Apo-Voriconazole

Uses

Aspergillosis, Candida albicans, Candidaemia, Candidemia, Candidiasis, Coccidioidomycosis, Deep tissue candida infections, Disseminated candidiasis, Fungal keratitis, Histoplasmosis, Invasive aspergillosis, Scedosporiosis and fusariosis

Apo-Voriconazole is also used to associated treatment for these conditions: Aspergillosis of the Central Nervous System, Aspergillosis of the Liver, Candidemia, Candidiasis, Coccidioidomycosis, Endocarditis caused by Aspergillus, Esophageal Candidiasis, Fungal meningitis caused by Exserohilum Infection, Fusarium infection, Histoplasmosis, Infections, Fungal, Invasive Aspergillosis, Osteomyelitis caused by Aspergillus, Penicillium marneffei infection, Peritonitis caused by Aspergillus, Scedosporium Infection, Sinusitis aspergillus, Aspergillus endophthalmitis, Disseminated Candidiasis, Refractory Fungal Infections, Refractory Oral Candidiasis

How Apo-Voriconazole works

Apo-Voriconazole is used to treat fungal infections caused by a variety of organisms but including Aspergillus spp. and Candida spp. Apo-Voriconazole is a triazole antifungal exhibiting fungistatic activity against fungal pathogens. Like other triazoles, voriconazole binds to 14-alpha sterol demethylase, also known as CYP51, and inhibits the demethylation of lanosterol as part of the ergosterol synthesis pathway in yeast and other fungi. The lack of sufficient ergosterol disrupts fungal cell membrane function and limits fungal cell growth. With fungal growth limited, the host's immune system is able to clear the invading organism.

Dosage

Apo-Voriconazole dosage

Adult:

• ≥40 kg: 400 mg (10 mL) 12 hrly for the 1st 24 hr, followed by 200 mg (5 mL) 12 hrly, may increase to 300 mg 12 hrly or reduce by decrements of 50 mg if necessary.
• <40 kg: 200 mg (5 mL) 12 hrly for the 1st 24 hr, followed by 100 mg (2.5 mL) 12 hrly, may increase to 150 mg 12 hrly or reduce by decrements of 50 mg if necessary. For oesophageal candidiasis: Treatment should be given for at least 14 days and continued for 7 days after symptoms resolved.

Child

:2-14 yr<50 kg: 9 mg/kg (Max: 350 mg) 12 hrly.

Should be taken on an empty stomach. Take at least 1 hr before or after meals.

Add 46 ml of water to the bottle containing 45 g of voriconazole to provide a susp containing 40 mg/mL. Shake vigorously for about 1 min.

Side Effects

Anaphylactoid reactions (e.g. flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, pruritus, rash). Photosensitivity reactions, skeletal effects e.g. fluorosis, periortitis (in long-term therapy), visual disturbances (e.g. abnormal or blurred vision, color vision change, photophobia), GI effects (nausea, vomiting, diarrhoea, abdominal pain), fever, rash, chills, headache, abnormal LFT result, tachycardia, hallucinations.

Toxicity

Symptoms of overdose include photophobia and possible QTc prolongation. In case of overdose, supportive care and ECG monitoring are recommended. Activated charcoal may aid in the removal of unabsorbed drug. Apo-Voriconazole is cleared by hemodialysis at a rate of 121 mL/min which may be helpful in removing absorbed drug. Carcinogenicity studies found hepatocellular adenomas in female rats at doses of 50 mg/kg and hepatocellular carcinomas found in male rats at doses of 6 and 50 mg/kg. These doses are equivalent to 0.2 and 1.6 times the recommended maintenance dose (RMD). Studies in mice detected hepatocellular carcinomas in males at doses of 100 mg/kg or 1.4 times the RMD. Hepatocellular adenomas were detected in both male and female mice.

