Voriconazole Accord

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Voriconazole Accord 50 mg film-coated tablets 

Voriconazole Accord 200 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Voriconazole Accord 50 mg film-coated tablets 

Each tablet contains 50 mg voriconazole. 

 

Excipient with known effect  

Each tablet contains 63 mg lactose (as monohydrate). 

 

Voriconazole Accord 200 mg film-coated tablets 

Each tablet contains 200 mg voriconazole.  

 

Excipient with known effect 

Each tablet contains 251 mg lactose (as monohydrate). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Voriconazole Accord 50 mg film-coated tablets 

 

White to off white, round, approximate 7.0 mm in diameter, film-coated tablets, debossed with ‘V50’ 

on one side and plain on the other side. 

 

Voriconazole Accord 200 mg film-coated tablets 

 

White to off white, oval, approximately 15.6 mm in length and 7.8 mm in width, film-coated tablets, 

debossed with ‘V200’ on one side and plain on the other side. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Voriconazole Accord, is a broad spectrum, triazole antifungal agent and is indicated in adults and 

children aged 2 years and above as follows: 

 

Treatment of invasive aspergillosis. 

 

Treatment of candidaemia in non-neutropenic patients. 

 

Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei). 

 

Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp. 

 

Voriconazole Accord should be administered primarily to patients with progressive, possibly life-

threatening infections. 

 

Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant 

(HSCT) recipients. 

 



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4.2 Posology and method of administration 

 

Posology 

 

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be 

monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see 

section 4.4). 

 

Voriconazole may also be available as powder for solution for infusion, powder and solvent for 

solution for infusion and powder for oral suspension, however not under this tradename. 

 

Treatment 

 

Adults  

Therapy must be initiated with the specified loading dose regimen of either intravenous or oral 

voriconazole to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of 

the high oral bioavailability (96 %; see section 5.2), switching between intravenous and oral 

administration is appropriate when clinically indicated.  

 

Detailed information on dosage recommendations is provided in the following table: 

 

 Intravenous Oral 

Patients 40 kg and 

above* 

Patients less than 40 kg* 

Loading dose 

regimen 

(first 24 hours) 

6 mg/kg every 12 

hours 

400 mg every 12 hours 200 mg every 12 hours 

Maintenance dose 

(after first 24 

hours) 

4 mg/kg twice 

daily 

200 mg twice daily 100 mg twice daily 

*This also applies to patients aged 15 years and older. 

 

Duration of treatment  

Treatment duration should be as short as possible depending on the patient’s clinical and 

mycological response. Long term exposure to voriconazole greater than 180 days (6 months) 

requires careful assessment of the benefit-risk balance (see sections 4.4 and 5.1). 

 

Dosage adjustment (Adults) 

If patient response to treatment is inadequate, the maintenance dose may be increased to 300 mg twice 

daily for oral administration. For patients less than 40 kg the oral dose may be increased to 150 mg 

twice daily. 

 

If patient is unable to tolerate treatment at a higher dose, reduce the oral dose by 50 mg steps to the 

200 mg twice daily (or 100 mg twice daily for patients less than 40 kg) maintenance dose. 

 

In case of use as prophylaxis, refer below. 

 

Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg) 

Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole 

more similarly to children than to adults.  

 

The recommended dosing regimen is as follows: 

 

 Intravenous  Oral 

Loading Dose Regimen  

(first 24 hours) 

9 mg/kg every 12 hours Not recommended 

Maintenance Dose 8 mg/kg twice daily  9 mg/kg twice daily  



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(after first 24 hours) (a maximum dose of 350 mg 

twice daily) 

Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatricpatients 

aged 2 to <12 years and 26 immunocompromised adolescents aged 12 to <17 years.  

 

It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be 

considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg 

intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral 

dose. 

 

These oral dose recommendations for children are based on studies in which voriconazole was 

administered as the powder for oral suspension. Bioequivalence between the powder for oral 

suspension and tablets has not been investigated in a paediatric population. Considering the assumed 

limited gastro-enteric transit time in paediatric patients, the absorption of tablets may be different in 

paediatric compared to adult patients. It is therefore recommended to use the oral suspension 

formulation in children aged  

2 to <12.  

 

All other adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight) 

Voriconazole should be dosed as adults. 

 

Dosage adjustment (Children [2 to <12 years] and young adolescents with low body weight [12 to 

14 years and <50 kg]) 

If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps (or by 

50 mg steps if the maximum oral dose of 350 mg was used initially). If patient is unable to tolerate 

treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg 

was used initially). 

 

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

(see sections 4.8 and 5.2).  

 

Prophylaxis in adults and children 

 

Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. 

Prophylaxis should be as short as possible depending on the risk for developing invasive fungal 

infection (IFI) as defined by neutropenia or immunosuppression. It may only be continued up to 

180 days after transplantation in case of continuing immunosuppression or graft versus host disease 

(GvHD) (see section 5.1).  

 

Dosage  

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age 

groups. Please refer to the treatment tables above. 

 

Duration of prophylaxis 

The safety and efficacy of voriconazole use for longer than 180 days has not been adequately studied 

in clinical trials. 

 

Use of voriconazole in prophylaxis for greater than 180 days (6 months) requires careful assessment of 

the benefit-risk balance (see sections 4.4 and 5.1). 

 

The following instructions apply to both treatment and prophylaxis 

 

Dosage adjustment 

For prophylaxis use, dose adjustments are not recommended in the case of lack of efficacy or 

treatment-related adverse events. In the case of treatment-related adverse events, discontinuation of 

voriconazole and use of alternative antifungal agents must be considered (see section 4.4 and 4.8) 

 



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Dosage adjustments in case of co-administration 

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is 

increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients 

less than 40 kg), see sections 4.4 and 4.5. 

 

The combination of voriconazole with rifabutin should, if possible be avoided. However, if the 

combination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mg 

to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see 

sections 4.4 and 4.5. 

 

Efavirenz may be coadministered 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 dosage of efavirenz should be restored 

(see sections 4.4 and 4.5)  

 

Elderly  

No dose adjustment is necessary for elderly patients (see section 5.2). 

 

Renal impairment 

The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. 

Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment 

(see section 5.2). 

 

Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4 hour haemodialysis session does 

not remove a sufficient amount of voriconazole to warrant dose adjustment. 

 

Hepatic impairment 

It is recommended that the standard loading dose regimens be used but that the maintenance dose be 

halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving 

voriconazole (see section 5.2). 

 

Voriconazole has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh 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 must only be used in patients with severe hepatic impairment if the 

benefit outweighs the potential risk. Patients with severe hepatic impairment must be carefully 

monitored for drug toxicity (see section 4.8). 

 

Paediatric population 

The safety and efficacy of voriconazole in children below 2 years has not been established. Currently 

available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be 

made. 

 

Method of administration 

 

Voriconazole Accord film-coated tablets are to be taken at least one hour before, or one hour 

following, a meal. 

 

4.3 Contraindications 

 

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 

 



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Coadministration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine 

since increased plasma concentrations of these medicinal products can lead to QTc prolongation and 

rare occurrences of torsades de pointes (see section 4.5). 

 

Coadministration with rifampicin, carbamazepine and phenobarbital since these medicinal products 

are likely to decrease plasma voriconazole concentrations significantly (see section 4.5). 

 

Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or 

higher is contraindicated, because efavirenz significantly decreases plasma voriconazole 

concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz 

plasma concentrations (see section 4.5, for lower doses see section 4.4). 

 

Coadministration with high-dose ritonavir (400 mg and above twice daily) because ritonavir 

significantly decreases plasma voriconazole concentrations in healthy subjects at this dose (see 

section 4.5, for lower doses see section 4.4). 

 

Coadministration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 

substrates, since increased plasma concentrations of these medicinal products can lead to ergotism (see 

section 4.5). 

 

Coadministration with sirolimus since voriconazole is likely to increase plasma concentrations of 

sirolimus significantly (see section 4.5). 

 

Coadministration with St John’s Wort (see section 4.5). 

 

4.4 Special warnings and precautions for use 

 

Hypersensitivity 

 

Caution should be used in prescribing Voriconazole Accord to patients with hypersensitivity to other 

azoles (see also section 4.8). 

 

Cardiovascular 

 

Voriconazole has been associated with QTc interval prolongation. There have been rare cases of 

torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic 

chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may have 

been contributory. Voriconazole should be administered with caution to patients with potentially 

proarrhythmic conditions, such as: 

 

 Congenital or acquired QTc -prolongation. 

 Cardiomyopathy, in particular when heart failure is present. 

 Sinus bradycardia. 

 Existing symptomatic arrhythmias. 

 Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances 
such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and 

corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.2). A 

study has been conducted in healthy volunteers which examined the effect on QTc interval of 

single doses of voriconazole up to 4 times the usual daily dose. No subject experienced an 

interval exceeding the potentially clinically relevant threshold of 500 msec (see section 5.1). 

 

Hepatic toxicity 

 

In clinical trials, there have been 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 haematological malignancy).Transient hepatic reactions, including hepatitis and 



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jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has 

usually been reversible on discontinuation of therapy (see section 4.8). 

 

Monitoring of hepatic function 

 

Patients receiving Voriconazole Accord must be carefully monitored for hepatic toxicity. Clinical 

management should include laboratory evaluation of hepatic function (specifically AST and ALT) at 

the initiation of treatment with Voriconazole Accord and at least weekly for the first month of 

treatment. Treatment duration should be as short as possible; however, if based on the benefit-risk 

assessment the treatment is continued (see section 4.2), monitoring frequency can be reduced to 

monthly if there are no changes in the liver function tests.  

 

If the liver function tests become markedly elevated, Voriconazole Accord should be discontinued, 

unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use.  

 

Monitoring of hepatic function should be carried out in both children and adults. 

 

Serious dermatological adverse reactions 

 

 Phototoxicity 
In addition Voriconazole Accord has been associated with phototoxicity including reactions such as 

ephelides, lentigo, actinic keratosis and pseudoporphyria. It is recommended that all patients, 

including children, avoid exposure to direct sunlight during Voriconazole Accord treatment and use 

measures such as protective clothing and sunscreen with high sun protection factor (SPF). 

 

 Squamous cell carcinoma of the skin (SCC) 
Squamous cell carcinoma of the skin has been reported in patients, some of whom have reported prior 

phototoxic reactions. If phototoxic reactions occur multidisciplinary advice should be sought, 

Voriconazole Accord discontinuation and use of alternative antifungal agents should be considered 

and the patient should be referred to a dermatologist. If Voriconazole Accord is continued, however, 

dermatologic evaluation should be performed on a systematic and regular basis, to allow early 

detection and management of premalignant lesions. Voriconazole Accord should be discontinued if 

premalignant skin lesions or squamous cell carcinoma are identified (see below the section under 

Long-term treatment). 

