Posaconazole

Posaconazole is an antifungal agent belonging to the pharmacological class of Triazoles.

Posaconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Candidiasis, Coccidioidomycosis, refractory to conventional therapy, Mucormycosis, salvage and step-down therapy, Prophylaxis against invasive fungal infections.

Posaconazole is absorbed with a median Tmax (time to reach maximum concentration) of approximately 3 to 5 hours. It has a large volume of distribution, estimated at 1774 L, indicating extensive distribution throughout the body. The drug exhibits high protein binding, with over 98% of posaconazole binding predominantly to albumin. In plasma, posaconazole circulates mainly as the parent compound. The majority of circulating metabolites are glucuronide conjugates formed through UDP glucuronidation, which is a phase 2 enzymatic process. Posaconazole does not have significant circulating oxidative metabolites mediated by CYP450 enzymes. The elimination of posaconazole occurs through both urine and faeces, with approximately 17% of the administered radiolabeled dose excreted in the form of metabolites.

The common side effects involved in using Posaconazole are Unusual taste in the mouth, Diarrhea, Dizziness, Sleepiness, Stomach pain, Swelling in the mouth, Vomiting, Weakness, Dry mouth, Fatigue

Posaconazole is available in the form of Delayed-release Tablets, Oral suspensions, and Intravenous Infusion.

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

Posaconazole belonging to the pharmacological class of Triazoles acts as an antifungal agent.

Posaconazole, as a triazole antifungal agent, exerts its antifungal activity by blocking the cytochrome P-450-dependent enzyme, sterol 14α-demethylase, in fungi. It achieves this by binding to the heme cofactor present in the enzyme. As a consequence of this interaction, the synthesis of ergosterol, a crucial component of the fungal cell membrane, is inhibited, and methylated sterol precursors accumulate. This disruption in the synthesis of ergosterol leads to the inhibition of fungal cell growth, ultimately resulting in the death of the fungal cells.

Posaconazole has been approved to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Candidiasis, Coccidioidomycosis, refractory to conventional therapy, Mucormycosis, salvage and step-down therapy, Prophylaxis against invasive fungal infections.

In a multiple-dose pharmacokinetic study conducted with pediatric patients, posaconazole was administered through two different formulations: intravenous injection and delayed-release oral suspension. For the intravenous administration, pediatric patients aged 2 to 6 years had a mean Cmax (maximum concentration) of 3,060 ng/mL and a median Tmax (time to reach maximum concentration) of 1.75 hours. In the same age group, patients aged 7 to 17 years had a slightly higher mean Cmax of 3,340 ng/mL and a median Tmax of 1.77 hours. On the other hand, for the delayed-release oral suspension, patients aged 2 to 6 years had a mean Cmax of 1,510 ng/mL with a median Tmax of 4 hours, while patients aged 7 to 17 years had a mean Cmax of 1,370 ng/mL and a median Tmax of 2.78 hours.

Posaconazole is found to be available in the form of Delayed-release Tablets, Oral suspensions, and Intravenous Infusion.

Posaconazole can be used in the following treatment:

• Aspergillosis
• Candidiasis
• Coccidioidomycosis, refractory to conventional therapy
• Mucormycosis, salvage and step-down therapy
• Prophylaxis against invasive fungal infections

Posaconazole can help to relieve symptoms and also for the treatment and maintenance of Aspergillosis, Candidiasis, Coccidioidomycosis, refractory to conventional therapy, Mucormycosis, salvage and step-down therapy, Prophylaxis against invasive fungal infections.

Posaconazole is approved for use in the following clinical indications:

• Aspergillosis
• Candidiasis
• Coccidioidomycosis, refractory to conventional therapy
• Mucormycosis, salvage and step-down therapy
• Prophylaxis against invasive fungal infections

Aspergillosis:

• Chronic cavitary pulmonary (alternative agent):
• Delayed-release tablet: 300 mg twice daily for 2 doses, then 300 mg once daily.
• IR suspension (off-label use): 200 mg 3 times daily or 400 mg twice daily.
• Invasive (including disseminated and extrapulmonary) (alternative agent for patients who are refractory to or intolerant of first-line agents):
• Delayed-release tablet: 300 mg twice daily for 2 doses, then 300 mg once daily.
• IR suspension (off-label use): 200 mg 3 times daily or 200 mg 4 times daily during hospitalization, then 400 mg twice daily as an outpatient.

