokinetic interaction was seen and no dosage adjustment of these drugs is recommended:

• Indinavir (CYP3A4 inhibitor and substrate): Repeat-dose administration of indinavir (800 mg TID for 10 days) had no significant effect on voriconazole Cmax and AUCτ following repeat-dose administration (200 mg every 12 hours for 17 days) in healthy subjects.

Repeat-dose administration of voriconazole (200 mg every 12 hours for 7 days) did not have a significant effect on steady-state Cmax and AUCτ of indinavir following repeat-dose administration (800 mg TID for 7 days) in healthy subjects.

Use in Special Populations

Patients with Renal impairment

In patients with moderate-to-severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the IV vehicle, HPBCD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of IV voriconazole.

Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy. Use in patients who are not undergoing hemodialysis is not recommended.

Voriconazole is hemodialyzed with clearance of 121 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

The IV vehicle, HPBCD, is hemodialysed with a clearance of 37.5 ± 24 mL/min.

Patients with Hepatic Impairment

It is recommended that the standard loading dose regimens be used but that the maintenance dose should be halved in patients with mild-to-moderate hepatic cirrhosis (Child-Pugh Classes A and B) receiving voriconazole.

Voriconazole has not been studied in patients with severe cirrhosis (Child-Pugh Class C).

There is limited data on the safety of voriconazole in patients with abnormal liver function tests (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) or total bilirubin >5 times the upper limit of normal).

Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.

Pregnant Women

There are no adequate data on the use of voriconazole in pregnant women available. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Voriconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

Risk Summary

Voriconazole can cause fetal harm when administered to a pregnant woman. There are no available data on the use of voriconazole in pregnant women. In animal reproduction studies, oral voriconazole was associated with fetal malformations in rats and fetal toxicity in rabbits. Cleft palates and hydronephrosis/hydroureter were observed in rat pups exposed to voriconazole during organogenesis at and above 10 mg/kg (0.3 times the RMD of 200 mg every 12 hours based on body surface area comparisons). In rabbits, embryo mortality, reduced fetal weight and increased incidence of skeletal variations, cervical ribs and extrasternal ossification sites were observed in pups when pregnant rabbits were orally dosed at 100 mg/kg (6 times the RMD based on body surface area comparisons) during organogenesis. Rats exposed to voriconazole from implantation to weaning experienced increased gestational length and dystocia, which were associated with increased perinatal pup mortality at the 10 mg/kg dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, inform the patient of the potential hazard to the fetus.

The background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively.

Lactating Women

Risk Summary

No data are available regarding the presence of voriconazole in human milk, the effects of voriconazole on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for voriconazole and any potential adverse effects on the breastfed child from voriconazole or from the underlying maternal condition.

Females and Males of Reproductive Potential

Contraception

Advise females of reproductive potential to use effective contraception during treatment with voriconazole. The co-administration of voriconazole with the oral contraceptive, 35 mcg ethinyl estradiol and 1 mg norethindrone, results in an interaction between these two drugs, but is unlikely to reduce the contraceptive effect. Monitoring for adverse reactions associated with oral contraceptives and voriconazole is recommended.

Pediatric Patients

The safety and effectiveness of voriconazole for IV injection have been established in pediatric patients aged 12 to 14 years weighing ≥50 kg and those aged 15 years and older regardless of body weight based on evidence from adequate and well-controlled studies in adult and pediatric patients and additional pediatric pharmacokinetic and safety data. A total of 51 pediatric patients aged 12 to <18 (N=51) from eight adult therapeutic trials provided safety information for voriconazole for IV injection use in the pediatric population.

Safety and effectiveness in pediatric patients below the age of 2 years has not been established. Therefore, voriconazole for IV injection is not recommended for pediatric patients less than 2 years of age.

A higher frequency of liver enzyme elevations was observed in the pediatric population.

The frequency of phototoxicity reactions is higher in the pediatric population. Squamous cell carcinoma has been reported in patients who experience photosensitivity reactions. Stringent measures for photo protection are warranted. Sun avoidance and dermatologic follow-up are recommended in pediatric patients experiencing photo-aging injuries, such as lentigines or ephelides, even after treatment discontinuation.

Voriconazole for IV injection has not been studied in pediatric patients with hepatic or renal impairment. Hepatic function and serum creatinine levels should be closely monitored in pediatric patients.

Geriatric Patients

In multiple-dose therapeutic trials of voriconazole, 9.2% of patients were ≥65 years of age and 1.8% of patients were ≥75 years of age. In a study in healthy subjects, the systemic exposure (AUC) and peak plasma concentrations (Cmax) were increased in elderly males compared with young males.

Pharmacokinetic data obtained from 552 patients from 10 voriconazole therapeutic trials showed that voriconazole plasma concentrations in the elderly patients were approximately 80 to 90% higher than those in younger patients after either IV or oral administration. However, the overall safety profile of the elderly patients was similar to that of the young so no dosage adjustment is recommended.

Effects on Ability to Drive and Use Machines

Voriconazole has moderate influence on the ability to drive and use machines. It may cause transient and reversible changes to vision, including blurring, altered/enhanced visual perception and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating machinery while experiencing these symptoms.

Undesirable Effects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Adults

Overview

The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), and hallucinations (2.4%). The treatment-related adverse events that most often led to discontinuation of voriconazole therapy were elevated liver function tests, rash, and visual disturbances.

