Orungal

Overdose

Symptoms:

In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this SmPC for Orungal.

Treatment:

In the event of an overdose, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Orungal cannot be removed by haemodialysis. No specific antidote is available.

Orungal price

We have no data on the cost of the drug.
However, we will provide data for each active ingredient

Contraindications

Orungal oral solution is contraindicated in patients with a known hypersensitivity to Orungal or to any of the excipients.

Co-administration of the following drugs is contraindicated with Orungal oral solution (see also 4.5 Interaction with other medicinal products and other forms of interaction):

- CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Orungal oral solution.).

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Pharmaceutical form

Capsules

Undesirable effects

Approximately 9% of patients can be expected to experience adverse reactions while taking Orungal. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological origin.

The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention:

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).

Adverse Drug Reactions
Blood and lymphatic system disorders
Uncommon	Leucopenia, Neutropenia, Thrombocytopenia
Immune system disorders
Not Known	Serum Sickness, Angioneurotic Oedema, Anaphylactic Reaction, Anaphylactoid Reaction, Hypersensitivity*
Metabolism and nutrition disorders
Uncommon	Hypokalaemia
Not Known	Hypertriglyceridemia
Nervous system disorders
Common	Headache
Uncommon	Peripheral Neuropathy*, Dizziness
Not Known	Paraesthesia, Hypoaesthesia
Eye disorders
Uncommon	Visual Disorders, including Vision Blurred and Diplopia
Ear and labyrinth disorder
Not Known	Tinnitus; Transient or permanent hearing loss*
Cardiac disorders
Not Known	Congestive Heart Failure*
Respiratory, thoracic and mediastinal disorders
Common	Dyspnoea
Not Known	Pulmonary Oedema
Gastrointestinal disorders
Common	Abdominal Pain, Vomiting, Nausea, Diarrhoea, Dysgeusia
Uncommon	Dyspepsia, Constipation
Not Known	Pancreatitis
Hepato-biliary disorders
Common	Hepatic enzyme increased
Uncommon	Hepatitis, Hyperbilirubinaemia
Not Known	Hepatotoxicity*, Acute hepatic failure*
Skin and subcutaneous tissue disorders
Common	Rash
Uncommon	Pruritus
Not Known	Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, urticaria, alopecia, photosensitivity
Musculoskeletal and connective tissue disorders
Not Known	Myalgia, arthralgia
Renal and urinary disorders
Not Known	Pollakiuria, urinary incontinence
Reproductive system and breast disorders
Not Known	Menstrual disorders, erectile dysfunction
General disorders and administration site conditions
Common	Pyrexia
Uncommon	Oedema Paediatric Population The safety of Orungal oral solution was evaluated in 250 paediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of Orungal for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data. Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were Vomiting (36.0%), Pyrexia (30.8%), Diarrhoea (28.4%), Mucosal inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension (14.0%), and Cough (11.2%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the 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 following: UK: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. IE: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected].

Preclinical safety data

).

Epidemiological data on exposure to Orungal during the first trimester of pregnancy - mostly in patients receiving short-term treatment for vulvovaginal candidosis - did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens.

Women of child-bearing potential:

Women of childbearing potential taking Orungal oral solution should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Orungal therapy.

Fertility:

In the rat, Orungal had no effect on male or female fertility at doses which exhibited signs of general toxicity. The effect in humans is unknown.

Lactation:

A very small amount of Orungal is excreted in human milk. Orungal Oral Solution must not be used during lactation.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss , which may occur in some instances, must be taken into account.

4.8 Undesirable effects

Approximately 9% of patients can be expected to experience adverse reactions while taking Orungal. In patients receiving prolonged (approximately 1 month) continuous treatment especially, the incidence of adverse events has been higher (about 15%). The most frequently reported adverse experiences have been of gastrointestinal, hepatic and dermatological origin.

The table below presents adverse drug reactions by System Organ Class. Within each System Organ Class, the adverse drug reactions are presented by incidence, using the following convention:

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).

