Voriconazole

Voriconazole is an antifungal agent belonging to the pharmacological class of Imidazoles.

Voriconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Blastomycosis, Candidiasis, treatment, Coccidioidomycosis, refractory to conventional therapy, Fusariosis, Neutropenic fever, Prophylaxis against invasive fungal infections, Scedosporiosis, Talaromycosis.

Voriconazole, an antifungal medication, is well-absorbed orally with a bioavailability of approximately 96% in healthy adults. Voriconazole exhibits good tissue distribution, reaching therapeutic levels in various tissues. It is primarily bound to plasma proteins at 58%. Hepatic metabolism, involving CYP2C9, CYP2C19, and CYP3A4, is responsible for its breakdown into metabolites, and elimination occurs mainly through hepatic metabolism, with less than 2% of the unchanged drug excreted in the urine.

The common side effects involved in using Voriconazole are Changes in vision., Skin rash., Headache and hallucinations, Rapid heart rate., Nausea and vomiting , Abnormal liver function test results.

Voriconazole is available in the form of Tablets, Oral suspensions, Intravenous Injection.

Voriconazole is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Voriconazole belonging to the pharmacological class of Imidazoles acts as an antifungal agent.

Voriconazole is an antifungal medication used to treat fungal infections caused by various organisms, including Aspergillus spp. and Candida spp. It belongs to the triazole class of antifungals and exerts its effect by inhibiting the activity of 14-alpha sterol demethylase, also known as CYP51. This enzyme is essential for the synthesis of ergosterol, a critical component of the fungal cell membrane. By blocking the demethylation of lanosterol, a precursor of ergosterol, voriconazole disrupts the formation of functional fungal cell membranes, leading to the inhibition of fungal growth. As a result, the immune system of the host is better able to eliminate the invading fungal pathogens.

Voriconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Blastomycosis, Candidiasis, treatment, Coccidioidomycosis, refractory to conventional therapy, Fusariosis, Neutropenic fever, Prophylaxis against invasive fungal infections, Scedosporiosis, Talaromycosis.

The maximum concentration (Tmax) of Voriconazole in the blood is achieved within 1-2 hours after oral administration. Co-administration with a high-fat meal decreases Cmax by 34% and AUC by 24%.

Voriconazole is found to be available in the form of Tablets, Oral suspensions, Intravenous Injection.

Voriconazole can be used in the following treatment:

• Aspergillosis
• Blastomycosis
• Candidiasis, treatment
• Coccidioidomycosis, refractory to conventional therapy
• Fusariosis
• Neutropenic fever
• Prophylaxis against invasive fungal infections
• Scedosporiosis
• Talaromycosis

Voriconazole can help to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Blastomycosis, Candidiasis, treatment, Coccidioidomycosis, refractory to conventional therapy, Fusariosis, Neutropenic fever, Prophylaxis against invasive fungal infections, Scedosporiosis, Talaromycosis.

Voriconazole is approved for use in the following clinical indications:

• Aspergillosis
• Blastomycosis
• Candidiasis, treatment
• Coccidioidomycosis, refractory to conventional therapy
• Fusariosis
• Neutropenic fever
• Prophylaxis against invasive fungal infections
• Scedosporiosis
• Talaromycosis

• Aspergillosis
• Allergic Bronchopulmonary (Alternative Agent):
• Oral: 200 mg twice daily for ≥16 weeks in combination with systemic corticosteroids. A loading dose of 400 mg twice daily for the first 2 doses may be given if needed.
• Chronic Cavitary Pulmonary:
• IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily.
• Oral: 200 mg twice daily, which may be increased to 300 mg twice daily based on therapeutic drug monitoring.
• Duration: ≥6 months; some patients require prolonged, potentially lifelong therapy.
• Invasive (including Disseminated and Extrapulmonary):
• IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily. Consider transitioning to the oral formulation once the patient can tolerate it.
• Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily).
• Duration: Minimum of 6 to 12 weeks, with the possibility of more prolonged treatment for immunosuppressed patients.
• Ocular (Off-label Use) - Endophthalmitis:
• Administer a combination of both intraocular and systemic antifungal therapy.
• Intravitreal Injection: 100 mcg per 0.1 mL (sterile water or NS) intravitreally once, repeat if necessary.
• Intracameral Injection: 50 mcg to 100 mcg per 0.1 mL (sterile water or NS) administered intracamerally (into the aqueous) once.
• Systemic: IV and Oral: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily.
• Ophthalmic: Instill 1% ophthalmic solution topically to the affected eye(s) every 1 hour initially, then adjust dosing based on response.

• Blastomycosis (Off-label Use):
• IV: 6 mg/kg twice daily for 2 doses, then 3 mg/kg twice daily.
• Oral: 200 to 400 mg twice daily.
• Duration: 6 to 12 months; ≥12 months recommended for severe cases and immunocompromised patients.