Precaution

Patients with potentially proarrhythmic conditions, risk for acute pancreatitis. Correct electrolyte disturbances e.g. hypokalaemia, hypomagnesaemia and hypocalcaemia prior to treatment. Hepatic and renal impairment. Pregnancy and lactation.

Interaction

Increased prothrombin time w/ oral anticoagulants. May increase plasma concentrations of ciclosporin and tacrolimus, long-acting opiates (e.g. oxycodone, methadone), NSAIDs (e.g. ibuprofen, diclofenac), omeprazole, short-acting opiates (e.g. alfentanil, fentanyl). Decreased voriconazole plasma concentration and increased phenytoin plasma concentrations when used concomitantly. May increase plasma concentration with oral contraceptives.

Food Interaction

• Take separate from meals. Take voriconazole at least one hour before or after eating for optimal absorption.

[Moderate] ADJUST DOSING INTERVAL: Food reduces the oral absorption and bioavailability of voriconazole.

According to the product labeling, administration of multiple doses of voriconazole with high-fat meals decreased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) by 34% and 24%, respectively, when the drug is administered as a tablet, and by 58% and 37%, respectively, when administered as the oral suspension.

MANAGEMENT: To ensure maximal oral absorption, voriconazole tablets and oral suspension should be taken at least one hour before or after a meal.

Apo-Voriconazole Drug Interaction

Major: fluticasone / salmeterol, apixaban, escitalopramModerate: esomeprazole, pantoprazole, montelukast, ondansetronMinor: sulfamethoxazole / trimethoprim, sulfamethoxazole / trimethoprimUnknown: lorazepam, diphenhydramine, mycophenolate mofetil, furosemide, metoprolol, acetaminophen, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, cetirizine

Apo-Voriconazole Disease Interaction

Major: hepatotoxicityModerate: QT prolongation, renal dysfunction, risk of pancreatitis

Volume of Distribution

The estimated volume of distribution of voriconazole is 4.6 L/kg . Population pharmacokinetic studies estimate the median volume of distribution to be 77.6 L with the central compartment estimated at 1.07 L/kg Apo-Voriconazole is known to achieve therapeutic concentrations in many tissues including the brain, lungs, liver, spleen, kidneys, and heart.

Elimination Route

The oral bioavailability is estimated to be 96% in healthy adults. Population pharmacokinetic studies report a reduced bioavailability pediatric patients with a mean of 61.8% (range 44.6–64.5%) thought to be due to differences in first-pass metabolism or due to differences in diet . Of note, transplant patients also have reduced bioavailability but this is known to increase with time after transplantation and may be due in part to gastrointestinal upset from surgery and some transplant medications. Tmax is 1-2 hours with oral administration. When administered with a high-fat meal Cmax decreases by 34% and AUC by 24%. pH does not have an effect on absorption of voriconazole. Differences in Cmax and AUC have been observed between healthy adult males and females with Cmax increasing by 83% and AUC by 113% although this has not been observed to significantly impact medication safety profiles.

Half Life

Apo-Voriconazole follows non-linear kinetics and has a terminal half-life of elimination which is dose-dependent.

Clearance

The clearance of voriconazole is estimated to be a mean of 5.25-7 L/h in healthy adults for the linear portion of the drug's kinetics.

Elimination Route

Apo-Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

Hypersensitivity. Co-admin with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine, rifampicin, carbamazepine, long-acting barbiturates (e.g. phenobarbital, mephobarbital), ergot alkaloids (e.g. ergotamine and dihydroergotamine), efavirenz (≥400 mg once daily), ritonavir (≥400 mg bid), sirolimus, rifabutin, St John's wort.

Acute Overdose

Symptom: Photophobia. Management: May remove via haemodialysis.

Storage Condition

Tablet: Store between 15-30° C. Powd for oral susp: Store between 2-8°C. Reconstituted oral susp: Store between 15-30° C (do not refrigerate or freeze), stable for up to 14 days.

Innovators Monograph

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