 

 Exfoliative cutaneous reactions 
Severe cutaneous adverse reactions (SCARs) including 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 with the use 

of voriconazole. If a patient develops a rash he should be monitored closely and Voriconazole Accord 

discontinued if lesions progress. 

 

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 Accord (see sections 4.2 and 5.1). 

 

Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term Voriconazole 

Accord 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 Accord discontinuation should be considered after multidisciplinary advice. 

 

Visual adverse reactions 

 



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There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis 

and papilloedema (see section 4.8). 

 

Renal adverse reactions 

 

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 

medicinal products and have concurrent conditions that may result in decreased renal function (see 

section 4.8). 

 

Monitoring of renal function 

 

Patients should be monitored for the development of abnormal renal function. This should include 

laboratory evaluation, particularly serum creatinine. 

 

Monitoring of pancreatic function 

 

Patients, especially children, with risk factors for acute pancreatitis (e.g., recent chemotherapy, 

haematopoietic stem cell transplantation [HSCT]), should be monitored closely during Voriconazole 

Accord treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation. 

 

Paediatric population 

 

Safety and effectiveness in paediatric subjects below the age of two years has not been established (see 

sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. A 

higher frequency of liver enzyme elevations was observed in the paediatric population (see 

section 4.8). Hepatic function should be monitored in both children and adults. Oral bioavailability 

may be limited in paediatric patients aged 2-<12 years with malabsorption and very low body weight 

for age. In that case, intravenous voriconazole administration is recommended. 

 

 Serious dermatological adverse reactions (including SCC) 
 

The frequency of phototoxicity reactions is higher in the paediatric population. As an evolution 

towards SCC has been reported, stringent measures for the photoprotection are warranted in this 

population of patients. In children experiencing photoaging injuries such as lentigines or ephelides, 

sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation. 

 

Prophylaxis 

 

In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including 

phototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation of 

voriconazole and use of alternative antifungal agents must be considered. 

 

Phenytoin (CYP2C9 substrate and potent CYP450 inducer) 

 

Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with 

voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit 

outweighs the risk (see section 4.5). 

 

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate) 

 

When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 

400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see 

sections 4.2, 4.3 and 4.5). 

 

Rifabutin (Potent CYP450 inducer) 

 



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Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g. uveitis) is 

recommended when rifabutin is coadministered with voriconazole. Concomitant use of voriconazole 

and rifabutin should be avoided unless the benefit outweighs the risk (see section 4.5). 

 

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate) 

 

Coadministration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided 

unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see sections 4.3 

and 4.5). 

 

Everolimus (CYP3A4 substrate, P-gp substrate)  

 

Coadministration of voriconazole with everolimus is not recommended because voriconazole is 

expected to significantly increase everolimus concentrations. Currently there are insufficient data to 

allow dosing recommendations in this situation (see section 4.5). 

 

Methadone (CYP3A4 substrate) 

 

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc 

prolongation, is recommended when coadministered with voriconazole since methadone levels 

increased following coadministration of voriconazole. Dose reduction of methadone may be needed 

(see section 4.5). 

 

Short-acting opiates (CYP3A4 substrate) 

 

Reduction in the dose of alfentanil, fentanyl and other short-acting opiates similar in structure to 

alfentanil and metabolised by CYP3A4 (e.g., sufentanil) should be considered when coadministered 

with voriconazole (see section 4.5). As the half-life of alfentanil is prolonged in a 4-fold manner when 

alfentanil is coadministered with voriconazole, and in an independent published study concomitant use 

of voriconazole with fentanyl resulted in an increase in the mean AUC0-∞ of fentanyl, frequent 

monitoring for opiate-associated adverse reactions (including a longer respiratory monitoring period) 

may be necessary. 

 

Long-acting opiates (CYP3A4 substrate) 

 

Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g., 

hydrocodone) should be considered when coadministered with voriconazole. Frequent monitoring for 

opiate-associated adverse reactions may be necessary (see section 4.5). 

 

Fluconazole(CYP2C9, CYP2C19 and CYP3A4 inhibitor) 

 

Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax 

and AUCτ of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and 

fluconazole that would eliminate this effect have not been established. Monitoring for 

voriconazole-associated adverse reactions is recommended if voriconazole is used sequentially after 

fluconazole (see section 4.5). 

 

Voriconazole Accord tablets contain lactose and should not be given to patients with rare hereditary 

problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 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 metabolised by these CYP450 isoenzymes. 

 



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Unless otherwise specified, drug interaction studies 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 medication 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), coadministration is contraindicated (see below and section 4.3). 

 

Interaction table 

 

Interactions between voriconazole and other medicinal products are listed in the table below (once 

daily as “QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”). The 

direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of 

the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk 

(*) indicates a two-way interaction. AUCτ, AUCt and AUC0-∞represent area under the curve over a 

dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, 

respectively. 

 

The interactions in the table are presented in the following order: contraindications, those requiring 

dose adjustment and careful clinical and/or biological monitoring, and finally those that have no 

significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field. 

 

Medicinal product 

[Mechanism of interaction] 

Interaction 

Geometric mean changes 

(%) 

Recommendations 

concerning 

coadministration 

Astemizole, cisapride, 

pimozide, quinidine and 

terfenadine 

[CYP3A4 substrates] 

Although not studied, 

increased plasma 

concentrations of these 

medicinal products can lead to 

QTc prolongation and rare 

occurrences of torsades de 

pointes 

Contraindicated (see section 4.3) 

Carbamazepine and long-

acting barbiturates (e.g., 

phenobarbital, mephobarbital) 

[potent CYP450 inducers] 

Although not studied, 

carbamazepine and long-acting 

barbiturates are likely to 

significantly decrease plasma 

voriconazole concentrations. 

Contraindicated (see section 4.3) 

Efavirenz (a non-nucleoside 

reverse transcriptase 

inhibitor) 

[CYP450 inducer; CYP3A4 

inhibitor and substrate] 

 

Efavirenz 400 mg QD, 

coadministered with 

voriconazole 200 mg BID* 

 

Efavirenz 300 mg QD, 

coadministered with 

voriconazole 400 mg BID* 

 

 

Efavirenz Cmax   38% 

Efavirenz AUCτ   44% 

Voriconazole Cmax   61% 

Voriconazole AUCτ  77% 

 

Compared to efavirenz 600 mg 

QD, Efavirenz Cmax ↔ 

Efavirenz AUCτ  17% 

 

Compared to voriconazole 

200 mg BID, 

Voriconazole Cmax  23% 

Voriconazole AUCτ  7% 

 

 

Use of standard doses of 

voriconazole with efavirenz doses of 

400 mg QD or higher is 

contraindicated (see section 4.3). 

 

Voriconazole may be coadministered 

with efavirenz if the voriconazole 

maintenance dose is increased to 

400 mg BID and the efavirenz dose 

is decreased to 300 mg QD. 

When voriconazole treatment is 

stopped, the initial dose of efavirenz 

should be restored (see section 4.2 

and 4.4). 

Ergot alkaloids (e.g., 

ergotamine and 

dihydroergotamine)  

Although not studied, 

voriconazole is likely to 

increase the plasma 

Contraindicated (see section 4.3) 



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[CYP3A4 substrates] concentrations of ergot 

alkaloids and lead to ergotism. 

Rifabutin 

[potent CYP450 inducer] 

 

300 mg QD 

 

 

300 mg QD (coadministered 

with voriconazole 350 mg 

BID)* 

 

 

300 mg QD (coadministered 

with voriconazole 400 mg 

BID)* 

 

 

 

Voriconazole Cmax   69% 

Voriconazole AUCτ  78% 

 

Compared to voriconazole 200 

mg BID, 

Voriconazole Cmax   4% 

Voriconazole AUCτ  32% 

 

Rifabutin Cmax  195% 

Rifabutin AUCτ 331% 

 

Compared to voriconazole 200 

mg BID, 

Voriconazole Cmax   104% 

Voriconazole AUCτ   87% 

Concomitant use of 

voriconazole and rifabutin 

should be avoided unless the 

benefit outweighs the risk. 

The maintenance dose of 

voriconazole may be increased 

to 5 mg/kg intravenously BID 

or from 200 mg to 350 mg 

orally BID (100 mg to 200 mg 

orally BID in patients less than 

40 kg) (see section 4.2). 

Careful monitoring of full 

blood counts and adverse 

reactions to rifabutin (e.g., 

uveitis) is recommended when 

rifabutin is coadministered 

with voriconazole. 

Rifampicin (600 mg QD) 

[potent CYP450 inducer] 
Voriconazole Cmax   93% 

Voriconazole AUCτ   96% 

Contraindicated (see section 4.3) 

Ritonavir (protease inhibitor) 

[potent CYP450 inducer; 

CYP3A4 inhibitor and 

substrate] 

 

High dose (400 mg BID) 

 

 

 

Low dose (100 mg BID)* 

 

 

 

 

Ritonavir Cmax  and AUCτ ↔ 

Voriconazole Cmax   66% 

Voriconazole AUCτ   82% 

 

Ritonavir Cmax  25% 

Ritonavir AUCτ   13% 

Voriconazole Cmax   24% 

Voriconazole AUCτ   39% 

 

 

 

Coadministration of voriconazole 

and high doses of ritonavir (400 mg 

and above BID) is contraindicated 

(see section 4.3). 

 

Coadministration of voriconazole 

and low dose ritonavir (100 mg BID) 

should be avoided, unless an 

assessment of the benefit/risk to the 

patient justifies the use of 

voriconazole. 

 

St John’s Wort 

[CYP450 inducer; P-gp 

inducer] 

300 mg TID (coadministered 

with voriconazole 400 mg 

single dose) 

 

In an independent published 

study,  

Voriconazole AUC0-∞  59% 
Contraindicated (see section 4.3) 

Everolimus 

[CYP3A4 substrate, P-gp 

substrate] 

Although not studied, 

voriconazole is likely to 

significantly increase the 

plasma concentrations of 

everolimus. 

Coadministration of voriconazole 

with everolimus is not recommended 

because voriconazole is expected to 

significantly increase everolimus 

concentrations (see section 4.4). 

