Voriconazole Accord - patient leaflet, side effects, dosage

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

• 1. NAME OF THE MEDICINAL PRODUCT

Voriconazole Accord 50 mg film-coated tablets

Voriconazole Accord 200 mg film-coated tablets

• 2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Voriconazole Accord 50 mg film-coated tablets

Each tablet contains 50 mg voriconazole.

Excipient with known effect

Each tablet contains 63 mg lactose (as monohydrate).

Voriconazole Accord 200 mg film-coated tablets

Each tablet contains 200 mg voriconazole.

Excipient with known effect

Each tablet contains 251 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

• 3. PHARMACEUTICAL FORM

Voriconazole Accord 50 mg film-coated tablets

White to off white, round, approximate 7.0 mm in diameter, film-coated tablets, debossed with ‘V50’ on one side and plain on the other side.

Voriconazole Accord 200 mg film-coated tablets

White to off white, oval, approximately 15.6 mm in length and 7.8 mm in width, film-coated tablets, debossed with ‘V200’ on one side and plain on the other side.

• 4. CLINICAL PARTICULARS

  • 4.1 Therapeutic indications

Voriconazole Accord, is a broad spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows:

Treatment of invasive aspergillosis.

Treatment of candidaemia in non-neutropenic patients.

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

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

Voriconazole Accord should be administered primarily to patients with progressive, possibly lifethreatening 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).

Voriconazole may also be available as powder for solution for infusion, powder and solvent for solution for infusion and powder for oral suspension, however not under this tradename.

Treatment

Adults

Therapy must be initiated with the specified loading dose regimen of either intravenous or oral voriconazole to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of the high oral bioavailability (96 %; see section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated.

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

This also applies to patients aged 15 years and older.

Duration of treatment

Treatment duration should be as short as possible depending on the patient’s clinical and mycological response. Long term exposure to voriconazole greater than 180 days (6 months) requires careful assessment of the benefit-risk balance (see sections 4.4 and 5.1).

Dosage adjustment (Adults)

If patient response to treatment is inadequate, the maintenance dose may be increased to 300 mg twice daily for oral administration. For patients less than 40 kg the oral dose may be increased to 150 mg twice daily.

If patient is unable to tolerate treatment at a higher dose, reduce the oral dose by 50 mg steps to the 200 mg twice daily (or 100 mg twice daily for patients less than 40 kg) maintenance dose.

In case of use as prophylaxis, refer below.

Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg) Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole more similarly to children than to adults.

The recommended dosing regimen is as follows:

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.

These oral dose recommendations for children are based on studies in which voriconazole was administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit time in paediatric patients, the absorption of tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2 to <12.

All other adolescents (12 to 14 years and >50 kg; 15 to 17 years regardless of body weight) Voriconazole should be dosed as adults.

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

If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patient is unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).

Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see sections 4.8 and 5.2).

Prophylaxis in adults and children

Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. Prophylaxis should be as short as possible depending on the risk for developing invasive fungal infection (IFI) as defined by neutropenia or immunosuppression. It may only be continued up to 180 days after transplantation in case of continuing immunosuppression or graft versus host disease (GvHD) (see section 5.1).

Dosage

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups. Please refer to the treatment tables above.

Duration of prophylaxis

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

Use of voriconazole in prophylaxis for greater than 180 days (6 months) requires careful assessment of the benefit-risk balance (see sections 4.4 and 5.1).

The following instructions apply to both treatment and prophylaxis

Dosage adjustment

For prophylaxis use, dose adjustments are not recommended in the case of lack of efficacy or treatment-related adverse events. In the case of treatment-related adverse events, discontinuation of voriconazole and use of alternative antifungal agents must be considered (see section 4.4 and 4.8)

Dosage adjustments in case of co-administration

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.

The combination of voriconazole with rifabutin should, if possible be avoided. However, if the combination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.

Efavirenz may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50 %, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see sections 4.4 and 4.5)

Elderly

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

Renal impairment

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

Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment (see section 5.2).

Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4 hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

Hepatic impairment

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving voriconazole (see section 5.2).

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

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

Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with severe hepatic impairment must be carefully monitored for drug toxicity (see section 4.8).

Paediatric population

The safety and efficacy of voriconazole in children below 2 years has not been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.

Method of administration

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

• 4.3 Contraindi­cations

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

Coadministration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine or ivabradine since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.5).

Coadministration with rifampicin, carbamazepine phenobarbital and St John’s Wort since these medicinal products are likely to decrease plasma voriconazole concentrations significantly (see section 4.5).

Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations (see section 4.5, for lower doses see section 4.4).

Coadministration with high-dose ritonavir (400 mg and above twice daily) because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects at this dose (see section 4.5, for lower doses see section 4.4).

