Voriconazole Hikma

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Voriconazole Hikma 200 mg powder for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 200 mg of voriconazole.  
 
After reconstitution each ml contains 10 mg of voriconazole. Once reconstituted further dilution is required 
before administration. 
 
Excipient with known effect 
 
Each vial contains 217.6 mg sodium. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for infusion (powder for infusion) 
 
White to off-white lyophilised cake.  
 
pH of the reconstituted solution is 4.0 to 7.0. 
 
Osmolality: 500± 50 mOsm/kg 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Voriconazole 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 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. 
 
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).  
 



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It is recommended that voriconazole is administered at a maximum rate of 3 mg/kg per hour over 1 to 3 
hours.  
 
Treatment 
 
Adults  
Voriconazole Hikma 200 mg powder for solution for infusion is for intravenous use only.  Oral dosage forms 
of voriconazole are available from other manufacturers. 
 
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  

*Oral dosage forms of voriconazole are available from other manufacturers 
**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 is unable to tolerate intravenous treatment at 4 mg/kg twice daily, reduce the dose to 3 mg/kg twice 
daily.  
 
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)  

*Oral dosage forms of voriconazole are available from other manufacturers 
Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatric patients 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.  
 
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 intravenous dose may be increased by 1 mg/kg steps. If 
patients are unable to tolerate treatment, reduce the intravenous dose by 1 mg/kg steps.  
 
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) 
 
Dosage adjustments in case of co-administration 
Rifabutin or phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is 
increased to 5 mg/kg intravenously twice daily, see sections 4.4 and 4.5.  
 
Efavirenz may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 
400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment 
with voriconazole is stopped, the initial dosage of efavirenz should be restored (see sections 4.4 and 4.5).  
 
Elderly 



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No dose adjustment is necessary for elderly patients (see section 5.2).  
 
Renal impairment  
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min), accumulation of the 
intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an 
assessment of the risk benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine 
levels should be closely monitored in these patients and, if increases occur, consideration should be given to 
changing to oral voriconazole therapy (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.  
 
The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.  
 
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 Hikma requires reconstitution and dilution (see section 6.6) prior to administration as an 
intravenous infusion. Not for bolus injection.  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  
 
Co-administration 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).  
 
Co-administration with rifampicin, carbamazepine and phenobarbital since these medicinal products are 
likely to decrease plasma voriconazole concentrations significantly (see section 4.5).  
 
Co-administration 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  thesedoses. Voriconazole also significantly increases efavirenz plasma concentrations (see 
section 4.5, for lower doses see section 4.4).  
 



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Co-administration 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).  
 
Co-administration 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).  
 
Co-administration with sirolimus, since voriconazole is likely to increase plasma concentrations of sirolimus 
significantly (see section 4.5).  
 
Co-administration 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 Hikma to patients with hypersensitivity to other azoles 
(see also section 4.8).  
 
Duration of treatment 
 
The duration of treatment with the intravenous formulation should be no longer than 6 months (see section 
5.3).  
 
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).  

 
Infusion-related reactions 
 
Infusion-related reactions, predominantly flushing and nausea, have been observed during administration of 
the intravenous formulation of voriconazole. Depending on the severity of symptoms, consideration should 
be given to stopping treatment (see section 4.8).  
 
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 jaundice, 



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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 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 and at least weekly for the first month of treatment. Treatment 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 Hikma 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 HIKMA 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 HIKMA 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 HIKMA discontinuation and use of alternative antifungal agents should be 
considered and the patient should be referred to a dermatologist. If VORICONAZOLE HIKMA is 
continued, however, dermatologic evaluation should be performed on a systematic and regular basis, 
to allow early detection and management of premalignant lesions. VORICONAZOLE HIKMA 
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 HIKMA 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 HIKMA (see sections 4.2 and 5.1). 

 
Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term 
VORICONAZOLE HIKMA 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 HIKMA discontinuation should be considered after multidisciplinary 



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advice. 

Visual adverse reactions 
 
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 
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 to <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 co-administered 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 that of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2, 4.3 and 
4.5).  



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Rifabutin (Potent CYP450 inducer)  
 
Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended 
when rifabutin is co-administered 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)  
 
Co-administration 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 4.5 and 4.3).  
 
