Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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


Duration of treatment
The duration of treatment with the intravenous formulation should be no longer than 6 months (see section 5.3).


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

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


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

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

Monitoring of hepatic function
Patients receiving voriconazole must be carefully monitored for hepatic toxicity. Clinical management should include laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatment with voriconazole and at least weekly for the first month of treatment. Treatment 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 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 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 Vortimal 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, Vortimal discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If Vortimal is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Vortimal 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 Vortimal 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 Vortimal (see sections 4.2 and 5.1).


Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term Voriconazole treatment.
Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis Vortimal 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 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).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)
Coadministration of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see sections 4.3 and 4.5).

Everolimus (CYP3A4 substrate, P-gp substrate)
Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently, there are insufficient data to allow dosing recommendations in this situation (see section 4.5).

Methadone (CYP3A4 substrate)
Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when coadministered with voriconazole since methadone levels increased following coadministration of voriconazole. Dose reduction of methadone may be needed (see section 4.5).

Short acting opiates (CYP3A4 substrate)
Reduction in the dose of alfentanil, fentanyl and other short-acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole (see section 4.5). As the half-life of alfentanil is prolonged in a 4 -fold manner when alfentanil is coadministered with voriconazole and in an independent published study, concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC0-∞ of fentanyl, frequent monitoring for opiate-associated adverse reactions (including a longer respiratory monitoring period) may be necessary.

Long-acting opiates (CYP3A4 substrate)
Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g., hydrocodone) should be considered when coadministered with voriconazole. Frequent monitoring for opiate-associated adverse reactions may be necessary (see section 4.5).

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)
Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUCτ of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established.
Monitoring for voriconazole associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole (see section 4.5).

Sodium content
This medical product contains 225.6 mg of sodium chloride per vial,equivalent to 11.3% of the WHO recommended maximum daily intake of 2 g sodium for an adult..

Effects on Driving

4.7    Effects on ability to drive and use machines

Vortimal 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.