Coadministration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, since increased plasma concentrations of these medicinal products can lead to ergotism (see section 4.5).

Coadministration with sirolimus since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see section 4.5).

Coadministration of voriconazole with naloxegol, a CYP3A4 substrate, since increased plasma concentrations of naloxegol can precipitate opioid withdrawal symptoms (see section 4.5).

Coadministration of voriconazole with tolvaptan since strong CYP3A4 inhibitors such as voriconazole significantly increase plasma concentrations of tolvaptan (see section 4.5).

Coadministration of voriconazole with lurasidone since significant increases in lurasidone exposure have the potential for serious adverse reactions (see section 4.5).

Coadministration with venetoclax at initiation and during venetoclax dose titration phase since voriconazole is likely to significantly increase plasma concentrations of venetoclax and increase risk of tumour lysis syndrome (see section 4.5).

• 4.4 Special warnings and precautions for use

Hypersensitivity

Caution should be used in prescribing Voriconazole Accord to patients with hypersensitivity to other azoles (see also section 4.8).

Cardiovascular

Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:

• Congenital or acquired QTc -prolongation.
• Cardiomyopathy, in particular when heart failure is present.
• Sinus bradycardia.
• Existing symptomatic arrhythmias.
• Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.2). A study has been conducted in healthy volunteers which examined the effect on QTc interval of single doses of voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec (see section 5.1).

Hepatic toxicity

In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly haematological malignancy).Tran­sient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy (see section 4.8).

Monitoring of hepatic function

Patients receiving Voriconazole Accord must be carefully monitored for hepatic toxicity. Clinical management should include laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatment with Voriconazole Accord and at least weekly for the first month of treatment. Treatment duration should be as short as possible; however, if based on the benefit-risk assessment the treatment is continued (see section 4.2), monitoring frequency can be reduced to monthly if there are no changes in the liver function tests.

If the liver function tests become markedly elevated, Voriconazole Accord should be discontinued, unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use.

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

Serious dermatological adverse reactions

• Phototoxicity

In addition Voriconazole Accord has been associated with phototoxicity including reactions such as ephelides, lentigo, actinic keratosis and pseudoporphyria. It is recommended that all patients, including children, avoid exposure to direct sunlight during Voriconazole Accord treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

• Squamous cell carcinoma of the skin (SCC)

Squamous cell carcinoma of the skin has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur multidisciplinary advice should be sought, Voriconazole Accord discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If Voriconazole Accord is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Voriconazole Accord should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified (see below the section under Long-term treatment).

• Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with the use of voriconazole. If a patient develops a rash he should be monitored closely and Voriconazole Accord discontinued if lesions progress.

Adrenal events

Reversible cases of adrenal insufficiency have been reported in patients receiving azoles, including voriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression (see section 4.5). Cushing’s syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole concomitantly with corticosteroids.

Patients on long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroids e.g., budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction both during treatment and when voriconazole is discontinued (see section 4.5). Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing’s syndrome or adrenal insufficiency.

Long-term treatment

Long term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessment of the benefit-risk balance and physicians should therefore consider the need to limit the exposure to Voriconazole Accord (see sections 4.2 and 5.1).

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

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

Visual adverse reactions

There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see section 4.8).

Renal adverse reactions

Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medicinal products and have concurrent conditions that may result in decreased renal function (see section 4.8).

Monitoring of renal function

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

Monitoring of pancreatic function

Patients, especially children, with risk factors for acute pancreatitis (e.g., recent chemotherapy, haematopoietic stem cell transplantation [HSCT]), should be monitored closely during Voriconazole Accord treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Paediatric population

Safety and effectiveness in paediatric subjects below the age of two years has not been established (see sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. A higher frequency of liver enzyme elevations was observed in the paediatric population (see section 4.8). Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in paediatric patients aged 2 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 coadministered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk (see section 4.5).

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)

When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2, 4.3 and 4.5).

Glasdegib (CYP3A4 substrate)

Coadministration of voriconazole is expected to increase glasdegib plasma concentrations and increase the risk of QTc prolongation (see section 4.5). If concomitant use cannot be avoided, frequent ECG monitoring is recommended.

Tyrosine kinase inhibitors (CYP3A4 substrate)

Coadministration of voriconazole with tyrosine kinase inhibitors metabolised by CYP3A4 is expected to increase tyrosine kinase inhibitor plasma concentrations and the risk of adverse reactions. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinical monitoring is recommended (see section 4.5).

Rifabutin (Potent CYP450 inducer)

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole. Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk (see section 4.5).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)

Coadministration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see sections 4.3 and 4.5).

Everolimus (CYP3A4 substrate, P-gp substrate)

Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see section 4.5).

Methadone (CYP3A4 substrate)

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when coadministered with voriconazole since methadone levels increased following coadministration of voriconazole. Dose reduction of methadone may be needed (see section 4.5).