Everolimus (CYP3A4 substrate, P-gp substrate) 
 
Co-administration 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 co-administered with voriconazole since methadone levels increased following co-
administration 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 co-administered with voriconazole 
(see section 4.5). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is co-
administered with voriconazole and in an independent published study, concomitant use of voriconazole with 
fentanyl resulted in an increase in the mean AUC 0-∞ 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).  
 
Sodium content 
 
This medicinal product contains 217.6 mg sodium per vial, equivalent to 10.9% of the WHO recommended 
maximum daily intake of 2 g sodium for an adult. 
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 



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plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma 
concentrations of substances metabolised by these CYP450 isoenzymes.  
 
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), 
co-administration 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 
co-administration  

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, co-
administered 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,  

   
   
   
 
Use of standard doses of 
voriconazole with efavirenz doses 
of 400 mg QD or higher is 
contraindicated (see section 4.3).  
   
   
Voriconazole may be co-
administered 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 



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Medicinal product  
[Mechanism of Interaction] 

Interaction  
Geometric mean changes (%)  

Recommendations concerning 
co-administration  

Voriconazole Cmax ↑ 23%  
Voriconazole AUCτ ↓ 7%  

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)  
[CYP3A4 substrates] 

Although not studied, 
voriconazole is likely to increase 
the plasma concentrations of ergot 
alkaloids and lead to ergotism.  

Contraindicated (see section 4.3)  

Rifabutin  
[potent CYP450 inducer]  
   
300 mg QD  
   
   
300 mg QD (co-administered with 
voriconazole 350 mg BID)*  
   
   
   
   
300 mg QD (co-administered 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%  

  
 
 
 
Co-administration of voriconazole 
and high doses of ritonavir 
(400 mg and above BID) is 
contraindicated (see section 4.3).  
 
 
Co-administration 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 (co-administered with 
voriconazole 400 mg single dose)  

   
In an independent published study,  
Voriconazole AUC0-∞ ↓ 59%  

   
Contraindicated (see section 4.3)  

Everolimus  Although not studied, Co-administration of voriconazole 



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Medicinal product  
[Mechanism of Interaction] 

Interaction  
Geometric mean changes (%)  

Recommendations concerning 
co-administration  

[CYP3A4 substrate, P-gp 
substrate] 

voriconazole is likely to 
significantly increase the plasma 
concentrations of everolimus.  

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.  

Phenytoin  
[CYP2C9 substrate and potent 
CYP450 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.  



13 

Medicinal product  
[Mechanism of Interaction] 

Interaction  
Geometric mean changes (%)  

Recommendations concerning 
co-administration  

Immunosuppressants  
[CYP3A4 substrates] 
Sirolimus (2 mg single dose)  
 
 
 
 
 
Ciclosporin (in stable renal 
transplant recipients receiving 
chronic ciclosporin therapy)  
 
 
 
 
 
 
 
 
 
 
Tacrolimus (0.1 mg/kg single dose)  

   
In an independent published study,  
Sirolimus Cmax ↑ 6.6-fold  
Sirolimus AUC0-∞ ↑ 11-fold  
 
 
 
 
Ciclosporin Cmax ↑ 13%  
Ciclosporin AUCτ ↑ 70%  
 
 
 
 
 
 
 
 
 
 
 
Tacrolimus Cmax ↑ 117%  
Tacrolimus AUCt ↑ 221%  

  
Co-administration 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 
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)  
   

 
  
   
S-Ibuprofen Cmax ↑ 20%  
S-Ibuprofen AUC0-∞ ↑ 100%  

 
   
   
Frequent monitoring for adverse 
reactions and toxicity related to 



14 

Medicinal product  
[Mechanism of Interaction] 

Interaction  
Geometric mean changes (%)  

Recommendations concerning 
co-administration  

  
Diclofenac (50 mg single dose)  

   
Diclofenac Cmax ↑ 114%  
Diclofenac AUC0-∞ ↑ 78%  

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/ethinylestradiol 
(1 mg/0.035 mg QD)  

Ethinylestradiol Cmax ↑ 36%  
Ethinylestradiol AUCτ ↑ 61%  
Norethisterone Cmax ↑ 15%  
Norethisterone AUCτ ↑ 53%  
Voriconazole Cmax ↑ 14%  
Voriconazole AUCτ ↑ 46%  

Monitoring for adverse reactions 
related to oral contraceptives, in 
addition to those for voriconazole, 
is recommended.  

