Orungal®: composition and pharmaceutical form
One capsule contains 100 mg of itraconazole as granules. The medicine contains sucrose, so it must not be taken by patients with rare hereditary fructose intolerance, glucose-galactose malabsorption syndrome or sucrase-isomaltase deficiency.
The capsule is swallowed whole and taken immediately after a full meal: absorption is then at its highest. It also depends on the acidity of the gastric juice: in achlorhydria or during treatment with medicines that reduce acid secretion, the capsule is best taken with an acidic drink such as a non-diet cola.
How Orungal® works
The active substance interferes with the building of the fungal cell membrane. In vitro itraconazole disrupted the synthesis of ergosterol, a sterol without which the fungal membrane cannot perform its functions; it is precisely this failure that ends in the death of the organism.
The spectrum covers dermatophytes, yeasts of the genus Candida and the agents of systemic and tropical mycoses. From skin and nails the active substance is cleared more slowly than from plasma, where after withdrawal the concentration falls to practically undetectable within 7–14 days. That is why the optimal result is reached 2–4 weeks after the end of treatment of skin infections and 6–9 months after that of nail infections.
Indications
The medicine is used in genital infections — vaginal and vulvar candidiasis; in infections of the skin, mucous membranes or eyes — dermatomycosis of the skin, pityriasis versicolor, oral candidiasis, fungal keratitis; and in onychomycoses caused by dermatophytes and/or yeasts.
A separate group is formed by systemic mycoses, in which itraconazole is prescribed only when first-line treatment has proved ineffective.
- systemic aspergillosis and systemic candidiasis;
- cryptococcosis including cryptococcal meningitis: with weakened immunity and also with any involvement of the central nervous system;
- histoplasmosis and blastomycosis, sporotrichosis and paracoccidioidomycosis, and other uncommon mycoses of systemic or tropical origin.
Method of use and dosage
The regimen and duration of treatment depend on the site and nature of the infection and range from a single day in vaginal candidiasis to a year in cryptococcosis; the duration is adjusted to the clinical response.
| Indication | Dose |
| Vulvar and vaginal candidiasis | 200 mg twice daily for 1 day or 200 mg daily for 3 days |
| Pityriasis versicolor / oral candidiasis | 200 mg daily for 7 days / 100 mg daily for 15 days |
| Dermatomycosis of the skin, including areas of increased keratinisation | 200 mg daily for 7 days or 100 mg daily for 15 days; in mycosis of the soles and palms 200 mg twice daily for 7 days or 100 mg daily for 30 days |
| Fungal keratitis | 200 mg daily for 21 days |
| Onychomycosis | pulse regimen — 200 mg twice daily for one week, 2 cycles for fingernails and 3 cycles for toenails with three-week breaks; continuous regimen — 200 mg daily for 3 months |
| Aspergillosis / systemic candidiasis | 200 mg daily for 2–5 months / 100–200 mg daily from 3 weeks to 7 months; in deep or disseminated lesions — 200 mg twice daily |
| Cryptococcosis / histoplasmosis / blastomycosis | 200 mg daily from 2 months to a year, in meningitis 200 mg twice daily / up to 200 mg twice daily for 8 months / up to 200 mg twice daily for 6 months |
| Sporotrichosis / paracoccidioidomycosis and chromomycosis | 100 mg daily for 3 months / 100–200 mg daily for 6 months |
In some patients with weakened immunity — with neutropenia, AIDS or after transplantation — the bioavailability of itraconazole falls and the dose sometimes has to be doubled. Data on the use of the capsules in children and in older people are limited: in both groups the medicine is prescribed only if the expected benefit outweighs the risk. Caution is required in hepatic impairment, while in renal impairment exposure to itraconazole turns out to be lower in some patients.
Contraindications
Hypersensitivity to the active substance or to any excipient. Pregnancy, except in life-threatening conditions. Concurrent use of a number of medicines metabolised by CYP3A4: their concentration rises in the presence of itraconazole, which may intensify or prolong both the therapeutic and the undesirable effect, up to prolongation of the QT interval and ventricular tachyarrhythmias, including life-threatening torsade de pointes.
The medicine is not used in patients with recognised ventricular dysfunction — congestive heart failure or a history of it — other than for the treatment of life-threatening or other severe infections. Women of childbearing age must use a reliable method of contraception throughout the course and continue it until the first menstrual period after the last dose.
Special warnings and precautions
In healthy volunteers given itraconazole intravenously a transient, asymptomatic decrease in left ventricular ejection fraction was observed, which resolved before the next infusion; whether this matters for the oral forms is not known. Itraconazole has been shown to have a negative inotropic effect, and cases of congestive heart failure have been described during its use, reported more often at the daily dose of 400 mg than at lower doses.
- risk factors for heart failure are taken to be ischaemic heart disease, valvular defects, serious lung diseases such as COPD, renal failure and other conditions with oedema; such patients are warned about the symptoms and, if these appear, the medicine is stopped;
- calcium antagonists themselves have a negative inotropic effect that adds to that of itraconazole, and itraconazole in turn slows their metabolism;
- very rarely severe hepatotoxicity has been seen, up to acute liver failure with a fatal outcome, part of the cases within the first month of treatment, so the patient must tell the doctor immediately about loss of appetite, nausea, vomiting, tiredness, abdominal pain or dark urine;
- transient or permanent hearing loss has been reported, in several cases in people taking quinidine at the same time; treatment is also stopped if symptoms of neuropathy related to the medicine appear, and when driving the possible dizziness and visual disturbances are taken into account.
