ORUNGAL caps. 100 mg. 15 caps

JANSSEN CILAG
ORUNGAL caps. 100 mg. 15 caps
€ 93.00
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Orungal capsules for oral use is prescribed for the treatment of:
   Obstetric complications: vulva-vaginal candidiasis. Dermatological / ophthalmic indications Tinea tinea fungal keratitis lisheyOralni candidiasis onychomycosis caused by dermatophytes and / or drozhdi.Sistemni mycosis Systemic aspergillosis and candidiasis



ORUNGAL caps. 100 mg. 15 caps
 

PHARMACEUTICAL FORM

Capsules for oral administration.
 

CLINICAL FEATURES

 

 Indications

 
Orungal capsules for oral use is prescribed for the treatment of:
  Gynecological indications:
 Vulva-vaginal candidiasis.
 Dermatological / ophthalmic indications
 
Tinea
  Tinea versicolor
  Oral candidiasis
 Fungal Keratitis
  onychomycosis caused by dermatophytes and / or yeasts.
  Systemic mycoses
- Systemic aspergillosis and candidiasis
- Cryptococcosis (including cryptococcal meningitis): In immunocompromised patients with cryptococcosis, and in all patients with cryptococcosis of the central nervous system Orungal is shown only when the first-line therapy is considered inappropriate or has proven ineffective
 
- Histoplasmosi 
- Blastomycosis
- Sporotrichosis
- Parakoktsidioidomikoza
- Other less common systemic mycoses or tropical
 

 Dosage and method of administration

 
For optimal resorption is essential Orungal capsules to be taken immediately after meals.
 
The capsules should be swallowed whole.
 
Elimination of itraconazole from skin and nail tissue is slower than its elimination from plasma. Optimal clinical and mycological effects in skin infections are achieved 2 to 4 weeks after treatment and nail infections for 6 to 9 months after treatment.
 
Use in children:
 
Data on the use of ORUNGAL capsules in children are limited, so this is not recommended unless the potential benefit outweighs the potential risks. (See Section 4.4. "Special warnings and precautions for use")
 
Use in patients with renal impairment
 
 
Bioavailability after oral administration of itraconazole may be reduced in patients with renal insufficiency. It is appropriate dose adjustment (See section 4.4. "Special warnings and precautions for use").
 
Use in patients with hepatic impairment:
 
Itraconazole is metabolized primarily in the liver. The plasma half-life of itraconazole in patients with liver cirrhosis is slightly extended. In cirrhotic patients with a decrease in oral bioavailability. It is appropriate dose adjustment (See section 4.4. Special warnings and precautions for use).
 

 Contraindications

 
 ORUNGAL capsules are contraindicated in patients with known hypersensitivity to itraconazole or any of the excipients.
  Concomitant administration of capsules ORUNGAL following medicinal products (see section "Interactions with other medicaments and other forms of interaction")
 
 CYP3A4 metabolised substrates that can prolong the QT-interval eg, astemizole, cisapride, dofetilide, levatsetilmetadol (levomethadyl) mizolastine, pimozide, quinidine, sertindole and terfenadine should not be coadministered with ORUNGAL capsules. As a result of co-administration may increase plasma concentrations of these substrates, leading to prolongation of the QT-interval prolongation and rare occurrences of torsade de pointes;
 CYP3A4 metabolized HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin;
  Triazolam and oral midazolam;
 
 Ergotilovi alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and metilergometrin (methylergonovine).
 
 ORUNGAL capsules should not be used during pregnancy (except in life-threatening cases. Look. Section 4.6. "Pregnancy and lactation").
 
 

 Special warnings and precautions for use

 
 
Effects on heart:
 
In a clinical study conducted with ORUNGAL intravenous in healthy volunteers was observed transient reduction of left ventricular ejection. This effect goes before the next infusion. The clinical relevance of these observations for oral administration is unknown.
 
Itraconazole showed a negative inotropic effect and there have been reports of congestive heart failure in the use of ORUNGAL capsules. ORUNGAL capsules should not be used in patients with congestive heart failure or a previous history of such disease unless the benefits of its application clearly outweighs the risk. In the individual benefit / risk assessment should take into account factors such as the severity of the indication, dosing regimen and duration, and individual risk factors for congestive heart failure. These risk factors include heart disease, such as coronary artery disease and valvular disease, significant pulmonary disease such as chronic obstructive pulmonary disease and renal failure or other oedematous states. Such patients should be informed about the signs and symptoms of congestive heart failure, it should be treated with caution and monitored for signs and symptoms of congestive heart failure during treatment, if such signs or symptoms occur during treatment intake ORUNGAL capsules should be discontinued
Calcium channel blockers can have negative effects inotoropen that can be added to that of itraconazole itrakonazolat may inhibit the metabolism of calcium channel blockers. So have a care should be exercised when co-administering itraconazole and calcium channel blockers (see section 4.5. "Interactions with other medicaments and other forms of interaction").
  