The data described in Table 6 below reflect exposure to voriconazole in 1,655 patients in the therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range, 11 to 90, including 51 patients aged 12 to 18 years), and was 78% White and 10% Black. In a total of 561 patients, duration of voriconazole therapy was >12 weeks with 136 patients receiving voriconazole for over 6 months. Table 5 includes all adverse events that were reported at an incidence of ≥2% during voriconazole therapy in the all-therapeutic studies population, Studies 307/602 and 608 combined, or Study 305, as well as events of concern that occurred at an incidence of <2%.

In Study 307/602, 381 patients (196 on voriconazole, 185 on amphotericin B) were treated to compare voriconazole with amphotericin B followed by other licensed antifungal therapy in the primary treatment of patients with acute invasive aspergillosis. The rate of discontinuation from voriconazole study medication due to adverse events was 21.4% (42/196 patients). In Study 608, 403 patients with candidemia were treated to compare voriconazole (272 patients) with the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from the voriconazole study medication due to adverse events was 19.5% out of 272 patients. Study 305 evaluated the effects of oral voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of esophageal candidiasis. The rate of discontinuation from voriconazole study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.

Table 6: Treatment-Emergent Adverse Events Rate ≥2% on Voriconazole or Adverse Events of Concern in All-Therapeutic Studies Population, Studies 307/602 and 608 Combined, or Study 305. Possibly Related to Therapy or Causality Unknown*

 

 

All

Therapeutic

Studies**

Studies 307/602 and 608 (IV/Oral Therapy)

Study 305 (Oral Therapy)

 

Vorico-nazole

N=1,655

Vorico-nazole

N=468

Ampho

B

N=185

Ampho B→

Fluco-nazole

N=131

Vorico-nazole

N=200

Fluco-nazole

N=191

N (%)

N (%)

N (%)

N (%)

N (%)

N (%)

Special Senses

Abnormal

vision

310 (18.7)

63 (13.5)

1 (0.5)

0

31 (15.5)

8 (4.2)

Photo-phobia

37 (2.2)

8 (1.7)

0

0

5 (2.5)

2 (1)

Chroma-topsia

20 (1.2)

2 (0.4)

0

0

2 (1)

0

Body as a Whole

Fever

94 (5.7)

8 (1.7)

25 (13.5)

5 (3.8)

0

0

Chills

61 (3.7)

1 (0.2)

36 (19.5)

8 (6.1)

1 (0.5)

0

Headache

49 (3)

9 (1.9)

8 (4.3)

1 (0.8)

0

1 (0.5)

Cardiovascular System

Tachy-cardia

39 (2.4)

6 (1.3)

5 (2.7)

0

0

0

Digestive System

Nausea

89 (5.4)

18 (3.8)

29 (15.7)

2 (1.5)

2 (1)

3 (1.6)

Vomiting

72 (4.4)

15 (3.2)

18 (9.7)

1 (0.8)

2 (1)

1 (0.5)

Liver function

tests abnormal

45 (2.7)

15 (3.2)

4 (2.2)

1 (0.8)

6 (3)

2 (1)

Cholestatic

jaundice

17 (1)

8 (1.7)

0

1 (0.8)

3 (1.5)

0

Metabolic and Nutritional Systems

Alkaline

phos-phatase

increased

59 (3.6)

19 (4.1)

4 (2.2)

3 (2.3)

10 (5)

3 (1.6)

Hepatic

enzymes

increased

30 (1.8)

11 (2.4)

5 (2.7)

1 (0.8)

3 (1.5)

0

SGOT

increased

31 (1.9)

9 (1.9)

0

1 (0.8)

8 (4)

2 (1)

SGPT

increased

29 (1.8)

9 (1.9)

1 (0.5)

2 (1.5)

6 (3)

2 (1)

Hypo-kalemia

26 (1.6)

3 (0.6)

    36

(19.5)

16 (12.2)

0

0

Bilirubi-nemia

15 (0.9)

5 (1.1)

3 (1.6)

2 (1.5)

1 (0.5)

0

Creatinine

increased

4 (0.2)

0

     59

(31.9)

10 (7.6)

1 (0.5)

0

Nervous System

Halluci-nations

39 (2.4)

13 (2.8)

1 (0.5)

0

0

0

Skin and Appendages

Rash

88 (5.3)

20 (4.3)

7 (3.8)

1 (0.8)

3 (1.5)

1 (0.5)

Urogenital

Kidney

function

abnormal

10 (0.6)

6 (1.3)

    40

(21.6)

9 (6.9)

1 (0.5)

1 (0.5)

Acute kidney

failure

7 (0.4)

2 (0.4)

11 (5.9)

7 (5.3)

0

0

               

* Study 307/602: invasive aspergillosis; Study 608: candidemia; Study 305: esophageal candidiasis

** Studies 303, 304, 305, 307, 309, 602, 603, 604, 608

Amphotericin B followed by other licensed antifungal therapy

See Special Warnings and Precautions for Use

Visual Disturbances

Voriconazole treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses.

The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field, and an alteration in color perception. The ERG measures electrical currents in the retina. The effects were noted early in administration of voriconazole and continued through the course of study drug dosing. At 14 days after end of dosing, ERG, visual fields and color perception returned to normal.

Dermatological Reactions

Dermatological reactions were common in the patients treated with voriconazole. The mechanism underlying these dermatologic adverse events remains unknown. 

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, have been reported during treatment with voriconazole. Erythema multiforme has also been reported during treatment with voriconazole for IV injection.

In addition, voriconazole has been associated with photosensitivity skin reactions such as pseudoporphyria, cheilitis, and cutaneous lupus erythematosus.

Less Common Adverse Events

The following adverse events occurred in <2% of all voriconazole-treated patients in all therapeutic studies (N=1,655). This listing includes events where a causal relationship to voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 6 above and does not include every event reported in the voriconazole clinical program.