Short-acting opiates (CYP3A4 substrate)

Reduction in the dose of alfentanil, fentanyl and other short-acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole (see section 4.5). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is coadministered with voriconazole, and in an independent published study concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUCo—v 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 AUCt 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).

Excipients

Lactose

This medicinal product contains contains lactose and should not be given to patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet. Patients on low sodium diets should be informed that this medicinal product is essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes, in particular for substances metabolised by CYP3A4 since voriconazole is a strong CYP3A4 inhibitor though the increase in AUC is substrate dependent (see Table below).

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 and ivabradine), coadministration is contraindicated (see below and section 4.3).

Interaction table

Interactions between voriconazole and other medicinal products are listed in the table below (once daily as “QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (^), below Q) or above (f) the 80–125% range. The asterisk () indicates a two-way interaction. AUCt, AUCt and AUGo-, 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

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

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

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

Women of child-bearing potential

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

Breast-feeding

The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with Voriconazole Accord.

Fertility

In an animal study, no impairment of fertility was demonstrated in male and female rats (see section 5.3).

• 4.7 Effects on ability to drive and use machines

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

• 4.8 Undesirable effects

Summary of safety profile

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

The most commonly reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.

The severity of the adverse reactions was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.

Tabulated list of adverse reactions

In the table below, since the majority of the studies were of an open nature, all causality adverse reactions and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ class, are listed.

Frequency categories are expressed as: Very common (^1/10); Common (>1/100 to <1/10); Uncommon (^1/1,000 to <1/100); Rare (^1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

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

Undesirable effects reported in subjects receiving voriconazole:

ADR identified post-marketing

• 1 Includes febrile neutropenia and neutropenia.

• 2 Includes immune thrombocytopenic purpura.

• 3 Includes nuchal rigidity and tetany.

• 4 Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.

• 5 Includes akathisia and parkinsonism.

• 6 See “Visual impairments” paragraph in section 4.8.

• 7 Prolonged optic neuritis has been reported post-marketing. See section 4.4.

• 8 See section 4.4.

• 9 Includes dyspnoea and dyspnoea exertional.

• 10 Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.

• 11 Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions

Visual impairments

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and xanthopsia) with voriconazole were very common. These visual impairments were transient and fully reversible, with the majority spontaneously resolving within 60 minutes and no clinically significant long-term visual effects were observed. There was evidence of attenuation with repeated doses of voriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairments may be associated with higher plasma concentrations and/or doses.

The mechanism of action is unknown, although the site of action is most likely to be within the retina. In a study in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment and were fully reversible on withdrawal of voriconazole.

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

Dermatological reactions

Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but these patients had serious underlying diseases and were receiving multiple concomitant medicinal products. The majority of rashes were of mild to moderate severity. Patients have developed severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxic epidermal necrolysis (TEN) (rare), drug reaction with

eosinophilia and systemic symptoms (DRESS) (rare) and erythema multiforme (rare) during treatment with voriconazole (see section 4.4).

If a patient develops a rash they should be monitored closely and Voriconazole Accord discontinued if lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been reported, especially during long-term therapy (see section 4.4).

There have been reports of squamous cell carcinoma of the skin in patients treated with Voriconazole Accord for long periods of time; the mechanism has not been established (see section 4.4).

Liver function tests

The overall incidence of transaminase increases>3xULN (not necessarily comprising an adverse event) in the voriconazole clinical programme was 18.0% (319/1,768) in adults and 25.8% (73/283) in paediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.

Voriconazole has been associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death (see section 4.4).

Prophylaxis

In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primary prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI, permanent discontinuation of voriconazole due to AEs was reported in 39.3% of subjects versus 39.6% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18 subjects (7.1%) treated with itraconazole.

Paediatric population

The safety of voriconazole was investigated in 288 paediatric patients aged 2 to <12 years (169) and 12 to<18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) in clinical trials. The safety of voriconazole was also investigated in 158 additional paediatric patients aged 2 to <12 years in compassionate use programs. Overall, the safety profile of voriconazole in paediatric population was similar to that in adults. However, a trend towards a higher frequency of liver enzyme elevations, reported as adverse events in clinical trials was observed in paediatric patients as compared to adults (14.2% transaminases increased in paediatrics compared to 5.3% in adults). Post-marketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who received voriconazole in a compassionate use programme, the following adverse reactions (for which a relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis(1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole is haemodialysed with a clearance of 121 ml/min. In an overdose, haemodialysis may assist in the removal of voriconazole from the body.