Potential interactions
 
ORUNGAL capsules can cause clinically significant drug-drug interactions (see Section 4.5. "Interactions with other medicaments and other forms of interaction").
 
Decreased gastric acidity:
 
Absorption of itraconazole capsules ORUNGAL is impaired by reduced gastric acidity. In patients who are also taking antacids (eg, aluminum hydroxide), these should be taken at least two hours after taking the capsules Orungal. In patients with ahlorhidriya, some AIDS patients and patients taking preparations to suppress acid secretion (eg, H2 blockers, proton pump inhibitors), it is recommended ORUNGAL capsules be taken with drinks such as Coca-Cola.
  
Use in children
 
Data on the use of Orungal capsules in children are limited. Application of Orungal capsules in children is not recommended unless the potential benefit outweighs the potential risks.
 
Hepatic effects:
 
Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure occurring when using ORUNGAL capsules. Some of these cases involved patients with pre-existing liver disease. Some of these cases occurred during the first month of treatment, including the first week. In patients taking ORUNGAL capsules should be done tracing functions. Patients should be instructed to promptly report to their physician signs and symptoms that may be manifestations of hepatitis such as anorexia, nausea, vomiting, weakness, abdominal pain or dark urine. In these patients, therapy should be discontinued immediately and liver function testing. Most cases of severe hepatotoxicity include patients with preexisting liver disease in systemic indications, had significant other medical conditions and / or are taking other hepatotoxic medications. Patients with elevated liver enzymes or active liver disease, and in patients with a history of liver toxicity when taking other medications should not be initiated ORUNGAL Capsules unless the expected benefit outweighs the risk of liver damage. In these cases, monitoring of liver enzymes.
 
Hepatic impairment:
 
Itraconazole is metabolized primarily in the liver. There was a slight decrease in oral bioavailability in patients with cirrhosis, which may require dose adjustment. Terminal half-life, however, was slightly increased. If necessary, the dose should be adjusted.
 
Renal impairment:
 
The oral bioavailability of itraconazole in patients with renal failure is lower. You may need a dose adjustment.
 
Immunocompromised patients
 
In some immunocompromised patients (eg neutropenic patients with AIDS or organ transplants), the bioavailability of ORUNGAL capsules can be reduced.
 
Patients with immediately life-threatening systemic fungal infections:
 
Due to its pharmacokinetic properties (see Section 5.2), ORUNGAL capsules are not recommended for initiating therapy in patients with life-threatening emergency systemic fungal infections.
 
Patients with AIDS
 
In patients with AIDS receiving treatment for systemic fungal infections such as sporotrichosis, histoplasmosis and cryptococcosis (meningeal and non-meningeal) and who are considered at risk of relapse, the physician must evaluate the need for maintenance treatment.
  
Neuropathy:
 
If a neuropathy, which may be due to treatment with ORUNGAL capsules, it should be discontinued.
Cross sensitivity:
 
No data on cross-hypersensitivity between itraconazole and other azole antifungals. ORUNGAL capsules should be prescribed with caution in patients with hypersensitivity to other azole derivatives.
 
Systemic candidiasis:
 
When systemic candida, assuming that strains of Candida were resistant to fluconazole, it can be argued that they are sensitive to itraconazole, which implies that their sensitivity should be checked before starting therapy ORUNGAL capsules.
 
 

 Interactions with other medicaments and other forms of interaction

 
 
Drugs affecting Absorption of itraconazole:
 
Drugs reduce stomach atsiditet impair the absorption of itraconazole capsules ORUNGAL (see Section 4.4. "Special warnings and precautions for use").
 
Drugs affecting the metabolism of itraconazole:
 
Itraconazole is mainly metabolised by the cytochrome CYP3A4.Itrakonazol is mainly metabolized by CYP3A4. Interaction studies have been performed with rifampicin, rifabutin and phenytoin, which are potent inducers of CYP3A4. Since the bioavailability of itraconazole and hydroxy was decreased in these studies to the extent of its effectiveness, the combination of itraconazole with these potent enzyme inducers is not recommended. Data on research pertaining to other enzyme inducers such as carbamazepine, phenobarbital and isoniazid, but can expect similar effects.
 
Potent inhibitors of this enzyme such as ritonavir, indinavir, clarithromycin and erythromycin may increase the bioavailability of itraconazole.
 
