Posaconazole

Dosage regimens for posaconazole are strictly determined by the indication and the formulation being used. Healthcare providers emphasize that the oral suspension and the delayed-release tablets are NOT interchangeable on a milligram-to-milligram basis because their bioavailability differs significantly.

Prophylaxis of Invasive Fungal Infections

• Delayed-Release Tablets: The standard adult dose is a loading dose of 300 mg (three 100 mg tablets) twice daily on the first day, followed by a maintenance dose of 300 mg once daily thereafter.
• Intravenous Injection: A loading dose of 300 mg twice daily on the first day, followed by 300 mg once daily.
• Oral Suspension: The typical dose is 200 mg (5 mL) three times daily. The duration of therapy is based on the recovery from neutropenia or the resolution of immunosuppression.

Treatment of Oropharyngeal Candidiasis (OPC)

• Oral Suspension: A loading dose of 100 mg (2.5 mL) twice daily on the first day, followed by 100 mg once daily for 13 days.
• Refractory OPC: For cases resistant to other drugs, the dose is typically 400 mg (10 mL) twice daily.

Treatment of Invasive Aspergillosis

• Delayed-Release Tablets/IV: A loading dose of 300 mg twice daily on Day 1, followed by 300 mg once daily. The duration is usually several weeks to months depending on clinical response.

Posaconazole is approved for use in pediatric patients as young as 2 years of age for certain indications.

• Prophylaxis and Treatment: For children weighing more than 40 kg, adult dosing is typically applied. For children weighing less than 40 kg, dosing is calculated based on body weight (mg/kg). For example, the recommended dose for prophylaxis in pediatric patients (2 to less than 18 years) using the DR tablets or IV is often 6 mg/kg (not to exceed 300 mg) once daily after a loading dose.
• Note: The safety and efficacy of posaconazole in children under 2 years of age have not been established.

Renal Impairment

For patients with mild to moderate renal impairment, no adjustment of the oral dose is required. However, in patients with moderate to severe renal impairment (Creatinine Clearance < 50 mL/min), the intravenous formulation should be used with caution. The IV formulation contains an excipient called Betadex Sulfobutyl Ether Sodium (SBECD), which can accumulate in patients with poor kidney function. In these cases, oral formulations are preferred unless the benefit of IV therapy outweighs the risk.

Hepatic Impairment

While posaconazole is not extensively metabolized by the liver, it is eliminated through the biliary tract. Data in patients with severe hepatic impairment are limited. Healthcare providers typically monitor liver function tests (LFTs) closely in these patients but may not necessarily adjust the initial dose unless toxicity occurs.

Elderly Patients

No overall differences in safety or effectiveness have been observed between elderly patients (65 years and older) and younger patients. Dose adjustments based solely on age are generally not required.

• Delayed-Release Tablets: These must be swallowed whole. Do not crush, chew, or break the tablets, as this destroys the delayed-release mechanism and may lead to improper absorption. They can be taken with or without food.
• Oral Suspension: This formulation must be taken with a full meal or a liquid nutritional supplement (like Ensure). If a patient cannot eat, the suspension should be taken with an acidic carbonated beverage (like ginger ale) to improve absorption. Shake the suspension well before each use.
• Intravenous Solution: This is administered only by a healthcare professional via a central line or peripheral venous catheter over approximately 90 minutes.
• Storage: Store all oral forms at room temperature (20°C to 25°C / 68°F to 77°F). Do not freeze the liquid suspension.

If you miss a dose, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and return to your regular schedule. Do not double the dose to catch up. For the oral suspension, missing doses or taking them without food can lead to treatment failure because the drug levels in your blood may drop below the effective range.

Symptoms of overdose are generally similar to the side effects of the drug, such as severe nausea or dizziness. In case of a suspected overdose, contact your local poison control center or seek emergency medical attention immediately. There is no specific antidote for posaconazole; treatment is supportive.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking the medication without medical guidance, as this can allow the fungal infection to return or become resistant.