Fluconazole (200 mg QD) 

[CYP2C9, CYP2C19 and 

CYP3A4 inhibitor] 

Voriconazole Cmax   57% 

Voriconazole AUCτ  79% 

Fluconazole Cmax ND 

Fluconazole AUCτ ND 

 

 

 

The reduced dose and/or frequency 

of voriconazole and 

fluconazole that would eliminate this 

effect have not been established. 

Monitoring for voriconazole-

associated adverse reactions is 

recommended if voriconazole is used 

sequentially after fluconazole. 

 



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Phenytoin 

[CYP2C9 substrate and 

potentCYP450 inducer] 

 

300 mg QD 

 

 

300 mg QD (co-administered 

with voriconazole 400 mg 

BID)* 

 

 

 

 

Voriconazole Cmax   49% 

Voriconazole AUCτ  69% 

 

Phenytoin Cmax   67% 

Phenytoin AUCτ  81% 

 

Compared to voriconazole 200 

mg BID, 

Voriconazole Cmax   34% 

Voriconazole AUCτ  39% 

 

Concomitant use of voriconazole and 

phenytoin should be avoided unless 

the benefit outweighs the risk. 

Careful monitoring of phenytoin 

plasma levels is recommended. 

 

Phenytoin may be co-administered 

with voriconazole if the maintenance 

dose of voriconazole is increased to 

5 mg/kg IV BID or from 200 mg to 

400 mg oral BID, (100 mg to 200 mg 

oral BID in patients less than 40 kg) 

(see section 4.2). 

Anticoagulants 

 

Warfarin (30 mg single dose, 

co- administered with 300 mg 

BID voriconazole) 

[CYP2C9 substrate] 

 

Other oral coumarins 

(e.g., phenprocoumon, 

acenocoumarol) 

[CYP2C9 and CYP3A4 

substrates] 

 

 

Maximum increase in 

prothrombin time was 

approximately 2-fold 

 

 

Although not studied, 

voriconazole may increase the 

plasma concentrations of 

coumarins that may cause an 

increase in prothrombin time 

 

 

Close monitoring of 

prothrombin time or other 

suitable anticoagulation tests is 

recommended and the dose of 

anticoagulants should be 

adjusted accordingly. 

Benzodiazepines (e.g., 

midazolam, triazolam, 

alprazolam) 

[CYP3A4 substrates] 

Although not studied 

clinically, 

voriconazole is likely to 

increase the plasma 

concentrations of 

benzodiazepines that are 

metabolised by CYP3A4 and 

lead to a prolonged sedative 

effect. 

Dose reduction of 

benzodiazepines should be 

considered. 

Immunosuppressants 

[CYP3A4 substrates] 

 

Sirolimus (2 mg single dose) 

 

 

 

 

 

Ciclosporin (in stable renal 

transplant recipients receiving 

chronic ciclosporin therapy) 

 

 

 

 

 

 

 

 

 

 

 

In an independent published 

study, 

Sirolimus Cmax  6.6-fold 

Sirolimus AUC0-∞ 11-fold 

 

 

 

Ciclosporin Cmax  13% 

Ciclosporin AUCτ  70% 

 

 

 

 

 

 

 

 

 

 

 

Coadministration of 

voriconazole and sirolimus is 

contraindicated (see section 

4.3).  

 

 

 

When initiating voriconazole 

in patients already on 

ciclosporin it is recommended 

that the ciclosporin dose be 

halved and ciclosporin level 

carefully monitored. Increased 

ciclosporin levels have been 

associated with nephrotoxicity. 

When voriconazole is 

discontinued, ciclosporin 

levels must be carefully 

monitored and the dose 



13  

 

 

Tacrolimus (0.1 mg/kg single 

dose) 

 

 

 

Tacrolimus Cmax  117% 

Tacrolimus AUCt  221% 

increased as necessary. 

 

When initiating voriconazole 

in patients already on 

tacrolimus, it is recommended 

that the tacrolimus dose be 

reduced to a third of the 

original dose and tacrolimus 

level carefully monitored. 

Increased tacrolimus levels 

have been associated with 

nephrotoxicity. When 

voriconazole is discontinued, 

tacrolimus levels must be 

carefully monitored and the 

dose increased as necessary. 

Long-Acting Opiates 

[CYP3A4 substrates] 

 

Oxycodone (10 mg single 

dose) 

 

 

In an independent published 

study, 

Oxycodone Cmax  1.7-fold 

 Oxycodone AUC0-∞  3.6-fold 

 

Dose reduction in oxycodone 

and other long-acting opiates 

metabolized by CYP3A4 

(e.g., hydrocodone) should be 

considered. Frequent 

monitoring for opiate associated 

adverse reactions may be necessary. 

Methadone (32-100 mg QD) 

[CYP3A4 substrate] 
R-methadone (active) Cmax  

31% 

R-methadone (active) AUCτ   

47% 

S-methadone Cmax  65% 

S-methadone AUCτ  103% 

Frequent monitoring for 

adverse reactions and toxicity 

related to methadone, 

including QTc prolongation, is 

recommended. Dose reduction 

of methadone may be needed. 

Non-Steroidal Anti- 

Inflammatory Drugs 

(NSAIDs) 

[CYP2C9 substrates] 

 

Ibuprofen (400 mg single 

dose) 

 

Diclofenac (50 mg single 

dose) 

 

 

 

 

S-Ibuprofen Cmax  20% 

S-Ibuprofen AUC0-∞  100% 

 

Diclofenac Cmax  114% 

Diclofenac AUC0-∞  78% 

 

 

 

Frequent monitoring for 

adverse reactions and toxicity 

related to NSAIDs is 

recommended. Dose reduction 

of NSAIDs may be needed. 

Omeprazole (40 mg QD)* 

[CYP2C19 inhibitor; 

CYP2C19 

and CYP3A4 substrate] 

Omeprazole Cmax 116% 

Omeprazole AUCτ  280% 

Voriconazole Cmax 15% 

Voriconazole AUCτ  41% 

 

Other proton pump inhibitors 

that are CYP2C19 substrates 

may also be inhibited by 

voriconazole and may result in 

increased plasma 

concentrations of these 

medicinal products. 

No dose adjustment of 

voriconazole is recommended. 

 

 

 

When initiating voriconazole 

in patients already receiving 

omeprazole doses of 40 mg or 

above, it is recommended that 

the omeprazole dose be halved. 

Oral Contraceptives* 

[CYP3A4 substrate; 

CYP2C19 

inhibitor] 

Norethisterone/ethinylestradi

Ethinylestradiol Cmax  36% 

Ethinylestradiol AUCτ  61% 

Norethisterone Cmax  15% 

Norethisterone AUCτ   53% 

Voriconazole Cmax  14% 

Monitoring for adverse 

reactions related to oral 

contraceptives, in addition to 

those for voriconazole, is 

recommended 



14  

ol 

(1 mg/0.035 mg QD) 
Voriconazole AUCτ  46% 

Short-acting Opiates 

[CYP3A4 substrates] 

 

Alfentanil (20 μg/kg single 

dose, with concomitant 

naloxone) 

 

Fentanyl (5 µg/kg single 

dose) 

 

 

 

In an independent published 

study, Alfentanil AUC0-∞  6-

fold. 

 

 

In an independent published 

study,  

Fentanyl AUC0-∞  1.34-fold 

Dose reduction of alfentanil, 

fentanyl and other short-acting 

opiates similar in structure to 

alfentanil and metabolised by 

CYP3A4 (e.g., sufentanil) 

should be considered. 

Extended and frequent 

monitoring for respiratory 

depression and other opiate 

associated adverse reactions is 

recommended. 

Statins (e.g., lovastatin) 

[CYP3A4 substrates] 

Although not studied 

clinically, voriconazole is 

likely to increase the plasma 

concentrations of statins that 

are metabolised by CYP3A4 

and could lead to 

rhabdomyolysis. 

Dose reduction of statins 

should be considered. 

Sulfonylureas (e.g., 

tolbutamide, glipizide, 

glyburide) 

[CYP2C9 substrates] 

Although not studied, 

voriconazole is likely to 

increase the plasma 

concentrations of 

sulfonylureas and cause 

hypoglycaemia. 

Careful monitoring of blood 

glucose is recommended. Dose 

reduction of sulfonylureas 

should be considered 

Vinca Alkaloids (e.g., 

vincristine and vinblastine) 

[CYP3A4 substrates] 

Although not studied, 

voriconazole is likely to 

increase the plasma 

concentrations of vinca 

alkaloids and lead to 

neurotoxicity. 

Dose reduction of vinca 

alkaloids should be considered. 

Other HIV Protease Inhibitors 

(e.g., saquinavir, amprenavir 

and nelfinavir)* 

[CYP3A4 substrates and 

inhibitors] 

Not studied clinically. In vitro 

studies show that voriconazole 

may inhibit the metabolism of 

HIV protease inhibitors and 

the metabolism of 

voriconazole may also be 

inhibited by HIV protease 

inhibitors. 

Careful monitoring for any 

occurrence of drug toxicity 

and/or lack of efficacy, and 

dose adjustment may be needed. 

Other Non-Nucleoside 

Reverse 

Transcriptase Inhibitors 

(NNRTIs) (e.g., delavirdine, 

nevirapine)* 

[CYP3A4 substrates, 

inhibitors 

or CYP450 inducers] 

Not studied clinically. In vitro 

studies show that the 

metabolism of voriconazole 

may be inhibited by NNRTIs 

and voriconazole may inhibit 

the metabolism of NNRTIs. 

The findings of the effect of 

efavirenz on voriconazole 

suggest that the metabolism of 

voriconazole may be induced 

by an NNRTI 

Careful monitoring for any 

occurrence of drug toxicity 

and/or lack of efficacy, and 

dose adjustment may be 

needed. 