BODY AS A WHOLE

Abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction, ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection-site pain, injection-site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain.

CARDIOVASCULAR

Atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsades de pointes).

DIGESTIVE

Anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema.

ENDOCRINE

Adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism.

HEMIC AND LYMPHATIC

Agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis,
disseminated intravascular coagulation (DIC), ecchymosis, eosinophilia, hypervolemia, leucopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura.

METABOLIC AND NUTRITIONAL

Albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia.

MUSCULOSKELETAL

Arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis.

NERVOUS SYSTEM

Abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, extrapyramidal syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgia, neuropathy, nystagmus, oculogyric crisis, paresthesia, psychosis, somnolence, suicidal ideation, tremor, vertigo.

RESPIRATORY SYSTEM

Cough increased, dyspnea, epistaxis, hemoptysis, hypoxia, lung edema, pharyngitis, pleural effusion, pneumonia, respiratory disorder, respiratory distress syndrome, respiratory tract infection, rhinitis, sinusitis, voice alteration.

SKIN AND APPENDAGES

Alopecia, angioedema, contact dermatitis, discoid lupus erythematosis, eczema, erythema multiforme, exfoliative dermatitis, fixed-drug eruption, furunculosis, herpes simplex, maculopapular rash, melanoma, melanosis, photosensitivity skin reaction, pruritus, pseudoporphyria, psoriasis, skin discoloration, skin disorder, skin dry, Stevens-Johnson syndrome, squamous cell carcinoma, sweating, toxic epidermal necrolysis, urticaria.

SPECIAL SENSES

Abnormality of accommodation, blepharitis, color blindness, conjunctivitis, corneal opacity, deafness, ear pain, eye pain, eye hemorrhage, dry eyes, hypoacusis, keratitis, keratoconjunctivitis, mydriasis, night blindness, optic atrophy, optic neuritis, otitis externa, papilloedema, retinal hemorrhage, retinitis, scleritis, taste loss, taste perversion, tinnitus, uveitis, visual field defect.

UROGENITAL

Anuria, blighted ovum, creatinine clearance decreased, dysmenorrhea, dysuria, epididymitis, glycosuria, hemorrhagic cystitis, hematuria, hydronephrosis, impotence, kidney pain, kidney tubular necrosis, metrorrhagia, nephritis, nephrosis, oliguria, scrotal edema, urinary incontinence, urinary retention, urinary tract infection, uterine hemorrhage, vaginal hemorrhage.

Clinical Laboratory Values in Adults

The overall incidence of transaminase increases >3x upper limit of normal (not necessarily comprising an adverse reaction) was 17.7% (268/1,514) in adult subjects treated with voriconazole for IV injection for therapeutic use in pooled clinical trials. Increased incidence of liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or resolved following dose adjustment, including discontinuation of therapy.

Voriconazole has been infrequently associated with cases of serious hepatic toxicity, including cases of jaundice and rare cases of hepatitis and hepatic failure, leading to death. Most of these patients had other serious underlying conditions.

Liver function tests should be evaluated at the start of and during the course of voriconazole therapy. Patients who develop abnormal liver function tests during voriconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to voriconazole.

Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function. It is recommended that patients are monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Tables 7 to 9 show the number of patients with hypokalemia and clinically significant changes in renal and liver function tests in three randomized, comparative multicenter studies. In Study 305, patients with esophageal candidiasis were randomized to either oral voriconazole or oral fluconazole. In Study 307/602, patients with definite or probable invasive aspergillosis were randomized to either voriconazole or amphotericin B therapy. In Study 608, patients with candidemia were randomized to either voriconazole or the regimen of amphotericin B followed by fluconazole.

Table 7: Protocol 305 - Patients with Esophageal Candidiasis

Clinically Significant Laboratory Test Abnormalities

 

 

Criteria*

Voriconazole

Fluconazole

n/N (%)

n/N (%)

T. Bilirubin

>1.5x ULN

8/185 (4.3)

7/186 (3.8)

AST

>3.0x ULN

38/187 (20.3)

15/186 (8.1)

ALT

>3.0x ULN

20/187 (10.7)

12/186 (6.5)

Alkaline phosphatase

>3.0x ULN

19/187 (10.2)

14/186 (7.5)

*Without regard to baseline value

n = number of patients with a clinically significant abnormality while on study therapy

N = total number of patients with at least one observation of the given lab test while on study therapy

ULN = upper limit of normal

Table 8: Protocol 307/602 - Primary Treatment of Invasive Aspergillosis

Clinically Significant Laboratory Test Abnormalities

 

 

          Criteria*

Voriconazole

Amphotericin B

n/N (%)

n/N (%)

T. Bilirubin

>1.5x ULN

35/180 (19.4)

46/173 (26.6)

AST

>3.0x ULN

21/180 (11.7)

18/174 (10.3)

ALT

>3.0x ULN

34/180 (18.9)

40/173 (23.1)

Alkaline phosphatase

>3.0x ULN

29/181 (16)

38/173 (22)

Creatinine

>1.3x ULN

39/182 (21.4)

102/177 (57.6)

Potassium

<0.9x LLN

30/181 (16.6)

70/178 (39.3)

*Without regard to baseline value

Amphotericin B followed by other licensed antifungal therapy

n = number of patients with a clinically significant abnormality while on study therapy

N = total number of patients with at least one observation of the given lab test while on study therapy

ULN = upper limit of normal

LLN = lower limit of normal

Table 9: Protocol 608 - Treatment of Candidemia

Clinically Significant Laboratory Test Abnormalities

 

 

 

Criteria*

Voriconazole

Amphotericin B followed by

Fluconazole

n/N (%)

n/N (%)