Candidiasis:

• Esophageal, fluconazole-refractory disease (alternative agent) (off-label use):
• Delayed-release tablet: 300 mg once daily.
• IR suspension: 400 mg twice daily.
• Oropharyngeal:
• Initial episode (alternative agent): IR suspension: 400 mg twice daily for 1 to 3 days, then 400 mg once daily for a total duration of 7 to 14 days.
• Fluconazole-refractory disease: IR suspension: 400 mg twice daily or 400 mg twice daily for 3 days, then 400 mg once daily. Duration is up to 28 days.

Coccidioidomycosis, refractory to conventional therapy:

• Nonmeningeal infection (e.g., bone and/or joint infection, pulmonary infection in select patients):
• Delayed-release tablet: 300 mg twice daily for 2 doses, then 300 mg once daily.
• IR suspension: 400 mg twice daily or 200 mg 3 times daily.
• Meningitis:
• Delayed-release tablet: 300 mg twice daily for 2 doses, then 300 mg once daily.
• IR suspension: 200 mg 4 times daily or 400 mg twice daily.

Mucormycosis, salvage and step-down therapy (off-label use):

• Oral:
• Delayed-release tablet: 300 mg twice daily for 2 doses, then 300 mg once daily.
• IR suspension: 200 mg 4 times daily or 400 mg twice daily.

Prophylaxis against invasive fungal infections:

• Hematology malignancy or hematopoietic cell transplant:
• Delayed-release tablet: 300 mg twice daily for 2 doses, then 300 mg once daily.
• IR suspension: 200 mg 3 times daily.
• Solid organ transplant (eg, lung transplant recipients) (alternative agent) (off-label use):
• Delayed-release tablet: 300 mg twice daily for 2 doses, then 300 mg once daily.
• IR suspension: 200 mg every 8 hours or 400 mg every 12 hours.

Posaconazole is available in the following dosage forms and strengths:

• Oral Suspension: Posaconazole is available as a liquid formulation with a concentration of 40mg/mL, and each bottle contains 105 mL of the suspension.
• Delayed-Release Tablet: Posaconazole is also provided in tablet form, with a strength of 100mg. These tablets are designed to release the medication slowly in the body.
• Injectable Solution: Posaconazole is available as an injectable solution with a concentration of 18mg/mL. Each vial contains 300mg of posaconazole in 16.7 mL of solution.

Delayed release Tablets, Oral suspensions, Intravenous Infusion.

• Dosage Adjustments in Kidney Patients:

For Tablets or Oral Suspension:

Severe renal impairment (eGFR <20 mL/min): Due to variability, closely monitor for breakthrough fungal infections.

For Injection:

Moderate-to-severe renal impairment (eGFR <50 mL/min): It is recommended to only use this medication if the benefits outweigh the potential risks.

The medication contains IV vehicle betadex sulfobutyl ether sodium [SBECD], which may accumulate in the body. If it is necessary to use this medication, it is important to closely monitor serum creatinine levels. If an increase is observed, it may be necessary to switch to oral therapy.

• Dosage Adjustments in Hepatic Impairment Patients:

Hepatic Impairment:

• Dosage adjustment is not required for patients with mild-to-severe hepatic impairment (Child-Pugh A to C). However, there is no specific study that has been conducted with the injection or tablets in patients with hepatic impairment.

