Orunit

Overdose

Symptoms:

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

Treatment:

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

Orunit price

Contraindications

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

Co-administration of the following drugs is contraindicated with Orunit 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 Orunit oral solution.).

Incompatibilities

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

Pharmaceutical form

Undesirable effects

Approximately 9% of patients can be expected to experience adverse reactions while taking Orunit. 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).

Preclinical safety data

Epidemiological data on exposure to Orunit 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 Orunit oral solution should use contraceptive precautions. Effective contraception should be continued until the next menstrual period following the end of Orunit therapy.

Fertility:

In the rat, Orunit 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 Orunit is excreted in human milk. Orunit Oral Solution must not be used during lactation.

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.

Approximately 9% of patients can be expected to experience adverse reactions while taking Orunit. 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).

Therapeutic indications

Orunit 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 Orunit, 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.

Orunit 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

Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotic for systemic use, triazole derivative.

ATC code: J02A C02

Mode of action

Orunit 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 Orunit, 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 Orunit

- Drug-transporter over-expression resulting in increased efflux of Orunit from fungal cells (i.e., removal of Orunit 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.

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 Orunit 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 Orunit may vary widely. Susceptibility in the table below is based on MIC90 < 1 mg Orunit/L. There is no correlation between in vitro susceptibility and clinical efficacy.

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

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

3 Natural intermediate susceptibility.

Paediatric Population

The tolerability and safety of Orunit 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 Orunit 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 Orunit were vomiting, abnormal liver function, and abdominal pain.

Pharmacokinetic properties

Use in patients with renal impairment

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

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

Co-administration of the following drugs is contraindicated with Orunit 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 Orunit oral solution.).

Cross-hypersensitivity

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

Cardiac effects

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

Orunit 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 Orunit. 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 Orunit 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 Orunit.

Use in children

Since clinical data on the use of Orunit 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 Orunit oral solution in elderly patients is limited, it is advised to use Orunit 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 Orunit 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 Orunit 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 Orunit oral solution in these circumstances.

Treatment of severely neutropenic patients

Orunit 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), Orunit 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 Orunit. 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 Orunit 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 Orunit, hence their sensitivity should be tested before the start of Orunit therapy

Interaction potential

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

Orunit 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 Orunit with these drugs may lead to subtherapeutic plasma levels of Orunit and thus treatment failure.

Orunit 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.

4.5.1. Drugs affecting the metabolism of Orunit:

Orunit 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 Orunit and hydroxy-Orunit was decreased in these studies to such an extent that efficacy may be largely reduced, the combination of Orunit 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 Orunit.

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

4.5.2.1 Orunit 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 Orunit on co-medicated drugs is considered.

The following drugs are contraindicated with Orunit:

- Astemizole, bepridil, cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole and terfenadine are contraindicated with Orunit 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 Orunit 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 Orunit.

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 Orunit, 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 Orunit remain to be established.

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

No inducing effects of Orunit 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 Orunit and imipramine, propranolol, diazepam, cimetidine, indometacin, tolbutamide and sulfamethazine.

Pregnancy:

Orunit 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 Orunit has shown reproduction toxicity (see

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Cross-hypersensitivity

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

Cardiac effects

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

Orunit 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 Orunit. 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 Orunit 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 Orunit.

Use in children

Since clinical data on the use of Orunit 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 Orunit oral solution in elderly patients is limited, it is advised to use Orunit 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 Orunit 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 Orunit 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 Orunit oral solution in these circumstances.

Treatment of severely neutropenic patients

Orunit 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), Orunit 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 Orunit. 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 Orunit 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 Orunit, hence their sensitivity should be tested before the start of Orunit therapy

Interaction potential

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

Orunit 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 Orunit with these drugs may lead to subtherapeutic plasma levels of Orunit and thus treatment failure.

Orunit 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, Orunit 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 Orunit oral solution.

Use in children

Since clinical data on the use of Orunit 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 Orunit oral solution in elderly patients is limited, it is advised to use Orunit 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 Orunit 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 Orunit 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.