Adverse Drug Reactions
Blood and lymphatic system disorders
Uncommon	Leucopenia, Neutropenia, Thrombocytopenia
Immune system disorders
Not Known	Serum Sickness, Angioneurotic Oedema, Anaphylactic Reaction, Anaphylactoid Reaction, Hypersensitivity*
Metabolism and nutrition disorders
Uncommon	Hypokalaemia
Not Known	Hypertriglyceridemia
Nervous system disorders
Common	Headache
Uncommon	Peripheral Neuropathy*, Dizziness
Not Known	Paraesthesia, Hypoaesthesia
Eye disorders
Uncommon	Visual Disorders, including Vision Blurred and Diplopia
Ear and labyrinth disorder
Not Known	Tinnitus; Transient or permanent hearing loss*
Cardiac disorders
Not Known	Congestive Heart Failure*
Respiratory, thoracic and mediastinal disorders
Common	Dyspnoea
Not Known	Pulmonary Oedema
Gastrointestinal disorders
Common	Abdominal Pain, Vomiting, Nausea, Diarrhoea, Dysgeusia
Uncommon	Dyspepsia, Constipation
Not Known	Pancreatitis
Hepato-biliary disorders
Common	Hepatic enzyme increased
Uncommon	Hepatitis, Hyperbilirubinaemia
Not Known	Hepatotoxicity*, Acute hepatic failure*
Skin and subcutaneous tissue disorders
Common	Rash
Uncommon	Pruritus
Not Known	Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, urticaria, alopecia, photosensitivity
Musculoskeletal and connective tissue disorders
Not Known	Myalgia, arthralgia
Renal and urinary disorders
Not Known	Pollakiuria, urinary incontinence
Reproductive system and breast disorders
Not Known	Menstrual disorders, erectile dysfunction
General disorders and administration site conditions
Common	Pyrexia
Uncommon	Oedema Paediatric Population The safety of Orungal oral solution was evaluated in 250 paediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of Orungal for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data. Based on pooled safety data from these clinical trials, the very common reported ADRs in paediatric patients were Vomiting (36.0%), Pyrexia (30.8%), Diarrhoea (28.4%), Mucosal inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension (14.0%), and Cough (11.2%). The nature of ADRs in paediatric patients is similar to that observed in adult subjects, but the incidence is higher in the 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 following: UK: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. IE: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected]. 4.9 Overdose Symptoms: In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this SmPC for Orungal. Treatment: In the event of an overdose, supportive measures should be employed. Activated charcoal may be given if considered appropriate. Orungal cannot be removed by haemodialysis. No specific antidote is available. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative. ATC code: J02A C02 Mode of action Orungal inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi. PK/PD relationship The PK/PD relationship for Orungal, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics. Mechanism(s) of resistance Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are - Over-expression of ERG11, the gene that encodes 14-alpha-demethylase (the target enzyme) - Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase for Orungal - Drug-transporter over-expression resulting in increased efflux of Orungal from fungal cells (i.e., removal of Orungal from its target) - Cross-resistance. Cross-resistance amongst members of the azole class of drugs has been observed within Candida species though resistance to one member of the class does not necessarily confer resistance to other azoles. Breakpoints Breakpoints for candida species are in preparation. Aspergillus Species1 MIC breakpoint (mg/L) ≤ S (Susceptible) >R (Resistant) Aspergillus flavus 1 2 Aspergillus fumigatus 1 2 Aspergillus nidulans 1 2 Aspergillus niger Insufficient evidence Aspergillus terreus Insufficient evidence Non species related breakpoints2 Insufficient evidence 1monitoring of Orungal trough concentrations in patients treated for fungal infection is recommended 2 The MIC values for isolates of A.niger and A.versicolor are in general higher than those for A.fumigatus. Whether this translates into a poorer clinical response is unknown The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable. The in vitro susceptibility of fungi to Orungal depends on the inoculum size, incubation temperature, growth phase of the fungi, and the culture medium used. For these reasons, the minimum inhibitory concentration of Orungal may vary widely. Susceptibility in the table below is based on MIC90 < 1 mg Orungal/L. There is no correlation between in vitro susceptibility and clinical efficacy. Commonly susceptible species Aspergillus spp.2 Blastomyces dermatitidis1 Candida albicans Candida parapsilosis Cladosporium spp. Coccidioides immitis1 Cryptococcus neoformans Epidermophyton floccosum Fonsecaea spp. 1 Geotrichum spp. Histoplasma spp. Malassezia (formerly Pityrosporum) spp. Microsporum spp. Paracoccidioides brasiliensis1 Penicillium marneffei1 Pseudallescheria boydii Sporothrix schenckii Trichophyton spp. Trichosporon spp. Species for which acquired resistance may be a problem Candida glabrata3 Candida krusei Candida tropicalis3 Inherently resistant organisms Absidia spp. Fusarium spp. Mucor spp. Rhizomucor spp. Rhizopus spp. Scedosporium proliferans Scopulariopsis spp. 1 These organisms may be encountered in patients who have returned from travel outside Europe. 2 Orungal-resistant strains of Aspergillus fumigatus have been reported. 