Dosage Adjustments in Pediatric Patients:

• Aspergillosis, Invasive - Prophylaxis: For pediatric patients, the recommended dose for prophylaxis is based on body weight:
• For patients weighing 7 kg to less than 12 kg: 35 mg (0.875 mL of the oral suspension) taken orally three times a day.
• For patients weighing 12 kg to less than 40 kg: 70 mg (1.75 mL of the oral suspension) taken orally three times a day.
• For patients weighing 40 kg or more: 200 mg (5 mL of the oral suspension) taken orally three times a day.
• Aspergillosis, Invasive - Treatment: For pediatric patients, the recommended dose for treatment is based on body surface area (BSA):
• BSA less than 1.5 m²: 100 mg (2.5 mL of the oral suspension) taken orally twice a day.
• BSA 1.5 m² to less than 2.5 m²: 200 mg (5 mL of the oral suspension) taken orally twice a day.
• BSA 2.5 m² or more: 300 mg (7.5 mL of the oral suspension) taken orally twice a day.
• Candidiasis, Oropharyngeal - Treatment: For pediatric patients, the recommended dose for treatment is based on body weight:
• For patients weighing 2 kg to less than 12 kg: 14 mg (0.35 mL of the oral suspension) taken orally twice a day.
• For patients weighing 12 kg to less than 40 kg: 70 mg (1.75 mL of the oral suspension) taken orally twice a day.
• For patients weighing 40 kg or more: 100 mg (2.5 mL of the oral suspension) taken orally twice a day.
• Candidiasis, Esophageal - Treatment: For pediatric patients, the recommended dose for treatment is based on body surface area (BSA):
• BSA less than 1.5 m²: 100 mg (2.5 mL of the oral suspension) taken orally twice a day.
• BSA 1.5 m² to less than 2.5 m²: 200 mg (5 mL of the oral suspension) taken orally twice a day.

• BSA 2.5 m² or more: 300 mg (7.5 mL of the oral suspension) taken orally twice a day.

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

• Food Intake: Posaconazole delayed-release tablets and oral suspension should be taken with a full meal or nutritional supplement to enhance its absorption. Taking the medication with food can significantly increase drug levels in the body.
• Grapefruit and Grapefruit Juice: Avoid consuming grapefruit or grapefruit juice while taking posaconazole. Grapefruit can interact with the drug and increase its levels in the blood, potentially leading to adverse effects.
• High-Fat Meals: Avoid consuming high-fat meals or large amounts of fatty foods before or after taking posaconazole, as this may affect drug absorption and bioavailability.
• Acidic Beverages: Do not take posaconazole oral suspension with acidic beverages like orange juice, as they may reduce its effectiveness. Use water or other non-acidic liquids to mix the oral suspension.

The dietary restriction should be individualized as per patient requirements.

Posaconazole may be contraindicated under the following conditions:

• Hypersensitivity to the active substance or any excipients in Posaconazole.
• Co-administration with sirolimus
• Co-administration with ergot alkaloids

• Avoid Co-administration with the Following Drugs:
• Terfenadine
• Astemizole
• Cisapride
• Pimozide
• Halofantrine
• Quinidine
• Potential Risks of Co-administration:
• Co-administration with the drugs listed above may lead to increased plasma concentrations of these medicines, resulting in QTc prolongation and rare occurrences of torsades de pointes.

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

Hypersensitivity Warning:

• There is no available information regarding cross-sensitivity between Posaconazole and other azole antifungal agents.
• Caution should be exercised when prescribing Posaconazole to patients with a known hypersensitivity to other azoles.

Hepatic Toxicity Warning:

• In clinical trials, rare cases of hepatic reactions were observed, such as mild to moderate elevations in liver function tests (ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis).
• Generally, the elevations in liver function tests were reversible upon discontinuation of therapy, and in some cases, they normalized without the need for drug interruption.
• During treatment with posaconazole, patients with serious underlying medical conditions, such as hematologic malignancy, have reported rare severe hepatic reactions, including cholestasis or hepatic failure, which have resulted in fatalities.
• These severe hepatic events were primarily seen in subjects receiving the 800 mg daily dose (400 mg BID or 200 mg QID) for another indication.