Cimetidine (400 mg BID) 

[non-specific CYP450 

inhibitor and increases 

gastric pH] 

Voriconazole Cmax  18% 

Voriconazole AUCτ  23% 

No dose adjustment 

Digoxin (0.25 mg QD) 

[P-gp substrate] 

Digoxin Cmax ↔ 

Digoxin AUCτ ↔ 

No dose adjustment 



15  

Indinavir (800 mg TID) 

[CYP3A4 inhibitor and 

substrate] 

Indinavir Cmax ↔ 

Indinavir AUCτ ↔ 

Voriconazole Cmax ↔ 

Voriconazole AUCτ ↔ 

No dose adjustment 

Macrolide antibiotics 

 

Erythromycin (1 g BID) 

[CYP3A4 inhibitor] 

 

Azithromycin (500 mg QD) 

 

 

Voriconazole Cmax and AUCτ 

↔ 

 

 

Voriconazole Cmax and AUCτ 

↔ 

 

The effect of voriconazole on 

either erythromycin or 

azithromycin is unknown 

No dose adjustment 

Mycophenolic acid (1 g 

single dose) 

[UDP-glucuronyl transferase 

substrate] 

 

Mycophenolic acid Cmax ↔ 

Mycophenolic acid AUCt ↔ 

No dose adjustment 

Prednisolone (60 mg single 

dose) 

[CYP3A4 substrate] 

Prednisolone Cmax   11% 

Prednisolone AUC0-∞  34% 

No dose adjustment 

Ranitidine (150 mg BID) 

[increases gastric pH] 

Voriconazole Cmax and AUCτ 

↔ 

No dose adjustment 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

 

There are no adequate data on the use of voriconazole in pregnant women available. 

 

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is 

unknown. 

 

Voriconazole Accord must not be used during pregnancy unless the benefit to the mother clearly 

outweighs the potential risk to the foetus. 

 

Women of child-bearing potential 

 

Women of child-bearing potential must always use effective contraception during treatment. 

 

Breast-feeding 

 

The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be 

stopped on initiation of treatment with Voriconazole Accord. 

 

Fertility 

 

In an animal study, no impairment of fertility was demonstrated in male and female rats (see 

section 5.3). 

 

4.7 Effects on ability to drive and use machines 

 

Voriconazole Accord 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 



16  

and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating 

machinery while experiencing these symptoms.  

 

4.8 Undesirable effects 

 

Summary of safety profile 

 

The safety profile of voriconazole in adults 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 

haematological malignancy, HIV infected patients with oesophageal candidiasis and refractory fungal 

infections, non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers.  

 

The most commonly reported adverse reactions were visual impairment, pyrexia, rash, vomiting, 

nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and 

abdominal pain. 

 

The severity of the adverse reactions was generally mild to moderate. No clinically significant 

differences were seen when the safety data were analysed by age, race, or gender. 

 

Tabulated list of adverse reactions 

 

In the table below, since the majority of the studies were of an open nature, all 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. 

 

Frequency categories are expressed as: 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). 

 

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.  

 

Undesirable effects reported in subjects receiving voriconazole: 

 

System 

Organ Class 

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 

 

Frequency 

not known 

(cannot be 

estimated 

from 

available 

data) 

Infections and 

infestations 

 sinusitis pseudomembranou

s colitis 

  

Neoplasms 

benign, 

malignant and 

unspecified 

(including 

cysts and 

polyps) 

    squamous 

cell 

carcinoma

* 



17  

System 

Organ Class 

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 

 

Frequency 

not known 

(cannot be 

estimated 

from 

available 

data) 

Blood and 

lymphatic 

system 

disorders 

 agranulocytosis1, 

pancytopenia, 

thrombocytopenia2

, leukopenia, 

anaemia 

bone marrow 

failure, 

lymphadenopathy, 

eosinophilia 

disseminated 

intravascular 

coagulation 

 

Immune 

system 

disorders 

  hypersensitivity anaphylactoid 

reaction 

 

Endocrine 

disorders 

  adrenal 

insufficiency, 

hypothyroidism 

hyperthyroidis

m 

 

Metabolism 

and nutrition 

disorders 

oedema 

peripheral 

hypoglycaemia, 

hypokalaemia, 

hyponatraemia 

   

Psychiatric 

disorders 

 depression, 

hallucination, 

anxiety, insomnia, 

agitation, 

confusional state 

   

Nervous 

system 

disorders  

headache convulsion, 

syncope, tremor, 

hypertonia3, 

paraesthesia, 

somnolence, 

dizziness 

brain oedema, 

encephalopathy4, 

extrapyramidal 

disorder5, 

neuropathy 

peripheral, ataxia, 

hypoaesthesia, 

dysgeusia 

hepatic 

encephalopathy

, Guillain-Barre 

syndrome, 

nystagmus 

 

Eye disorders  visual 

impairment6 
retinal 

haemorrhage 

optic nerve 

disorder7, 

papilloedema8, 

oculogyric crisis, 

diplopia, scleritis, 

blepharitis 

optic atrophy, 

corneal opacity 

 

Ear and 

labyrinth 

disorders  

  hypoacusis, 

vertigo, tinnitus 

  



18  

System 

Organ Class 

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 

 

Frequency 

not known 

(cannot be 

estimated 

from 

available 

data) 

Cardiac 

disorders  

 arrhythmia 

supraventricular, 

tachycardia, 

bradycardia 

 

ventricular 

fibrillation, 

ventricular 

extrasystoles, 

ventricular 

tachycardia, 

electrocardiogram 

QT prolonged, 

supraventricular 

tachycardia 

torsades de 

pointes, 

atrioventricular 

block complete, 

bundle branch 

block, nodal 

rhythm 

 

Vascular 

disorders  

 hypotension, 

phlebitis 

thrombophlebitis, 

lymphangitis 

  

Respiratory, 

thoracic and 

mediastinal 

disorders  

respiratory 

distress9 
acute respiratory 

distress syndrome, 

pulmonary 

oedema 

   

Gastrointestin

al disorders  

diarrhoea, 

vomiting, 

abdominal 

pain, nausea 

cheilitis, 

dyspepsia, 

constipation, 

gingivitis 

peritonitis, 

pancreatitis, 

swollen tongue, 

duodenitis, 

gastroenteritis, 

glossitis 

  

Hepatobiliary 

disorders  

liver function 

test abnormal 

jaundice, jaundice 

cholestatic, 

hepatitis10 

hepatic failure, 

hepatomegaly, 

cholecystitis, 

cholelithiasis 

  

Skin and 

subcutaneous 

tissue 

disorders  

rash dermatitis 

exfoliative, 

alopecia, rash 

maculo-papular, 

pruritus, erythema 

Stevens-Johnson 

syndrome, 

phototoxicity, 

purpura, urticaria, 

dermatitis allergic, 

rash papular, rash 

macular, eczema 

toxic epidermal 

necrolysis, 

angioedema, 

actinic 

keratosis*, 

pseudoporphyri

a erythema 

multiforme, 

psoriasis, drug 

eruption, drug 

reaction with 

eosinophilia 

and systemic 

symptoms 

(DRESS) 

cutaneous 

lupus 

erythemato

sus*, 

ephelides*, 

lentigo* 

Musculoskele

tal and 

connective 

tissue 

disorders  

 back pain arthritis  periostitis* 



19  

System 

Organ Class 

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 

 

Frequency 

not known 

(cannot be 

estimated 

from 

available 

data) 

Renal and 

urinary 

disorders  

 renal failure acute, 

haematuria 

renal tubular 

necrosis, 

proteinuria, 

nephritis 

  

General 

disorders and 

administratio

n site 

conditions  

pyrexia chest pain, face 

oedema11, 

asthenia, chills 

infusion site 

reaction, influenza 

like illness 

  

Investigations  blood creatinine 

increased 

blood urea 

increased, blood 

cholesterol 

increased 

  

*ADR identified post-marketing 
1 Includes febrile neutropenia and neutropenia. 
2 Includes immune thrombocytopenic purpura. 
3 Includes nuchal rigidity and tetany. 
4 Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy. 
5 Includes akathisia and parkinsonism. 
6 See “Visual impairments” paragraph in section 4.8. 
7 Prolonged optic neuritis has been reported post-marketing. See section 4.4. 
8 See section 4.4. 
9 Includes dyspnoea and dyspnoea exertional. 
10 Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity. 
11 Includes periorbital oedema, lip oedema, and oedema mouth. 

 

Description of selected adverse reactions 

 

Visual impairments 

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, 

colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, 

scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and 

xanthopsia) with voriconazole were very common.  These visual impairments were transient and fully 

reversible, with the majority spontaneously resolving within 60 minutes and no clinically significant 

long-term visual effects were observed. There was evidence of attenuation with repeated doses of 

voriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and were 

not associated with long-term sequelae. Visual impairments may be associated with higher plasma 

concentrations and/or doses. 

 

The mechanism of action is unknown, although the site of action is most likely to be within the retina. 

In a study in healthy volunteers investigating the impact of voriconazole on retinal function, 

voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG 

measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment 

and were fully reversible on withdrawal of voriconazole. 

 

There have been post-marketing reports of prolonged visual adverse events (see section 4.4). 

 

Dermatological reactions 



20  

Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but 

these patients had serious underlying diseases and were receiving multiple concomitant medicinal 

products. The majority of rashes were of mild to moderate severity. Patients have developed severe 

cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxic 

epidermal necrolysis (TEN) (rare), drug reaction with 

eosinophilia and systemic symptoms (DRESS) (rare) and erythema multiforme (rare) during treatment 

with voriconazole (see section 4.4). 

 

If a patient develops a rash they should be monitored closely and Voriconazole Accord discontinued if 

lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been 

reported, especially during long-term therapy (see section 4.4). 

 

There have been reports of squamous cell carcinoma of the skin in patients treated with Voriconazole 

Accord for long periods of time; the mechanism has not been established (see section 4.4). 

 

Liver function tests 

The overall incidence of transaminase increases>3xULN (not necessarily comprising an adverse 

event) in the voriconazole clinical programme was 18.0% (319/1,768) in adults and 25.8% (73/283) in 

paediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. 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 

following dose adjustment, including discontinuation of therapy. 

 

Voriconazole has been associated with cases of serious hepatic toxicity in patients with other serious 

underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death 

(see section 4.4). 

 

Prophylaxis 

In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primary 

prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI, 

permanent discontinuation of voriconazole due to AEs was reported in 39.3% of subjects versus 

39.6% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent 

discontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18 

subjects (7.1%) treated with itraconazole. 

 

Paediatric population 

The safety of voriconazole was investigated in 288 paediatric patients aged 2 to <12 years (169) and 

12 to<18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) in 

clinical trials. The safety of voriconazole was also investigated in 158 additional paediatric patients 

aged 2 to <12 years in compassionate use programs. Overall, the safety profile of voriconazole in 

paediatric population was similar to that in adults. However, a trend towards a higher frequency of 

liver enzyme elevations, reported as adverse events in clinical trials was observed in paediatric 

patients as compared to adults (14.2% transaminases increased in paediatrics compared to 5.3% in 

adults). Post-marketing data suggest there might be a higher occurrence of skin reactions (especially 

erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who 

received voriconazole in a compassionate use programme, the following adverse reactions (for which 

a relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1), 

arrhythmia (1), pancreatitis(1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) 

and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients. 