• Candidiasis, Treatment:
• Candidemia (Neutropenic and Non-neutropenic Patients) - Including Disseminated Candidiasis (Alternative Agent):
• IV: 400 mg twice daily for 2 doses, then 200 to 300 mg IV or orally twice daily or weight-based dosing (6 mg/kg IV twice daily for 2 doses, then 3 to 4 mg/kg IV or orally twice daily).
• Step-down Therapy (Clinically Stable Patients with Negative Repeat Cultures): Oral: 200 mg twice daily; for susceptible Candida glabrata, use 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily).
• Duration: ≥14 days after the first negative blood culture and resolution of signs/symptoms; longer for metastatic complications.
• Cardiac Infection, Native or Prosthetic Valve Endocarditis or Device Infection (Off-label Use):
• Step-down Therapy (Clinically Stable, Blood Culture–Negative Patients Following Initial Non-azole Parenteral Therapy): Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily).
• Duration: Varies based on the type of infection.
• Endophthalmitis (with or without Vitritis) (Off-label Use):
• Administer a combination of intraocular and systemic antifungal therapy.
• Intravitreal Injection: 100 mcg per 0.1 mL (sterile water or NS) intravitreally once.
• Intracameral Injection: 50 mcg per 0.1 mL (sterile water or NS) intracamerally once.
• Ophthalmic: Topical application of 1% ophthalmic solution to the affected eye(s) every 1 hour.
• Systemic: IV and Oral: 400 mg twice daily for 2 doses, then 200 to 300 mg twice daily or weight-based dosing (6 mg/kg twice daily for 2 doses, then 3 to 4 mg/kg twice daily).

• Coccidioidomycosis, Refractory to Conventional Therapy (Off-label Use):
• Nonmeningeal Infection (e.g., Bone and/or Joint Infection, Pulmonary Infection in Select Patients):
• Oral: 400 mg twice daily for 2 doses, then 200 mg twice daily.
• Duration: Varies based on the site and severity of infection and the patient's immune status.
• Meningitis:
• Oral: 400 mg twice daily for 2 doses, followed by 200 to 400 mg twice daily.
• Duration: Lifelong therapy due to high relapse rate.

• Fusariosis (Alternative Agent):
• Invasive:
• IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily.
• Oral: 200 mg twice daily following improvement with initial IV therapy.
• Duration: Prolonged and varies based on clinical response and patient immune status.
• Keratitis:
• Ophthalmic: Topical application of 1% ophthalmic solution to the affected eye(s) every 1 hour, with dosing interval adjustment based on response.
• Duration: Several months are often warranted.

• Neutropenic Fever (Empiric Antifungal Therapy) (Alternative Agent) (Off-label Use):
• IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily.
• Oral: 200 to 300 mg twice daily or weight-based dosing (3 to 4 mg/kg twice daily).
• Prophylaxis Against Invasive Fungal Infections (Alternative Agent) (Off-label Use):
• Hematologic Malignancy or Post-Hematopoietic Cell Transplant:
• IV: 4 mg/kg twice daily.
• Oral: 200 mg twice daily.
• Solid Organ Transplant:
• IV: 4 mg/kg twice daily; may give a loading dose of 6 mg/kg twice daily for the first 2 doses.
• Oral: 200 mg twice daily; may give a loading dose of 400 mg twice daily for the first 2 doses.

• Scedosporiosis:
• IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily.
• Oral: 400 mg twice daily for 2 doses, then 200 to 300 mg twice daily.
• Duration: Often prolonged and varies based on clinical response and patient immune status.

• Talaromycosis (Formerly Penicilliosis) (Alternative Agent) (Off-label Use):
• Treatment, Mild Disease (Skin Lesions Without Bloodstream Infection):
• Oral: 400 mg twice daily for 2 doses, then 200 mg twice daily for 12 weeks, followed by long-term suppression therapy.
• Treatment, Moderate to Severe Disease:
• Induction Therapy: IV: 6 mg/kg twice daily for 2 doses, then 4 mg/kg twice daily for at least 3 days. Oral: 200 mg twice daily for a total of 12 weeks.
• If Oral Therapy Used for Induction: Give 600 mg twice daily for 2 doses, then 400 mg twice daily for 2 weeks, then 200 mg twice daily for 10 weeks. Continue with long-term suppression therapy after either regimen.
• Long-term Suppression Therapy (Secondary Prophylaxis):
• Oral: 200 mg twice daily until cellular immunity is restored for patients with HIV (when CD4 count >100 cells/mm3 and virologic suppression with antiretroviral therapy is sustained for ≥6 months).