3 Natural intermediate susceptibility. Paediatric Population The tolerability and safety of Orungal oral solution was studied in the prophylaxis of fungal infections in 103 neutropenic paediatric patients aged 0 to14 years (median 5 years) in an open-label uncontrolled phase III clinical study. Most patients (78%) were undergoing allogenic bone marrow transplantation for haematological malignancies. All patients received 5 mg/kg/day of Orungal oral solution as a single or divided dose. Due to the design of the study, no formal conclusion with regard to efficacy could be derived. The most common adverse events considered definitely or possibly related to Orungal were vomiting, abnormal liver function, and abdominal pain. 5.2 Pharmacokinetic properties Orungal General pharmacokinetic characteristics Peak plasma concentrations are reached within 2.5 hours following administration of the oral solution. As a consequence of non-linear pharmacokinetics, Orungal accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax and AUC values 4 to 7-fold higher than those seen after a single dose. Steady-state Cmax values of about 2 μg/ml are reached after oral administration of 200 mg once daily. The terminal half-life of Orungal generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, Orungal plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Orungal mean total plasma clearance following intravenous administration is 278 ml /min. Orungal clearance decreases at higher doses due to saturable hepatic metabolism. Absorption Orungal is rapidly absorbed after administration of the oral solution. Peak plasma concentrations of the unchanged drug are reached within 2.5 hours following an oral dose under fasting conditions. The observed absolute bioavailability of Orungal under fed conditions is about 55% and increases by 30 % when the oral solution is taken in fasting conditions. Orungal exposure is greater with the oral solution than with the capsule formulation when the same dose of drug is given.. Distribution Most of the Orungal in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy- metabolite). It has also a marked affinity for lipids. Only 0.2% of the Orungal in plasma is present as free drug. Orungal is distributed in a large apparent volume in the body (> 700 L), suggesting its extensive distribution into tissues: Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid. Metabolism Orungal is extensively metabolised by the liver into a large number of metabolites. The main metabolite is hydroxy-Orungal, which has in vitro antifungal activity comparable to Orungal. Trough plasma concentrations of the hydroxy-Orungal are about twice those of Orungal. As shown in in vitro studies, CYP 3A4 is the major enzyme that is involved in the metabolism of Orungal. Elimination Orungal is excreted mainly as inactive metabolites to about 35% in urine and to about 54% with faeces within one week of an oral solution dose. Renal excretion of Orungal and the active metabolite hydroxy-Orungal account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, faecal excretion of unchanged drug ranges from 3% to 18% of the dose. As re-distribution of Orungal from keratinous tissues appears to be negligible, elimination of Orungal from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin - where Orungal can be detected as early as 1 week after start of treatment - for at least six months after the end of a 3-month treatment period. Special Populations Hepatic Impairment: Orungal is predominantly metabolised in the liver. A pharmacokinetic study using a single 100 mg dose of Orungal (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. A statistically significant reduction in average Cmax (47%) and a two fold increase in the elimination half-life (37 ± 17 versus 16 ±5 hours) of Orungal were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to Orungal, based on AUC, was similar in cirrhotic patients and in healthy subjects.Data are not available in cirrhotic patients during long-term use of Orungal. Renal Impairment: Limited data are available on the use of oral Orungal in patients with renal impairment. A pharmacokinetic study using a single 200-mg dose of Orungal (four 50-mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 ml/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of Orungal (Tmax, Cmax, and AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of Orungal in patients with mild (defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20-49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar to that in healthy subjects (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to Orungal, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of Orungal. Dialysis has no effect on the half-life or clearance of Orungal or hydroxy-Orungal. Paediatric Population: Two pharmacokinetic studies have been conducted in neutropenic children aged 6 months to 14 years in which Orungal oral solution was administered 5 mg/kg once or twice daily. The exposure to Orungal was somewhat higher in older children (6 to 14 years) compared to younger children. In all children, effective plasma concentrations of Orungal were reached within 3 to 5 days after initiation of treatment and maintained throughout treatment. Hydroxypropyl-ß-Cyclodextrin The oral bioavailability of hydroxypropyl-β-cyclodextrin given as a solubilizer of Orungal in oral solution is on average lower than 0.5% and is similar to that of hydroxypropyl-β-cyclodextrin alone. This low oral bioavailability of hydroxypropyl-β-cyclodextrin is not modified by the presence of food and is similar after single and repeated administrations. 5.3 Preclinical safety data Orungal Nonclinical data on Orungal revealed no indications for genotoxicity, primary carcinogenicity or impairment of fertility. At high doses, effects were observed in the adrenal cortex, liver and the mononuclear phagocyte system but appear to have a low relevance for the proposed clinical use. Orungal was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats and mice at high doses. A global lower bone mineral density was observed in juvenile dogs after chronic Orungal administration, and in rats, a decreased bone plate activity, thinning of the zona compacta of the large bones, and an increased bone fragility was observed. Hydroxypropyl-β-cyclodextrin Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction and development. In a rat carcinogenicity study hydroxypropyl-β-cyclodextrin produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of the large intestine adenocarcinomas is low and the mechanism of exocrine pancreatic adenocarcinomas induction not considered relevant to humans.