• 5. PHARMACOLOGICAL PROPERTIES

  • 5.1 Pharmacody­namic properties

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

Mode of action

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Pharmacokinetic/phar­macodynamic relationship

In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individual subjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and 3742 ng/ml (inter-quartile range 2027 to 6302 ng/ml), respectively. A positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies was not found and this relationship has not been explored in prophylaxis studies.

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both liver function test abnormalities and visual disturbances. Dose adjustments in prophylaxis studies have not been explored.

Clinical efficacy and safety

In vitro , voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole resistant C. krusei and resistant strains of C. glabrata and C. albicans ) and fungicidal activity against all Aspergillus species tested. In addition voriconazole shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which have limited susceptibility to existing antifungal agents.

Clinical efficacy defined as partial or complete response, has been demonstrated for Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis and limited numbers of C. dubliniensis, C. inconspicua, and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.

Other treated fungal infections (often with either partial or complete response) included isolated cases of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. IncludingT. beigelii infections.

In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited by concentrations of voriconazole in the range 0.05 to 2 ^g/ml.

In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.

Breakpoints

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C.tropicalis, C. glabrata andC. krusei , all of which usually exhibit minimal inhibitory concentration (MICs) of less than 1 mg/L for voriconazole.

However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida to species level. If antifungal susceptibility testing is available, the MIC results may be interpreted using breakpoint criteria established by European Committee on Antimicrobial Susceptibility Testing (EUCAST).

EUCAST Breakpoints

Clinical experience

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

Aspergillus infections – efficacy in aspergillosis patients with poor prognosis

Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of voriconazole versus conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study in 277immunocompro­mised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2–85 days). After IV voriconazole therapy, the median duration of oral voriconazole therapy was 76 days (range 2232 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 5 in the amphotericin B followed by fluconazole group also had mycologically proven infection in deep tissue. Patients with renal failure were excluded from this study. The median treatment duration was 15 days in both treatment arms. In the primary analysis, successful response as assessed by a Data Review Committee (DRC) blinded to study medicinal product was defined as resolution/im­provement in all clinical signs and symptoms of infection with eradication of Candida from blood and infected deep tissue sites 12 weeks after the end of therapy (EOT). Patients who did not have an assessment 12 weeks after EOT were counted as failures. In this analysis a successful response was seen in 41 % of patients in both treatment arms.

In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 6, or 12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazole had successful response rates of 65% and 71%, respectively. The Investigator’s as­sessment of successful outcome at each of these time points is shown in the following table.

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 in3/3 C.krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) infections. The clinical efficacy data were supported by limited susceptibility da­ta.

Scedosporium and Fusarium infections

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

Scedosporium spp

Successful response to voriconazole therapy was seen in 16 (6 complete, 10 partial responses) of 28 patients with S. apiospermum and in 2 (both partial responses) of 7 patients with S. prolificans infection. In addition, a successful response was seen in 1 of 3 patients with infections caused by more than one organism including Scedosporium spp.

Fusarium spp

Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole. Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis had an infection caused by several organisms; 2 of them had a successful outcome.

The majority of patients receiving voriconazole treatment of the above mentioned rare infections were intolerant of, or refractory to, prior antifungal therapy.

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

Voriconazole was compared to itraconazole as primary prophylaxis in an open-label, comparative, multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI. Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT (without stopping for >14 days) and survival with no proven or probable IFI for 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:

* 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

* 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

* Primary endpoint of study

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

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

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

Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative, multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary endpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, and 4 with other IFI. The median duration of study drug prophylaxis was 95.5 days in the MITT group.

Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT, including one candidemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The survival rate at Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40).

Duration of treatment

In clinical trials, 705 patients received voriconazole therapy for greater than 12 weeks, with 164 patients receiving voriconazole for over 6 months.

Paediatric population

Fifty-three paediatric patients aged 2 to <18 years were treated with voriconazole in two prospective, open-label, non-comparative, multi-center clinical trials. One study enrolled 31 patients with possible, proven or probable invasive aspergillosis (IA), of whom 14 patients had proven or probable IA and were included in the MITT efficacy analyses. The second study enrolled 22 patients with invasive candidiasis including candidaemia (ICC), and esophageal candidiasis (EC) requiring either primary or salvage therapy, of whom 17 were included in the MITT efficacy analyses. For patients with IA the overall rates of global response at 6 weeks were 64.3% (9/14), the global response rate was 40% (2/5) 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 nonlinear 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 (AUCT).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 AUCT are reduced by 34 % and 24 %, respectively. The absorption of voriconazole is not affected by changes in gastric pH.

Distribution

The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%. Cerebrospinal fluid samples from eight patients in a compassionate programme showed detectable voriconazole concentrations in all patients.

Biotransformation

In vitro studies showed that voriconazole is metabolised by, the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4.

The inter-individual variability of voriconazole pharmacokinetics is high.

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 (AUCT) than their homozygous extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser counterparts.