Voriconazole is available in the following dosage forms and strengths:

• Oral Suspension: The oral suspension contains 200mg of voriconazole per 5mL of liquid.
• Injection, Powder for Reconstitution: The injection form comes as a powder that needs to be reconstituted before use. Each reconstituted dose contains 200mg of voriconazole.
• Tablets: Voriconazole is also available in tablet form, with options of 50mg and 200mg strengths.

Tablets, Oral suspensions, Intravenous Injection.

Dosage Adjustments in Kidney Patients:

Renal impairment (CrCl <50 mL/min): The oral form should be used for maintenance; avoid intravenous (IV) administration due to the potential accumulation of the IV vehicle (SBECD).

Dosage Adjustments in Hepatic Impairment Patients:

Hepatic impairment:

• Mild-moderate (Child-Pugh A or B): Administer the standard loading dose, but reduce the maintenance dose by 50%.
• Severe (Child-Pugh C): There are no available data for dosing in severe hepatic impairment.
• Hepatitis B or C: There are no available data for dosing in patients with hepatitis B or C.

Inadequate response:

• Increase the oral maintenance dose from 200 mg every 12 hours to 300 mg every 12 hours.
• For patients weighing less than 40 kg: Increase the oral maintenance dose from 100 mg every 12 hours to 150 mg every 12 hours.

Dosage Adjustments in Pediatric Patients:

• Aspergillosis, Invasive, including Disseminated and Extrapulmonary Infection; Treatment:
• Oral Suspension: 8 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Tablets: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Candidiasis, Prophylaxis for Patients at High Risk of Invasive Candidiasis:
• Oral Suspension: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Tablets: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Candidiasis, Invasive; Treatment:
• Oral Suspension: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Tablets: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Candidiasis, Endocarditis/Implantable Cardiac Devices; Treatment:
• Oral Suspension: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Tablets: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Candidiasis, Esophageal, Treatment:
• Oral Suspension: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Tablets: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Candidiasis, Oropharyngeal, Fluconazole-Refractory; Treatment:
• Oral Suspension: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Tablets: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Candidiasis, Endophthalmitis, Voriconazole-Susceptible Isolates:
• Oral Suspension: 8 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Tablets: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Scedosporiosis, Fusariosis; Treatment:
• Oral Suspension: 8 mg/kg (up to a maximum of 350 mg) every 12 hours.
• Tablets: 9 mg/kg (up to a maximum of 350 mg) every 12 hours.

When taking Voriconazole, there are certain dietary restrictions that should be followed to ensure the medication's effectiveness and safety:

• Grapefruit and Grapefruit Juice: Avoid consuming grapefruit or grapefruit juice while taking voriconazole. Grapefruit can inhibit the activity of certain enzymes in the liver, leading to increased levels of voriconazole in the blood, which may result in adverse effects or reduced drug efficacy.
• High-Fat Meals: Taking voriconazole with high-fat meals may affect its absorption and reduce its effectiveness. It is recommended to take voriconazole on an empty stomach or with a light meal for optimal absorption and therapeutic effect.
• Caffeinated Beverages: Some individuals may experience increased nervousness or jitteriness when consuming caffeine while taking voriconazole. It is advisable to monitor caffeine intake and adjust as needed to minimize any adverse effects.
• Certain Foods with Tyramine: Voriconazole may interact with foods that contain tyramine, such as aged cheeses, cured meats, and fermented foods. This interaction can lead to an increase in blood pressure, which may be hazardous for individuals with certain medical conditions.
• Vitamin K-Rich Foods: If taking voriconazole and anticoagulant medications (e.g., warfarin), avoid making significant changes in vitamin K intake from green leafy vegetables and other vitamin K-rich foods. Consistent vitamin K intake helps maintain stable anticoagulant therapy.
• Antacids and Acid-Reducing Agents: Taking voriconazole with certain antacids or acid-reducing medications may reduce its absorption. If antacids are needed, take them at least two hours before or after voriconazole.

The dietary restriction should be individualized as per patient requirements.

Voriconazole may be contraindicated under the following conditions:

• Hypersensitivity Contraindication: Voriconazole is not recommended for patients with known hypersensitivity to voriconazole or its excipients. There is limited information regarding cross-sensitivity between Voriconazole (voriconazole) and other azole antifungal agents. Caution should be exercised when prescribing Voriconazole to patients with hypersensitivity to other azoles.