 

 Effect of itraconazole on the metabolism of other drugs:

 
3.1. Itraconazole can inhibit the transformation of drugs that are metabolized by enzymes of the cytochrome ON. This can lead to increased and / or extension of their effects, including side effects. When appointed concomitant medications should be taken into account information about the way of the metabolism of other drugs. After stopping treatment, itraconazole plasma levels decline gradually, depending on the dose and duration of treatment (see section 5.2. "Pharmacokinetic properties"). This should be considered for the inhibitory effect of itraconazole on other drugs.
 
Examples:
> Drugs that should not be used concomitantly with itraconazole:
 
, Astemizole, cisapride, dofetilide, levatsetilmetadol (levomethadyl) mizolastine, pimozide, triazolam, quinidine, sertindole and terfenadine are contraindicated while implementing ORUNGAL capsules, as this may result in increased plasma concentrations of these drugs, which in turn Party may cause prolongation of the QT-interval prolongation and rare occurrences of torsade de pointes.
-CYP3A4 metabolized HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin.
- Triazolam and oral midazolam.
- Ergotilovi alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and metilergometrin (methylergonovine).
During concomitant administration of itraconazole and calcium channel blockers should be approached with caution. In addition to pharmacokinetic interactions involving the enzyme CYP3A4, which metabolizes drugs, calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole.
> Drugs should be used with caution, and their plasma levels, effects or side effects should be monitored. Concurrent use with itraconazole their dosage should be reduced if necessary:
-Oral anticoagulants 
- H1V 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 verapamil and dihydropyridine;
- Certain immunosuppressive agents: ciclosporin, tacrolimus, rapamycin (also known as sirolimus);
-CYP3A4 metabolized HMG-CoA reductase inhibitors such as atorvastatin.
 
Some butezonid as glucocorticoids, dexamethasone and methylprednisolone
 
-Other: digoxin, carbamazepine, cilostazol, buspirone, alfentanil, alprazolam, brotizolam, midazolam IV, disopiramid, eletriptan, halofantrine, rifabutin, Repaglinide, ebastin, reboksetin. The importance of increasing concentration and clinical relevance of these changes with concomitant to be established.
 
 

 There was no interaction of itraconazole with AZT (zidovudine) and fluvastatin.


 

There was no induction of the metabolism of ethinylestradiol and norethisterone of itraconazole.
 
 

Effect on protein binding:

 
In vitro studies have shown that the interaction does not occur at the level of protein binding between itraconazole and imipramine, propranolol, diazepam, cimetidine, indomethacin, tolbutamide and sulfadimidine.
 
 
Pregnancy and lactation
 
Pregnancy
 
ORUNGAL capsules should not be used during pregnancy, except in life-threatening situations when the potential benefit outweighs the potential risk to the fetus (see section 4.3. "Contraindications").
 
In animal studies, itraconazole showed toxicity to reproduction (see Section 5.3. "Preclinical safety data").
 
There is limited information on the use of ORUNGAL capsules during pregnancy. In post-marketing experience, cases of congenital abnormalities. These cases include skeletal, urogenital, cardiovascular and oftalmichni and chromosomal malformations and multiplenni. There is no causal connection with ORUNGAL kapsuli.Nyama epidemiological data showing an increased risk of malformations in implementing ORUNGAL capsules during the first trimester of pregnancy - especially for patients on short-term treatment of vulvar and vaginal candidiasis - compared with a control group of patients which is not exposed to other known teratogens.
 
 
Women of childbearing age:
 
Women of childbearing age receiving ORUNGAL capsules should use contraceptive precautions. Effective contraception should be continued until the first menstruation after stopping treatment with ORUNGAL capsules.
 
Lactation
 
Very small amount of itraconazole is excreted in human milk. The expected benefit of treatment with capsules ORUNGAL exceed the potential risk for breastfeeding. In case of doubt, breastfeeding should be discontinued.
 
Effects on ability to drive and use machines
 
None known.
 
Adverse Reactions
 
Clinical trials:
 
The table below lists adverse reactions reported by patients in clinical trials (pooled data) performed with ORUNGAL capsules for the treatment of onychomycosis and dermatomycoses. Included are all the side effects (incidence of 1% or more) reported in patients treated with ORUNGAL. Approximately 28% of patients treated with ORUNGAL capsules and about 23% of patients receiving placebo reported at least one adverse reaction. Adverse events were summarized without regard to the assessment of the case by the researchers. The most common adverse events in clinical trials were related to the gastrointestinal tract.
 