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 AUC∞ ↑ 6-fold  
 
 
In an independent published study,  
Fentanyl AUC∞ ↑ 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)*  

Not studied clinically. In vitro 
studies show that voriconazole 
may inhibit the metabolism of 

Careful monitoring for any 
occurrence of drug toxicity and/or 
lack of efficacy, and dose 



15 

Medicinal product  
[Mechanism of Interaction] 

Interaction  
Geometric mean changes (%)  

Recommendations concerning 
co-administration  

[CYP3A4 substrates and inhibitors] HIV protease inhibitors and the 
metabolism of voriconazole may 
also be inhibited by HIV protease 
inhibitors.  

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 a 
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  

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.  



16 

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



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) 
 

Infections and 
infestations 

 sinusitis pseudomembranous 
colitis 

  

Neoplasms 
benign, 
malignant and 
unspecified 
(including 
cysts and 
polyps) 

    squamous 
cell 
carcinoma* 

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 

hyperthyroidism  

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, drug 
reaction with 
eosinophilia and 
systemic 
symptoms 
(DRESS), 
angioedema, 
Actinic 
keratosis*,  
pseudoporphyria 
erythema 
multiforme, 
psoriasis, drug 
eruption 

cutaneous 
lupus 
erythemato
sus* 
ephelides*, 
lentigo* 

Musculoskelet
al 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 
administration 
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 impairmentswere 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 
impairmentswere 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  
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 



20 

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 patients develop a rash they should be monitored closely and Voriconazole Hikma 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 for long 
periods of time; the mechanism has not been established (see section 4.4).  
 
Liver function tests 
The overall incidence of transaminase increases >3 xULN (not necessarily comprising an adverse event) in 
the voriconazole clinical programme was 18.0% (319/1768) 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).  
 
Infusion-related reactions 
During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type 
reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, 
pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion (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 
 



21 

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 
 
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. The intravenous vehicle, SBECD, is 
haemodialysed with a clearance of 55 ml/min. In an overdose, haemodialysis may assist in the removal of 
voriconazole and SBECD from the body. 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antimycotics for systemic use, – triazole derivatives ATC code: J02AC03 
 
Mode of action 
 
Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of 
fungal cytochrome P-450-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.  

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


22 

 
Other treated fungal infections (often with 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, Penicillium spp. including P. marneffei, 
Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigelii infections.  
 
In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris 
spp., Cladophialophora spp., 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 and C. krusei, all of which usually exhibit minimum 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.  



23 

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 277 immunocompromised 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 seven 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 2-232 days).  
 
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 five 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 at 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 %)  



24 

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 seen in 3/3 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; two 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 180 days 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 Voriconazole 
N=224 

Itraconazole 
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 



25 

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 
 
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 Voriconazole 
(N=98) 

Itraconazole 
(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 Voriconazole 
(N=125) 

Itraconazole 
(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 



26 

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) 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 
 



27 

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.  
 
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 
radiolabelled 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 (18-45 years). 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 12 to <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 



28 

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 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 adolescents/adults. Based on the population pharmacokinetic analysis, 12- to 14-
year-old adolescents weighing less than 50 kg should receive children's doses (see section 4.2).  
 
Renal impairment  
In patients with moderate to severe renal dysfunction (serum creatinine levels >2.5 mg /dl), accumulation of 
the intravenous vehicle, SBECD, occurs (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 postnatal 
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 impairment of male or female 
fertility in rats at exposures similar to those obtained in humans at therapeutic doses.  
 



29 

Preclinical data on the intravenous vehicle, SBECD indicated that the main effects were vacuolation of 
urinary tract epithelium and activation of macrophages in the liver and lungs in the repeated-dose toxicity 
studies. As GPMT (guinea pig maximisation test) result was positive, prescribers should be aware of the 
hypersensitivity potential of the intravenous formulation. Standard genotoxicity and reproduction studies 
with the excipient SBECD reveal no special hazard for humans. Carcinogenicity studies were not performed 
with SBECD. An impurity, present in SBECD, has been shown to be an alkylating mutagenic agent with 
evidence for carcinogenicity in rodents. This impurity should be considered a substance with carcinogenic 
potential in humans. In the light of these data the duration of treatment of the intravenous formulation should 
be no longer than 6 months. 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sulphobutylether beta cyclodextrin sodium (SBECD)  
 
6.2 Incompatibilities 
 
This medicinal product must not be mixed with other medicinal products except those mentioned in section 
6.6. . When the Voriconazole Hikma infusion is complete, the line may be used for administration of other 
intravenous products.  
 