Therapeutic indications

Orungal oral solution is indicated:

- For the treatment of oral and/or oesophageal candidosis in HIV-positive or other immunocompromised patients.

- As prophylaxis of deep fungal infections anticipated to be susceptible to Orungal, when standard therapy is considered inappropriate, in patients with haematological malignancy or undergoing bone marrow transplant, and who are expected to become neutropenic (i.e. < 500 cells/µl). At present there are insufficient clinical efficacy data in the prevention of aspergillosis.

Orungal oral solution is indicated for use in adults.

Consideration should be given to national and/or local guidance regarding the appropriate use of antifungal agents.

Pharmacotherapeutic group

Antimycotic for systemic use, triazole derivative.

Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative.

ATC code: J02A C02

Mode of action

Orungal inhibits fungal 14α-demethylase, resulting in a depletion of ergosterol and disruption of membrane synthesis by fungi.

PK/PD relationship

The PK/PD relationship for Orungal, and for triazoles in general, is poorly understood and is complicated by limited understanding of antifungal pharmacokinetics.

Mechanism(s) of resistance

Resistance of fungi to azoles appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are

- Over-expression of ERG11, the gene that encodes 14-alpha-demethylase (the target enzyme)

- Point mutations in ERG11 that lead to decreased affinity of 14-alpha-demethylase for Orungal

- Drug-transporter over-expression resulting in increased efflux of Orungal from fungal cells (i.e., removal of Orungal from its target)

- Cross-resistance. Cross-resistance amongst members of the azole class of drugs has been observed within Candida species though resistance to one member of the class does not necessarily confer resistance to other azoles.

Breakpoints

Breakpoints for candida species are in preparation.

