Voriole

Voriconazole.

VORIOLE 50: Each film coated tablet contains Voriconazole Ph. Eur. 50 mg.
VORIOLE 200: Each film coated tablet contains Voriconazole Ph. Eur. 200 mg.
Product contains Lactose.
Excipients/Inactive Ingredients: Lactose monohydrate, Pregelatinised starch, Croscarmellose sodium, Povidone & magnesium stearate.
Coating: Hypromellose, Titanium dioxide and Triacetin.

Pharmacology: Mechanism of Action: Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.
Pharmacokinetics: Absorption: Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is estimated to be 96 %. Bioequivalence was established between the 200 mg tablets and the 40mg/ml oral suspension when administered as a 200 mg dose. When multiple doses of voriconazole are administered with high fat meals, C_max and AUCτ are reduced by 34 % and 24 %, respectively. The absorption of voriconazole is not affected by changes in gastric pH.
Distribution: The volume of distribution at steady state for voriconazole is estimated to be 4.6 l/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58 %. Cerebrospinal fluid samples from eight patients in a compassionate programme showed detectable voriconazole concentrations in all patients.
Biotransformation: In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. The inter-individual variability of voriconazole pharmacokinetics is high.
In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15-20 % of Asian populations may be expected to be poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5 %. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher voriconazole exposure (AUCτ) than their homozygous extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser counterparts.
The major metabolite of voriconazole is the N-oxide, which accounts for 72 % of the circulating radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.
Elimination: Voriconazole is eliminated via hepatic metabolism with less than 2 % of the dose excreted unchanged in the urine.
After administration of a radiolabelled dose of voriconazole, approximately 80 % of the radioactivity is recovered in the urine after multiple intravenous dosing and 83 % in the urine after multiple oral dosing. The majority (> 94 %) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.
The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.
Special Populations: Gender: In an oral multiple dose study, C_max and AUCτ for healthy young females were 83 % and 113 % higher, respectively, than in healthy young males (18-45 years). In the same study, no significant differences in C_max and AUCτ were observed between healthy elderly males and healthy elderly females (≥ 65 years).
In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustment based on gender is necessary.
Elderly: In an oral multiple dose study C_max and AUCτ in healthy elderly males (≥ 65 years) were 61 % and 86 % higher, respectively, than in healthy young males (18-45 years). No significant differences in C_max and AUCτ were observed between healthy elderly females (≥ 65 years) and healthy young females (18-45 years).
In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly.
Paediatric: The recommended doses in children and adolescent patients are based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised paediatric patients aged 2 to <12 years and 26 immunocompromised adolescent patients aged 12 to <17 years. Multiple intravenous doses of 3, 4, 6, 7 and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6 mg/kg, and 200 mg twice daily were evaluated in 3 paediatric pharmacokinetic studies. Intravenous loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and 300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-subject variability was observed in paediatric patients compared to adults.
A comparison of the paediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUCτ) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
The higher intravenous maintenance dose in paediatric patients relative to adults reflects the higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in paediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended.
Voriconazole exposures in the majority of adolescent patients were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some young adolescents with low body weight compared to adults. It is likely that these subjects may metabolize voriconazole more similarly to children than to adults. Based on the population pharmacokinetic analysis, 12- to 14-year-old adolescents weighing less than 50 kg should receive children's doses.
Renal impairment: Film-coated tablets: In an oral single dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41-60 ml/min) to severe (creatinine clearance <20 ml/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment.
Hepatic impairment: After an oral single dose (200 mg), AUC was 233 % higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired hepatic function.
In an oral multiple dose study, AUCτ was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C).

Voriconazole is a broad spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows: Treatment of invasive aspergillosis.
Treatment of candidaemia in non-neutropenic patients.
Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).
Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp., or invasive fluconazole-resistant Candida spp. (including C. krusei).
Voriconazole should be administered primarily to patients with progressive, possibly life-threatening infections.
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy.

RECOMMENDED DOSING SCHEDULE: Adults and a subgroup of adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight): Therapy must be initiated with the specified loading dose regimen of either intravenous or oral Voriconazole to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of the high oral bioavailability (96 %), switching between intravenous and oral administration is appropriate when clinically indicated.
Adult: over 18 years, body weight over 40 kg, 400 mg every 12 hours for 2 doses then 200 mg every 12 hours, increased if necessary to 300 mg every 12 hours; body weight over 40 kg, 200 mg every 12 hours for 2 doses then 100 mg every 12 hours, increased if necessary to 150 mg every 12 hours.
Detailed information on dosage recommendations is provided in the following table: See Table 1.

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Dosage adjustment: Film-coated tablets: If patient response is inadequate, the maintenance dose may be increased to 300 mg twice daily for oral administration. For patients less than 40 kg the oral dose may be increased to 150 mg twice daily.
If patients are unable to tolerate treatment at these higher doses reduce the oral dose by 50 mg steps to the 200 mg twice daily (or 100 mg twice daily for patients less than 40 kg) maintenance dose.
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg).
The combination of voriconazole with rifabutin should, if possible be avoided. However, if the combination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg).
Efavirenz may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored.
Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg): The recommended dosing regimen is as follows: See Table 2.