Blood products and short-term infusion of concentrated solutions of electrolytes 
 
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior 
to initiation of voriconazole therapy (see sections 4.2 and 4.4). Voriconazole Hikma must not be 
administered simultaneously with any blood product or any short-term infusion of concentrated solutions of 
electrolytes, even if the two infusions are running in separate lines.  
 
Total parenteral nutrition 
 
Total parenteral nutrition (TPN) need not be discontinued when prescribed with Voriconazole Hikma, but 
does need to be infused through a separate line. If infused through a multiple-lumen catheter, TPN needs to 
be administered using a different port from the one used for Voriconazole Hikma. Voriconazole Hikma must 
not be diluted with 4.2 % Sodium Bicarbonate Infusion. Compatibility with other concentrations is unknown.  
 
This medicinal product must not be mixed with other medicinal products except those mentioned in section 
6.6. 
 
6.3 Shelf life 
 
2 years 
 
After reconstitution 
 
Chemical and physical in-use stability has been demonstrated for 36 hours at 2°C to 8° C for the 
reconstituted solution. 
 
After dilution 
 
Chemical and physical stability of the of the diluted solutions for infusion has been demonstrated for 36 
hours at 2°C to 8°C followed by 3 hours at room temperature. 
 
From a microbiological point of view, once reconstituted, the product must be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and would 



30 

normally not be longer than 24 hours at 2°C to 8°C (in a refrigerator), unless reconstitution has taken place in 
controlled and validated aseptic conditions.  
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special temperature storage conditions. Store in the original 
package in order to protect from light. 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  
 
30 ml clear Type I glass vial closed with a chlorobutyl rubber stopper and sealed with an aluminium flip off 
seal with a red plastic matte top button. Packs of 1 or 5 vials. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
The powder is reconstituted with either 19 ml of water for injections or 19 ml of sodium chloride 9 mg/ml 
(0.9%) solution for injection to obtain an extractable volume of 20 ml of clear concentrate containing 
10 mg/ml of voriconazole.  It is recommended that a standard 20 ml (non-automated) syringe be used to 
ensure that the exact amount (19.0 ml) of water for injections or sodium chloride 9 mg/ml (0.9%) solution 
for injection is dispensed.  
 
After reconstitution with 19 ml of water for injections or sodium chloride 9 mg/ml (0.9%) solution for 
injection a clear solution is obtained. 
 
This medicinal product is for single use only and any unused solution should be discarded and only clear 
solutions without particles should be used.  
 
For administration, the required volume of the reconstituted concentrate is added to a recommended 
compatible infusion solution (detailed below) to obtain a final voriconazole solution containing 0.5-5 mg/ml.  
 
Required Volumes of 10 mg/ml Voriconazole Hikma Concentrate  
 
Body 
Weight 
(kg)  

Volume of Voriconazole Hikma Concentrate (10 mg/ml) required for:  

3 mg/kg dose 
(number of 
vials)  

4 mg/kg dose 
(number of 
vials)  

6 mg/kg dose 
(number of 
vials)  

8 mg/kg dose 
(number of 
vials)  

9 mg/kg dose 
(number of 
vials) 

10  -  4.0 ml (1)  -  8.0 ml (1)  9.0 ml (1)  

15  -  6.0 ml (1)  -  12.0 ml (1)  13.5 ml (1)  

20  -  8.0 ml (1)  -  16.0 ml (1)  18.0 ml (1)  

25  -  10.0 ml (1)  -  20.0 ml (1)  22.5 ml (2)  

30  9.0 ml (1)  12.0 ml (1)  18.0 ml (1)  24.0 ml (2)  27.0 ml (2)  

35  10.5 ml (1)  14.0 ml (1)  21.0 ml (2)  28.0 ml (2)  31.5 ml (2)  

40  12.0 ml (1)  16.0 ml (1)  24.0 ml (2)  32.0 ml (2)  36.0 ml (2)  



31 

45  13.5 ml (1)  18.0 ml (1)  27.0 ml (2)  36.0 ml (2)  40.5 ml (3)  