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

Elimination

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

After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.

Pharmacokinetics in special patient groups

Gender

In an oral multiple dose study, Cmax and AUCt 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 AUCt 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 AUCt 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 AUCt 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 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 (AUCt) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

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

Voriconazole exposures in the majority of adolescent patients were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some young adolescents with low body weight compared to adults. It is likely that these subjects may metabolize voriconazole more similarly to children than to adults. Based on the population pharmacokinetic analysis, 12 to 14 year old adolescents weighing less than 50 kg should receive children’s doses (see section 4.2).

Renal impairment

In an oral single dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41–60 ml/min) to severe (creatinine clearance < 20ml/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment. (see sections 4.2 and 4.4).

Hepatic impairment

After an oral single-dose (200 mg), AUC was 233 % higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired hepatic function.

In an oral multiple-dose study, AUCT was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C) (see sections 4.2 and 4.4).

• 5.3 Preclinical safety data

Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicity occurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common with other antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes. Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special hazard for humans.

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

• 6. PHARMACEUTICAL PARTICULARS

  • 6.1 List of excipients

Tablet core

Lactose monohydrate

Pregelatinized starch

Croscarmellose sodium

Povidone

Magnesium stearate

Film-coating

Hypromellose

Titanium dioxide (E171)

Lactose monohydrate

Triacetin

• 6.2 Incompati­bilities

Not applicable.

• 6.3 Shelf life 4 years

• 6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

• 6.5 Nature and contents of container

PVC / Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 or 100 film-coated tablets or unit dose PVC / Aluminium blister in pack sizes of 10×1, 14×1, 28×1, 30×1, 56×1 or 100×1 film-coated tablets.

Not all pack sizes may be marketed.

• 6.6 Special precautions for disposal

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

• 7. MARKETING AUTHORISATION HOLDER

Accord Healthcare S.L.U.

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

Edifici Est 6a planta,

08039 Barcelona,

Spain

• 8. MARKETING AUTHORISATION NUMBER(S)

Voriconazole Accord 50 mg film-coated tablets

EU/1/13/835/001–009,

EU/1/13/835/019–024

Voriconazole Accord 200 mg film-coated tablets

EU/1/13/835/010–018,

EU/1/13/835/025–030

• 9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF THE AUTHORISATION

Date of first authorisation: 16 May 2013

Date of latest renewal: 8th February 2018

• 10. DATE OF REVISION OF THE TEXT

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

Agency.

• 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

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

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

Accord Healthcare Limited

Sage House 319 Pinner Road

North Harrow, Middlesex, HA1 4HF

United Kingdom

Pharmadox Healthcare Ltd.

KW20A Kordin Industrial Park,

Paola, PLA 3000

Malta

Accord Healthcare Polska Sp.z o.o., ul. Lutomierska 50,95–200 Pabianice, Poland

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht,

The Netherlands

The printed package leaflet of the medicinal product must state the name and address of the manufacturer responsible for the release of the concerned batch

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal products subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION

• Periodic safety update reports (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/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT

The marketing authorisation holder (MAH) shall perform the 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.

• – 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.

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

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

• 1. NAME OF THE MEDICINAL PRODUCT

Voriconazole Accord 50 mg film-coated tablets voriconazole

• 2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 50 mg voriconazole.

• 3. LIST OF EXCIPIENTS

Contains lactose monohydrate. See leaflet for further information.

• 4. PHARMACEUTICAL FORM AND CONTENTS 2 film-coated tablets

10 film-coated tablets

14 film-coated tablets

20 film-coated tablets

28 film-coated tablets

30 film-coated tablets

50 film-coated tablets

56 film-coated tablets 100 film-coated tablets 10×1 film-coated tablets 14×1 film-coated tablets 28×1 film-coated tablets 30×1 film-coated tablets 56×1 film-coated tablets

100×1 film-coated tablets

• 5. METHOD AND ROUTE (S) OF ADMINISTRATION

Read the package leaflet before use. Oral use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING (S), IF NECESSARY

• 8. EXPIRY DATE

EXP

• 9. SPECIAL STORAGE CONDITIONS

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Accord Healthcare S.L.U.

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

Edifici Est 6a planta,

08039 Barcelona,

Spain

• 12. MARKETING AUTHORISATION NUMBER (S)

EU/1/13/835/001 2 film-coated tablets

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

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

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

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

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

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

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

EU/1/13/835/0­09 100 film-coated tablets

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

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

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

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

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

EU/1/13/835/0­24 100×1 film-coated tablets

• 13. BATCH NUMBER

Lot

• 14. GENERAL CLASSIFICATION FOR SUPPLY

• 15. INSTRUCTIONS ON USE

• 16. INFORMATION IN BRAILLE

Voriconazole Accord 50 mg

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

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

• 1. NAME OF THE MEDICINAL PRODUCT

Voriconazole Accord 50 mg film-coated tablets voriconazole

• 2. NAME OF THE MARKETING AUTHORISATION HOLDER

Accord

• 3. EXPIRY DATE

EXP

• 4. BATCH NUMBER

Lot

• 5. OTHER

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

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

• 1. NAME OF THE MEDICINAL PRODUCT

Voriconazole Accord 200 mg film-coated tablets voriconazole

• 2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 200 mg voriconazole.