Most patients tolerate posaconazole well, but like all systemic antifungals, it can cause side effects. Common reactions reported in clinical trials (occurring in more than 10% of patients) include:

• Gastrointestinal Distress: Nausea, vomiting, diarrhea, and abdominal pain are the most frequently cited issues. These usually occur early in treatment and may diminish as the body adjusts to the medication.
• Headache: A persistent but usually mild to moderate headache may occur.
• Hypokalemia (Low Potassium): Posaconazole can cause a drop in blood potassium levels. Patients may feel weak, experience muscle cramps, or notice a skipping heartbeat. Healthcare providers will monitor electrolytes frequently.
• Pyrexia (Fever): A mild increase in body temperature is common in the patient populations typically receiving this drug (e.g., those with neutropenia).

• Dizziness and Fatigue: Some patients report feeling unusually tired or lightheaded.
• Rash: A mild skin rash or itching (pruritus) may develop.
• Elevated Liver Enzymes: Increases in ALT, AST, and bilirubin are observed in some patients, necessitating regular blood work.
• Anemia or Thrombocytopenia: A decrease in red blood cells or platelets, though this is often confounded by the patient's underlying condition (like leukemia).

• Adrenal Insufficiency: Azole antifungals can occasionally interfere with the production of steroid hormones in the adrenal glands, leading to fatigue, low blood pressure, and weight loss.
• Pancreatitis: Inflammation of the pancreas, characterized by severe upper abdominal pain radiating to the back.
• Visual Disturbances: While more common with other azoles, rare instances of blurred vision have been reported.

> Warning: Stop taking Posaconazole and call your doctor immediately if you experience any of these serious symptoms:

• Hepatotoxicity (Liver Damage): Signs include yellowing of the skin or eyes (jaundice), dark urine, pale stools, severe nausea, or pain in the upper right side of the stomach. Rare cases of liver failure and death have occurred, primarily in patients with serious underlying medical conditions.
• QT Prolongation and Arrhythmias: Posaconazole can affect the electrical rhythm of the heart. Seek emergency care for fainting, severe dizziness, or a fast/irregular heartbeat (palpitations).
• Severe Allergic Reactions (Anaphylaxis): Symptoms include hives, difficulty breathing, swelling of the face, lips, tongue, or throat.
• Severe Electrolyte Imbalance: Extreme weakness, leg cramps, or a 'fluttering' in the chest could indicate dangerously low potassium or magnesium.

When posaconazole is used for several months (as in chronic prophylaxis), healthcare providers monitor for:

• Cumulative Liver Stress: Long-term elevation of liver enzymes may require a change in therapy.
• Hormonal Changes: Prolonged inhibition of sterol pathways might theoretically affect testosterone or cortisol levels, although this is less common with posaconazole than with older azoles like ketoconazole.
• Skeletal Effects: While more commonly associated with voriconazole, any long-term azole therapy warrants monitoring for bone pain or changes, though this is rare for posaconazole.

No FDA black box warnings are currently issued for Posaconazole. However, the warnings regarding Hepatotoxicity and QT Prolongation are considered "Major Warnings" in the prescribing information and carry the same level of clinical importance as a boxed warning for prescribing physicians.

Report any unusual symptoms to your healthcare provider. Even mild symptoms should be discussed, as they may require a dosage adjustment or closer monitoring of your blood chemistry.

Posaconazole is a high-potency medication that requires careful clinical oversight. It is not a simple 'antibiotic' for common infections but a targeted therapy for life-threatening fungal pathogens. Patients must be aware that the success of the treatment depends on maintaining consistent levels of the drug in the blood, which is heavily influenced by how the drug is taken (especially the oral suspension).

There are no FDA black box warnings for Posaconazole as of 2024. However, the FDA requires prominent warnings in the 'Warnings and Precautions' section regarding liver injury and heart rhythm changes.