Monitoring of Hepatic Function:

• Hepatic function should be evaluated at the beginning of posaconazole therapy and regularly during treatment.
• Patients who develop abnormal liver function tests during posaconazole therapy should be closely monitored for the development of more severe hepatic injury.
• Laboratory evaluation of hepatic function, including liver function tests and bilirubin, is recommended.
• Discontinuation of posaconazole should be considered if clinical signs and symptoms consistent with liver disease develop, possibly attributable to posaconazole.

Cyclosporine Drug Interaction Warning:

• Clinical efficacy studies reported cases of elevated cyclosporine levels resulting in rare serious adverse events, including nephrotoxicity, leukoencephalopathy, and death.
• Dose reduction and increased clinical monitoring of cyclosporine and tacrolimus should be performed when initiating posaconazole therapy

Arrhythmias and QT Prolongation:

• Some azoles, including posaconazole, have been associated with QT interval prolongation on the electrocardiogram (ECG).
• A multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean QTc interval.
• A case of torsades de pointes was reported in a seriously ill patient taking posaconazole, with multiple confounding risk factors, including cardiotoxic chemotherapy history, hypokalemia, and concomitant medications.
• Posaconazole should be used cautiously in patients with potentially proarrhythmic conditions and should not be administered with drugs known to prolong the QTc interval and are metabolized through CYP3A4.
• Correction of potassium, magnesium, and calcium levels should be attempted before starting posaconazole treatment.

It is advisable to avoid alcohol consumption during posaconazole treatment, as it may increase the risk of liver toxicity and other adverse effects.

Posaconazole is eliminated in the milk of lactating rats. However, the excretion of posaconazole in human breast milk has not been studied. Therefore, Posaconazole should be avoided by nursing mothers unless the benefits to the mother significantly outweigh any potential risks to the infant.

Pregnancy:

Pregnancy Category C

Studies conducted on rats have shown that posaconazole can lead to skeletal malformations, including cranial malformations and missing ribs when administered at doses equal to or higher than 27 mg/kg (approximately 1.4 times the 400 mg BID regimen based on steady-state plasma concentrations in healthy volunteers). The no-effect dose for malformations in rats was found to be 9 mg/kg, which is approximately 0.7 times the exposure achieved with the 400 mg BID regimen.

However, no malformations were observed in rabbits, even at doses as high as 80 mg/kg. In rabbits, the no-effect dose was determined to be 20 mg/kg, while higher doses of 40 mg/kg and 80 mg/kg (approximately 2.9 or 5.2 times the exposure achieved with the 400 mg BID regimen) resulted in an increase in resorptions. In rabbits administered 80 mg/kg, there was a reduction in body weight gain in females and a decrease in litter size.

As there are no adequate and well-controlled studies conducted in pregnant women, the use of posaconazole during pregnancy should be carefully considered and limited to situations where the potential benefits to the mother outweigh the potential risks to the fetus.

There are certain food-related warnings and precautions to consider when using posaconazole:

• Food Intake: Posaconazole delayed-release tablets and oral suspension should be taken with a full meal or nutritional supplement to enhance its absorption. Taking the medication with food can significantly increase drug levels in the body.
• Grapefruit and Grapefruit Juice: Avoid consuming grapefruit or grapefruit juice while taking posaconazole. Grapefruit can interact with the drug and increase its levels in the blood, potentially leading to adverse effects.
• Alcohol: It is advisable to avoid alcohol consumption during posaconazole treatment, as it may increase the risk of liver toxicity and other adverse effects.
• High-Fat Meals: Avoid consuming high-fat meals or large amounts of fatty foods before or after taking posaconazole, as this may affect drug absorption and bioavailability.
• Acidic Beverages: Do not take posaconazole oral suspension with acidic beverages like orange juice, as they may reduce its effectiveness. Use water or other non-acidic liquids to mix the oral suspension.