• Drug Interaction Contraindications:

a. Pimozide, quinidine, or ivabradine: Co-administration of Voriconazole with these drugs is contraindicated due to the potential for increased plasma concentrations, leading to QT prolongation and rare occurrences of torsade de pointes.

b. Sirolimus: Voriconazole should not be co-administered with sirolimus as it significantly increases sirolimus concentrations.

c. Rifampin, carbamazepine, long-acting barbiturates, and St. John's Wort: Concomitant use of Voriconazole with these drugs is contraindicated as they are likely to significantly decrease plasma voriconazole concentrations.

d. Efavirenz (doses of 400 mg every 24 hours or higher): Standard doses of voriconazole with high-dose efavirenz are contraindicated as efavirenz significantly reduces plasma voriconazole concentrations. Voriconazole, in turn, increases efavirenz plasma concentrations.

e. Ritonavir (high-dose 400 mg every 12 hours): Voriconazole should not be co-administered with high-dose ritonavir as it significantly decreases plasma voriconazole concentrations. Low-dose ritonavir (100 mg every 12 hours) co-administration should be avoided unless there is a benefit/risk assessment justifying the use of voriconazole.

f. Rifabutin: Voriconazole and rifabutin should not be co-administered since Voriconazole increases rifabutin plasma concentrations, and rifabutin decreases voriconazole plasma concentrations.

g. Ergot alkaloids (ergotamine and dihydroergotamine): Voriconazole should not be used in conjunction with ergot alkaloids as it may increase their plasma concentrations, leading to ergotism.

h. Naloxegol: Voriconazole and naloxegol should not be co-administered as Voriconazole may increase naloxegol plasma concentrations, potentially precipitating opioid withdrawal symptoms.

i. Tolvaptan: Co-administration of Voriconazole with tolvaptan is contraindicated because it may increase tolvaptan plasma concentrations and raise the risk of adverse reactions.

j. Venetoclax at initiation and ramp-up phase: Voriconazole should not be co-administered with venetoclax in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) due to the potential for an increased risk of tumour lysis syndrome.

k. Lurasidone: Voriconazole should not be co-administered with lurasidone as it may result in significant increases in lurasidone exposure and pose the risk of serious adverse reactions.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

Hepatic Toxicity

• Serious Hepatic Reactions: Uncommon cases of serious hepatic reactions, including clinical hepatitis, cholestasis, and fulminant hepatic failure (including fatalities), have been reported during Voriconazole treatment. These reactions are more likely to occur in patients with serious underlying medical conditions, particularly haematological malignancy. Some cases have occurred in patients without other identifiable risk factors. Liver dysfunction is usually reversible upon discontinuation of therapy.
• Pediatric Population: The pediatric population may experience a higher frequency of liver enzyme elevations during Voriconazole treatment. Hepatic function should be monitored in both adult and pediatric patients.

Arrhythmias and QT Prolongation

• QT Interval Prolongation: Voriconazole, like some other azoles, may prolong the QT interval on electrocardiograms. Rare cases of arrhythmias, including ventricular arrhythmias such as torsade de pointes, cardiac arrests, and sudden deaths, have been reported in patients taking voriconazole. These cases typically involve seriously ill patients with multiple risk factors, such as cardiotoxic chemotherapy history, cardiomyopathy, hypokalemia, and concurrent medications known to prolong the QT interval.
• Cautionary Use: Patients with conditions that can potentially cause irregular heartbeats, such as congenital or acquired QT prolongation, cardiomyopathy (especially with heart failure), sinus bradycardia, and those taking medications known to prolong the QT interval, should be cautious when taking Voriconazole. It is important to correct potassium, magnesium, and calcium levels before and during the course of Voriconazole therapy.

Infusion-Related Reactions

• Anaphylactoid-Type Reactions: Uncommonly, anaphylactoid-type reactions may occur during the intravenous Voriconazole infusion. These reactions include flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, and rash. If such reactions occur, consider stopping the infusion.

Visual Disturbances

• Prolonged Visual Adverse Reactions: The effect of Voriconazole on visual function is uncertain if treatment exceeds 28 days. Postmarketing reports indicate prolonged visual adverse reactions, including optic neuritis and papilledema. If treatment continues beyond 28 days, monitor visual function, including visual acuity, visual field, and colour perception.

Severe Cutaneous Adverse Reactions

• It is important to be aware that using Voriconazole may lead to severe cutaneous adverse reactions (SCARs) like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), as well as drug reaction with eosinophilia and systemic symptoms (DRESS). These reactions can be very serious and even life-threatening. If you experience a severe cutaneous adverse reaction while using Voriconazole, it is recommended to discontinue use immediately.

Photosensitivity

• Photosensitivity Skin Reaction: Voriconazole has been linked to photosensitivity skin reactions. Patients, including pediatric patients, should avoid direct sunlight during Voriconazole treatment and use protective measures like clothing and high-SPF sunscreen. If phototoxic reactions occur, consider Voriconazole discontinuation.

Renal Toxicity

• Acute Renal Failure: Acute renal failure has been observed in Voriconazole-treated patients, especially those receiving concomitant nephrotoxic medications or having conditions affecting renal function. Monitor renal function during Voriconazole treatment.

Adrenal Dysfunction

• Azole-Induced Adrenal Insufficiency: Reversible cases of azole-induced adrenal insufficiency, including Cushing's syndrome, have been reported with Voriconazole use. Patients receiving Voriconazole and corticosteroids should be closely monitored for adrenal dysfunction.