Hepatotoxicity

Serious hepatic reactions, including liver failure and fatalities, have been reported. These reactions are usually seen in patients with severe underlying conditions (such as hematologic malignancy). Liver function tests (LFTs), specifically ALT, AST, and bilirubin, must be evaluated at the start of therapy and periodically during treatment. If LFTs become significantly elevated, your doctor may decide to discontinue the drug.

QT Prolongation

Some azoles, including posaconazole, have been associated with prolongation of the QT interval on an electrocardiogram (ECG). This increases the risk of a dangerous heart rhythm called Torsades de Pointes. This risk is higher if you:

• Have a pre-existing heart condition (like congestive heart failure).
• Have a slow heart rate (bradycardia).
• Are taking other medications that also prolong the QT interval.
• Have uncorrected electrolyte imbalances (low potassium, magnesium, or calcium).

Allergic Reactions

While rare, hypersensitivity reactions can occur. If you have ever had an allergic reaction to other 'azole' antifungals (like fluconazole, voriconazole, or itraconazole), you must inform your doctor, as cross-sensitivity is possible.

Vincristine Toxicity

In pediatric and adult patients receiving vincristine (a chemotherapy drug), taking posaconazole can lead to increased levels of vincristine in the blood. This can cause severe nerve damage (neurotoxicity), seizures, and other serious problems. Coadministration should be avoided unless the benefit outweighs the risk.

If you are on posaconazole, expect regular medical check-ups including:

• Liver Function Tests (LFTs): To monitor for hepatotoxicity.
• Electrolytes: Specifically potassium, magnesium, and calcium levels.
• Therapeutic Drug Monitoring (TDM): Your doctor may check the level of posaconazole in your blood to ensure it is high enough to be effective but not so high as to be toxic.
• ECG: To monitor heart rhythm, especially if you have other risk factors.

Posaconazole may cause dizziness or sleepiness in some individuals. Use caution when driving or operating heavy machinery until you know how this medication affects you.

There is no direct contraindication between alcohol and posaconazole; however, alcohol can strain the liver. Since posaconazole also carries a risk of hepatotoxicity, it is generally advised to limit alcohol consumption during treatment to avoid unnecessary liver stress.

Do not stop taking posaconazole suddenly without consulting your doctor. Fungal infections can be very resilient; stopping the medication early may allow the infection to return or lead to the development of antifungal resistance. There is no 'withdrawal syndrome' associated with posaconazole, but the underlying infection may flare up.

> Important: Discuss all your medical conditions, especially heart or liver problems, with your healthcare provider before starting Posaconazole.

Certain drugs must NEVER be used with posaconazole because the interaction can be life-threatening:

• Sirolimus: Posaconazole significantly increases sirolimus blood levels (up to 9-fold), leading to severe toxicity.
• Ergot Alkaloids (e.g., Ergotamine, Dihydroergotamine): Posaconazole can increase these levels, leading to 'ergotism' (severe constriction of blood vessels, potentially causing gangrene).
• CYP3A4 Substrates that Prolong QT: Drugs like pimozide and quinidine should not be taken with posaconazole due to the extreme risk of fatal heart arrhythmias.
• HMG-CoA Reductase Inhibitors (Statins): Specifically simvastatin, lovastatin, and atorvastatin. Posaconazole increases their levels, which can cause rhabdomyolysis (muscle breakdown and kidney failure).

• Cyclosporine and Tacrolimus: Posaconazole increases the levels of these immunosuppressants. Doses of cyclosporine or tacrolimus usually need to be reduced (often by 25-66%) and blood levels monitored daily when starting posaconazole.
• Vincristine: As mentioned, posaconazole increases vincristine levels, leading to severe neurotoxicity. Avoid coadministration if possible.
• Midazolam (Oral): Levels can increase 5-fold, leading to prolonged sedation and respiratory depression.