Table: Adverse reactions reported in patients treated with capsules ORUNGAL frequency> 1%. ORUNGAL capsules N = 929 (%) Placebo N = 661 (%) 
Body as a whole
Disorders of the central and peripheral nervous syste
Headache
 Gastrointestinal disturbances
Nausea
Diarrhea
Abdominal pain
Dyspepsia
Flatulence
Hepatobiliary disorders
Impaired liver function
Respiratory system  
Rhinitis  
Infection of the upper respiratory tract
Sinusitis  
Skin and skin structure
 
Rash
 
Post-marketing experience:
 
For all organs and systems of the adverse reactions are listed under headings of frequency using the following convention:
 Very common (> 1/10)
 
Frequent (> 1/100, <1/10)
  Not very common (> 1/1000, <1/100)
 Rare (> 1/10000, <1/1000)
  Very rare (<1/10000), including isolated reports.
 
The frequency of reported adverse reactions are based on post-marketing experience with all forms of ORUNGAL: capsules and oral solution Orungal
 
 

Pharmacological Properties

 

 Farmakodinashchni properties

 
Farmakoterapvtichna classification:
 
Systemic antifungal use, triazole derivative.
 
Itraconazole is a triazole derivative with broad spectrum of activity. > Immune system disorders
  Very rare: anaphylaxis, anaphylactic and allergic reactions.
 Metabolism and nutrition disorders
  Very rare: hypokalemia.
 Nervous System
  Very rare: peripheral neuropathy, headache, dizziness.
 Cardiac disorders
  Very rare: congestive heart failure.
 Respiratory, thoracic and mediastinal disorders
  Very rare: pulmonary edema.
  Gastro-intestinal disorders
 Very rare: abdominal pain, vomiting, dyspepsia, nausea, diarrhea and constipation.
  Hepatobiliary disorders
  Very rare serious hepatotksichnost (including some cases of fatal acute liver failure), hepatitis, reversible increases in liver enzymes.
  Skin and subcutaneous tissue disorders
  Very rare: Stevens-Johnson syndrome, angioedema, urticaria, alopecia, fotosenzitivnost, rash, itching.
  Disorders of the Reproductive system and breast disorders
  Very rare: menstrual disorders.
  General disorders and local conditions
 Rarely: edema.
 
Overdose
 
No overdose.
 
In case of overdose, the patient should be treated symptomatically with supportive measures. In the first hours after ingestion of the drug may be gastric lavage. Discretion may be given activated charcoal. There is no specific antidote. Itraconazole is not removed by hemodializa.Nyama specific antidote.
 
In vitro studies have shown that itraconazole inhibits the growth of a broad spectrum of fungi pathogenic to humans at concentrations ranging from <0.025 to 0.8 jig / ml.
 
They include:
 
dermatophytes (Trichophyton spp., Microsporum spp., Epidermophyton fioccosum); yeasts (Candida spp., SCP. C. albicans, C. glabrata and C krusei, Cryptococcus neoformans, Pityrosporum spp., Trichosporon spp., Geotrichum spp.); Aspergillus spp.; Histoplasma spp., Paracocclnoides brasiiiensis; Sporothrix schenckii; Fonsecaea spp.; Cladosporium spp.; Blastomyces dermatitidis; Pseudallescheria boydii; Penicillinum marneffei and various other yeasts and fungi.
 
Candida glabrata and Candida tropicalis are generally the least susceptible Candida species representatives of some isolates showing different resistance to itraconazole in vitro.Osnovnite types of fungi that are not suppressed by itraconazole are Zygomycetes (eg Rhizopus spp., Rhizomucor spp., Mucor spp., and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.In vitro studies have shown that itraconazole violates the synthesis of ergosterol in mycotic cells. Ergosterol, a vital component of the fungal cell membrane. Violation of its synthesis has antifungal effect.
 

Pharmacokinetics

 
General pharmacokinetic characteristics:
 
The pharmacokinetics of itraconazole were studied in healthy subjects, special populations and patients after single and multiple dosing. Basically intarkonazol is well absorbed. Peak plasma concentrations are reached 2 to 5 hours after administration of the oral solution. Itraconazole undergoes greater hepatic metabolism by allowing multiple metabolites. The main metabolite is hydroxy plasma concentrations approximately two times higher than those of the unchanged drug. Terminal half-life of itraconazole is about 17 hours after a single dose and increases to 34 to 42 hours after repeat dosing. The pharmacokinetics of itraconazole is typical non-linear and therefore shows accumulation in plasma after multiple dosing. Steady-state concentrations are reached within 15 days with values of C mah about 0,5 pg / ml, 1,1 pg / m! and 2 pg / mi after oral administration of 100 mg once daily, 200 mg once daily and 200 mg twice daily. After discontinuation of treatment, itraconazole plasma concentrations decreased to almost undetectable levels in 7 days. Itrakonazoloviyat clearance decreases at higher doses due to the mechanism of saturation of its hepatic metabolism. Itraconazole is excreted as inactive metabolites in the urine (- 35%) and feces (~ 54%).
 