 

Reporting of suspected adverse reactions 

 

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


21  

4.9 Overdose 

 

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who 

received up to five times the recommended intravenous dose of voriconazole. A single adverse 

reaction of photophobia of 10 minutes duration was reported. 

 

There is no known antidote to voriconazole. 

 

Voriconazole is haemodialysed with a clearance of 121 ml/min. In an overdose, haemodialysis may 

assist in the removal of voriconazole from the body. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1 Pharmacodynamic properties 

 

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02A C03 

 

Mode of action 

 

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the 

inhibition of fungal cytochrome P450-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 cytochrome P-

450 enzymes than for various mammalian cytochrome P-450 enzyme systems. 

 

Pharmacokinetic/pharmacodynamic relationship 

 

In 10 therapeutic studies, the median for the average and maximum plasma concentrations in 

individual subjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and 

3742 ng/ml (inter-quartile range 2027 to 6302 ng/ml), respectively. A positive association between 

mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies 

was not found and this relationship has not been explored in prophylaxis studies. 

 

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations 

between plasma voriconazole concentrations and both liver function test abnormalities and visual 

disturbances. Dose adjustments in prophylaxis studies have not been explored. 

 

Clinical efficacy and safety 

 

In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against 

Candida species (including fluconazole resistant C. krusei and resistant strains of C. glabrata and C. 

albicans) and fungicidal activity against all Aspergillus species tested. In addition voriconazole shows 

in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium 

or Fusarium which have limited susceptibility to existing antifungal agents. 

 

Clinical efficacy defined as partial or complete response, has been demonstrated for Aspergillus spp. 

including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., including C. 

albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis and limited numbers of C. 

dubliniensis, C. inconspicua, and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. 

prolificans and Fusarium spp. 

 

Other treated fungal infections (often with either partial or complete response) included isolated cases 

of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., 

Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, 

Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, 



22  

Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and 

Trichosporon spp. includingT. beigelii infections. 

 

In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., 

Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited 

by concentrations of voriconazole in the range 0.05 to 2 μg/ml. 

 

In vitro activity against the following pathogens has been shown, but the clinical significance is 

unknown: Curvularia spp. and Sporothrix spp. 

 

Breakpoints 

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should 

be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted 

before the results of the cultures and other laboratory studies are known; however, once these results 

become available, anti-infective therapy should be adjusted accordingly. 

 

The species most frequently involved in causing human infections include C. albicans, C. 

parapsilosis, C.tropicalis, C. glabrata andC. krusei, all of which usually exhibit minimal inhibitory 

concentration (MICs) of less than 1 mg/L for voriconazole. 

 

However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for 

C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than 

are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify 

Candida to species level. If antifungal susceptibility testing is available, the MIC results may be 

interpreted using breakpoint criteria established by European Committee on Antimicrobial 

Susceptibility Testing (EUCAST). 

 

EUCAST Breakpoints 

 

Candida species MIC breakpoint (mg/L) 

≤S (Susceptible) >R (Resistant) 

Candida albicans1 0.125 0.125 

Candida tropicalis1 0.125 0.125 

Candida parapsilosis1 0.125 0.125 

Candida glabrata2  Insufficient evidence 

Candida krusei3  Insufficient evidence 

Other Candida spp.4 Insufficient evidence 
1 Strains with MIC values above the Susceptible (S) breakpoint are rare, or not yet reported. The 

identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the 

result is confirmed the isolate sent to a reference laboratory. 
2 In clinical studies, response to voriconazole in patients with C glabrata infections was 21% lower 

compared to C. albicans, C. parapsilosis and C. tropicalis. In vitro data showed a slight increase of 

resistance of C. glabrata to voriconazole. 
3 In clinical studies, response to voriconazole in C. krusei infections was similar to C. albicans, C. 

parapsilosis and C. tropicalis. However, as there were only 9 cases available for EUCAST analysis, 

there is currently insufficient evidence to set clinical breakpoints for C. krusei. 
4 EUCAST has not determined non-species related breakpoints for voriconazole. 

 

Clinical experience 

 

Successful outcome in this section is defined as complete or partial response. 

 

Aspergillus infections – efficacy in aspergillosis patients with poor prognosis  

 

Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit 

of voriconazole versus conventional amphotericin B in the primary treatment of acute invasive 

aspergillosis was demonstrated in an open, randomised, multicentre study in 277immunocompromised 



23  

patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 

6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 

hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 

200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2-85 days). 

After IV voriconazole therapy, the median duration of oral voriconazole therapy was 76 days (range 2-

232days). 

 

A satisfactory global response (complete or partial resolution of all attributable symptoms, signs, 

radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole-

treated patients compared to 31% of patients treated with comparator. The 84-day survival rate for 

voriconazole was statistically significantly higher than that for the comparator and a clinically and 

statistically significant benefit was shown in favour of voriconazole for both time to death and time to 

discontinuation due to toxicity. 

 

This study confirmed findings from an earlier, prospectively designed study where there was a 

positive outcome in subjects with risk factors for a poor prognosis, including graft versus host disease, 

and, in particular, cerebral infections (normally associated with almost 100% mortality). 

 

The studies included cerebral, sinus, pulmonary and disseminated aspergillosis in patients with bone 

marrow and solid organ transplants, haematological malignancies, cancer and AIDS. 

 

Candidaemia in non-neutropenic patients 

 

The efficacy of voriconazole compared to the regimen of amphotericin B followed by fluconazole in 

the primary treatment of candidaemia was demonstrated in an open, comparative study. Three hundred 

and seventy non-neutropenic patients (above 12 years of age) with documented candidaemia were 

included in the study, of whom 248 were treated with voriconazole. Nine subjects in the voriconazole 

group and 5 in the amphotericin B followed by fluconazole group also had mycologically proven 

infection in deep tissue. Patients with renal failure were excluded from this study. The median 

treatment duration was 15 days in both treatment arms. In the primary analysis, successful response as 

assessed by a Data Review Committee (DRC) blinded to study medicinal product was defined as 

resolution/improvement in all clinical signs and symptoms of infection with eradication of Candida 

from blood and infected deep tissue sites 12 weeks after the end of therapy (EOT). Patients who did 

not have an assessment 12 weeks after EOT were counted as failures. In this analysis a successful 

response was seen in 41 % of patients in both treatment arms. 

 

In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 

6, or 12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazole 

had successful response rates of 65% and 71%, respectively. The Investigator’s assessment of 

successful outcome at each of these time points is shown in the following table. 

 

Timepoint Voriconazole 

(N=248) 

Amphotericin B 

→ fluconazole 

(N=122) 

EOT 178 (72%) 88 (72%) 

2 weeks after EOT 125 (50%) 62 (51%) 

6 weeks after EOT 104 (42%) 55 (45%) 

12 weeks after EOT 104 (42%) 51 (42%) 

 

Serious refractory Candida infections 

 

The study comprised 55 patients with serious refractory systemic Candida infections (including 

candidaemia, disseminated and other invasive candidiasis) where prior antifungal treatment, 

particularly with fluconazole, had been ineffective. Successful response was seen in 24 patients (15 

complete, 9 partial responses). In fluconazole-resistant non albicans species, a successful outcome was 



24  

seen in3/3 C.krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) 

infections. The clinical efficacy data were supported by limited susceptibility data. 

 

Scedosporium and Fusarium infections 

 

Voriconazole was shown to be effective against the following rare fungal pathogens: 

 

Scedosporium spp 

Successful response to voriconazole therapy was seen in 16 (6 complete, 10 partial responses) of 28 

patients with S. apiospermum and in 2 (both partial responses) of 7 patients with S. prolificans 

infection. In addition, a successful response was seen in 1 of 3 patients with infections caused by more 

than one organism including Scedosporium spp. 

 

Fusarium spp 

Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole. Of 

these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with 

fusariosis had an infection caused by several organisms; 2 of them had a successful outcome. 

 

The majority of patients receiving voriconazole treatment of the above mentioned rare infections were 

intolerant of, or refractory to, prior antifungal therapy. 

 

Primary Prophylaxis of Invasive Fungal Infections – Efficacy in HSCT recipients without prior proven 

or probable IFI 

 

Voriconazole was compared to itraconazole as primary prophylaxis in an open-label, comparative, 

multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable 

IFI. Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT 

(without stopping for >14 days) and survival with no proven or probable IFI for 180days after HSCT. 

The modified intent-to-treat (MITT) group included 465 allogeneic HSCT recipients with 45% of 

patients having AML. From all patients 58% were subject to myeloablative conditions regimens. 

Prophylaxis with study drug was started immediately after HSCT: 224 received voriconazole and 241 

received itraconazole. The median duration of study drug prophylaxis was 96 days for voriconazole 

and 68 days for itraconazole in the MITT group. 

 

Success rates and other secondary endpoints are presented in the table below: 

 

Study Endpoints Voriconazo

le 

N=224 

Itraconazo

le 

N=241 

Difference in 

proportions and the 

95% confidence 

interval (CI)  

P-

Value 

Success at day 180* 109 (48.7%) 80 (33.2%) 16.4% (7.7%, 

25.1%)** 

0.0002

** 

Success at day 100  121 (54.0%) 96 (39.8%) 15.4% (6.6%, 

24.2%)** 

0.0006

** 

Completed at least 100 days of 

study drug prophylaxis  

120 (53.6%) 94 (39.0%) 14.6% (5.6%, 23.5%) 0.0015 

Survived to day 180 184 (82.1%) 197 

(81.7%) 

0.4% (-6.6%, 7.4%) 0.9107 

Developed proven or probable 

IFI to day 180 

3 (1.3%) 5 (2.1%) -0.7% (-3.1%, 1.6%) 0.5390 

Developed proven or probable 

IFI to day 100 

2 (0.9%) 4 (1.7%) -0.8% (-2.8%, 1.3%) 0.4589 

Developed proven or probable 

IFI while on study drug 

0 3 (1.2%) -1.2% (-2.6%, 0.2%) 0.0813 

* Primary endpoint of the study 

** Difference in proportions, 95% CI and p-values obtained after adjustment for randomization 

 



25  

The breakthrough IFI rate to Day 180 and the primary endpoint of the study, which is Success at Day 

180, for patients with AML and myeloablative conditioning regimens respectively, is presented in the 

table below: 

 

AML 
 

Study endpoints Voriconazo

le  

(N=98)  

  

Itraconazo

le 

(N=109) 

Difference in proportions 

and the 95% confidence 

interval (CI) 

Breakthrough IFI – Day 

180 

1 (1.0%)  2 (1.8%) -0.8% (-4.0%, 2.4%) ** 

Success at Day 180* 55 (56.1%) 45 (41.3%) 14.7% (1.7%, 27.7%)*** 

* Primary endpoint of study 

** Using a margin of 5%, non inferiority is demonstrated  

***Difference in proportions, 95% CI obtained after adjustment for randomization 

 

Myeloablative conditioning regimens 

 

Study endpoints Voriconazo

le  

(N=125)  

  

Itraconazo

le 

(N=143) 

Difference in proportions 

and the 95% confidence 

interval (CI) 

Breakthrough IFI – Day 

180 

2 (1.6%) 3 (2.1%)  -0.5% (-3.7%, 2.7%) ** 

Success at Day 180* 70 (56.0%) 53 (37.1%) 20.1% (8.5%, 31.7%)*** 

* Primary endpoint of study 

** Using a margin of 5%, non inferiority is demonstrated  

*** Difference in proportions, 95% CI obtained after adjustment for randomization  

 

Secondary Prophylaxis of IFI – Efficacy in HSCT recipients with prior proven or probable IFI 

 

Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative, 

multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary 

endpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The 

MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, 

and 4 with other IFI. The median duration of study drug prophylaxis was 95.5 days in the MITT 

group. 