T. Bilirubin

>1.5x ULN

50/261 (19.2)

31/115 (27)

AST

>3.0x ULN

40/261 (15.3)

16/116 (13.8)

ALT

>3.0x ULN

22/261 (8.4)

15/116 (12.9)

Alkaline phosphatase

>3.0x ULN

59/261 (22.6)

26/115 (22.6)

Creatinine

>1.3x ULN

39/260 (15)

32/118 (27.1)

Potassium

<0.9x LLN

43/258 (16.7)

35/118 (29.7)

*Without regard to baseline value

n = number of patients with a clinically significant abnormality while on study therapy

N = total number of patients with at least one observation of the given lab test while on study therapy

ULN = upper limit of normal

LLN = lower limit of normal

Clinical Trials Experience in Pediatric Patients

The safety of voriconazole for IV injection was investigated in pediatric patients, including

52 pediatric patients <18 years of age who were enrolled in the adult therapeutic studies.

Hepatic-related Adverse Reactions in Pediatric Patients

The frequency of hepatic-related adverse reactions in pediatric patients exposed to voriconazole for IV injection in therapeutic studies was numerically higher than that of adults (28.6% compared with 24.1%, respectively). The higher frequency of hepatic adverse reactions in the pediatric population was mainly due to an increased frequency of liver enzyme elevations (21.9% in pediatric patients compared with 16.1% in adults), including transaminase elevations (ALT and AST combined) 7.6% in the pediatric patients compared with 5.1% in adults.

Postmarketing Experience in Adult and Pediatric Patients

The following adverse reactions have been identified during post-approval use of voriconazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adults

SKELETAL: Fluorosis and periostitis have been reported during long-term voriconazole therapy .

EYE DISORDERS: prolonged visual adverse reactions, including optic neuritis and papilledema .

SKIN AND APPENDAGES: drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported.

ENDOCRINE DISORDERS: adrenal insufficiency, Cushing’s syndrome (when voriconazole has been used concomitantly with corticosteroids).

Pediatric Patients

There have been postmarketing reports of pancreatitis in pediatric patients.

Others

The safety profile of voriconazole in adults given below is based on an integrated safety database of more than 2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults in prophylaxis trials. This represents a heterogeneous population, containing patients with hematological malignancy, HIV-infected patients with esophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidemia or aspergillosis, and healthy volunteers.

Pyrexia was one of most commonly reported adverse reactions (in addition to those mentioned above).

All other causality adverse reactions and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ class, are listed below.

Frequency categories are expressed as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Blood and Lymphatic System Disorders

UNCOMMON: bone marrow failure

Immune System Disorders

UNCOMMON: hypersensitivity

Nervous System Disorders

UNCOMMON: neuropathy peripheral, dysgeusia

Eye Disorders

VERY COMMON: visual impairment

UNCOMMON: optic nerve disorder#

Cardiac Disorders

COMMON: arrhythmia supraventricular

UNCOMMON: ventricular extrasystoles

Respiratory, Thoracic and Mediastinal Disorders

COMMON: acute respiratory distress syndrome, pulmonary edema

Gastrointestinal Disorders

UNCOMMON: swollen tongue 

Hepatobiliary Disorders

COMMON: jaundice cholestatic

UNCOMMON: hepatomegaly

Skin and Subcutaneous Tissue Disorders

COMMON: erythema

UNCOMMON: dermatitis allergic, rash popular, rash macular

RARE: drug reaction with eosinophilia and systemic symptoms (DRESS), actinic keratosis*, medicinal eruption

Renal and Urinary Disorders

UNCOMMON: proteinuria

General Disorders and Administration Site Conditions

UNCOMMON: infusion-site reaction, influenza-like illness

Investigations

UNCOMMON: blood urea increased, blood cholesterol increased

# Prolonged optic neuritis has been reported postmarketing

*Adverse reaction identified postmarketing

Reporting of Side Effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@Cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

In clinical trials, there were three cases of accidental overdose. All occurred in pediatric patients who received up to five times the recommended IV dose of voriconazole. A single adverse event of photophobia of 10 minutes’ duration was reported.

There is no known antidote to voriconazole.

Voriconazole is hemodialysed, with a clearance of 121 mL/min. The IV vehicle, HPBCD, is hemodialysed with a clearance of 37.5 ± 24 mL/min. In an overdose, hemodialysis may assist in the removal of voriconazole and HPBCD from the body.

Pharmacological Properties

Mechanism of Action

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal CYP450-mediated 14-alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14-alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal CYP450 enzymes than for various mammalian CYP450 enzyme systems.

Antimicrobial Activity

Voriconazole has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections:

Aspergillus fumigatus

Aspergillus flavus

Aspergillus niger

Aspergillus terreus

Candida albicans

Candida glabrata (in clinical studies, the voriconazole MIC90 was 4 mcg/mL)*

Candida krusei

Candida parapsilosis

Candida tropicalis

Fusarium spp., including Fusarium solani

Scedosporium apiospermum

*In clinical studies, voriconazole MIC90 for C. glabrata baseline isolates was 4 mcg/mL; 13/50 (26%) C. glabrata baseline isolates were resistant (MIC ≥4 mcg/mL) to voriconazole. However, based on 1,054 isolates tested in surveillance studies, the MIC was 1 mcg/mL.