• 3. LIST OF EXCIPIENTS

Contains lactose monohydrate. See leaflet for further information.

• 4. PHARMACEUTICAL FORM AND CONTENTS 2 film-coated tablets

10 film-coated tablets

14 film-coated tablets

20 film-coated tablets

28 film-coated tablets

30 film-coated tablets

50 film-coated tablets

56 film-coated tablets 100 film-coated tablets 10×1 film-coated tablets 14×1 film-coated tablets 28×1 film-coated tablets 30×1 film-coated tablets 56×1 film-coated tablets

100×1 film-coated tablets

• 5. METHOD AND ROUTE (S) OF ADMINISTRATION

Read the package leaflet before use. Oral use.

• 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

• 7. OTHER SPECIAL WARNING (S), IF NECESSARY

• 8. EXPIRY DATE

EXP

• 9. SPECIAL STORAGE CONDITIONS

• 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

• 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Accord Healthcare S.L.U.

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

Edifici Est 6a planta,

08039 Barcelona,

Spain

• 12. MARKETING AUTHORISATION NUMBER (S)

EU/1/13/835/010 2 film-coated tablets

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

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

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

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

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

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

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

EU/1/13/835/0­18 100 film-coated tablets

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

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

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

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

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

EU/1/13/835/0­30 100×1 film-coated tablets

• 13. BATCH NUMBER

Lot

• 14. GENERAL CLASSIFICATION FOR SUPPLY

• 15. INSTRUCTIONS ON USE

• 16. INFORMATION IN BRAILLE

Voriconazole Accord 200 mg

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC:

SN:

NN:

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

• 1. NAME OF THE MEDICINAL PRODUCT

Voriconazole Accord 200 mg film-coated tablets voriconazole

• 2. NAME OF THE MARKETING AUTHORISATION HOLDER

Accord

• 3. EXPIRY DATE

EXP:

• 4. BATCH NUMBER

Lot:

• 5. OTHER

B.PACKAGE LEAFLET

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

What is in this leaflet

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

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

• 3. How to take Voriconazole Accord

• 4. Possible side effects

• 5. How to store Voriconazole Accord

• 6. Content of the pack and other information

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

Voriconazole Accord contains the active substance voriconazole. Voriconazole Accord is an antifungal medicine. It works by killing or stopping the growth of the fungi that cause infections.

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

• invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
• candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic

patients (patients without abnormally low white blood cells count),

• serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another antifungal medicine),
• serious fungal infections caused by Scedosporium sp.or Fusarium sp. (two different species of fungi).

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

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

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

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

Do not take Voriconazole Accord

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

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other medicines, even those that are obtained without a prescription, or herbal medicines.

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

Terfenadine (used for allergy)

Astemizole (used for allergy)

Cisapride (used for stomach problems)

Pimozide (used for treating mental illness)

Quinidine (used for irregular heart beat)

Ivabradine (used for symptoms of chronic heart failure)

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)

Naloxegol (used to treat constipation specifically caused by pain medicines, called opioids, (e.g., morphine, oxycodone, fentanyl, tramadol, codeine))

Tolvaptan (us ed to treat hyponatremia (low levels of sodium in your blood) or to slow kidney function decline in patients with polycystic kidney disease)

Lurasidone (used to treat depression)

Venetoclax (used to treat patients with chronic lymphocytic leukaemia-CLL)

Warnings and precautions

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

• you have had an allergic reaction to other azoles.
• you are suffering from, or have ever suffered from liver disease. If you have liver disease, your doctor may prescribe a lower dose of Voriconazole Accord. Your doctor should also monitor your liver function while you are being treated with Voriconazole Accord by doing blood tests.
• you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of electrocardiogram (ECG) called ‘long QTc syndrome’.

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed areas of skin and use sunscreen with high sun protection factor (SPF),, as an increased sensitivity of skin to the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with Voriconazole Accord:

• tell your doctor immediately if you develop

o sunburn

o severe skin rash or blisters.

o bone pain

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that skin cancer could develop with long-term use of Voriconazole Accord.

If you develop signs of ‘adrenal insufficiency’ where the adrenal glands do not produce adequate amounts of certain steroid hormones such as cortisol which may lead to symptoms such as: chronic, or long lasting fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, please tell your doctor.