Aspergillus Species1	MIC breakpoint (mg/L)
	≤ S (Susceptible)	>R (Resistant)
Aspergillus flavus	1	2
Aspergillus fumigatus	1	2
Aspergillus nidulans	1	2
Aspergillus niger	Insufficient evidence
Aspergillus terreus	Insufficient evidence
Non species related breakpoints2	Insufficient evidence
1monitoring of Orungal trough concentrations in patients treated for fungal infection is recommended 2 The MIC values for isolates of A.niger and A.versicolor are in general higher than those for A.fumigatus. Whether this translates into a poorer clinical response is unknown

The prevalence of acquired resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

The in vitro susceptibility of fungi to Orungal depends on the inoculum size, incubation temperature, growth phase of the fungi, and the culture medium used. For these reasons, the minimum inhibitory concentration of Orungal may vary widely. Susceptibility in the table below is based on MIC90 < 1 mg Orungal/L. There is no correlation between in vitro susceptibility and clinical efficacy.

Commonly susceptible species

Aspergillus spp.2

Blastomyces dermatitidis1

Candida albicans

Candida parapsilosis

Cladosporium spp.

Coccidioides immitis1

Cryptococcus neoformans

Epidermophyton floccosum

Fonsecaea spp. 1

Geotrichum spp.

Histoplasma spp.

Malassezia (formerly Pityrosporum) spp.

Microsporum spp.

Paracoccidioides brasiliensis1

Penicillium marneffei1

Pseudallescheria boydii

Sporothrix schenckii

Trichophyton spp.

Trichosporon spp.

Species for which acquired resistance may be a problem

Candida glabrata3

Candida krusei

Candida tropicalis3

Inherently resistant organisms

Absidia spp.

Fusarium spp.

Mucor spp.

Rhizomucor spp.

Rhizopus spp.

Scedosporium proliferans

Scopulariopsis spp.

1 These organisms may be encountered in patients who have returned from travel outside Europe.

2 Orungal-resistant strains of Aspergillus fumigatus have been reported.

3 Natural intermediate susceptibility.

Paediatric Population

The tolerability and safety of Orungal oral solution was studied in the prophylaxis of fungal infections in 103 neutropenic paediatric patients aged 0 to14 years (median 5 years) in an open-label uncontrolled phase III clinical study. Most patients (78%) were undergoing allogenic bone marrow transplantation for haematological malignancies. All patients received 5 mg/kg/day of Orungal oral solution as a single or divided dose. Due to the design of the study, no formal conclusion with regard to efficacy could be derived. The most common adverse events considered definitely or possibly related to Orungal were vomiting, abnormal liver function, and abdominal pain.

Pharmacokinetic properties

, Special populations, Hepatic impairment)

Use in patients with renal impairment

Limited data are available on the use of oral Orungal in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

4.3 Contraindications

Orungal oral solution is contraindicated in patients with a known hypersensitivity to Orungal or to any of the excipients.

Co-administration of the following drugs is contraindicated with Orungal oral solution (see also 4.5 Interaction with other medicinal products and other forms of interaction):

- CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Orungal oral solution.).

4.4 Special warnings and precautions for use

Cross-hypersensitivity

There is no information regarding cross hypersensitivity between Orungal and other azole antifungal agents. Caution should be used in prescribing Orungal Oral Solution to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with Orungal IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.

Orungal has been shown to have a negative inotropic effect and has been associated with reports of congestive heart failure. Interaction with other medicinal products).

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Orungal. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Orungal treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking Orungal.

Use in children

Since clinical data on the use of Orungal oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.

Use in elderly

Since clinical data on the use of Orungal oral solution in elderly patients is limited, it is advised to use Orungal oral solution in these patients only if the potential benefit outweighs the potential risks.

Hepatic impairment

Limited data are available on the use of oral Orungal in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Renal impairment

Limited data are available on the use of oral Orungal in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Prophylaxis in neutropenic patients

In clinical trials diarrhoea was the most frequent adverse event. This disturbance of the gastrointestinal tract may result in impaired absorption and may alter the microbiological flora potentially favouring fungal colonisation. Consideration should be given to discontinuing Orungal oral solution in these circumstances.