Embryo-Fetal Toxicity

• Potential Fetal Harm: Voriconazole can cause fetal harm if administered to pregnant women. Inform patients of the potential risk to the fetus, and advise females of reproductive potential to use effective contraception during Voriconazole treatment.

Laboratory Tests

• Electrolyte Disturbances: Correct electrolyte disturbances like hypokalemia, hypomagnesemia, and hypocalcemia before and during Voriconazole therapy. Monitor renal and hepatic function through laboratory evaluation.

Pancreatitis

• Risk of Pancreatitis: Voriconazole-treated patients with risk factors for acute pancreatitis should be monitored for the development of pancreatitis during treatment.

Skeletal Adverse Reactions

• Fluorosis and Periostitis: Long-term Voriconazole therapy has been associated with fluorosis and periostitis. Discontinue Voriconazole if a patient develops skeletal pain and radiologic findings consistent with these conditions.

Clinically Significant Drug Interactions

• Drug Interactions: Voriconazole may interact with other medications, significantly altering their concentrations or pharmacokinetics/pharmacodynamics.

Galactose Intolerance

Lactose Content: Voriconazole tablets contain lactose and should not be given to patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Avoid or limit alcohol consumption while on voriconazole treatment. Alcohol may interact with voriconazole, leading to an increased risk of side effects, liver damage, or reduced drug efficacy.

There is currently no available data on the presence of voriconazole in human milk or its effects on breastfed infants or milk production. Therefore, it is important to consider the developmental and health advantages of breastfeeding, taking into account the mother's clinical requirement for Voriconazole and the potential adverse effects it may have on the breastfed child or the underlying maternal condition.

Pregnancy:

Pregnancy Category D

Women of childbearing potential should consistently use effective contraception while undergoing treatment with voriconazole.

Adequate and well-controlled studies in pregnant women are not available for voriconazole. However, it is known to cause harm to the fetus when administered to pregnant women. Therefore, if this medication is used during pregnancy or if a patient becomes pregnant while taking it, they should be informed about the potential risk to the fetus. Voriconazole should not be used during pregnancy unless the benefits to the mother clearly outweigh the potential risks to the fetus.

Reproduction studies conducted in rats have shown that voriconazole is teratogenic (causing cleft palate, hydronephrosis, and hydroureter) at doses of 10 mg/kg or higher, which corresponds to approximately 0.3 times the human exposure based on body surface area comparisons. In pregnant rats, plasma estradiol was reduced at all dose levels of voriconazole. Treatment with voriconazole in rats also led to increased gestational length and dystocia, which was associated with an increased perinatal pup mortality at the 10 mg/kg dose. In rabbits, voriconazole increased embryo lethality and reduced fetal weight.

Grapefruit and Grapefruit Juice: Avoid consuming grapefruit or grapefruit juice while taking voriconazole. Grapefruit can inhibit the activity of certain enzymes in the liver, leading to increased levels of voriconazole in the blood, which may result in adverse effects or reduced drug efficacy.

High-Fat Meals: Taking voriconazole with high-fat meals may affect its absorption and reduce its effectiveness. It is recommended to take voriconazole on an empty stomach or with a light meal for optimal absorption and therapeutic effect.

Alcohol: Avoid or limit alcohol consumption while on voriconazole treatment. Alcohol may interact with voriconazole, leading to an increased risk of side effects, liver damage, or reduced drug efficacy.

Caffeinated Beverages: Some individuals may experience increased nervousness or jitteriness when consuming caffeine while taking voriconazole. It is advisable to monitor caffeine intake and adjust as needed to minimize any adverse effects.

Certain Foods with Tyramine: Voriconazole may interact with foods that contain tyramine, such as aged cheeses, cured meats, and fermented foods. This interaction can lead to an increase in blood pressure, which may be hazardous for individuals with certain medical conditions.

Vitamin K-Rich Foods: If taking voriconazole and anticoagulant medications (e.g., warfarin), avoid making significant changes in vitamin K intake from green leafy vegetables and other vitamin K-rich foods. Consistent vitamin K intake helps maintain stable anticoagulant therapy.

Antacids and Acid-Reducing Agents: Taking voriconazole with certain antacids or acid-reducing medications may reduce its absorption. If antacids are needed, take them at least two hours before or after voriconazole.