The following data are available, but their clinical significance is unknown. At least 90% of the following fungi exhibit an in vitro MIC less than or equal to the susceptible breakpoint for voriconazole against isolates of similar genus or organism group. However, the effectiveness of voriconazole in treating clinical infections due to these fungi has not been established in adequate and well-controlled clinical trials:

Candida lusitaniae

Candida guilliermondii

Drug Resistance

A potential for development of resistance to voriconazole is well known. The mechanisms of resistance may include mutations in the gene ERG11 (encodes for the target enzyme, lanosterol 14-α-demethylase), upregulation of genes encoding the ATP-binding cassette efflux transporters, i.e., Candida drug resistance (CDR) pumps and reduced access of the drug to the target, or some combination of those mechanisms. The frequency of drug resistance development for the various fungi for which this drug is indicated is not known.

Fungal isolates exhibiting reduced susceptibility to fluconazole or itraconazole may also show reduced susceptibility to voriconazole, suggesting cross-resistance can occur among these azoles. The relevance of cross-resistance and clinical outcome has not been fully characterized. Clinical cases where azole cross-resistance is demonstrated may require alternative antifungal therapy.

Pharmacodynamic Properties

Exposure-Response Relationship For Efficacy and Safety

In 10 clinical trials (N=1,121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 μg/mL (inter-quartile range 1.21 to 4.44 μg/mL) and 3.79 μg/mL (inter-quartile range 2.06 to 6.31 μg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N=280) could not detect a positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy. However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances.

Cardiac Electrophysiology

A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24-hour post-dose observation period. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1,600 mg of voriconazole and after ketoconazole 800 mg were all <10 msec. Females exhibited a greater increase in QTc than males, although all mean changes were <10 msec. Age was not found to affect the magnitude of increase in QTc. No subject in any group had an increase in QTc of ≥60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown.

Pharmacokinetic Properties

The pharmacokinetics of voriconazole has been characterized in healthy subjects, special populations and patients.

The pharmacokinetics of voriconazole is non-linear due to the saturation of its metabolism. The inter-individual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg q12h to 300 mg q12h leads to an approximately 2.5-fold increase in exposure AUC; similarly, increasing the IV dose from 3 mg/kg q12h to 4 mg/kg q12h produces an approximately 2.5-fold increase in exposure (Table 10).

Table 10: Geometric Mean (%CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens

 

6 mg/kg IV (Loading Dose)

3 mg/kg

IV q12h

4 mg/kg

IV q12h

400 mg Oral

(Loading Dose)

200 mg

Oral q12h

300 mg

Oral q12h

N

35

23

40

17

48

16

AUC12 (mcg·h/mL)

13.9 (32)

13.7 (53)

33.9 (54)

9.31 (38)

12.4 (78)

34 (53)

Cmax (mcg/mL)

3.13 (20)

3.03 (25)

4.77 (36)

2.30 (19)

2.31 (48)

4.74 (35)

Cmin (mcg/mL)

--

0.46 (97)

1.73 (74)

--

0.46 (120)

1.63 (79)

Note: Parameters were estimated based on non-compartmental analysis from five pharmacokinetic studies.

AUC = area under the curve over 12-hour dosing interval, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration, CV = coefficient of variation.

When the recommended IV loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV q12h on day 1 followed by 3 mg/kg IV q12h). Without the loading dose, accumulation occurs during twice-daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.

Absorption

The pharmacokinetic properties of voriconazole are similar following administration by the IV and oral routes. Based on a population pharmacokinetic analysis of pooled data in healthy subjects (N=207), the oral bioavailability of voriconazole is estimated to be 96% (CV, 13%). Bioequivalence was established between the 200 mg tablet and the 40 mg/mL oral suspension when administered as a 400 mg q12h loading dose followed by a 200 mg q12h maintenance dose.

Maximum plasma concentrations (Cmax) are achieved 1 to 2 hours after dosing. When multiple doses of voriconazole are administered with high-fat meals, the mean Cmax and AUCτ are reduced by 34% and 24%, respectively, when administered as a tablet and by 58% and 37%, respectively, when administered as the oral suspension.

In healthy subjects, the absorption of voriconazole is not affected by co-administration of drugs that are known to increase gastric pH such as oral ranitidine, cimetidine or omeprazole.

Distribution

The volume of distribution for voriconazole at the steady state is estimated to be 4.6 L/kg, suggesting extensive distribution into the tissues. Plasma protein-binding is estimated to be 58% and was shown to be independent of plasma concentrations achieved following single and multiple oral doses of 200 mg or 300 mg (approximate range: 0.9 to 15 mcg/mL). Varying degrees of hepatic and renal impairment do not affect the protein-binding of voriconazole.

Metabolism

In vitro studies showed that voriconazole is metabolized by the hepatic CYP450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism.

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabeled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.

Excretion

Voriconazole is eliminated via hepatic metabolism, with less than 2% of the dose excreted unchanged in the urine.

After administration of a single radiolabeled dose of either oral or IV voriconazole, preceded by multiple oral or IV dosing, approximately 80 to 83% of the radioactivity is recovered in the urine. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and IV dosing.

As a result of non-linear pharmacokinetics, the terminal half-life of voriconazole is dose-dependent and, therefore, not useful in predicting the accumulation or elimination of voriconazole.

Special Populations

Patients with Renal Impairment

In a single-oral dose (200 mg) study in 24 subjects with normal renal function and mild-to-severe renal impairment, systemic exposure (AUC) and peak plasma concentration (Cmax) of voriconazole were not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild-to-severe renal impairment.

In a multiple-dose study of IV voriconazole (6 mg/kg IV loading dose x 2, then 3 mg/kg IV x 5.5 days) in 7 patients with moderate renal dysfunction (creatinine clearance, 30 to 50 mL/min), the systemic exposure (AUC) and peak plasma concentrations (Cmax) were not significantly different from those in 6 subjects with normal renal function.