Treatment of severely neutropenic patients

Orungal oral solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (See 5.2 Pharmacokinetic properties), Orungal oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with Orungal. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Neuropathy

If neuropathy occurs that may be attributable to Orungal oral solution, the treatment should be discontinued.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to Orungal, hence their sensitivity should be tested before the start of Orungal therapy

Interaction potential

Orungal Oral Solution has a potential for clinically important drug interactions.

Orungal should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort)). The use of Orungal with these drugs may lead to subtherapeutic plasma levels of Orungal and thus treatment failure.

Orungal oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Also contains ethanol less than 100mg per dose.

4.5 Interaction with other medicinal products and other forms of interaction

4.5.1. Drugs affecting the metabolism of Orungal:

Orungal is mainly metabolised through the cytochrome CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent enzyme inducers of CYP3A4. Since the bioavailability of Orungal and hydroxy-Orungal was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of Orungal with these potent enzyme inducers is not recommended. No formal study data are available for other enzyme inducers, such as carbamazepine, Hypericum perforatum (St John's Wort), phenobarbital and isoniazid, but similar effects should be anticipated.

Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of Orungal.

4.5.2. Effect of Orungal on the metabolism of other drugs:

4.5.2.1 Orungal can inhibit the metabolism of drugs metabolised by the cytochrome 3A family. Pharmacokinetic Properties). This should be taken into account when the inhibitory effect of Orungal on co-medicated drugs is considered.

The following drugs are contraindicated with Orungal:

- Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Orungal oral solution since co-administration may result in increased plasma concentrations of these substrates, which can lead to QT prolongation and rare occurrences of torsade de pointes.

- CYP3A4 metabolized HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin.

- Triazolam and oral midazolam.

- Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).

- Eletriptan

- Nisoldipine

Caution should be exercised when co-administering Orungal with calcium channel blockers due to an increased risk of congestive heart failure. In addition to possible pharmacokinetic interactions involving the drug metabolising enzyme CYP3A4, calcium channel blockers can have negative inotropic effects which may be additive to those of Orungal.

The following drugs should be used with caution, and their plasma concentrations, effects or side effects should be monitored. Their dosage, if co-administered with Orungal, should be reduced if necessary:

- Oral anticoagulants;

- HIV protease inhibitors such as ritonavir, indinavir, saquinavir;

- Certain antineoplastic agents such as busulfan, docetaxel, trimetrexate and vinca alkaloids;

- CYP3A4 metabolised calcium channel blockers such as dihydropyridines and verapamil;

- Certain immunosuppressive agents: ciclosporin, tacrolimus, rapamycin (also known as sirolimus);

- Certain glucocorticosteroids such as budesonide, dexamethasone, fluticasone and methylprednisolone;

- Digoxin (via inhibition of P-glycoprotein)

- Others: cilostazol, disopyramide, carbamazepine, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, rifabutin, ebastine, repaglinide, fentanyl, halofantrine, reboxetine and loperamide. The importance of the concentration increase and the clinical relevance of these changes during the co-administration with Orungal remain to be established.

4.5.2.2 No interaction of Orungal with zidovudine (AZT) and fluvastatin has been observed.

No inducing effects of Orungal on the metabolism of ethinyloestradiol and norethisterone were observed.

4.5.3. Effect on protein binding:

In vitro studies have shown that there are no interactions on the plasma protein binding between Orungal and imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide and sulfamethazine.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Orungal oral solution must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the foetus (see 4.3 Contraindications).

In animal studies Orungal has shown reproduction toxicity (see

Name of the medicinal product

Orungal

Qualitative and quantitative composition

Itraconazole

Special warnings and precautions for use

Cross-hypersensitivity

There is no information regarding cross hypersensitivity between Orungal and other azole antifungal agents. Caution should be used in prescribing Orungal Oral Solution to patients with hypersensitivity to other azoles.

Cardiac effects

In a healthy volunteer study with Orungal IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed.

Orungal has been shown to have a negative inotropic effect and has been associated with reports of congestive heart failure. Interaction with other medicinal products).