The adverse reactions related to Voriconazole can be categorized as follows:

More Common:

• Difficulty seeing at night
• Fever
• Increased sensitivity of the eyes to sunlight
• Itching, rash
• Joint or muscle pain
• Trouble breathing
• Unusual bleeding or bruising
• Unusual tiredness or weakness
• Painful or difficult urination
• Red irritated eyes
• Black, tarry stools
• Blistering, peeling, loosening of the skin
• Chest pain
• Chills
• Cough
• Diarrhea
• Red skin lesions, often with a purple centre
• Sores, ulcers, or white spots on the lips or in the mouth
• Swollen glands
• Vision changes

Less Common:

• Confusion
• Dark urine
• Decreased urine output
• Dizziness
• Dry mouth
• Faintness or lightheadedness when standing up suddenly from a lying or sitting position
• Feeling of warmth
• Redness of the face, neck, arms, and occasionally, the upper chest
• Scaling, redness, burning, pain, or other signs of inflammation of the lips
• Increased thirst
• Irregular or pounding heartbeat
• Loss of appetite
• Muscle pain or cramps
• Muscle spasms or twitching
• Rash with flat lesions or small raised lesions on the skin

Rare:

• Irritability
• Redness or other discolouration of the skin
• Agitation
• Blistering, peeling, or loosening of the skin
• Hostility or anger
• Increased sensitivity of the skin to sunlight
• Seeing things that are not there
• Severe sunburn

The clinically relevant drug interactions of Voriconazole are briefly summarized here:

Effects of Other Drugs on Voriconazole

• Voriconazole Metabolism by Hepatic Cytochrome P450 Enzymes

Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP3A4. Studies show that voriconazole has the highest affinity for CYP2C19, followed by CYP2C9, and a lower affinity for CYP3A4. Drugs that inhibit or induce these enzymes may respectively increase or decrease voriconazole systemic exposure (plasma concentrations).

Contraindicated Concomitant Administration

• Rifampin (Potent CYP450 Inducer): Co-administration of voriconazole with rifampin resulted in a significant reduction (approximately 93% and 96%) in steady state Cmax and AUCτ of voriconazole, making this combination contraindicated.
• Ritonavir (Potent CYP450 Inducer and Inhibitor): Co-administration of high-dose (400 mg) and low-dose (100 mg) ritonavir with voriconazole decreased its steady-state Cmax and AUCτ, leading to contraindication for high-dose and caution for low-dose co-administration.
• St. John's Wort (CYP450 Inducer): Voriconazole exposure decreased by 59% when co-administered with St. John's Wort, necessitating contraindication due to long-term use of St. John's Wort, leading to reduced voriconazole exposure.
• Carbamazepine and Long-Acting Barbiturates (Potent CYP450 Inducers): Although not studied in vitro or in vivo, it is expected that co-administration of voriconazole with carbamazepine or long-acting barbiturates significantly reduces plasma voriconazole concentrations, hence, contraindicated.

Significant Drug Interactions Requiring Dosage Adjustment

• Fluconazole (CYP2C9, CYP2C19, and CYP3A4 Inhibitor): Co-administration of voriconazole and fluconazole resulted in an increase in voriconazole exposure; caution is advised when using these drugs sequentially.

Minor or No Significant Pharmacokinetic Interactions

• Cimetidine (Non-Specific CYP450 Inhibitor): Co-administration of cimetidine slightly increased voriconazole exposure.
• Ranitidine (Increases Gastric pH): No significant effect on voriconazole exposure when co-administered with ranitidine.
• Macrolide Antibiotics: Erythromycin or azithromycin co-administered with voriconazole had no significant effect on voriconazole exposure.
• Effects of Voriconazole on Other Drugs

Voriconazole inhibits CYP2C19, CYP2C9, and CYP3A4 in vitro, with less inhibition potency for CYP3A4 compared to other azoles like ketoconazole and itraconazole. The major metabolite of voriconazole, voriconazole N-oxide, inhibits CYP2C9 and CYP3A4 to a greater extent than CYP2C19. This potential inhibition may increase the systemic exposure of drugs metabolized by these enzymes.

Coadministration of Voriconazole and Drugs with Increased Systemic Exposure (Contraindicated)

• Sirolimus (CYP3A4 Substrate): Coadministration of voriconazole significantly increased sirolimus exposure, making this combination contraindicated.
• Terfenadine, Astemizole, Cisapride, Pimozide, and Quinidine (CYP3A4 Substrates): Although not studied in vitro or in vivo, coadministration of voriconazole with these drugs may inhibit their metabolism, leading to increased plasma concentrations and potential QT prolongation and torsade de pointes. Therefore, this combination is contraindicated.
• Ergot Alkaloids: Although not studied in vitro or in vivo, voriconazole may increase plasma concentrations of ergot alkaloids, leading to ergotism. Hence, coadministration with ergot alkaloids is contraindicated.