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Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatric patients aged 2 to <12 years and 26 immunocompromised adolescents aged 12 to <17 years.
It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
These oral dose recommendations for children are based on studies in which Voriconazole was administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit time in paediatrics, the absorption of tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2-<12.
Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied.
Dose adjustment: If patient response is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patients are unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).
Duration of treatment: Treatment should be as short as possible depending on the patients' clinical and mycological response.
For long term treatment greater than 6 months. a careful assessment of the benefit-risk balance should be considered.
The duration of treatment with the intravenous formulation should be no longer than 6 months. For voriconazole in general, long term treatment greater than 6 months requires careful assessment of the benefit-risk balance.
Elderly: No dose adjustment is necessary for elderly patients.
Renal impairment: Film-coated tablets: The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment.
Voriconazole is haemodialysed with a clearance of 121 ml/min. A four hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.
Hepatic impairment: It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving voriconazole.
Voriconazole has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).
There is limited data on the safety of Voriconazole in patients with abnormal Liver Function Tests (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (AP), or total bilirubin >5 times the upper limit of normal).
Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic impairment must be carefully monitored for drug toxicity.
Paediatric population: The safety and efficacy of Voriconazole in children below 2 years has not been established.
Method of administration: Voriconazole film-coated tablets are to be taken at least one hour before, or one hour following, a meal.

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported.
There is no known antidote to voriconazole.

Hypersensitivity to the active substance or to any of the excipients used in manufacture of Drug Product.
Co-administration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes.
Co-administration with rifampicin, carbamazepine and phenobarbital since these medicinal products are likely to decrease plasma voriconazole concentrations significantly.
Coadministration with high dose efavirenz (400 mg and above once daily) because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at this dose.
Co-administration with high dose ritonavir (400 mg and above twice daily) because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects at this dose.
Co-administration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, since increased plasma concentrations of these medicinal products can lead to ergotism.
Co-administration with sirolimus, since voriconazole is likely to increase plasma concentrations of sirolimus significantly.
Coadministration with St John's Wort.
Acute porphyria.
Hepatic impairment: in mild to moderate hepatic cirrhosis use usual initial dose then halve subsequent doses; no information available for severe hepatic cirrhosis - manufacturer advises use only if potential benefit outweighs risk.
Renal impairment: intravenous vehicle may accumulate if eGFR less than 50 ml/minute/1.73 m² - use intravenous infusion only if potential benefit outweighs risk, and monitor renal function; alternatively, use tablets or oral suspension (no dose adjustment required).

Electrolyte disturbances, cardiomyopathy, bradycardia, symptomatic arrhythmias, history of QT interval prolongation, concomitant use with other drugs that prolong QT interval; avoid exposure to sunlight; patients at risk of pancreatitis; monitor renal function.

Nausea, vomiting, abdominal pain, diarrhoea, jaundice, oedema, hypotension, respiratory distress syndrome, sinusitis headache, chest pain, dizziness, asthenia, anxiety, depression, confusion, agitation, hallucinations, paraesthesia, tremor, influenza-like symptoms, hypoglycaemia, haematuria, blood disorders (including anaemia, thrombocytopenia, leucopenia, pancytopenia), acute renal failure, hypokalaemia, visual disturbances (including altered perception, blurred vision, and photophobia), rash, pruritus, photosensitivity, alopecia, cheilitis, injection-site reactions.
Less commonly: dyspepsia, duodenitis, cholecystitis, pancreatitis, hepatitis, constipation, arrhythmias, syncope, raised serum cholesterol, hypersensitivity reactions (including flushing), ataxia, nystagmus, hypoaesthesia, adrenocortical insufficiency, arthritis, blepharitis, optic neuritis, scleritis, glossitis, gingivitis, psoriasis, Stevens-Johnson syndrome.
Rarely: pseudomembranous colitis, taste disturbances (more common with oral suspensions), convulsions, insomnia, tinnitus, hearing disturbances, extrapyramidal effects, hypertonia, hypothyroidism, hyperthyroidism, discoid lupus erythematosus, toxic epidermal necrolysis, pseudoporphyria, retinal haemorrhage, optic atrophy, also reported squamous cell carcinoma of skin (particularly in presence of phototoxicity or in the immunosuppressed).

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes.
Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID). These results are relevant to other populations and routes of administration.
Voriconazole should be administered with caution in patients with concomitant medication that is known to prolong QT interval.
When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide) co-administration is contraindicated.
Interaction table: Interactions between voriconazole and other medicinal products are listed in the table as follows (once daily as "QD", twice daily as "BID", three times daily as "TID" and not determined as "ND"). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range.
The asterisk (*) indicates a two-way interaction. AUCτ, AUC_t and AUC_0-∞ represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively.
The interactions in the table are presented in the following order: contraindications, those requiring dose adjustment and careful clinical and/or biological monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field. (See Tables 3a and 3b.)

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Do not store above 30°C. Protect from light and moisture.

Antifungals

J02AC03 - voriconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

POM

FC tab 50 mg x 10's. 200 mg x 10's.