50  15.0 ml (1)  20.0 ml (1)  30.0 ml (2)  40.0 ml (2)  45.0 ml (3)  

55  16.5 ml (1)  22.0 ml (2)  33.0 ml (2)  44.0 ml (3)  49.5 ml (3)  

60  18.0 ml (1)  24.0 ml (2)  36.0 ml (2)  48.0 ml (3)  54.0 ml (3)  

65  19.5 ml (1)  26.0 ml (2)  39.0 ml (2)  52.0 ml (3)  58.5 ml (3)  

70  21.0 ml (2)  28.0 ml (2)  42.0 ml (3)  -  -  

75  22.5 ml (2)  30.0 ml (2)  45.0 ml (3)  -  -  

80  24.0 ml (2)  32.0 ml (2)  48.0 ml (3)  -  -  

85  25.5 ml (2)  34.0 ml (2)  51.0 ml (3)  -  -  

90  27.0 ml (2)  36.0 ml (2)  54.0 ml (3)  -  -  

95  28.5 ml (2)  38.0 ml (2)  57.0 ml (3)  -  -  

100  30.0 ml (2)  40.0 ml (2)  60.0 ml (3)  -  -  
 
The reconstituted solution can be diluted with:  
 
Sodium chloride 9 mg/ml (0.9%) solution for injection  
Compound sodium lactate intravenous infusion  
5% glucose and lactated ringer's intravenous infusion  
5% glucose and 0.45% sodium chloride intravenous infusion  
5% glucose intravenous infusion  
5% glucose in 20 mEq potassium chloride intravenous infusion  
0.45% sodium chloride intravenous infusion  
5% glucose and 0.9% sodium chloride intravenous infusion  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Hikma Farmacêutica (Portugal), S.A. 
Estrada do Rio da Mó n.º 8, 8A e 8B, Fervença 
2705-906 Terrugem SNT 
Portugal 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1004/001 1 Pack 
EU/1/15/1004/002 5 Pack 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 27 May 2015 
Date of latest renewal: 
 
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. 
 



32 

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 

 
 



33 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Hospira UK Ltd 
Horizon, Honey Lane, Hurley, 
Maidenhead, SL6 6RJ 
United Kingdom  
 
Pfizer Service Company BVBA 
Hoge Wei 10, 
Zaventen, 1930, 
Belgium 
 
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 product subject to medical prescription. 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs 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 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 marketing authorisation holder (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.  

 
 
• 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. 



34 

- 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. 

 



35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



36 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



37 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer carton 1 (or 5) vials 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Voriconazole Hikma 200 mg powder for solution for infusion 
voriconazole 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 200 mg of voriconazole. 
After reconstitution each ml contains 10 mg of voriconazole. 
 
 
3. LIST OF EXCIPIENTS 
 
Excipient: sulpfobutylether beta cyclodextrin sodium (SBECD).  See leaflet for further information. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion 
1 vial 
5 vials 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Intravenous use only 
Reconstitute and dilute before use. 
Single use vial 
 
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 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from light. 
 
 



38 

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 
 
Hikma Farmacêutica (Portugal), S.A. 
Estrada do Rio da Mó n.º 8, 8A e 8B, Fervença 
2705-906 Terrugem SNT 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/15/1004/001 
EU/1/15/1004/002 
 
 
13. BATCH NUMBER 
 
BN 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
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 SMALL IMMEDIATE PACKAGING UNITS 
 
Vial label 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Voriconazole Hikma 200 mg powder for infusion 
voriconazole 
Intravenous use 
 
2. METHOD OF ADMINISTRATION 
 
Reconstitute and dilute before use – see leaflet. 
 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
BN 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
 
6. OTHER 
 
 
 



40 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



41 

 
Package leaflet: Information for the user 

 
Voriconazole Hikma 200 mg powder for solution for infusion 

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 Hikma is and what it is used for  
2. What you need to know before you take Voriconazole Hikma 
3. How to take Voriconazole Hikma 
4. Possible side effects  
5. How to store Voriconazole Hikma 
6. Contents of the pack and other information 
 
 
1. What Voriconazole Hikma is and what it is used for 
 
Voriconazole Hikma contains the active substance voriconazole. Voriconazole Hikma 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 cell 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 Hikma is intended for patients with worsening, possibly life-threatening, fungal infections. 
 