Coadministration of Voriconazole with Drugs Requiring Careful Monitoring or Dosage Adjustment

• Alfentanil, Fentanyl, Oxycodone, Methadone (CYP3A4 Substrates): Coadministration of voriconazole increased the exposure of these drugs, necessitating frequent monitoring for adverse events and possible dosage reduction to avoid toxicity.
• Cyclosporine, Tacrolimus (CYP3A4 Substrates): Coadministration of voriconazole increased exposure to these drugs, requiring dose reduction, particularly during voriconazole initiation. Monitoring cyclosporine levels is essential to prevent nephrotoxicity.
• Warfarin, Oral Coumarin Anticoagulants (CYP2C9, CYP3A4 Substrates): Voriconazole may elevate plasma concentrations of these drugs, necessitating close monitoring of prothrombin time and anticoagulant dosage adjustment.
• Statins, Benzodiazepines, Calcium Channel Blockers, Sulfonylureas (CYP3A4 or CYP2C9 Substrates): Although not studied clinically, voriconazole may affect metabolism, increasing plasma concentrations of these drugs. Dose adjustment and monitoring for adverse effects are advised during coadministration.

Voriconazole Interactions with Other Drugs

1. Vinca Alkaloids (CYP3A4 substrates): Although not studied in vitro or in vivo, voriconazole may elevate plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine), leading to neurotoxicity. Hence, consideration of dose adjustment for vinca alkaloids is recommended.

2. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs; CYP2C9 substrates): Two independent published studies indicated that coadministration of voriconazole with ibuprofen and diclofenac resulted in increased plasma concentrations of these NSAIDs. Thus, a reduction in ibuprofen and diclofenac dosage may be necessary during concurrent use with voriconazole. Similar precautions should be taken with other NSAIDs metabolized by CYP2C9, such as celecoxib, naproxen, lornoxicam, and meloxicam.

No Dosage Adjustment Required:

• Prednisolone (CYP3A4 substrate): Voriconazole slightly increased prednisolone exposure, but no dose adjustment is necessary.
• Digoxin (P-glycoprotein mediated transport): Voriconazole did not significantly affect digoxin levels.
• Mycophenolic Acid (UDP-glucuronyl transferase substrate): Voriconazole had no significant effect on mycophenolic acid levels.

Contraindicated Two-Way Interactions:

• Rifabutin (potent CYP450 inducer): Coadministration with voriconazole is contraindicated due to significant changes in plasma concentrations of both drugs.
• Efavirenz (non-nucleoside reverse transcriptase inhibitor): Standard doses of voriconazole and efavirenz must not be coadministered. Dose adjustments are needed if voriconazole and efavirenz are used together.
• Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Coadministration with voriconazole may require dose adjustment and frequent monitoring of plasma phenytoin concentrations.
• Omeprazole (CYP2C19 inhibitor and substrate): Dose adjustment of omeprazole may be necessary when coadministered with voriconazole.

Other Significant Interactions:

• Indinavir and other HIV protease inhibitors: Voriconazole may interact with these drugs, necessitating frequent monitoring for drug toxicity.
• Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs): In vitro findings suggest potential interactions between voriconazole and NNRTIs, requiring close monitoring for drug toxicity and possible dose adjustments.

The following are the side effects involving Voriconazole:

• Changes in vision.
• Skin rash.
• Headache and hallucinations.
• Rapid heart rate.
• Nausea and vomiting.
• Abnormal liver function test results.

The use of Voriconazole should be prudent in the following group of special populations:

Pregnancy:

Pregnancy Category D

Women of childbearing potential should consistently use effective contraception while undergoing treatment with voriconazole.

Adequate and well-controlled studies in the pregnant women are not available for voriconazole. However, it is known to cause harm to the fetus when administered to pregnant women. Therefore, if this medication is used during pregnancy or if a patient becomes pregnant while taking it, they should be informed about the potential risk to the fetus. Voriconazole should not be used during pregnancy unless the benefits to the mother clearly outweigh the potential risks to the fetus.

Reproduction studies conducted in rats have shown that voriconazole is teratogenic (causing cleft palate, hydronephrosis, and hydroureter) at doses of 10 mg/kg or higher, which corresponds to approximately 0.3 times the human exposure based on body surface area comparisons. In pregnant rats, plasma estradiol was reduced at all dose levels of voriconazole. Treatment with voriconazole in rats also led to increased gestational length and dystocia, which was associated with increased perinatal pup mortality at the 10 mg/kg dose. In rabbits, voriconazole increased embryo lethality and reduced fetal weight.

Lactation:

There is currently no available data on the presence of voriconazole in human milk or its effects on breastfed infants or milk production. Therefore, it is important to consider the developmental and health advantages of breastfeeding, taking into account the mother's clinical requirement for Voriconazole and the potential adverse effects it may have on the breastfed child or the underlying maternal condition.

Pediatric:

The safety as well as effectiveness of Voriconazole have been established in pediatric patients aged 2 years and older based on well-controlled studies in both adults and pediatric populations, along with additional pharmacokinetic and safety data specific to pediatric patients. Safety information was obtained from a total of 105 pediatric patients, including 26 patients aged 2 to less than 12 and 79 patients aged 12 to less than 18, from 2 non-comparative Phase 3 pediatric studies and eight adult therapeutic trials.

