Voriconazole Hikma (previously Voriconazole Hospira) · 4.1 Therapeutic indications · 1

HOS-096988 · has-adverse-reaction-information · PDF-Seite 19

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 19 trials. This represents a heterogeneous population, containing patients with haematological malignancy, HIV-infected patients with oesophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers. The most commonly reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain. The severity of the adverse reactions was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender. Tabulated list of adverse reactions In the table below, since the majority of the studies were of an open nature all causality adverse reactions, and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ classare listed. Frequency categories are expressed as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Undesirable effects reported in subjects receiving voriconazole: System Very common Common Uncommon Rare Frequency Organ Class ≥ 1/10 ≥ 1/100 ≥ 1/1,000 to < ≥ 1/10,000 to < not known to < 1/10 1/100 1/1,000 (cannot be estimated from available data) Infections and sinusitis

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HOS-096984 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Interacting drugs listed in this section and section 4.5 are a guide and not considered a comprehensive list of all possible drugs that may be contraindicated. Coadministration of voriconazole is contraindicated with medicinal products that are highly dependent on CYP3A4 for metabolism, and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions (see section 4.5): • Terfenadine • Astemizole • Cisapride • Pimozide • Lurasidone • Quinidine 5 • Ivabradine • Ergot alkaloids (e.g., ergotamine, dihydroergotamine) • Sirolimus • Naloxegol • Tolvaptan • Finerenone • Eplerenone • Voclosporin • Venetoclax: Coadministration contraindicated at initiation and during venetoclax dose titration phase. Coadministration of voriconazole is contraindicated with medicinal products that induce CYP3A4 and significantly reduce voriconazole plasma concentrations: Coadministration with rifampicin, carbamazepine, long-acting barbiturates e.g., phenobarbital and St. John’s Wort (see section 4.5). • Efavirenz Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated (see section 4.5). For information on coadministration of voriconazole and lower doses of efavirenz (see section 4.4). • Ritonavir Coadministration with high dose ritonavir (400 mg and above twice daily) is contraindicated (see section 4.5), For information on coadministration with lower doses (see section 4.4).

HOS-096983 · has-indication-information · PDF-Seite 2

Voriconazole is a broad-spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows: • Treatment of invasive aspergillosis. • Treatment of candidaemia in non-neutropenic patients • Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei). • Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp. Voriconazole should be administered primarily to patients with progressive, possibly life-threatening infections. Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant (HSCT) recipients.

HOS-096986 · has-interaction-information · PDF-Seite 10

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), co-administration is contraindicated (see below and section 4.3). Interaction table Interactions between voriconazole and other medicinal products are listed in the table below (once daily as “QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”) ordered by therapeutic class. The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUCτ, AUCt and AUC0-∞ represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively. 10 Medicinal products listed in the table are a guide and not considered a comprehensive list of all possible medicinal products that are contraindicated or may interact with voriconazole Medicinal product Interaction Recommendations concerning geometric mean changes (%) coadministration Antacids Cimetidine (400 mg BID) Voriconazole Cmax ↑ 18% No dose adjustment [non-specific CYP450 inhibitor Voriconazole AUCτ ↑ 23% and increases gastric pH] Omeprazole (40 mg Q

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HOS-096987 · has-pregnancy-information · PDF-Seite 19

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 Hikma must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. Women of child-bearing potential Women of child-bearing potential must always use effective contraception during treatment. Breast-feeding The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with Voriconazole Hikma. Fertility In an animal study, no impairment of fertility was demonstrated in male and female rats (see section 5.3).

HOS-096985 · has-warning-information · PDF-Seite 6

Hypersensitivity Caution should be used in prescribing Voriconazole Hikma to patients with hypersensitivity to other azoles (see also section 4.8). Duration of treatment The duration of treatment with the intravenous formulation should be no longer than 6 months (see section 5.3). Cardiovascular Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as: • Congenital or acquired QTc prolongation • Cardiomyopathy, in particular when heart failure is present • Sinus bradycardia • Existing symptomatic arrhythmias • Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.2). A study has been conducted in healthy volunteers which examined the effect on QTc interval of single doses of voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec (see section 5.1). 6 Infusion-related reactions Infusion-related reactions, predominantly flushing and nausea, have been observed during administration of the intravenous formulation of voriconazole. Depending on the severity of symptoms, consideration should be given to stopping treatment (see section 4.8). Hepatic toxicity In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly haematological malignancy). Transient hepatic reactions, including hepatitis and jaundice, 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 vori

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