However, in patients with moderate renal dysfunction (creatinine clearance, 30 to 50 mL/min), accumulation of the IV vehicle, HPBCD, occurs.

A pharmacokinetic study in subjects with renal failure undergoing hemodialysis showed that voriconazole is dialyzed with clearance of 121 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

In patients with normal renal function, the pharmacokinetic profile of HPBCD, an ingredient of voriconazole IV for injection formulation, has a short half-life of 1 to 2 hours and demonstrates no accumulation following successive daily doses. In healthy subjects and in patients with mild to severe renal insufficiency, the majority (>85%) of an 8 g dose of HPBCD is eliminated in the urine. In subjects with mild, moderate and severe renal impairment, half-life values were increased over normal values by approximately two-, four- and six-fold, respectively. In these patients, successive infusions may result in accumulation of HPBCD until steady state is reached. HPBCD s removed by hemodialysis, with a clearance of 37.5 ± 24 mL/min.

Patients with Hepatic Impairment

After a single oral dose (200 mg) of voriconazole in 8 patients with mild (Child-Pugh Class A) and 4 patients with moderate (Child-Pugh Class B) hepatic impairment, the mean systemic exposure (AUC) was 3.2-fold higher than in age- and weight-matched controls with normal hepatic function. There was no difference in mean peak plasma concentrations (Cmax) between the groups. When only the patients with mild (Child-Pugh Class A) hepatic impairment were compared with controls, there was still a 2.3-fold increase in the mean AUC in the group with hepatic impairment compared with controls.

In an oral multiple-dose study, AUCτ was similar in 6 subjects with moderate hepatic impairment (Child-Pugh Class B) given a lower maintenance dose of 100 mg twice daily compared with 6 subjects with normal hepatic function given the standard 200 mg twice-daily maintenance dose. The mean peak plasma concentrations (Cmax) were 20% lower in the hepatically impaired group.

No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh Class C).

Pediatric Patients

Voriconazole exposures in the majority of pediatric patients aged 12 to <17 years were comparable with those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some pediatric patients aged 12 to <17 years with low body weight compared with adults.

The recommended doses in children and adolescent patients are based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised pediatric patients aged 2 to <12 years and 26 immunocompromised adolescent patients aged 12 to <17 years. Multiple IV doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg and 200 mg twice daily were evaluated in three paediatric pharmacokinetic studies. IV loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 mg IV dose twice daily and 300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability was observed in pediatric patients compared with adults.

A comparison of the pediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUC) in children following administration of a 9 mg/kg IV loading dose was comparable with that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable with those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable with that in adults following 200 mg oral twice daily. An 8 mg/kg IV dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

The higher IV maintenance dose in pediatric patients relative to adults reflects the higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in pediatric patients with malabsorption and very low body weight for their age. In that case, IV voriconazole administration is recommended.

Voriconazole exposures in the majority of adolescent patients were comparable with those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some young adolescents with low body weight compared with adults. It is likely that these subjects may metabolize voriconazole more similarly to children than to adolescents/adults. Based on the population pharmacokinetic analysis, 12- to 14-year-old adolescents weighing <50 kg should receive children's doses.

Gender

In a multiple oral dose study, the mean Cmax and AUCτ  for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18 to 45 years), after tablet dosing. In the same study, no significant differences in the mean Cmax and AUCτ were observed between healthy elderly males and healthy elderly females (>65 years of age). In a similar study, after dosing with the oral suspension, the mean AUC for healthy young females was 45% higher than in healthy young males whereas the mean Cmax was comparable between genders. The steady-state trough voriconazole concentrations (Cmin) seen in females were 100% and 91% higher than in males receiving the tablet and the oral suspension, respectively.

In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female subjects were similar. Therefore, no dosage adjustment based on gender is necessary.

Geriatric

In an oral multiple-dose study, the mean Cmax and AUCτ in healthy elderly males (aged ≥65 years) were 61% and 86% higher, respectively, than in young males (aged 18 to 45 years). No significant differences in the mean Cmax and AUCτ were observed between healthy elderly females (aged ≥65 years) and healthy young females (aged 18 to 45 years).

In the clinical program, no dosage adjustment was made on the basis of age. An analysis of pharmacokinetic data obtained from 552 patients from 10 voriconazole clinical trials showed that the median voriconazole plasma concentrations in the elderly patients (aged >65 years) were approximately 80% to 90% higher than those in the younger patients (aged ≤65 years) after either IV or oral administration.

However, the safety profile of voriconazole in young and elderly subjects was similar and, therefore, no dosage adjustment is necessary for the elderly.

Patients at Risk of Aspergillosis

The observed voriconazole pharmacokinetics in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or hematopoietic tissue) was similar to healthy subjects.

Non-Clinical Properties

Animal Toxicology or Pharmacology

Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicity occurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common with other antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In 2-year carcinogenicity studies conducted in rats and mice, rats were given oral doses of 6, 18 or 50 mg/kg voriconazole or 0.2, 0.6 or 1.6 times the recommended maintenance dose on an mg/m2 basis. Hepatocellular adenomas were detected in females at 50 mg/kg and hepatocellular carcinomas were found in males at 6 and 50 mg/kg. Mice were given oral doses of 10, 30 or 100 mg/kg voriconazole or 0.1, 0.4 or 1.4 times the RMD (recommended maintenance dose) on an mg/m2 basis. In mice, hepatocellular adenomas were detected in males and females and hepatocellular carcinomas were detected in males at 1.4 times the RMD of voriconazole.