However, Voriconazole has not been studied in pediatric patients below the age of 2 years, and as a result, it is not recommended for use in this age group.

A higher frequency of liver enzyme elevations was observed in the pediatric patients. Additionally, it should be noted that phototoxicity reactions are more frequent in the pediatric population. In some cases, patients who experience photosensitivity reactions have developed squamous cell carcinoma. Therefore, strict photoprotection measures are essential. Pediatric patients experiencing photoaging injuries like lentigines or ephelides should continue to avoid sun exposure and receive dermatologic follow-up even after discontinuing Voriconazole treatment .

Voriconazole has not been specifically studied in pediatric patients with hepatic or renal impairment . Therefore, close monitoring of hepatic function and serum creatinine levels is recommended in pediatric patients.

Geriatric Use:

In therapeutic trials of voriconazole involving multiple doses, 9.2% of the patients were aged ≥65 years, and 1.8% were aged ≥75 years. In a study conducted with healthy subjects, it was observed that elderly males had increased systemic exposure (AUC) and peak plasma concentrations (Cmax) compared to young males.

Analysis of pharmacokinetic data from 552 patients across 10 voriconazole therapeutic trials revealed that elderly patients had approximately 80% to 90% higher voriconazole plasma concentrations than younger patients, whether the drug was administered intravenously or orally. Despite these differences in drug concentrations, the overall safety profile of the elderly patients was found to be similar to that of the younger patients. As a result, no dosage adjustment is recommended for elderly patients receiving voriconazole treatment.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Voriconazole.

During clinical trials, there were three instances of accidental overdose with voriconazole. These cases occurred in pediatric patients who had received up to five times the recommended intravenous dose of the drug. One adverse reaction reported in these cases was photophobia, which lasted for approximately 10 minutes.

It is important to note that there is currently no known antidote for voriconazole.

Voriconazole has a hemodialysis clearance rate of 121 mL/min, and the intravenous vehicle used for administration, SBECD has a hemodialysis clearance rate of 55 mL/min. In cases of overdose, hemodialysis may be employed to aid in the elimination of voriconazole and SBECD from the body.

Pharmacodynamics:

Voriconazole is an antifungal drug belonging to the triazole class, which acts as a fungistatic agent by inhibiting fungal growth. It is prescribed to treat infections caused by fungi. However, it is essential to be aware that some patients may experience hepatotoxic and photosensitivity reactions as side effects of this medication.

Pharmacokinetics:

Absorption

● The pharmacokinetic properties of voriconazole are comparable when administered intravenously or orally.

● During a population pharmacokinetic analysis of 207 healthy individuals, it was estimated that the oral bioavailability of voriconazole is

● 96% with a coefficient of variation of 13%. Further, it was found that the 200 mg tablet and the 40 mg/mL oral suspension are bioequivalent when administered as a 400 mg Q12h loading dose followed by a 200 mg Q12h maintenance dose.

● Maximum plasma concentrations (Cmax) are typically reached 1-2 hours after dosing.

● Administration of voriconazole with high-fat meals reduces mean Cmax and AUCτ by 34% and 24%, respectively, for the tablet, and 58% and 37%, respectively, for the oral suspension.

Distribution

● Voriconazole exhibits an extensive distribution into tissues, with an estimated volume of distribution at steady state being 4.6 L/kg.

● Plasma protein binding is approximately 58% and remains independent of plasma concentrations achieved with single and multiple oral doses of 200 mg or 300 mg.

● Hepatic and renal insufficiency do not impact the protein binding of voriconazole.

Metabolism

● In vitro studies indicate that voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, including CYP2C19, CYP2C9, and CYP3A4.

● CYP2C19 is significantly involved in voriconazole metabolism, and its activity is subject to genetic polymorphism.

● Poor metabolizers of CYP2C19, more prevalent in Asian populations (15-20%) than in Caucasians and Blacks (3-5%), exhibit approximately 4-fold higher voriconazole exposure (AUCτ).

● Heterozygous extensive metabolizers have, on average, 2-fold higher voriconazole exposure than homozygous extensive metabolizers.

Excretion

● Voriconazole is mostly metabolized by the liver, and only a small fraction (less than 2%) of the dose is excreted unchanged in the urine.

● When a radiolabeled dose of oral or intravenous voriconazole

● is given, around 80-83% of the radioactivity is found in the urine. The majority of the total radioactivity (more than 94%) is eliminated within the first 96 hours after both oral and intravenous dosing.

Terminal Half-life

● The terminal half-life of voriconazole is dose-dependent due to non-linear pharmacokinetics, and therefore, it is not useful in predicting the accumulation or elimination of voriconazole.

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