 

Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT, 

including one candidemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The 

survival rate at Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40). 

 

Duration of treatment 

 

In clinical trials, 705 patients received voriconazole therapy for greater than 12 weeks, with 164 

patients receiving voriconazole for over 6 months. 

 

Paediatric population 

 

Fifty-three paediatric patients aged 2 to <18 years were treated with voriconazole in two prospective, 

open-label, non-comparative, multi-center clinical trials. One study enrolled 31 patients with possible, 

proven or probable invasive aspergillosis (IA), of whom 14 patients had proven or probable IA and 

were included in the MITT efficacy analyses. The second study enrolled 22 patients with invasive 

candidiasis including candidaemia (ICC), and esophageal candidiasis (EC) requiring either primary or 

salvage therapy, of whom 17 were included in the MITT efficacy analyses. For patients with IA the 

overall rates of global response at 6 weeks were 64.3% (9/14), the global response rate was 40% (2/5) 



26  

for patients 2 to <12 years and 77.8% (7/9) for patients 12 to <18 years of age. For patients with ICC 

the global response rate at EOT was 85.7% (6/7) and for patients with EC the global response rate at 

EOT was 70% (7/10). The overall rate of response (ICC and EC combined) was 88.9% (8/9) for 2 to 

<12 years old and 62.5% (5/8) for 12 to <18 years old. 

 

Clinical studies examining QTc interval 

 

A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QTc 

interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole. 

The placebo- adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of 

voriconazole were 5.1, 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. 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. 

 

5.2 Pharmacokinetic properties 
 

General pharmacokinetic characteristics 

 

The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations 

and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk 

of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the 

observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-

linear pharmacokinetics were in agreement with those observed in healthy subjects. 

 

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than 

proportional increase in exposure is observed with increasing dose. It is estimated that, on average, 

increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in 

exposure (AUCτ).The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) 

achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 

40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended 

intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state 

are achieved within the first 24 hours of dosing. 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 

 

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum 
plasma concentrations (Cmax) achieved 1-2 hours after dosing. The absolute bioavailability of 

voriconazole after oral administration is estimated to be 96%.When multiple doses of voriconazole are 

administered with high fat meals, Cmax and AUCτ are reduced by 34 % and 24 %, respectively. The 

absorption of voriconazole is not affected by changes in gastric pH. 

 

Distribution 

 

The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting 

extensive distribution into tissues. Plasma protein binding is estimated to be 58%. Cerebrospinal fluid 

samples from eight patients in a compassionate programme showed detectable voriconazole 

concentrations in all patients. 

 

Biotransformation 

 

In vitro studies showed that voriconazole is metabolised by, the hepatic cytochrome P450 isoenzymes 

CYP2C19, CYP2C9 and CYP3A4. 

 

The inter-individual variability of voriconazole pharmacokinetics is high. 

 



27  

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. 

This enzyme exhibits genetic polymorphism. For example, 15-20 % of Asian populations may be 

expected to be poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 

3-5 %. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor 
metabolisers have, on average, 4-fold higher voriconazole exposure (AUCτ) than their homozygous 

extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on 

average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser 

counterparts. 

 

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. 

 

Elimination 

 

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

in the urine. 

 

After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is 

recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral 

dosing. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral 

and intravenous dosing. 

 

The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg 

(orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of 

the accumulation or elimination of voriconazole. 

 

Pharmacokinetics in special patient groups 

 

Gender 

In an oral multiple dose study, Cmax and AUCτ for healthy young females were 83% and 113% higher, 

respectively, than in healthy young males (18-45years). In the same study, no significant differences in 
Cmax and AUCτ were observed between healthy elderly males and healthy elderly females (≥65 years). 

 

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile 

and plasma concentrations observed in male and female patients were similar. Therefore, no dosage 

adjustment based on gender is necessary. 

 

Elderly 

In an oral multiple-dose study Cmax and AUCτ in healthy elderly males (≥65 years) were 61% and 86 

% higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax 
and AUCτ   were observed between healthy elderly females (≥65 years) and healthy young females 

(18-45 years). 

 

In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship between 

plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly 

patients was similar and, therefore, no dosage adjustment is necessary for the elderly (see section 4.2). 

 

Paediatric population 

The recommended doses in children and adolescent patients are based on a population 

pharmacokinetic analysis of data obtained from 112 immunocompromised paediatric patients aged 2 to 

<12 years and 26 immunocompromised adolescent patients aged 12to <17 years. Multiple intravenous 

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 3 paediatric 

pharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 

mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one 



28  

adolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patients 

compared to adults. 

 

A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted 

total exposure (AUCτ) in children following administration of a 9 mg/kg IV loading dose was 

comparable to 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 to 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 to 

that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide 

voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose. 

 

The higher intravenous maintenance dose in paediatric 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 paediatric patients with malabsorption and very low body 

weight for their age. In that case, intravenous voriconazole administration is recommended. 

 

Voriconazole exposures in the majority of adolescent patients were comparable to those in adults 

receiving the same dosing regimens. However, lower voriconazole exposure was observed in some 

young adolescents with low body weight compared to adults. It is likely that these subjects may 

metabolize voriconazole more similarly to children than to adults. Based on the population 

pharmacokinetic analysis, 12 to 14 year old adolescents weighing less than 50 kg should receive 

children’s doses (sees ection4.2). 

 

Renal impairment 

In an oral single dose (200 mg) study in subjects with normal renal function and mild (creatinine 

clearance 41-60 ml/min) to severe (creatinine clearance < 20ml/min) renal impairment, the 

pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma 

protein binding of voriconazole was similar in subjects with different degrees of renal impairment. (see 

sections 4.2 and 4.4). 

 

Hepatic impairment 

After an oral single-dose (200 mg), AUC was 233 % higher in subjects with mild to moderate hepatic 

cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding 

of voriconazole was not affected by impaired hepatic function. 

 
In an oral multiple-dose study, AUCτ was similar in subjects with moderate hepatic cirrhosis (Child-

Pugh B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function 

given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic 

cirrhosis (Child-Pugh C) (see sections 4.2 and 4.4). 

 

5.3 Preclinical safety data 
 

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. Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential 

did not reveal a special hazard for humans. 

 

In reproduction studies, voriconazole was shown to be teratogenic in rats and embryotoxic 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 labour 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 



29  

impairment of male or female fertility in rats at exposures similar to those obtained in humans at 

therapeutic doses. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Tablet core 

 

Lactose monohydrate 

Pregelatinized starch 

Croscarmellose sodium 

Povidone 

Magnesium stearate 

 

Film-coating 

 

Hypromellose 

Titanium dioxide (E171) 

Lactose monohydrate 

Triacetin  

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

4 years 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions. 

 

6.5 Nature and contents of container 

 

PVC / Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 or 100 film-coated tablets or unit 

dose PVC / Aluminium blister in pack sizes of 10x1, 14x1, 28x1, 30x1, 56x1 or 100x1 film-coated 

tablets. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona, s/n,  

Edifici Est 6ª planta,  

08039 Barcelona,  
Spain 
 



30  

8. MARKETING AUTHORISATION NUMBER(S) 
 

Voriconazole Accord 50 mg film-coated tablets 
 
EU/1/13/835/001-009, 

EU/1/13/835/019-024 

 

Voriconazole Accord 200 mg film-coated tablets 

 

EU/1/13/835/010-018, 

EU/1/13/835/025-030 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 16 May 2013 

Date of latest renewal: 8th February 2018 

 

 

10. DATE OF REVISION OF THE TEXT 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency. http://www.ema.europa.eu 

 

 

  

http://www.ema.europa.eu/


31  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE  

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



32  

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer(s) responsible for batch release 

 

Accord Healthcare Limited 

Sage House 

319 Pinner Road 

North Harrow, Middlesex, 

HA1 4HF 

United Kingdom 

 

Pharmadox Healthcare Ltd. 

KW20A Kordin Industrial Park, 

Paola, PLA 3000  

Malta 

 

Accord Healthcare Polska Sp.z o.o., 

ul. Lutomierska 50,95-200 Pabianice, Poland 

 

Accord Healthcare B.V.,  

Winthontlaan 200,  

3526 KV Utrecht,  

The Netherlands 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal products subject to medical prescription. 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

 Periodic safety update reports  
 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the   

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached.  



33  

  

 Additional risk minimisation measures 
 

 Health Care Professional (HCP) Question and Answer Brochure for Phototoxicity, SCC and 
Hepatic toxicity;  

- Advises HCPs on the risks of phototoxicity, skin SCC and liver toxicity associated with 
voriconazole use.  

- Provides HCPs with the current recommendations to monitor and manage these risks.  
- Reminds HCPs of use of the HCP Checklist and the Patient Alert Card and how to obtain 

additional copies.  

 

 Health Care Professional (HCP) Checklist for Phototoxicity, SCC and Hepatic toxicity:  
- Reminds HCPs of the risks of phototoxicity, skin SCC and hepatotoxicity reported with 

voriconazole use.  

- Provides HCPs with the current recommendations to monitor and manage these risks.  
- Reminds HCPs to discuss with the patient/care giver the risks of phototoxicity/skin SCC 

and hepatotoxicity, what to look for, how and when to seek immediate attention.  