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of Orungal. Some of these cases involved patients with no pre-existing liver disease. Some of these cases have been observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving Orungal treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted. Most cases of serious hepatotoxicity involved patients who had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. In patients with raised liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment should not be started unless the expected benefit exceeds the risk of hepatic injury. In patients with impaired hepatic function liver enzyme should be carefully monitored when taking Orungal.

Use in children

Since clinical data on the use of Orungal oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.

Use in elderly

Since clinical data on the use of Orungal oral solution in elderly patients is limited, it is advised to use Orungal oral solution in these patients only if the potential benefit outweighs the potential risks.

Hepatic impairment

Limited data are available on the use of oral Orungal in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Renal impairment

Limited data are available on the use of oral Orungal in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Prophylaxis in neutropenic patients

In clinical trials diarrhoea was the most frequent adverse event. This disturbance of the gastrointestinal tract may result in impaired absorption and may alter the microbiological flora potentially favouring fungal colonisation. Consideration should be given to discontinuing Orungal oral solution in these circumstances.

Treatment of severely neutropenic patients

Orungal oral solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (See 5.2 Pharmacokinetic properties), Orungal oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with Orungal. Several of these reports included concurrent administration of quinidine which is contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Neuropathy

If neuropathy occurs that may be attributable to Orungal oral solution, the treatment should be discontinued.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to Orungal, hence their sensitivity should be tested before the start of Orungal therapy

Interaction potential

Orungal Oral Solution has a potential for clinically important drug interactions.

Orungal should not be used within 2 weeks after discontinuation of treatment with CYP 3A4 inducing agents (rifampicin, rifabutin, phenobarbital, phenytoin, carbamazepine, Hypericum perforatum (St. John´s wort)). The use of Orungal with these drugs may lead to subtherapeutic plasma levels of Orungal and thus treatment failure.

Orungal oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Also contains ethanol less than 100mg per dose.

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss , which may occur in some instances, must be taken into account.

Dosage (Posology) and method of administration

For optimal absorption, Orungal oral solution should be taken without food (patients are advised to refrain from eating for at least 1 hour after intake).

A graduated measuring cup is provided to measure out the correct dose.

For the treatment of oral and/or oesophageal candidosis, the liquid should be swished around the oral cavity (approx. 20 seconds) and swallowed. There should be no rinsing after swallowing.

Treatment of oral and/or oesophageal candidosis: 200 mg (20 ml) per day in two intakes, or alternatively in one intake, for 1 week. If there is no response after 1 week, treatment should be continued for another week.

Treatment of fluconazole resistant oral and/or oesophageal candidosis: 100 to 200 mg (10-20 ml) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should be continued for another 2 weeks. The 400mg daily dose should not be used for longer than 14 days if there are no signs of improvement.

Prophylaxis of fungal infections: 5 mg/kg per day administered in two intakes. In clinical trials, prophylaxis treatment was started immediately prior to the cytostatic treatment and generally one week before transplant procedure. Almost all proven deep fungal infections occurred in patients reaching neutrophil counts below 100 cells/µl. Treatment was continued until recovery of neutrophils (i.e. > 1000 cells/µl).

Pharmacokinetic parameters from clinical studies in neutropenic patients demonstrate considerable intersubject variation. Blood level monitoring should be considered particularly in the presence of gastrointestinal damage, diarrhoea and during prolonged courses of Orungal oral solution.

Use in children

Since clinical data on the use of Orungal oral solution in paediatric patients is limited, its use in children is not recommended unless the potential benefit outweighs the potential risks.

Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5 mg/kg per day administered in two intakes.

Use in elderly

Since clinical data on the use of Orungal oral solution in elderly patients is limited, it is advised to use Orungal oral solution in these patients only if the potential benefit outweighs the potential risks.

Use in patients with hepatic impairment

Limited data are available on the use of oral Orungal in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Use in patients with renal impairment

Limited data are available on the use of oral Orungal in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population.

Special precautions for disposal and other handling

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