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

Common:

• Headache
• Nausea
• Vomiting
• Diarrhea
• Fatigue
• Sleepiness
• Stomach pain
• Gas
• Dry mouth
• Skin rash

Less Common :

• Dizziness
• Loss of appetite
• Swelling in the mouth
• Weakness

Rare :

• Abnormal taste in the mouth
• Numbness, prickling, or tingling sensations

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

Interactions with Immunosuppressants Metabolized by CYP3A4

• Sirolimus
• Posaconazole increases sirolimus blood concentrations by approximately 9-fold, leading to sirolimus toxicity.
• Contraindicated: Posaconazole should not be used with sirolimus.
• Tacrolimus
• Posaconazole significantly increases Cmax and AUC of tacrolimus.
• Initiate posaconazole treatment with approximately one-third of the original tacrolimus dose and closely monitor tacrolimus levels.
• Cyclosporine
• Posaconazole increases cyclosporine whole blood concentrations.
• Start posaconazole treatment with approximately three-fourths of the original cyclosporine dose and monitor cyclosporine levels closely.

Interactions with CYP3A4 Substrates

• Pimozide and Quinidine
• Concomitant use of posaconazole with these drugs may lead to increased plasma concentrations, resulting in QTc prolongation and torsades de pointes.
• Contraindicated: Posaconazole should not be used with pimozide and quinidine.
• HMG-CoA Reductase Inhibitors (Statins)
• Posaconazole increases simvastatin plasma concentrations approximately 10-fold.
• Contraindicated: Posaconazole should not be used with statins primarily metabolized by CYP3A4.
• Ergot Alkaloids
• Posaconazole may increase plasma concentrations of ergot alkaloids, leading to ergotism.
• Contraindicated: Posaconazole should not be used with ergot alkaloids.
• Benzodiazepines Metabolized by CYP3A4
• Posaconazole increases midazolam plasma concentrations by approximately 5-fold.
• Closely monitor patients for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4.

Interactions with Anti-HIV Drugs

• Efavirenz
• Efavirenz decreases posaconazole plasma concentrations.
• Use concomitantly with caution if the benefit outweighs the risks.
• Ritonavir, Atazanavir, and Fosamprenavir
• Posaconazole increases plasma concentrations of these drugs.
• Monitor patients for adverse effects and toxicity during coadministration.

Interactions with Rifabutin, Phenytoin, Gastric Acid Suppressors/Neutralizers, Vinca Alkaloids, Calcium Channel Blockers, Digoxin, and Gastrointestinal Motility Agents

• Coadministration with posaconazole may result in altered plasma concentrations of these drugs.
• Dose adjustments and close monitoring are recommended in certain cases.

The following are the side effects involving Posaconazole:

• Unusual taste in the mouth
• Diarrhea
• Dizziness
• Sleepiness
• Stomach pain
• Swelling in the mouth
• Vomiting
• Weakness
• Dry mouth
• Fatigue
• Gas
• Headache
• Decreased appetite
• Nausea
• Numbness, tingling, or prickling sensations
• Skin rash

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

Pregnancy:

Pregnancy Category C

Studies conducted on rats have shown that posaconazole can lead to skeletal malformations, including cranial malformations and missing ribs when administered at doses equal to or higher than 27 mg/kg (approximately 1.4 times the 400 mg BID regimen based on steady-state plasma concentrations in healthy volunteers). The no-effect dose for malformations in rats was found to be 9 mg/kg, which is approximately 0.7 times the exposure achieved with the 400 mg BID regimen.

However, no malformations were observed in rabbits, even at doses as high as 80 mg/kg. In rabbits, the no-effect dose was determined to be 20 mg/kg, while higher doses of 40 mg/kg and 80 mg/kg (approximately 2.9 or 5.2 times the exposure achieved with the 400 mg BID regimen) resulted in an increase in resorptions. In rabbits administered 80 mg/kg, there was a reduction in body weight gain in females and a decrease in litter size.

As there are no adequate and well-controlled studies conducted in pregnant women, the use of posaconazole during pregnancy should be carefully considered and limited to situations where the potential benefits to the mother outweigh the potential risks to the fetus.