If you develop signs of ‘Cushing’s syn­drome’ where the body produces too much of the hormone cortisol which may lead to symptoms such as: weight gain, fatty hump between the shoulders, a rounded face, darkening of the skin on the stomach, thighs breasts, and arms, thinning skin, bruising easily, high blood sugar, excessive hair growth, excessive sweating, please tell your doctor.

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

Children and adolescents

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

Other medicines and Voriconazole Accord

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those that are obtained without a prescription.

Some medicines, when taken at the same time as Voriconazole Accord, may affect the way Voriconazole Accord works or Voriconazole Accord may affect the way they work.

Tell your doctor if you are taking the following medicine, as treatment with Voriconazole Accord at the same time should be avoided if possible:

• Ritonavir (used for treating HIV) in doses of 100 mg twice daily
• Glasdegib (used for treating cancer) – if you need to use both drugs your doctor will monitor

your heart rhythm frequently

Tell your doctor if you are taking either of the following medicines, as treatment with Voriconazole Accord at the same time should be avoided if possible, and a dose adjustment of voriconazole may be required:

• Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood counts and side effects to rifabutin will need to be monitored.
• Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood concentration of phenytoin will need to be monitored during your treatment with Voriconazole Accord and your dose may be adjusted.

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be required to check that the medicines and/ or Voriconazole Accord are still having the desired effect:

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

Ciclosporin (used in transplant patients)

Tacrolimus (used in transplant patients)

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

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

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

Omeprazole (used for treating ulcers)

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

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

Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used for treating cancer) Tretinoin (used to treat leukaemia)

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

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

Methadone (used to treat heroin addiction)

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

• Oxycodone and other long acting opiates such as hydrocodone (used for moderate to severe pain)
• Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and
• inflammation)
• Fluconazole (used for fungal infections)
• Everolimus (used for treating advanced kidney cancer and in transplant patients)
• Letermovir (used for preventing cytomegalovirus (CMV) disease after bone marrow transplant)
• Ivacaftor: used to treat cystic fibrosis

Pregnancy and breast-feeding

Voriconazole Accord must not be taken during pregnancy, unless indicated by your doctor. Effective contraception must be used in women of childbearing potential. Contact your doctor immediately if you become pregnant while taking Voriconazole Accord.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

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

Voriconazole Accord contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor before taking Voriconazole Accord.

Voriconazole Accord contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per 50 mg tablet, that is to say essentially ‘sodium free’.

This medicine contains less than 1 mmol sodium (23 mg) per 200 mg tablet, that is to say essentially ‘sodium-free’.

3. How to take Voriconazole Accord

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

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

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

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

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

Use in children and adolescents

The recommended dose for children and teenagers is as follows: _____________­___________________

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

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

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

If you or your child are taking Voriconazole Accord for prevention of fungal infections, your doctor may stop giving Voriconazole Accord if you or your child develop treatment related side effects.

If you take more Voriconazole Accord than you should

If you take more tablets than prescribed (or if someone else takes your tablets) you must seek medical advice or go to the nearest hospital casualty department immediately. Take your box of Voriconazole Accord tablets with you. You may experience abnormal intolerance to light as a result of taking more Voriconazole Accord than you should.

If you forget to take Voriconazole Accord

It is important to take your Voriconazole Accord tablets regularly at the same time each day. If you forget to take one dose, take your next dose when it is due. Do not take a double dose to make up for a forgotten dose.

If you stop taking Voriconazole Accord

It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness of your medicine. Therefore unless your doctor instructs you to stop treatment, it is important to keep taking Voriconazole Accord correctly, as described above.

Continue taking Voriconazole Accord until your doctor tells you to stop. Do not stop treatment early because your infection may not be cured. Patients with a weakened immune system or those with difficult infections may require long-term treatment to prevent the infection from returning.

When Voriconazole Accord treatment is stopped by your doctor you should not experience any effects.

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

4. Possible side effects

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

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

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

• – Rash

• – Jaundice; Changes in blood tests of liver function

• – Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people

• – Visual impairment (change in vision including blurred vision, visual color alterations, abnormal intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of the usual field of vision, spots before the eyes)

• – Fever

• – Rash

• – Nausea, vomiting, diarrhoea

• – Headache

• – Swelling of the extremities

• – Stomach pains

• – Breathing difficulties

• – Elevated liver enzymes

Common: may affect up to 1 in 10 people

• – Inflammation of the sinuses, inflammation of the gums, chills, weakness

• – Low numbers of some types, including severe, of red (sometimes immune-related) and/or white

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

• – Low blood sugar, low blood potassium, low sodium in the blood

• – Anxiety, depression, confusion, agitation, inability to sleep, hallucinations

• – Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin sensations, increase in muscle tone, sleepiness, dizziness