With raised liver enzyme activity, active liver disease and a history of hepatic toxicity from other medicines, itraconazole is not used unless the condition is severe or life-threatening, and in such patients liver function is monitored. Data on cross-hypersensitivity to other azoles are limited, so with intolerance of compounds from this group the medicine is prescribed with caution. If systemic candidiasis is caused by Candida strains resistant to fluconazole, susceptibility to itraconazole cannot be assumed. For starting the treatment of mycoses that are immediately life-threatening the medicine is not recommended.
Interaction with other medicines
Itraconazole is metabolised mainly by CYP3A4 and is itself a potent inhibitor of CYP3A4 and of P-glycoprotein. Hence interactions in two directions: other substances change the concentration of itraconazole, while it, together with its metabolite hydroxyitraconazole, raises the concentration of medicines that follow the same route.
- the concentration of itraconazole is lowered by medicines that reduce gastric acidity: antacids are taken at least an hour before the capsule or two hours after it;
- the same effect comes from potent CYP3A4 inducers: the antituberculous rifampicin, rifabutin and isoniazid, the antiepileptics carbamazepine, phenobarbital and phenytoin, the antivirals efavirenz and nevirapine; they are withdrawn two weeks before the start of therapy, otherwise the antifungal effect is monitored and the dose increased;
- the concentration of itraconazole is raised by potent CYP3A4 inhibitors — ciprofloxacin, clarithromycin, erythromycin, indinavir, ritonavir, telaprevir; such patients are watched closely and the dose reduced if necessary;
- contraindicated during treatment and for two weeks after withdrawal: methadone, disopyramide, dofetilide, dronedarone, quinidine, ticagrelor, terfenadine, ergot alkaloids, irinotecan, pimozide, oral midazolam, triazolam, ivabradine, eplerenone, cisapride, lovastatin, simvastatin;
- among the inadvisable combinations: apixaban and rivaroxaban, sunitinib and nilotinib, everolimus, aliskiren, simeprevir, salmeterol, darifenacin, vardenafil, tamsulosin, fentanyl, colchicine;
- acceptable under monitoring are digoxin, atorvastatin, repaglinide, coumarin anticoagulants, glucocorticosteroids, alprazolam, haloperidol, quetiapine, risperidone and a number of cytostatics;
- the concentration of meloxicam, on the contrary, may fall, so its dose is adjusted if necessary.
Some of the restrictions depend on organ status: telithromycin is contraindicated in severe renal or hepatic impairment, fesoterodine in moderate and severe impairment, and colchicine in any impairment of either. The danger of these combinations persists after the course as well: in cirrhosis and in the presence of CYP3A4 inhibitors the concentration of itraconazole falls more slowly than the usual 7–14 days.
Pregnancy and breastfeeding
The medicine should not be used during pregnancy except in life-threatening cases where the expected benefit to the mother outweighs the risk of harm to the fetus. Animal studies revealed a harmful effect on reproduction, and in the rat model passage across the placenta was shown. After marketing, cases of congenital malformations have been recorded — deformities of the skeleton, the urogenital tract, the cardiovascular system and the organ of vision, chromosomal aberrations and multiple developmental defects — although a causal relationship with itraconazole has not been established.
Epidemiological data on use in the first trimester, mainly in patients on short courses for vaginal and vulvar candidiasis, did not show an increased risk of malformations compared with the control group. Women of childbearing age must use reliable contraception until the first menstrual period after the end of treatment. A very small amount of itraconazole passes into breast milk: during breastfeeding the benefit and the risk are weighed up, and in case of any doubt feeding is stopped.
Adverse reactions
Safety was assessed in 8499 patients in 107 open and double-blind studies; each received at least one dose in the treatment of mycosis of the skin or nails. In no fewer than 1% headache (1.6%), nausea (1.6%) and abdominal pain (1.3%) were recorded.
- in fewer than 1% of patients: sinusitis, upper respiratory tract infections, leukopenia, hypersensitivity, taste disturbances, paraesthesia, tinnitus, constipation, diarrhoea, vomiting, liver function disorders, itching, rash, urticaria, erectile and menstrual cycle disorders, oedema;
- very rarely after marketing: serum sickness, angioneurotic oedema, anaphylactic reaction, hypertriglyceridaemia, tremor, visual disturbances, hearing loss, congestive heart failure, pancreatitis, severe hepatotoxicity with several deaths from acute liver failure;
- very rare skin reactions: toxic epidermal necrolysis, Stevens — Johnson syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, vasculitis, photosensitivity.
In 165 patients aged from 1 to 17 years who took part in 14 studies, the most common were headache (3.0%), vomiting (3.0%), abdominal pain (2.4%), diarrhoea (2.4%), liver function disorders (1.2%), arterial hypotension, nausea and urticaria (1.2% each). The nature of the adverse reactions in children and adolescents is broadly the same as in adults, but their frequency is higher.
Overdose
Adverse events in overdose broadly coincide with those that occur with the ordinary use of itraconazole. There is no specific antidote, and removal of the medicine by haemodialysis is impossible.
Help comes down to maintaining vital functions. Activated charcoal is used when the doctor considers such a measure appropriate in the particular situation.
How to get a prescription for Orungal® online
The medicine is prescription-only, and the conversation with the doctor revolves around the heart and the liver. The doctor will ask about heart failure and heart disease, chronic lung disease, conditions with oedema, liver disease and raised liver enzymes, intolerance of other azoles and — because of the sucrose in the composition — about fructose intolerance and glucose-galactose malabsorption.
It is worth listing separately every medicine being taken, including over-the-counter ones: itraconazole's list of forbidden combinations is one of the longest, and the restriction stays in force for two more weeks after the course. Medicines that reduce gastric acidity matter too: they impair absorption. Pregnancy is ruled out before treatment starts, and contraception is continued until the first menstrual period after withdrawal. The doctor will assess these circumstances during the online consultation and, if there are no contraindications, will issue an electronic prescription.