Voriconazole demonstrated clastogenic activity (mostly chromosome breaks) in human lymphocyte cultures in vitro. Voriconazole was not genotoxic in the Ames assay, CHO HGPRT assay, the mouse micronucleus assay or the in vivo DNA repair test (unscheduled DNA synthesis assay).

Voriconazole administration induced no impairment of male or female fertility in rats dosed at 50 mg/kg or 1.6 times the RMD. In reproduction studies, voriconazole was shown to be teratogenic in rats and embryo toxic in rabbits at systemic exposures equal to those obtained in humans with therapeutic doses. In the pre- and post-natal development study in rats at exposures lower than those obtained in humans with therapeutic doses, voriconazole prolonged the duration of gestation and labor and produced dystocia with consequent maternal mortality and reduced perinatal survival of pups. The effects on parturition are probably mediated by species-specific mechanisms, involving reduction of oestradiol levels, and are consistent with those observed with other azole antifungal agents. Voriconazole administration induced no impairment of male or female fertility in rats at exposures similar to those obtained in humans at therapeutic doses.

Description

VORITEK IV contains voriconazole, an azole antifungal agent is available as a lyophilized powder for solution for IV infusion.

Voriconazole is designated chemically as (2R,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2- butanol with an empirical formula of

C16H14 F3N5O and a molecular weight of 349.3.

Pharmaceutical Particulars

Incompatibility

Voriconazole for IV injection must not be diluted with 4.2% Sodium Bicarbonate Infusion. The mildly alkaline nature of this diluent caused slight degradation of voriconazole for IV injection after 24 hours storage at room temperature. Although refrigerated storage is recommended following reconstitution, use of this diluent is not recommended as a precautionary measure. Compatibility with other concentrations is unknown.

Voriconazole for IV injection must not be infused into the same line or cannula concomitantly with other IV products. When the voriconazole infusion is complete, the line may be used for administration of other IV products.

Blood Products and Concentrated Short-Term Infusion of Concentrated Solutions of Electrolytes

Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcaemia should be corrected prior to initiation of voriconazole therapy. Voriconazole must not be administered simultaneously with any blood product or any short-term infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate lines.

Total Parenteral Nutrition (TPN)

Total parenteral nutrition (TPN) need not be discontinued when prescribed with voriconazole, but does need to be infused through a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole. Voriconazole must not be diluted with 4.2% Sodium Bicarbonate Infusion. Compatibility with other concentrations is unknown.

This medicinal product must not be mixed with other medicinal products except those mentioned in the Posology and Administration section.

Shelf-Life

As on the pack.

Packaging Information

VORITEK IV: Powder for solution for injection is supplied in a single-use vial as a sterile lyophilized powder equivalent to 200 mg voriconazole and 3,200 mg hydroxypropylbeta cyclodextrin (HPBCD) along with 20 mL Sterile Water for Injections I.P. in an FFS plastic ampoule.

Storage and Handling Instructions

Keep all medicines out of the reach of children.

Before Reconstitution

Store protected from moisture, at a temperature not exceeding 30˚C.

After Reconstitution

The reconstitution solution should be used immediately or used within 24 hours when stored at 2˚to 8˚C.

Patient Counseling Information

  1. What VORITEK IV is and what it is used for

VORITEK IV contains the active substance voriconazole. VORITEK IV is an antifungal medicine. It works by killing or stopping the growth of the fungi that cause infections. VORITEK IV is intended for use in patients with worsening, possibly life-threatening, fungal infections.

Voriconazole for injection is a prescription medicine used to treat certain serious fungal infections in your blood and body. These infections are called “aspergillosis,” “esophageal candidiasis,” “scedosporium,” “fusarium,” and “candidemia”.

It is not known if voriconazole for IV injection is safe and effective in children younger than 2 years of age.

This product should only be used under the supervision of a doctor.

  1. What you need to know before you use VORITEK IV

Do not take VORITEK IV (voriconazole for IV injection) if you

  • are allergic to voriconazole or any of the ingredients in voriconazole for

injection (see the end of this leaflet for a complete list of ingredients in voriconazole for

injection); and/or,

  • are taking any of the following medicines:
  • cisapride
  • pimozide
  • quinidine
  • sirolimus
  • rifampin
  • carbamazepine
  • phenobarbital
  • efavirenz
  • ritonavir
  • rifabutin
  • ergotamine, dihydroergotamine (ergot alkaloids)
  • St. John’s wort (herbal supplement)
  • naloxegol
  • tolvaptan
  • ivabradine
  • venetoclax

Ask your healthcare provider or pharmacist if you are not sure if you are taking any of the medicines listed above.

Do not start taking a new medicine without talking to your healthcare provider or pharmacist.

Before you take voriconazole for IV injection, tell your healthcare provider about all of your medical conditions, including the following:

  • Have or ever had heart disease, or an abnormal heart rate or rhythm. Your healthcare provider may order a test to check your heart (EKG) before starting voriconazole for IV injection.
  • Have low potassium levels, low magnesium levels, and low calcium levels. Your healthcare provider may do blood tests before starting and during treatment with voriconazole for IV injection.
  • Have liver or kidney problems. Your healthcare provider may do blood tests to make sure you can take voriconazole for IV injection.
  • Are pregnant or plan to become pregnant. Voriconazole for IV injection can harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Women who can become pregnant should use effective birth control while taking voriconazole for IV injection. Talk to your healthcare provider about birth control methods that may be right for you.
  • Are breastfeeding or plan to breastfeed. It is not known if voriconazole for IV injection passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take voriconazole for IV injection.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Voriconazole for injection may affect the way other medicines work, and other medicines may affect how voriconazole for IV injection works.

