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Serious and Otherwise Important Adverse Reactions

The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:

• Hypersensitivity [see CONTRAINDICATIONS]
• Arrhythmias and QT Prolongation [see WARNINGS AND PRECAUTIONS]
• Hepatic Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of NOXAFIL (posaconazole oral suspension) cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of posaconazole therapy has been assessed in 1844 patients in clinical trials. This includes 605 patients in the active-controlled prophylaxis studies, 557 patients in the active-controlled OPC studies, 239 patients in refractory OPC studies, and 443 patients from other indications. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy, neutropenia post-chemotherapy, graft vs. host disease post hematopoietic stem cell transplant, and HIV infection, as well as non-neutropenic patients. This patient population was 71% male, had a mean age of 42 years (range 8-84 years, 6% of patients were ≥ 65 years of age and 1% was < 18 years of age), and were 64% white, 16% Hispanic, and 36% non-white (including 14% black). Posaconazole therapy was given to 171 patients for ≥ 6 months, with 58 patients receiving posaconazole therapy for ≥ 12 months. Table 1 presents treatment-emergent adverse reactions observed at an incidence of > 10% in posaconazole prophylaxis studies. Table 2 presents treatment-emergent adverse reactions observed at an incidence of at least 10% in the OPC/rOPC studies.

Prophylaxis of Aspergillus and Candida

In the 2 randomized, comparative prophylaxis studies, the safety of posaconazole 200 mg three times a day was compared to fluconazole 400 mg once daily or itraconazole 200 mg twice a day in severely immunocompromised patients.

The most frequently reported adverse reactions ( > 30%) in the prophylaxis clinical trials were fever, diarrhea and nausea.

The most common adverse reactions leading to discontinuation of posaconazole in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).

TABLE 1: Study 1 and Study 2. Number (%) of Randomized Subjects Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10% in the Posaconazole or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)

HIV Infected Subjects With OPC

In 2 randomized comparative studies in OPC, the safety of posaconazole at a dose of ≤ 400 mg QD in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg QD. An additional 239 HIV-infected patients with refractory OPC received posaconazole in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose and the remainder received the ≤ 400-mg QD dose.

In the OPC/rOPC studies, the most common adverse reactions were fever, diarrhea, nausea, headache, and vomiting.

The most common adverse reactions that led to treatment discontinuation of posaconazole in the Controlled OPC Pool included respiratory insufficiency (1%) and pneumonia (1%). In the refractory OPC pool, the most common adverse reactions that led to treatment discontinuation of posaconazole were AIDS (7%) and respiratory insufficiency (3%).

TABLE 2: Treatment-Emergent Adverse Reactions With Frequency of at Least 10% in OPC Studies (Treated Population)

Adverse reactions were reported more frequently in the pool of patients with refractory OPC. Among these highly immunocompromised patients with advanced HIV disease, serious adverse reactions (SARs) were reported in 55% (132/239). The most commonly reported SARs were fever (13%) and neutropenia (10%).

Less Common Adverse Reactions

Clinically significant adverse reactions reported during clinical trials in prophylaxis, OPC/rOPC or other trials with posaconazole which occurred in less than 5% of patients are listed below:

• Blood and lymphatic system disorders: hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, neutropenia aggravated
• Endocrine disorders: adrenal insufficiency
• Nervous system disorders: paresthesia
• Immune system disorders: allergic reaction [see CONTRAINDICATIONS]
• Cardiac disorders: Torsades de pointes [see WARNINGS AND PRECAUTIONS]
• Vascular disorders: pulmonary embolism
• Liver and Biliary System Disorders: bilirubinemia, hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice, SGOT Increased, SGPT Increased
• Metabolic and Nutritional Disorders: Hypokalemia
• Platelet, Bleeding, and Clotting Disorders: Thrombocytopenia
• Renal & Urinary System Disorders: Renal Failure Acute

Clinical Laboratory Values

In healthy volunteers and patients, elevation of liver function test values did not appear to be associated with higher plasma concentrations of posaconazole. The majority of abnormal liver function tests were minor, transient, and did not lead to discontinuation of therapy.

For the prophylaxis studies, the number of patients with changes in liver function tests from Common Toxicity Criteria (CTC) Grade 0, 1, or 2 at baseline to Grade 3 or 4 during the study is presented in Table 3.

TABLE 3: Study 1 and Study 2. Changes in Liver Function Test Results From CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4

The number of patients treated for OPC with clinically significant liver function test (LFT) abnormalities at any time during the studies is provided in Table 4. (LFT abnormalities were present in some of these patients prior to initiation of the study drug).

TABLE 4: Clinically Significant Laboratory Test Abnormalities Without Regard to Baseline Value

Postmarketing Experience

No clinically significant postmarketing adverse reactions were identified that have not previously been reported during clinical trials experience.