• – Bleeding in the eye

• – Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting, low blood pressure, inflammation of a vein (which may be associated with the formation of a blood clot)

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

• – Constipation, indigestion, inflammation of the lips

• – Jaundice, inflammation of the liver and liver injury

• – Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red area on the skin that is covered with small confluent bumps, redness of the skin

• – Itchiness

• – Hair loss

• – Back pain

• – Kidney failure, blood in the urine, changes in kidney function tests

Uncommon: may affect up to 1 in 100 people

• – Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the

gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

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

• – Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil

• – Depressed function of the adrenal gland, underactive thyroid gland

• – Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, tingling or burning in the hands or feet

• – Problems with balance or coordination

• – Swelling of the brain

• – Double vision, serious conditions of the eye including: pain and inflammation of the eyes and eyelids, abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic disc swelling

• – Decreased sensitivity to touch

• – Abnormal sense of taste

• – Hearing difficulties, ringing in the ears, vertigo

• – Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the tongue

• – Enlarged liver, liver failure, gallbladder disease, gallstones

• – Joint inflammation, inflammation of the veins under the skin (which may be associated with the formation of a blood clot)

• – Inflammation of the kidney, proteins in the urine, damage to the kidney

• – Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses

• – Abnormal electrocardiogram (ECG)

• – Blood cholesterol increased, blood urea increased

• – Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes painful blisters and sores of the skin and mucous membranes, especially in the mouth, inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, skin redness and irritation, red or purple discoloration of the skin which may be caused by low platelet count, eczema

• – Infusion site reaction

• – Allergic reaction or exaggerated immune response

Rare: may affect up to 1 in 1000 people

• – Overactive thyroid gland

• – Deterioration of brain function that is a serious complication of liver disease

• – Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye

• – Bullous photosensitivity

• – A disorder in which the body’s immune system attacks part of the peripheral nervous system

• – Heart rhythm or conduction problems (sometimes life threatening)

• – Life threatening allergic reaction

• – Disorder of blood clotting system

• – Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis, subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition that causes large portions of the epidermis, the skin’s outermost layer, to detach from the layers of skin below

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

Side effects with frequency not known:

• - Freckles and pigmented spots

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

• – Skin cancer

• – Inflammation of the tissue surrounding the bone

• – Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease called cutaneous lupus erythematosus

As Voriconazole Accord has been known to affect the liver and the kidney, your doctor should monitor the function of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains or if your stools have a different consistency.

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

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated liver enzymes were also observed more frequently in children.

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

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. Y ou can also report side effects directly via the national reporting system listed inBy reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Voriconazole Accord

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

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last day of that month.

This medicine does not require any special storage conditions.

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

6. Contents of the pack and other information

What Voriconazole Accord contains

• The active substance is voriconazole. Each tablet contains either 50 mg voriconazole (for Voriconazole Accord 50 mg film-coated tablets) or 200 mg voriconazole (for VoriconazoleAccord 200 mg film-coated tablets).
• The other ingredients are lactose monohydrate, pregelatinised starch, croscarmellose sodium, povidone and magnesium stearate which make up the tablet core and hypromellose, titanium dioxide (E171), lactose monohydrate and triacetin which make up the film-coat (see section 2, Voriconazole Accord 50 mg film-coated tablets or Voriconazole Accord 200 mg film-coated tablets contain lactose and sodium).

What Voriconazole Accord looks like and contents of the pack

Voriconazole Accord 50 mg film-coated tablets are supplied as white to off white, round, approximate 7.0mm in diameter, film-coated tablets, debossed with ‘V50’ on one side and plain on the other side.

Voriconazole Accord 200 mg film-coated tablets are supplied as white to off white, oval, approximately 15.6 mm in length and 7.8 mm in width, film-coated tablets, debossed with ‘V200’ on one side and plain on the other side.

Voriconazole Accord 50 mg film-coated tablets and 200mg film-coated tablets are available as packs of 2, 10, 14, 20, 28, 30, 50, 56 and 100 or unit dose blister packs (PVC / Aluminium) containing 10×1, 14×1, 28×1, 30×1, 56×1 or 100×1 film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Accord Healthcare S.L.U.

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

Edifici Est 6a planta,

08039 Barcelona,

Spain

Manufacturer

Accord Healthcare Limited,

Sage House, 319 Pinner Road,

North Harrow, Middlesex, HA1 4HF,

United Kingdom

Pharmadox Healthcare Ltd.

KW20A Kordin Industrial Park,

Paola, PLA 3000

Malta

Accord Healthcare Polska Sp.z o.o., ul. Lutomierska 50,95–200 Pabianice, Poland

Accord Healthcare B.V.,

Winthontlaan 200,

3526 KV Utrecht, The Netherlands

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

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

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