Voriconazole October 2015 Risk Management Plan. Voriconazole

Transcription

1 Voriconazole October 2015

2 VI.2 VI.2.1 Elements for a Public Summary Overview of disease epidemiology Invasive aspergillosis (IA) is the most devastating of Aspergillus related diseases, targeting severely immunocompromised patients. Those most at risk for this life threatening disease are individuals with hematological malignancies such as leukemia; solid organ and hematopoietic stem cell transplant patients; patients on prolonged corticosteroid therapy, which is commonly utilized for the prevention and/or treatment of graft versus host disease in transplant patients; individuals with genetic immunodeficiencies such as chronic granulomatous disease (CGD); and individuals infected with human immunodeficiency virus. Mortality rates range from 40% to 90% in high risk populations and are dependent on factors such as host immune status, the site of infection, and the treatment regimen applied. (Dagenais, 2009). Candidemia is a major cause of morbidity and mortality in the health care setting. However, the incidence of candidemia is increasing with greater complexity of surgical procedures, patient populations at higher risk of infection, and changes in patient demographic characteristics. Prolongation of survival among critically ill patients, especially in the intensive care unit setting, has led to increased use of invasive procedures, intravenous catheters, and intravenous hyperalimentation, all of which are risk factors for candidemia. Recently, the introduction of additional antifungal agents has led to new strategies for empirical and prophylactic therapies. An increasing number of candidial infections are now caused by non Candida albicans Candida species. Candidemia remains associated with high crude and attributable mortality rates and with increased costs of care and duration of hospitalization. Attributable mortality has been reported to range from 5% to 71%, and crude mortality rates have been reported to be as high as 81%. Inappropriate therapy or delays in initiation of therapy have also been linked to increased mortality. (Horn, 2009). In the 1990s, the incidence of invasive candidiasis was reported at one institution to be 15%, and accounted for 88% of all invasive fungal infections in hematopoietic cell transplantation. In the most recent data, this proportion has changed. The incidence of invasive candidiasis is now 1.1% for hematopoietic cell transplantation and just under 2% for solid organ transplantation. In hematopoietic cell transplantation and lung transplantation, invasive candidiasis is the next largest proportion of invasive fungal infections after invasive aspergillosis, at 28% and 23%, respectively. In solid organ transplantation, approximately half (52.9%) of invasive fungal infection cases were invasive candidiasis. Invasive candidiasis made up the highest proportion of invasive fungal infections across the remaining transplant types. Azole resistance was first noted in Candida species in patients with acquired immunodeficiency syndrome. There was a total of 348 isolates tested against fluconazole, and 33% were found to be resistant compared with 11% in isolates from patients without acquired immunodeficiency syndrome. This was related to prolonged exposure and use for such conditions as Candida esophagitis. (Kriengkauykiat, 2011). The most frequent filamentous fungi (moulds) isolated are Aspergillus spp., but Fusarium spp., Scedosporium spp., Penicillium spp. and Zygomycetes are increasingly seen (Marr et al., 2002; Husain et al., 2003). Several reasons have been proposed for the increase in invasive fungal infections, including the use of antineoplastic and immunosuppressive agents, broad spectrum antibiotics, and prosthetic devices and grafts, and more aggressive surgery. Patients with burns, neutropenia, HIV infection and pancreatitis are also predisposed to fungal infection (Eggimann et al., 2003). In haematopoietic stem cell transplant recipients, the incidence of both Fusarium spp. and Rhizopus spp. Infection doubled in the period , whilst that of Scedosporium spp. remained stable (Marr et al., 2002). Overall, these genera accounted for 18% of all mould infections in this group of patients. Infection with Scedosporium spp. Was more likely to occur whilst the patient was still neutropenic, whilst infection with Zygomycetes was more likely to occur later, corresponding to episodes of graft versus host disease (Ribes et al., 2000). 2