Absorption:
 
Itraconazole is rapidly absorbed after oral administration of the oral solution. Peak plasma concentrations are reached within 2 to 5 hours after oral administration. The observed absolute bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when taking the capsules immediately after eating.
 
Distribution:
 
Most of itraconazole in plasma is bound to proteins (99.8%) as the major binding component is albumin (99.6% for hydroxy metabolite). There is also a distinct affinity for lipids. Only 0.2% of the itraconazole in plasma is presented as a free drug. Itraconazole is distributed in large amounts in the body (> 700 L), indicating extensive tissue distribution:
 
Concentration in the lungs, kidneys, liver, bone, stomach, spleen and muscles is two to three times higher than the corresponding concentrations in blood plasma. The ratio of brain / plasma is approximately 1. Keratin distribution in tissues, particularly the skin, is more than four times higher than in plasma.
 
Metabolism:
 
Itraconazole is extensively metabolized in the liver to multiple metabolites. Chief hydroxy metabolite whose antifungal activity in vitro is comparable to itrakonzol. Plasma concentrations of hydroxy are about two times higher than that of itraconazole.
 
In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole.
 
Excretion
 
Itraconazole is excreted as inactive metabolites, 35% in urine for one week and about 54% in the faeces. Renal excretion of the drug initially in quantities of less than 0.03% of the dose, while faecal excretion of nepromenetoto drug varies between 3 and 18% of the dose.
 
Since redistribution of itraconazole keratin tissues is negligible elimination of itraconazole from these tissues is associated with regeneration of the epidermis. Back concentration in plasma concentration of itraconazole in skin is still available in 2 to 4 weeks after cessation of 4 weeks of treatment and itraconazole keratin of the nails can be detected one week after the start of treatment and at least 6 months after 3-month course of treatment.
 
 

 Preclinical safety data

 
 
Itraconazole:
 
Itraconazole has been tested in standard clinical studies on acute toxicity bezopasnost.Prouchvaniyata with itraconazole in mice, rats, guinea pigs and dogs showed wide therapeutic range. Studies on the sub (chronic) toxicity after oral administration in rats and dogs showed multiple target organs or tissues: adrenal cortex, liver and mononuclear phagocyte system and disorders of lipid metabolism presented as ksantomni cells in various organs.
 
Histological examination of the adrenal cortex have shown that high doses of itraconazole causes a reversible increase in cellular hypertrophy zona reticularis and fasciculata, which is sometimes associated with thinning of the zona glomerulosa. At high doses, there are also reversible liver changes. There are small changes of the sinusoidal cells and hepatocytes of vakualizatsiya, subsequently indicator of cellular dysfunction, but without seeing hepatitis or hepatocellular necrosis. Histological changes in the mononuclear phagocyte system is mainly characterized by the presence of macrophages with increased protein material in various parenchymal tissue.
 
No evidence of mutagenic potential of itraconazole.
 
Itraconazole is not a primary carcinogen in rats and mice. In male rats, however, there is a high prevalence of soft tissue sarcoma, which is attributed to the increase in non-neoplastic chronic inflammatory reactions in the connective tissue as a result of elevated levels of cholesterol and holesteroza connective tissue.
 
No evidence of a primary effect on fertility treatment with itraconazole. It was found that high doses of itraconazole causes a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats and mice. Teratogenicity in rats is expressed in large skeletal defects in mice - the encephalocele and makroglosiya.Nablyudavano is an overall reduction in bone density in young dogs after chronic administration of itraconazole.
 
In three toxicology studies in rats, itraconazole causes bone defects. These disabilities include reducing the activity of bone plates, thinning of the zona compacta of the large bones, and increased bone fragility.
 
 

 PHARMACEUTICAL PARTICULARS


 


 excipients

 
Sugar spheres NF Hypromellose 2910 5mPa.s PhEur. Macrogol NFSamata capsule contains titanium dioxide E171, E132 sodium indigotine carmine, gelatin and erythrosine E127.
  
 

incompatibilities

 
None known.
 

 Expiration date

 
Three years.
  

 Special precautions for storage

 
Store at temperatures between 15 ° and 30 ° C. Protect myakto of reach of children.
 

Description and contents of container

 
Orungal a pink and blue capsules containing 100 mg itraconazole as pellets packed in blisters by 4 and 15 capsules.
€ 93.00
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