Lactation:

Posaconazole is eliminated in the milk of lactating rats. However, the excretion of posaconazole in human breast milk has not been studied. Therefore, Posaconazole should be avoided by nursing mothers unless the benefits to the mother significantly outweigh any potential risks to the infant.

Pediatric:

Twelve patients aged 13 to 17 years received a daily dose of 600 mg (200 mg three times a day) for the prophylaxis of invasive fungal infections. The safety profile observed in these patients under the age of 18 appeared comparable to that observed in adults. Pharmacokinetic data from ten of these pediatric patients revealed that the mean steady-state average posaconazole concentration (Cav) was similar to that of adults (≥18 years of age).

In another study for a different indication, a total of sixteen patients aged 8 to 17 years were treated with a daily dose of 800 mg (400 mg twice a day or 200 mg four times a day). Based on pharmacokinetic data from twelve of these pediatric patients, their mean steady-state average posaconazole concentration (Cav) was similar to that of adults (≥18 years of age).

Geriatric Use:

Among the 605 patients who received posaconazole in the prophylaxis clinical trials, 63 individuals (10%) were over 65 years old. Additionally, in another indication, 48 patients who were over 65 years old were treated with posaconazole at doses exceeding 800 mg per day. Overall, no significant differences in safety were found between the geriatric patients and their younger counterparts. Consequently, there is no recommendation for dosage adjustment in geriatric patients based on these findings.

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

In clinical trials, certain patients were administered posaconazole at doses of up to 1600 mg per day, and no distinct adverse events were observed compared to lower doses. Furthermore, an accidental overdose occurred in one patient who took 1200 mg twice daily for three days, but no adverse events related to the overdose were reported by the investigator.

It is worth noting that posaconazole is not eliminated from the body through hemodialysis.

Pharmacodynamics:

Posaconazole is an antifungal medication that shares structural similarities with itraconazole. It is derived from itraconazole by replacing chlorine substituents with fluorine in the phenyl ring and hydroxylating the triazolone side chain. These alterations result in improved potency and a broader spectrum of activity for the drug. Depending on the context, posaconazole can exhibit both fungicidal and fungistatic actions.

Pharmacokinetics:

● Routes of Administration

Posaconazole is available in various formulations for oral administration, including immediate-release suspension, delayed-release suspension, and delayed-release tablets. Additionally, it can be administered intravenously as an infusion.

● Distribution and Protein Binding

Posaconazole exhibits significant distribution into body tissues, with a mean volume of distribution of 261 L (range: 226 to 295 L). It has high protein binding, with more than 98% of the drug binding predominantly to albumin in the plasma.

● Metabolism and Elimination

In plasma, posaconazole mainly exists as the parent compound. The primary circulating metabolites are glucuronide conjugates formed through UDP glucuronidation, involving phase 2 enzymes. There are no major circulating metabolites resulting from CYP450 (oxidative) pathways; however, posaconazole has been shown to inhibit CYP3A4 enzymes.

Posaconazole is mainly eliminated through faeces, accounting for 71% of the radiolabeled dose up to 120 hours, with the parent drug being the predominant form (66% of the radiolabeled dose). Renal elimination is a minor pathway responsible for excreting 13% of the radiolabeled dose in urine for up to 120 hours, with less than 0.2% of the radiolabeled dose being present as the parent drug.

● Elimination Half-Lives for Different Formulations

The elimination half-lives for posaconazole vary based on the formulation used. For the immediate-release oral suspension, the mean elimination half-life is 35 hours (range: 20 to 66 hours). The delayed-release tablet has an elimination half-life of 26 to 31 hours, while the injection for infusion has an elimination half-life of 27 hours. The elimination half-life for the delayed-release suspension has not been determined.

● Affect on Cytochrome P450 Isoenzymes and Drug Transporters

Posaconazole is metabolized through UDP glucuronidation and acts as a substrate for, and potential inhibitor of, P-glycoprotein (P-gp). Additionally, it is a potent inhibitor of the CYP3A4 enzyme.

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