3 Risk factors for invasive aspergillosis after allogeneic hematopoietic stem cell transplantation (HSCT) are multifactorial and differ according to timing after HSCT. Increased attention should be placed on understanding the immunopathogenesis of fungal disease after HSCT. Invasive fungal infections are now a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). After the introduction of fluconazole prophylaxis in the 1990s, the incidence of candidemia decreased, coinciding with the emergence of invasive mold infections (IMIs), particularly invasive aspergillosis (IA). The epidemiology of IMI continues to evolve; recently, the emergence of non Aspergillus molds, such as Zygomycetes, Fusarium species, and Scedosporium species, has been noted. (Garcia Vidal, 2008). VI.2.2 Summary of treatment benefits Voriconazole is a new triazole developed for the treatment of life threatening fungal infections. The drug is available for both oral and intravenous administration; the oral formulation has excellent bioavailability. Review of isolates of yeasts and 3216 isolates of filamentous fungi showed voriconazole to have broad spectrum activity against pathogenic yeasts including intrinsically fluconazole resistant isolates such as Candida krusei. Successful therapy with compassionate use of voriconazole for the treatment of candidemia and invasive candidiasis in patients intolerant of or refractory to other antifungal agents has been reported in a Study that showed that voriconazole may be a suitable agent for salvage treatment of invasive candidiasis, even in the setting of previous azole exposure and C. krusei infection. (Pemán, 2006) The Infectious Diseases Society of America (IDSA) considers voriconazole the drug of choice for primary treatment of invasive aspergillosis in most patients and IV amphotericin B the preferred alternative. For salvage therapy in patients refractory to or intolerant of primary antifungal therapy, IDSA recommends amphotericin B, caspofungin, micafungin, posaconazole, or itraconazole. For empiric or preemptive therapy of presumed aspergillosis, IDSA recommends amphotericin B, caspofungin, itraconazole, or voriconazole (Walsh, 2008). Voriconazole is used for the treatment of candidemia in nonneutropenic patients and for the treatment of disseminated Candida infections involving the skin, abdomen, kidney, bladder wall, or wounds. The drug has been effective in Candida albicans, C. tropicalis, C. parapsilosis, C. glabrata, and C. krusei infections (AHFS, 2014). Voriconazole is indicated in patients 12 years or older for treatment of serious fungal infections caused by Scedosporium apiospermum and Fusarium species including Fusarium solani, in patients intolerant of or refractory to other therapy. In pooled analyses, treatment with voriconazole produced successful responses in 15 of 24 patients (63%) with Scedosporium apiospermum and 9 of 21 patients (43%) with Fusarium species (FDA, 2011). VI.2.3 Unknowns relating to treatment benefits The safety and efficacy of voriconazole in children below 2 years has not been established. Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied. There are no adequate and well controlled studies of voriconazole use in pregnant women. Until additional data are available, caution should be exercised with its use in pregnant women. According to the manufacturer, voriconazole was teratogenic and embryotoxic in rats and rabbits, respectively, and can cause fetal harm when administered to pregnant women. Female patients of childbearing potential should use effective contraception during treatment. If the patient becomes pregnant while taking voriconazole or if voriconazole is used during pregnancy, the patient should be counseled regarding the possible hazard to the fetus (DrugDex, 2014). 3

4 No reports describing the use of voriconazole during human lactation are available, and the effects on the nursing infant from exposure to the drug in breast milk are unknown. Until more data are available, voriconazole should be used in nursing women only if the benefit clearly outweighs the potential risk to the infant (DrugDex, 2014) It is a well known fact that off label use occurs frequently in most therapeutic areas which can sometimes be more frequent than those for the approved indications. Although wide spread use of antifungals without supporting evidence has raised concerns for the emergence of resistance and adverse events, there is limited information on the efficacy and utilization patterns of systemic antifungals in routine clinical practice. (Ascioglu, 2014) VI.2.4 Summary of safety concerns Risk What is known Preventability Hepatic toxicity QTc prolongation Visual events (including optic neuritis, papilloedema and other visual concerns) Phototoxicity Pheripheral neuropaty 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 hepatic impairment must be carefully monitored for drug toxicity. Voriconazole has been associated with an abnormality of electrocardiogram (ECG). There have been uncommon cases of abnormal electrocardiogram in patients taking voriconazole. You have to talk to your doctor if you have cardiomyopathy, irregular heartbeat, slow heart rate or an abnormality of electrocardiogram (ECG) called long QT syndrome. There have been reports of prolonged visual adverse reactions, including blurring of vision, uncomfortable sensitivity to light, visual impairment, involuntary movement of the eye, abnormal eye movement, damage to the optic nerve. Voriconazole has been associated with an increased sensitivity of skin to the sun s UV rays. It is recommended that all patients, including children, avoid intense or prolonged exposure to direct sunlight during voriconazole treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF). Voriconazole has been uncommonly associated with nerve injury resulting in numbness, pain, tingling or burning in the hands or feet. Development of HCP check list and Questions and Answer Brochure Development of HCP Checklist, HCP Question and Answer Brochure Patient Alert Card 4

5 Risk What is known Preventability Squamous cell carcinoma There have been reports of skin cancer in patients treated with voriconazole for long periods of time. 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 and the patient should be referred to a dermatologist. Development of HCP Checklist, HCP Question and Answer Brochure Patient Alert Card Important potential risks: Risk What is known Preventability Skin cancers (non SCC) Suicide related events In patients with photosensitivity skin reactions and additional risk factors, premalignant skin lesions have been reported during long term therapy. If you develop skin disorders as sunburn, severe skin rash or blisters and bone pain while being treated with voriconazole tell your doctor immediately. There is a lack of conclusive data indicating causal relationship at this time. Missing information Risk What is known Effects in pregnancy Effects in paediatric Off label use Resistance There are no adequate data from the use of voriconazole in pregnant women. Voriconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. The safety and efficacy of voriconazole in children below 2 years has not been established. This medicinal product has to be used in the authorized indications. There is no information about safety and efficacy of voriconazole for other indications. Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to 5

6 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. VI.2.5 Summary of additional risk measures by safety concern All medicines have a Summary of Product Characteristics (SmPC) which provides physicians, pharmacists and other health care professionals with details on how to use the medicine, the risks and recommendations for minimising them. An abbreviated version of this in lay language is provided in the form of the package leaflet (PL). The measures in these documents are known as routine risk measures. The Summary of Product Characteristics and the Package leaflet for Voriconazol NORMON can be found on the web pages of the national competent authorities in the EU. VI.2.6 Planned post authorisation development plan Neither planned studies nor studies imposed by the Committee for Medicinal Products for Human Use (CHMP)/National Competent Authorities (NCA) are foreseen for the aforementioned product. Therefore, there is no need to perform with post authorisation efficacy studies (PAES) or post authorisation safety studies (PASS). List of studies in post authorisation development plan Not applicable. Studies which are a condition of the marketing authorisation Not applicable. VI.2.7 Summary of changes to the over time Not applicable. 6