- Reminds HCPs to provide a Patient Alert Card to the patient.  
 

 Patient Alert Card for Phototoxicity and SCC:  
- Reminds patients of the risk of phototoxicity and skin SCC.  
- Reminds patients when and how to report relevant signs and symptoms of phototoxicity and 

skin cancer.  

- Reminds patients to take steps to minimize the risk of skin reactions and skin SCC (by 
avoiding exposure to direct sunlight, use of a sunscreen and protective clothing) and inform 

HCPs if they experience relevant skin abnormalities. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



34  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



35  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



36  

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON (Blister pack for 50 mg film-coated tablets – Pack of 2, 10, 14, 20, 28, 30, 50, 56, 100) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Voriconazole Accord 50 mg film-coated tablets 

voriconazole 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 50 mg voriconazole. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose monohydrate. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

2 film-coated tablets 

10 film-coated tablets 

14 film-coated tablets 

20 film-coated tablets 

28 film-coated tablets 

30 film-coated tablets 

50 film-coated tablets 

56 film-coated tablets 

100 film-coated tablets 

10x1 film-coated tablets 

14x1 film-coated tablets 

28x1 film-coated tablets 

30x1 film-coated tablets 

56x1 film-coated tablets 

100x1 film-coated tablets 

 

 

5. METHOD AND ROUTE (S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING (S), IF NECESSARY 

 

 



37  

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona, s/n,  

Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

12. MARKETING AUTHORISATION NUMBER (S) 

 

EU/1/13/835/001 2 film-coated tablets 

EU/1/13/835/002 10 film-coated tablets 

EU/1/13/835/003 14 film-coated tablets 

EU/1/13/835/004 20 film-coated tablets 

EU/1/13/835/005 28 film-coated tablets 

EU/1/13/835/006 30 film-coated tablets 

EU/1/13/835/007 50 film-coated tablets 

EU/1/13/835/008 56 film-coated tablets 

EU/1/13/835/009 100 film-coated tablets 

EU/1/13/835/019 10x1 film-coated tablets 

EU/1/13/835/020 14x1 film-coated tablets 

EU/1/13/835/021 28x1 film-coated tablets 

EU/1/13/835/022 30x1 film-coated tablets 

EU/1/13/835/023 56x1 film-coated tablets 

EU/1/13/835/024 100x1 film-coated tablets 

 

 

13. BATCH NUMBER  

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Voriconazole Accord 50 mg 

 



38  

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



39  

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

Blister (Blister foil for 50 mg film-coated tablets (all blister packs)) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Voriconazole Accord 50 mg film-coated tablets 

voriconazole 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

  



40  

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON (Blister pack for 200 mg film-coated tablets – Pack of 2, 10, 14, 20, 28, 30, 50, 56, 100) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Voriconazole Accord 200 mg film-coated tablets 

voriconazole 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 200 mg voriconazole. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose monohydrate. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

2 film-coated tablets 

10 film-coated tablets 

14 film-coated tablets 

20 film-coated tablets 

28 film-coated tablets 

30 film-coated tablets 

50 film-coated tablets 

56 film-coated tablets 

100 film-coated tablets 

10x1 film-coated tablets 

14x1 film-coated tablets 

28x1 film-coated tablets 

30x1 film-coated tablets 

56x1 film-coated tablets 

100x1 film-coated tablets 

 

 

5. METHOD AND ROUTE (S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING (S), IF NECESSARY 

 

 



41  

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona, s/n,  

Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

12. MARKETING AUTHORISATION NUMBER (S) 

 

EU/1/13/835/010 2 film-coated tablets 

EU/1/13/835/011 10 film-coated tablets 

EU/1/13/835/012 14 film-coated tablets 

EU/1/13/835/013 20 film-coated tablets 

EU/1/13/835/014 28 film-coated tablets 

EU/1/13/835/015 30 film-coated tablets 

EU/1/13/835/016 50 film-coated tablets 

EU/1/13/835/017 56 film-coated tablets 

EU/1/13/835/018 100 film-coated tablets 

EU/1/13/835/025 10x1 film-coated tablets 

EU/1/13/835/026 14x1 film-coated tablets 

EU/1/13/835/027 28x1 film-coated tablets 

EU/1/13/835/028 30x1 film-coated tablets 

EU/1/13/835/029 56x1 film-coated tablets 

EU/1/13/835/030 100x1 film-coated tablets 

 

 

13. BATCH NUMBER  

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Voriconazole Accord 200 mg 

 



42  

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 



43  

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

Blister (Blister foil for 200 mg film-coated tablets (all blister packs)) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Voriconazole Accord 200 mg film-coated tablets 

voriconazole 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Accord 

 

 

3. EXPIRY DATE 

 

EXP: 

 

 

4. BATCH NUMBER 

 

Lot: 

 

 

5. OTHER 

 

 

  



44  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B.PACKAGE LEAFLET 



45  

Package Leaflet: Information for the user 

 

Voriconazole Accord 50 mg film-coated tablets 

Voriconazole Accord 200 mg film-coated tablets 

voriconazole 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

 Keep this leaflet. You may need to read it again. 

 If you have any further questions, ask your doctor, pharmacist or nurse. 

 This medicine has been prescribed for you only. Do not pass it on to others. It may harm  them, 
even if their signs of illness are the same as yours. 

 If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Voriconazole Accord is and what it is used for 

2.  What you need to know before you take Voriconazole Accord 

3.  How to take Voriconazole Accord 

4.  Possible side effects 

5.  How to store Voriconazole Accord 

6.  Content of the pack and other information 

 

 

1. What Voriconazole Accord is and what it is used for 

 

Voriconazole Accord contains the active substance voriconazole. Voriconazole Accord is an 

antifungal medicine. It works by killing or stopping the growth of the fungi that cause infections. 

 

It is used for the treatment of patients (adults and children over the age of 2) with: 

 invasive aspergillosis (a type of fungal infection due to Aspergillus sp), 

 candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic 
patients (patients without abnormally low white blood cells count), 

 serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another 
antifungal medicine), 

 serious fungal infections caused by Scedosporium sp.or Fusarium sp. (two different species  
of fungi). 

 

Voriconazole Accord is intended for patients with worsening, possibly life-threatening, fungal 

infections. 

 

Prevention of fungal infections in high risk bone marrow transplant recipients. 

 

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

 

 

2. What you need to know before you take Voriconazole Accord 

 

Do not take Voriconazole Accord 

If you are allergic to voriconazole or any of the other ingredients of this medicine (listed in section 6). 

 

It is very important that you inform your doctor or pharmacist if you are taking or have taken any 

other medicines, even those that are obtained without a prescription, or herbal medicines. 

 

The medicines in the following list must not be taken during your course of Voriconazole Accord 

treatment: 



46  

 

 Terfenadine (used for allergy) 

 Astemizole (used for allergy) 

 Cisapride (used for stomach problems) 

 Pimozide (used for treating mental illness) 

 Quinidine (used for irregular heart beat) 

 Rifampicin (used for treating tuberculosis) 

 Efavirenz (used for treating HIV) in doses of 400 mg and above once daily 

 Carbamazepine (used to treat seizures) 

 Phenobarbital (used for severe insomnia and seizures) 

 Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine) 

 Sirolimus (used in transplant patients) 

 Ritonavir (used for treating HIV) in doses of 400 mg and more twice daily 

 St John’s Wort (herbal supplement) 
 

Warnings and precautions 

Talk to your doctor, pharmacist or nurse before taking Voriconazole Accord if: 

 

 you have had an allergic reaction to other azoles. 

 you are suffering from, or have ever suffered from liver disease. If you have liver disease, your 
doctor may prescribe a lower dose of Voriconazole Accord. Your doctor should also monitor 

your liver function while you are being treated with Voriconazole Accord by doing blood tests. 

 you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality 
of electrocardiogram (ECG) called ‘long QTc syndrome’. 

 

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun 

exposed areas of skin and use sunscreen with high sun protection factor (SPF),, as an increased 

sensitivity of skin to the sun’s UV rays can occur. These precautions are also applicable to children. 

 

While being treated with Voriconazole Accord: 

 tell your doctor immediately if you develop  
o sunburn 
o severe skin rash or blisters. 
o bone pain 

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who 

after consultation may decide that it is important for you to be seen on a regular basis. There is a small 

chance that skin cancer could develop with long-term use of Voriconazole Accord.  

 

Your doctor should monitor the function of your liver and kidney by doing blood tests. 

 

Children and adolescents 

Voriconazole Accord should not be given to children younger than 2 years of age. 

 

Other medicines and Voriconazole Accord  

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines, including those that are obtained without a prescription. 

 

Some medicines, when taken at the same time as Voriconazole Accord, may affect the way 

Voriconazole Accord works or Voriconazole Accord may affect the way they work. 

 

Tell your doctor if you are taking the following medicine, as treatment with Voriconazole Accord at 

the same time should be avoided if possible: 

 

 Ritonavir (used for treating HIV) in doses of 100 mg twice daily 
 



47  

Tell your doctor if you are taking either of the following medicines, as treatment with Voriconazole 

Accord at the same time should be avoided if possible, and a dose adjustment of voriconazole may be 

required: 

 

 Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your 
blood counts and side effects to rifabutin will need to be monitored. 

 Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your 
blood concentration of phenytoin will need to be monitored during your treatment with 

Voriconazole Accord and your dose may be adjusted. 

 

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring 

may be required to check that the medicines and/ or Voriconazole Accord are still having the desired 

effect: 

 

 Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down 
clotting of the blood) 

 Ciclosporin (used in transplant patients) 

 Tacrolimus (used in transplant patients) 

 Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes) 

 Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol) 

 Benzodiazepines (e.g midazolam, triazolam) (used for severe insomnia and stress) 

 Omeprazole (used for treating ulcers) 

 Oral contraceptives (if you take Voriconazole Accord whilst using oral contraceptives, you may 
get side effects such as nausea and menstrual disorders) 

 Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer) 

 Indinavir and other HIV protease inhibitors (used for treating HIV) 

 Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used 
for treating HIV) (some doses of efavirenz can NOT be taken at the same time as Voriconazole 

Accord ) 

 Methadone (used to treat heroin addiction) 

 Alfentanil and fentanyl and other short-acting opiates such as sufentanil (painkillers used for 
surgical procedures) 

 Oxycodone and other long acting opiates such as hydrocodone (used for moderate to severe 
pain) 

 Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and 

 inflammation) 

 Fluconazole (used for fungal infections) 

 Everolimus (used for treating advanced kidney cancer and in transplant patients) 
 

Pregnancy and breast-feeding 

Voriconazole Accord must not be taken during pregnancy, unless indicated by your doctor. Effective 

contraception must be used in women of childbearing potential. Contact your doctor immediately if 

you become pregnant while taking Voriconazole Accord. 