• Rifampin and Phenytoin: These drugs induce the enzymes that clear posaconazole, which can drop posaconazole levels by 50-90%, making the antifungal ineffective. These combinations should generally be avoided.
• Calcium Channel Blockers: Levels of drugs like diltiazem or verapamil may increase, leading to low blood pressure or slow heart rate.
• Digoxin: Posaconazole can increase digoxin levels; monitor for digoxin toxicity (nausea, halos in vision).

• High-Fat Meals: For the oral suspension, a high-fat meal is required to achieve therapeutic levels. Without food, the drug may not work.
• Grapefruit Juice: Grapefruit is a known inhibitor of CYP3A4. While posaconazole is also an inhibitor, adding grapefruit can further complicate the metabolic profile and increase the risk of side effects.

• St. John's Wort: This herbal supplement is a potent inducer of metabolic enzymes and can significantly lower the concentration of posaconazole in the blood, leading to treatment failure.
• Quercetin: May interfere with the transport of the drug, though clinical data are limited.

Posaconazole does not typically interfere with standard laboratory tests, but its effect on liver enzymes and electrolytes will be reflected in blood chemistry panels. Always inform the lab and your doctor of all medications you are taking.

Mechanism of Interaction

The primary mechanism for these interactions is the inhibition of Cytochrome P450 3A4 (CYP3A4) by posaconazole. Many drugs are broken down by this enzyme; when posaconazole blocks it, those other drugs build up to toxic levels. Conversely, drugs that 'speed up' enzymes (inducers like Rifampin) cause posaconazole to be cleared too quickly.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. A complete medication reconciliation is mandatory before starting posaconazole.

Posaconazole must NEVER be used in the following circumstances:

• Known Hypersensitivity: If you have had a severe allergic reaction (anaphylaxis, Stevens-Johnson Syndrome) to posaconazole or any other azole antifungal (e.g., fluconazole, voriconazole, itraconazole).
• Coadministration with Sirolimus: Due to the risk of extreme sirolimus toxicity.
• Coadministration with Ergot Alkaloids: Due to the risk of ergotism and peripheral ischemia.
• Coadministration with Certain Statins: Specifically lovastatin and simvastatin, due to the risk of rhabdomyolysis.
• Coadministration with QT-Prolonging CYP3A4 Substrates: Such as pimozide or quinidine, due to the risk of sudden cardiac death.

In these cases, a healthcare provider will perform a careful risk-benefit analysis:

• Severe Hepatic Impairment: The risk of further liver injury must be weighed against the need for the antifungal.
• Pre-existing Pro-arrhythmic Conditions: Such as congenital long QT syndrome or severe cardiomyopathy. The risk of Torsades de Pointes is significantly elevated.
• Moderate to Severe Renal Impairment (for IV formulation): Due to the accumulation of the SBECD vehicle. If the patient cannot take oral medication, the IV form may be used with frequent monitoring of serum creatinine.

There is a high likelihood of cross-sensitivity among the azole class. If a patient has experienced a mild rash with fluconazole, posaconazole might be used with caution. However, if the reaction was severe (e.g., toxic epidermal necrolysis), posaconazole is generally considered contraindicated. Always disclose your full allergy history to your medical team.

> Important: Your healthcare provider will evaluate your complete medical history and current medication list before prescribing Posaconazole to ensure it is safe for you.

Posaconazole is classified under the FDA's Pregnancy and Lactation Labeling Rule (PLLR). There are no adequate and well-controlled studies in pregnant women. However, animal studies have shown that posaconazole can cause skeletal malformations and embryotoxicity at doses similar to human exposures.

• Risk Summary: Posaconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Clinical Considerations: If a woman becomes pregnant while taking this drug, she should be informed of the potential hazards to the fetus.