Prevention of fungal infections in high risk bone marrow transplant recipients 
This medicinal product should only be used under the supervision of a doctor. 
 
 
2. What you need to know before you take Voriconazole Hikma 
 
Do not take Voriconazole Hikma: 
- If you are allergic to the active ingredient voriconazole or to sulfobutylether beta cyclodextrin sodium 

(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 Voriconazole Hikma treatment: 
 

• Terfenadine (used for allergy) 



42 

• 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 Hikma 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 Hikma.  Your doctor should also monitor your 
liver function while you are being treated with Voriconazole Hikma 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 Hikma: 

• 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 Hikma. 
 
Your doctor should monitor the function of your liver and kidneys by doing blood tests. 
 
Children and adolescents 
Voriconazole Hikma should not be given to children younger than 2 years of age. 
 
Other medicines and Voriconazole Hikma 
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 Hikma, may affect the way that Voriconazole 
Hikma works or Voriconazole Hikma may affect the way they work. 
 
Tell your doctor if you are taking the following medicine, as treatment with Voriconazole Hikma at the same 
time should be avoided if possible: 

• Ritonavir (used for treating HIV) in doses of 100 mg twice daily 
 
Tell your doctor if you are taking either of the following medicines, as treatment with Voriconazole Hikma at 
the same time should be avoided if possible, and a dose adjustment of voriconazole may be required: 



43 

• 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 
Hikma 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 Hikma 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 Hikma 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 Hikma) 
• 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 treating fungal infections) 
• Everolimus (used for treating advanced kidney cancer and in transplant patients) 

 
Pregnancy and breast-feeding  
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. 
 
Voriconazole Hikma must not be used 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 being treated with Voriconazole Hikma. 
 
 
Driving and using machines 
Voriconazole Hikma may cause blurring of vision or uncomfortable sensitivity to light.  While affected, do 
not drive or operate any tools or machines.  Tell your docotor if you experience this. 
 
Voriconazole Hikma contains sodium 
This medicine contains 217.6 mg sodium (main component of cooking/table salt) in each vial. This is 
equivalent to 10.9% of the recommended maximum daily dietary intake of sodium for an adult. 
 
3. How to take Voriconazole Hikma 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure. 
 
Your doctor will determine your dose depending on your weight and the type of infection you have. 
 
Your doctor may change your dose depending upon your condition. 



44 

 
The recommended dose for adults (including elderly patients) is as follows: 
 Intravenous 
Dose for the first 24 hours 
(Loading Dose) 

6 mg/kg every 12 hours for the 
first 24 hours 

Dose after the first 24 hours 
(Maintenance Dose) 

4 mg/kg twice a day 

 
Depending on your response to treatment, your doctor may decrease the dose to 3 mg/kg twice daily. 
 
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: 
 Intravenous 
 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) 

9 mg/kg every 12 hours for the 
first 24 hours 

6 mg/kg every 12 hours for the 
first 24 hours 

Dose after the first 24 hours 
(Maintenance Dose) 

8 mg/kg twice a day 4 mg/kg twice a day 

 
Depending upon your response to treatment, your doctor may increase or decrease the daily dose. 
  
Voriconazole Hikma powder for solution for infusion will be reconstituted and diluted to the correct 
concentration by your hospital pharmacist or nurse.  (Please refer to the end of this leaflet for further 
information). 
 
This will be given to you by intravenous infusion (into a vein) at a maximum rate of 3 mg/kg per hour over 1 
to 3 hours. 
 
If you or your child are taking Voriconazole Hikma for prevention of fungal infections, your doctor may 
stop giving Voriconazole Hikma if you or your child develop treatment related side effects.  
 
 
If a dose of Voriconazole Hikma has been forgotten: 
As you will be given this medicine under close medical supervision, it is unlikely that a dose would be 
missed.  However, tell your doctor or pharmacist if you think that a dose has been forgotten. 
 
If you stop taking Voriconazole Hikma 
Voriconazole Hikma treatment will continue for as long as your doctor advises, however the duration of 
treatment with voriconazole should be no more than 6 months. 
 
Patients with a weakened immune system or those with difficult infections may require long term treatment 
to prevent the infection from returning.  You may be switched from the intravenous infusion to tablets once 
your condition improves. 
 