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before taking this medicine. 

 

Driving and using machines 

Voriconazole Accord may cause blurring of vision or uncomfortable sensitivity to light. While 

affected, do not drive or operate any tools or machines. Contact your doctor if you experience this. 

 

Voriconazole Accord contains lactose 

If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor 

before taking Voriconazole Accord. 

 

 



48  

3. How to take Voriconazole Accord  

 

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 

if you are not sure. 

 

Your doctor will determine your dose depending on your weight and the type of infection you have. 

 

The recommended dose for adults (including elderly patients) is as follows: 

 Tablets 

Patients 40 kg and above  Patients less than 40 kg 

Dose for the first 24 hours 

(Loading Dose) 

400 mg every 12 hours  

for the first 24 hours 

200 mg every 12 hours 

for the first 24 hours 

Dose after the first 24 hours 

(Maintenance Dose) 

200 mg twice a day 100 mg twice a day 

 

Depending on your response to treatment, your doctor may increase the daily dose to 300 mg twice a 

day. 

 

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis. 

 

Use in children and adolescents 

 

The recommended dose for children and teenagers is as follows: 

 Tablets 

 Children aged 2 to less than 

12 years and teenagers aged 12 to 

14 years weighing less than 50 kg 

Teenagers aged 12 to 14 years 

weighing 50 kg or more; and all 

teenagers older than 14 

Dose for the first 24 

hours  

(Loading Dose) 

Your treatment will be 

started as an infusion 

400 mg every 12 hours 

for the first 24 hours 

Dose after the first 24 

hours 

(Maintenance Dose) 

9 mg/kg twice a day 

(a maximum dose of 350 mg 

twice daily) 

200 mg twice a day 

 

Depending on your response to treatment, your doctor may increase or decrease the daily dose. 

 

 Tablets must only be given if the child is able to swallow tablets. 
 

Take your tablet at least one hour before, or one hour after a meal. Swallow the tablet whole with 

some water. 

 

If you or your child are taking Voriconazole Accord for prevention of fungal infections, your doctor 

may stop giving Voriconazole Accord if you or your child develop treatment related side effects. 

 

If you take more Voriconazole Accord than you should 

If you take more tablets than prescribed (or if someone else takes your tablets) you must seek medical 

advice or go to the nearest hospital casualty department immediately. Take your box of Voriconazole 

Accord tablets with you. You may experience abnormal intolerance to light as a result of taking more 

Voriconazole Accord than you should. 

 

If you forget to take Voriconazole Accord 

It is important to take your Voriconazole Accord tablets regularly at the same time each day. If you 

forget to take one dose, take your next dose when it is due. Do not take a double dose to make up for a 

forgotten dose. 

 

If you stop taking Voriconazole Accord 



49  

It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness 

of your medicine. Therefore unless your doctor instructs you to stop treatment, it is important to keep 

taking Voriconazole Accord correctly, as described above. 

 

Continue taking Voriconazole Accord until your doctor tells you to stop. Do not stop treatment early 

because your infection may not be cured. Patients with a weakened immune system or those with 

difficult infections may require long-term treatment to prevent the infection from returning. 

 

When Voriconazole Accord 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. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

If any side effects occur, most are likely to be minor and temporary. However, some may be serious 

and need medical attention. 

 

Serious side effects – Stop taking Voriconazole Accord and see a doctor immediately 

- Rash 

- Jaundice; Changes in blood tests of liver function 

- Pancreatitis 

 

Other side effects 

 

Very common: may affect more than 1 in 10 people 

 

- Visual impairment (change in vision including blurred vision, visual color alterations, abnormal 
intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night 

blindness, swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, 

loss of part of the usual field of vision, spots before the eyes) 

- Fever 
- Rash 
- Nausea, vomiting, diarrhoea 
- Headache 
- Swelling of the extremities 
- Stomach pains 
- Breathing difficulties 
- Elevated liver enzymes 
 

Common: may affect up to 1 in 10 people 

 

- Inflammation of the sinuses, inflammation of the gums, chills, weakness 
- Low numbers of some types, including severe, of red (sometimes immune-related) and/or white 

blood cells (sometimes with fever), low numbers of cells called platelets that help the blood to 

clot 

- Low blood sugar, low blood potassium, low sodium in the blood 
- Anxiety, depression, confusion, agitation, inability to sleep, hallucinations  
- Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin sensations, 

increase in muscle tone, sleepiness, dizziness 

- Bleeding in the eye  
- Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting, low blood 

pressure, inflammation of a vein (which may be associated with the formation of a blood clot) 



50  

- Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid 
accumulation in the lungs 

- Constipation, indigestion, inflammation of the lips 
- Jaundice, inflammation of the liver and liver injury 
- Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, 

red area on the skin that is covered with small confluent bumps, redness of the skin 

- Itchiness 
- Hair loss 
- Back pain 
- Kidney failure, blood in the urine, changes in kidney function tests 
 

Uncommon: may affect up to 1 in 100 people 

 

- Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the 
gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic 

vessels 

- Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the 
abdominal organ 

- Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil 
- Depressed function of the adrenal gland, underactive thyroid gland 
- Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, 

tingling or burning in the hands or feet 

- Problems with balance or coordination 
- Swelling of the brain 
- Double vision, serious conditions of the eye including: pain and inflammation of the eyes and 

eyelids, abnormal eye movement, damage to the optic nerve  resulting in vision impairment, 

optic disc swelling 

- Decreased sensitivity to touch 
- Abnormal sense of taste 
- Hearing difficulties, ringing in the ears, vertigo  
- Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of 

the tongue  

- Enlarged liver, liver failure, gallbladder disease, gallstones 
- Joint inflammation, inflammation of the veins under the skin (which may be associated with the 

formation of a blood clot) 

- Inflammation of the kidney, proteins in the urine, damage to the kidney 
- Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses 
- Abnormal electrocardiogram (ECG) 
- Blood cholesterol increased, blood urea increased 
- Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes 

painful blisters and sores of the skin and mucous membranes, especially in the mouth, 

inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or 

sun, skin redness and irritation, red or purple discoloration of the skin which may be caused by 

low platelet count, eczema 

- Infusion site reaction 
- Allergic reaction or exaggerated immune response 
 

Rare: may affect up to 1 in 1000 people 

 

- Overactive thyroid gland 
- Deterioration of brain function that is a serious complication of liver disease  
- Loss of most fibers in the optic nerve,  clouding of the cornea, involuntary movement of the eye 
- Bullous photosensitivity 
- A disorder in which the body’s immune system attacks part of the peripheral nervous system  
- Heart rhythm or conduction problems (sometimes life threatening) 
- Life threatening allergic reaction 
- Disorder of blood clotting system 



51  

- Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis, 
subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin 

with silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin 

condition that causes large portions of the epidermis, the skin’s outermost layer, to detach from 

the layers of skin below 

- Small dry scaly skin patches, sometimes thick with spikes or ‘horns’ 
 

Side effects with frequency not known: 

- Freckles and pigmented spots 

 

Other significant side effects whose frequency is not known, but should be reported to your doctor 

immediately: 

- Skin cancer  
- Inflammation of the tissue surrounding the bone  
- Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune 

disease called cutaneous lupus erythematosus 

 

As Voriconazole Accord has been known to affect the liver and the kidney, your doctor should 

monitor the function of your liver and kidney by doing blood tests. Please advise your doctor if you 

have any stomach pains or if your stools have a different consistency. 

 

There have been reports of skin cancer in patients treated with Voriconazole Accord for long periods 

of time.  

 

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in 

children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, 

who after consultation may decide that it is important for you or your child to be seen on a regular 

basis. Elevated liver enzymes were also observed more frequently in children. 

 

If any of these side effects persist or are troublesome, please tell your doctor. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 

 

 

5. How to store Voriconazole Accord  

 

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 label. The expiry date refers to the 

last day of that month. 

 

This medicine does not require any special storage conditions. 

 

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. 

 

 

6. Contents of the pack and other information 

 

What Voriconazole Accord contains 

 The active substance is voriconazole. Each tablet contains either 50 mg voriconazole (for 
Voriconazole Accord 50 mg film-coated tablets) or 200 mg voriconazole (for 

VoriconazoleAccord 200 mg film-coated tablets). 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


52  

 The other ingredients are lactose monohydrate, pregelatinised starch, croscarmellose sodium, 
povidone and magnesium stearate which make up the tablet core and hypromellose, titanium 

dioxide (E171), lactose monohydrate and triacetin which make up the film-coat. 

 

What Voriconazole Accord looks like and contents of the pack 

Voriconazole Accord 50 mg film-coated tablets are supplied as white to off white, round, approximate 

7.0mm in diameter, film-coated tablets, debossed with ‘V50’ on one side and plain on the other side. 

 

Voriconazole Accord 200 mg film-coated tablets are supplied as white to off white, oval, 

approximately 15.6 mm in length and 7.8 mm in width, film-coated tablets, debossed with ‘V200’ on 

one side and plain on the other side. 

 

Voriconazole Accord 50 mg film-coated tablets and 200mg film-coated tablets are available as packs 

of 2, 10, 14, 20, 28, 30, 50, 56 and 100 or unit dose blister packs (PVC / Aluminium) containing 10x1, 

14x1, 28x1, 30x1, 56x1 or 100x1 film-coated tablets. 

 

Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder  

 

Accord Healthcare S.L.U.  

World Trade Center, Moll de Barcelona, s/n,  

Edifici Est 6ª planta,  

08039 Barcelona,  

Spain 

 

Manufacturer 

 

Accord Healthcare Limited,  

Sage House, 319 Pinner Road, 

North Harrow, Middlesex, HA1 4HF, 

United Kingdom 

 

Pharmadox Healthcare Ltd. 

KW20A Kordin Industrial Park, 

Paola, PLA 3000  

Malta 

 

Accord Healthcare Polska Sp.z o.o., 

ul. Lutomierska 50,95-200 Pabianice, Poland 

 

Accord Healthcare B.V.,  

Winthontlaan 200,  

3526 KV Utrecht,  

The Netherlands 

 

This leaflet was last approved in {MM/YYYY}. 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	LABELLING AND PACKAGE LEAFLET
	A. LABELLING
	B.PACKAGE LEAFLET