Know what medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

Driving and using machines

VORITEK IV may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive or operate any tools or machines. Tell your doctor if you experience this.

VORITEK IV contains sodium

Talk to your doctor or pharmacist if you need 6 or more vials daily for a prolonged period, especially if you have been advised to follow a low-salt (sodium) diet.

VORITEK IV contains hydroxypropylbeta Cyclodextrin

If you have a kidney disease, talk to your doctor before you receive this medicine.

Avoid direct sunlight. Voriconazole for IV injection can make your skin sensitive to the sun and the light from sunlamps and tanning beds.

You could get severe sunburn. Use sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to your healthcare provider if you get sunburn.

  1. How to use VORITEK IV

Voriconazole may be prescribed to you as voriconazole for IV injection (IV infusion).

• Voriconazole for IV injection will be given to you by a healthcare provider over 1 to 3 hours.

Patients with a weakened immune system or those with difficult infections may require long-term treatment to prevent the infection from returning. You may be switched from the IV infusion to tablets once your condition improves.

When VORITEK IV treatment is stopped by your doctor you should not experience any effects.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

  1. Possible side effects of VORITEK IV

Voriconazole for IV injection may cause serious side effects including the following:

• Liver problems. Symptoms of liver problems may include

  • itchy skin;
  • yellowing of your eyes;
  • feeling very tired;
  • flu-like symptoms; and,
  • nausea or vomiting

• Vision changes. Symptoms of vision changes may include

  • blurred vision;
  • changes in the way you see colors; and,
  • sensitivity to light (photophobia)

• Serious heart problems. Voriconazole for IV injection may cause changes in your heart rate or rhythm, including your heart stopping (cardiac arrest).

• Allergic reactions. Symptoms of an allergic reaction may include

  • fever;
  • sweating;
  • feeling like your heart is beating fast (tachycardia);
  • chest tightness;
  • trouble breathing;
  • feeling faint;
  • nausea;
  • itching; and,
  • skin rash.

• Kidney problems. Voriconazole for IV injection may cause new or worse problems with kidney function, including kidney failure. Your healthcare provider should check your kidney function while you are taking voriconazole for IV injection. Your healthcare provider will decide if you can keep taking voriconazole for IV injection.

• Serious skin reactions. Symptoms of serious skin reactions may include

  • rash or hives;
  • mouth sores;
  • blistering or peeling of your skin; and,
  • trouble swallowing or breathing.
  • Adrenal gland problems. Voriconazole for injection may cause reduced adrenal function (adrenal insufficiency). Voriconazole for injection may cause overactive adrenal function (Cushing’s syndrome) when voriconazole is used at the same time with corticosteroids.

    Symptoms of adrenal insufficiency include

  • feeling tired;
  • lack of energy;
  • weakness;
  • nausea and vomiting;
  • feeling dizzy or lightheaded;
  • weight loss; and
  • abdominal pain.

     Symptoms of Cushing’s syndrome include

  • weight gain;
  • fatty hump between the shoulders (buffalo hump) and a rounded face (moon face);
  • darkening of the skin on the stomach, thighs, breasts, and arms;
  • thinning skin;
  • bruising easily;
  • high blood sugar;
  • excessive hair growth; and
  • excessive sweating.
  • Bone problems. Voriconazole for injection may cause weakening of bones and bone pain. Tell your healthcare provider if you have bone pain.

Call your healthcare provider or go to the nearest hospital emergency room right away if

you have any of the symptoms listed above.

The most common side effects of voriconazole for IV injection include

  • vision changes;
  • rash;
  • vomiting;
  • nausea;
  • headache;
  • fast heart beat (tachycardia);
  • hallucinations (seeing or hearing things that are not there);
  • abnormal liver function tests;
  • fever; and
  • chills.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of voriconazole for IV injection.

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@Cipla.com. You can also report side effects directly via the national Pharmacovigilance Programme of India by calling on 1800 180 3024 or you can report to Cipla Ltd. on 1800 267 7779. By reporting side effects, you can help provide more information on the safety of this product.

  1. How to store VORITEK IV

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated on the carton and the vial after “EXP”. The expiry date refers to the last day of that month.

Before opening, store protected from moisture, at a temperature not exceeding 30˚C. From a microbiological point of view, once reconstituted, the product must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2° to 8°C (in a refrigerator), unless reconstitution has taken place in controlled validated aseptic conditions. Reconstituted VORITEK IV needs to be diluted with a compatible infusion solution first before it is infused.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

Keep voriconazole for IV injection, as well as all other medicines, out of the reach of children.

  1. Contents of the pack and other information

What VORITEK IV contains:

- The active substance is voriconazole. Each vial contains 200 mg of voriconazole. After reconstitution, each mL of the solution contains 10 mg of voriconazole.

- Other ingredients:

Hydroxypropyl Betadex U.S.P;

Sodium Hydroxide I.P.

Hydrochloric Acid l.P.   

Details of The Manufacturer

Mfd. by Gufic Biosciences Limited,

Unit No. 1, Mfg. Lic. No.: G/28/64

N. H. No. 8, Near Grid, Kabilpore 396424, Navsari, Gujarat (INDIA)

Unit No. 2, Mfg. Lic. No.: G/28/1499

Survey No. 171, N.H. No. 8, Near Grid, Kabilpore 396424, Navsari, Gujarat (INDIA)

Marketed by CIPLA LTD.

Registered Office:

Cipla House, Peninsula Business Park,  Ganpatrao Kadam Marg,

Lower Parel, Mumbai – 400 013, India

Details of Permission or License Number with Date

G/28/64 dated 28.07.2021

G/28/1499 dated 16.09.2021

Date of Revision

16/09/2021