When Voriconazole Hikma 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. 
 



45 

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 Hikma and see a doctor immediately 

• Rash 
• Jaundice; changes in blood tests of liver function 
• Pancreatitis which may present with severe abdominal pain 

 
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 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) 
• 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 
organs 

• Enlarged lymph glands (sometimes painful), , failure of blood marrow, (increased eosinophil) 
• Depressed function of the adrenal gland, underactive thyroid gland 



46 

• 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 that (sometimes life threatening) 
• Life threatening allergic reaction  
• Disorder of blood clotting system 
• 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 
 



47 

Reactions during the infusion have occurred uncommonly with Voriconazole Hikma (including flushing, 
fever, sweating, increased heart rate and shortness of breath).  Your doctor may stop the infusion if this 
occurs. 
 
As Voriconazole Hikma has been known to affect the liver and the kidney, your doctor should monitor the 
function of your liver and kidneys 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 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. 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 Hikma 
 
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 after EXP. The expiry date refers 
to the last day of that month. 
 
This medicine does not require any special temperature storage conditions. Store in the original package in 
order to protect from light. 
 
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 Hikma contains  
- The active substance is voriconazole. Each vial contains 200 mg voriconazole, equivalent to 10 mg/ml 

solution when reconstituted as directed by your hospital pharmacist or nurse. 
- The other ingredient is sulfobutylether beta cyclodextrin sodium. 
 
 
What Voriconazole Hikma looks like and contents of the pack 
 
Voriconazole Hikma is a white to off-white lyophilised cake. 
 
Voriconazole Hikma is presented in packs of 1 or 5 glass vials as a powder for solution for infusion. Not all 
pack sizes may be marketed. 
 
 
Marketing Authorisation Holder 
Hikma Farmacêutica (Portugal), S.A. 
Estrada do Rio da Mó n.º 8, 8A e 8B, Fervença 
2705-906 Terrugem SNT 

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


48 

Portugal 
 
Manufacturer 
Hospira UK Ltd 
Horizon, Honey Lane, Hurley, 
Maidenhead, SL6 6RJ 
United Kingdom  
 
Pfizer Service Company BVBA 
Hoge Wei 10, 
Zaventen, 1930, 
Belgium 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
AT / BE / DE / NL 
Hikma Pharma GmbH 
Tel: +49 89-45450-302 
 

IT 
Hikma Italia S.p.A. 
Tél/Tel: + 39 0382 1751801 
 

BG / CY / CZ / DK / EE / ES / EL / FI / HR / 
HU / IE / IS / LI / LT / LU / LV / MT / NO / PL 
/ PT / RO / SE / SI / SK 
Hikma Farmacêutica (Portugal), S.A. 
Tel.: +351 219 608 410 
 

UK 
Consilient Health Ltd 
Tel.: +44(0)203 751 1888 

FR 
Laboratoires Delbert 
Tel.: +331 46 99 68 20 
 

 

  
  
 
This leaflet was last revised in MM/YYYY. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.  
 
----------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
 
Reconstitution and dilution information 
Voriconazole Hikma powder for solution for infusion needs to first be reconstituted with either 19 ml of 
water for injections or 19 ml of sodium chloride 9 mg/ml (0.9%) solution for injection to obtain an 
extractable volume of 20 ml of clear concentrate containing 10 mg/ml voriconazole. 
 
It is recommended that a standard 20 ml (non-automated) syringe be used to ensure that the exact amount 
(19.0 ml) of water for injections or of sodium chloride 9 mg/ml (0.9%) solution for injection is dispensed. 
 
After reconstitution with 19 ml of water for injections or sodium chloride 9 mg/ml (0.9%) solution for 
injection, a clear solution is obtained. 
 

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


49 

The required volume of the reconstituted concentrate is then added to a recommended compatible infusion 
solution listed below to obtain a final Voriconazole Hikma solution containing 0.5 to 5 mg/ml of 
voriconazole. 
 
This medicinal product is for single use only and any unused solution should be discarded and only clear 
solutions without particles should be used. 
 
Not for administration as a bolus injection. 
 
Prior to use this medicine does not require any special temperature storage conditions. Store in the original 
package in order to protect from light. 
 