It is not known whether posaconazole is excreted in human milk. In animal studies (rats), posaconazole was found to be excreted in milk at concentrations higher than those in the plasma. Because of the potential for serious adverse reactions in nursing infants (such as liver toxicity or heart rhythm issues), a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Posaconazole is approved for the prophylaxis of invasive fungal infections and the treatment of invasive aspergillosis in pediatric patients 2 years of age and older.

• Dosing: Dosing in children is typically weight-based.
• Safety: The side effect profile in children is generally similar to that in adults, though monitoring for vincristine interactions is especially critical in pediatric oncology settings.
• Not Approved: The drug is not approved for use in infants under 2 years of age, as safety and efficacy have not been established in this age group.

Clinical trials included a significant number of patients aged 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. However, elderly patients often have a higher incidence of decreased renal or hepatic function and are more likely to be on multiple medications (polypharmacy), which increases the risk of drug interactions. Dose adjustments based on age alone are not required, but close monitoring is advised.

• Oral Formulations: No dose adjustment is needed for patients with any degree of renal impairment.
• Intravenous Formulation: In patients with an estimated glomerular filtration rate (eGFR) < 50 mL/min, the IV vehicle (SBECD) may accumulate. In these patients, the oral delayed-release tablets are the preferred treatment option. If IV therapy is necessary, kidney function must be monitored closely.

Posaconazole has not been extensively studied in patients with severe hepatic impairment. Because the drug is primarily eliminated via the bile, hepatic dysfunction could theoretically increase drug levels. While no specific dose adjustment is recommended in the labeling, healthcare providers are advised to use the drug with caution and monitor liver function tests frequently in this population.

> Important: Special populations require individualized medical assessment. Always consult with a specialist if the patient falls into one of these categories.

Posaconazole is a highly potent inhibitor of the enzyme lanosterol 14-alpha-demethylase (also known as CYP51). This enzyme is a critical component of the ergosterol biosynthesis pathway in fungi. By binding to the heme iron within the enzyme's active site, posaconazole prevents the demethylation of lanosterol into 4,4-dimethylcholesta-8,14,24-trien-3-beta-ol, which is a precursor to ergosterol.

The depletion of ergosterol leads to significant structural damage to the fungal cell membrane. Furthermore, the accumulation of methylated sterol precursors alters the membrane's permeability and inhibits the function of other membrane-bound enzymes, such as chitin synthase. This results in the cessation of fungal growth (fungistatic) or cell death (fungicidal), depending on the organism.

The relationship between the concentration of posaconazole and its clinical effect is typically measured by the ratio of the Area Under the Curve (AUC) to the Minimum Inhibitory Concentration (MIC) of the pathogen (AUC/MIC). Higher drug exposure is directly correlated with better clinical outcomes in invasive fungal infections. There is no evidence of a 'ceiling effect' within therapeutic ranges, but higher levels increase the risk of hepatotoxicity and GI distress.

| Parameter | Value |

|---|---|

| Bioavailability | ~54% (Suspension with food), higher for DR Tablets |

| Protein Binding | >98% (primarily to albumin) |

| Half-life | 26 to 35 hours |

| Tmax | 4 to 5 hours (DR Tablets) |

| Metabolism | Primarily via UDP-glucuronidation (Phase II) |

| Excretion | Fecal 77% (unchanged), Renal 14% |

• Molecular Formula: C37H42F2N8O4
• Molecular Weight: 700.78 g/mol
• Solubility: Highly lipophilic; practically insoluble in water at neutral pH. Solubility increases in acidic environments, which is why the oral suspension requires food or acidic beverages for optimal absorption.
• Structure: A triazole derivative featuring a core triazole ring and a long side chain that enhances its binding affinity to the 14-alpha-demethylase enzyme compared to first-generation azoles.

Posaconazole is a member of the Triazole Antifungal class. It is often grouped with 'second-generation' or 'extended-spectrum' azoles, which also includes voriconazole and isavuconazole. These drugs are distinguished from 'first-generation' azoles (like fluconazole) by their activity against molds like Aspergillus.