Required volumes of 10 mg/ml Voriconazole Hikma Concentrate 
 

Body Weight 
(kg) 

Volume of Voriconazole Hikma Concentrate (10 mg/ml) required for: 
3 mg/kg dose 
(number of 

vials) 

4 mg/kg dose 
(number of 

vials) 

6 mg/kg dose 
(number of 

vials) 

8 mg/kg dose 
(number of 

vials) 

9 mg/kg dose 
(number of 

vials) 
10 - 4.0 ml (1) - 8.0 ml (1) 9.0 ml (1) 
15 - 6.0 ml (1) - 12.0 ml (1) 13.5 ml (1) 
20 - 8.0 ml (1) - 16.0 ml (1) 18.0 ml (1) 
25 - 10.0 ml (1) - 20.0 ml (1) 22.5 ml (2) 
30 9.0 ml (1) 12.0 ml (1) 18.0 ml (1) 24.0 ml (2) 27.0 ml (2) 
35 10.5 ml (1) 14.0 ml (1) 21.0 ml (2) 28.0 ml (2) 31.5 ml (2) 
40 12.0 ml (1) 16.0 ml (1) 24.0 ml (2) 32.0 ml (2) 36.0 ml (2) 
45 13.5 ml (1) 18.0 ml (1) 27.0 ml (2) 36.0 ml (2) 40.5 ml (3) 
50 15.0 ml (1) 20.0 ml (1) 30.0 ml (2) 40.0 ml (2) 45.0 ml (3) 
55 16.5 ml (1) 22.0 ml (2) 33.0 ml (2) 44.0 ml (3) 49.5 ml (3) 
60 18.0 ml (1) 24.0 ml (2) 36.0 ml (2) 48.0 ml (3) 54.0 ml (3) 
65 19.5 ml (1) 26.0 ml (2) 39.0 ml (2) 52.0 ml (3) 58.5 ml (3) 
70 21.0 ml (2) 28.0 ml (2) 42.0 ml (3) - - 
75 22.5 ml (2) 30.0 ml (2) 45.0 ml (3) - - 
80 24.0 ml (2) 32.0 ml (2) 48.0 ml (3) - - 
85 25.5 ml (2) 34.0 ml (2) 51.0 ml (3) - - 
90 27.0 ml (2) 36.0 ml (2) 54.0 ml (3) - - 
95 28.5 ml (2) 38.0 ml (2) 57.0 ml (3) - - 

100 30.0 ml (2) 40.0 ml (2) 60.0 ml (3) - - 
 
Voriconazole Hikma is a single dose unpreserved sterile lyophile.   
 
Stability after reconstitution: 
Chemical and physical in-use stability has been demonstrated for 36 hours at 2°C to 8° C for the 
reconstituted solution. 
 
Stability after dilution: 
Chemical and physical stability of the of the diluted solutions for infusion has been demonstrated for 36 
hours at 2°C to 8°C followed by 3 hours at room temperature. 
 
From a microbiological point of view, once reconstituted, the product must be used immediately. If not used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and would 
normally not be longer than 24 hours at 2°C to 8°C (in a refrigerator), unless reconstitution has taken place in 
controlled and validated aseptic conditions.  
 
Compatible infusion solutions: 
The reconstituted solution can be diluted with: 



50 

 
Sodium chloride 9 mg/ml (0.9%) solution for injection 
Compound sodium lactate intravenous infusion 
5% glucose and lactated ringer’s intravenous infusion 
5% glucose and 0.45% sodium chloride intravenous infusion 
5% glucose intravenous infusion 
5% glucose in 20 mEq potassium chloride intravenous infusion 
0.45% sodium chloride intravenous infusion 
5% glucose and 0.9% sodium chloride intravenous infusion 
 
The compatibility of Voriconazole Hikma with diluents other than listed above (or listed below under 
‘Incompatibilities’) is unknown. 
 
Incompatibilities: 
 
Voriconazole Hikma must not be infused into the same line or cannula concomitantly with other drug 
infusions, including parenteral nutrition (e.g. Aminofusin 10% Plus). 
 
Infusions of blood products must not occur simultaneously with Voriconazole Hikma. 
 
Infusion of total parenteral nutrition can occur silmultaneously with Voriconazole Hikma but not in the same 
line or cannula. 
 
Voriconazole Hikma must not be diluted with 4.2% sodium bicarbonate infusion. 

 


	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
	A. LABELLING
	B. PACKAGE LEAFLET