Posaconazole is primarily metabolized via UDP glucuronidation and is a substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Posaconazole is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by posaconazole [see CLINICAL PHARMACOLOGY].

Immunosuppressants Metabolized by CYP3A4

Sirolimus: Concomitant administration of posaconazole with sirolimus increases the sirolimus blood concentrations by approximately 9 fold and can result in sirolimus toxicity. Therefore, posaconazole is contraindicated with sirolimus [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

Tacrolimus: Posaconazole has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of posaconazole treatment, reduce the tacrolimus dose to approximately one-third of the original dose. Frequent monitoring of tacrolimus whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the tacrolimus dose adjusted accordingly [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Cyclosporine: Posaconazole has been shown to increase cyclosporine whole blood concentrations in heart transplant patients upon initiation of posaconazole treatment. It is recommended to reduce cyclosporine dose to approximately three-fourths of the original dose upon initiation of posaconazole treatment. Frequent monitoring of cyclosporine whole blood trough concentrations should be performed during and at discontinuation of posaconazole treatment and the cyclosporine dose adjusted accordingly [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

CYP3A4 Substrates

Concomitant administration of posaconazole with CYP3A4 substrates such as pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and rare occurrences of torsades de pointes. Therefore, posaconazole is contraindicated with these drugs. [see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS].

HMG-CoA reductase Inhibitors (Statins) Metabolized Through CYP3A4

Concomitant administration of posaconazole with simvastatin increases the simvastatin plasma concentrations by approximately 10 fold. Therefore, posaconazole is contraindicated with HMG-CoA reductase inhibitor simvastatin [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

Although not studied clinically with statins other than simvastatin, posaconazole may increase the plasma concentrations of statins that are metabolized by CYP3A4. Increased plasma statin concentrations can be associated with rhabdomyolysis. It is recommended that patients be monitored for adverse events and dose reduction of the statin be considered during co-administration with posaconazole.

Ergot Alkaloids

Most of the ergot alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism. Therefore, posaconazole is contraindicated with ergot alkaloids [see CONTRAINDICATIONS].

Benzodiazepines Metabolized by CYP3A4

Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5 fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines. Patients must be monitored closely for adverse effects associated with high plasma concentrations of benzodiazepines metabolized by CYP3A4 and benzodiazepine receptor antagonists must be available to reverse these effects. [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Anti-HIV Drugs

Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases posaconazole plasma concentrations [see CLINICAL PHARMACOLOGY]. It is recommended to avoid concomitant use of efavirenz with posaconazole unless the benefit outweighs the risks.

Ritonavir and Atazanavir: Ritonavir and atazanavir are metabolized by CYP3A4 and posaconazole increases plasma concentrations of these drugs [see CLINICAL PHARMACOLOGY]. Frequent monitoring of adverse effects and toxicity and dosage adjustments of ritonavir and atazanavir should be performed during co-administration with posaconazole.

Rifabutin

Rifabutin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, Co-administration of rifabutin with posaconazole increases rifabutin plasma concentrations [see CLINICAL PHARMACOLOGY]. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring of breakthrough fungal infections as well as frequent monitoring of full blood counts and adverse reactions due to increased rifabutin plasma concentrations (e.g., uveitis, leukopenia) are recommended.

Phenytoin

Phenytoin induces UDP-glucuronidase and decreases posaconazole plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, co-administration of phenytoin with posaconazole increases phenytoin plasma concentrations [see CLINICAL PHARMACOLOGY]. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring of breakthrough fungal infections is recommended and frequent monitoring of phenytoin concentrations should be performed while coadministered with posaconazole and dose reduction of phenytoin should be considered.

Gastric Acid Suppressors/Neutralizers

Cimetidine (an H₂-recpetor antagonist) and esomeprazole (a proton pump inhibitor) decrease posaconazole plasma concentrations [see CLINICAL PHARMACOLOGY]. It is recommended to avoid concomitant use of cimetidine and esomeprazole with posaconazole unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring of breakthrough fungal infections is recommended. No clinically relevant effects were observed when posaconazole is concomitantly used with antiacids and H₂-receptor antagonists other than cimetidine. No dosage adjustment of posaconazole is required when posaconazole is concomitantly used with antacids and H₂-receptor antagonists other than cimetidine.

Vinca Alkaloids

Most of the vinca alkaloids are substrates of CYP3A4. Posaconazole may increase the plasma concentrations of vinca alkaloids (e.g., vincristine and vinblastine) which may lead to neurotoxicity. Therefore, it is recommended that dose adjustment of the vinca alkaloid be considered.

Calcium Channel Blockers Metabolized by CYP3A4

Posaconazole may increase the plasma concentrations of calcium channel blockers metabolized by CYP3A4 (e.g., verapamil, diltiazem, nifedipine, nicardipine, felodipine). Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is recommended during coadministration. Dose reduction of calcium channel blockers may be needed.

Digoxin

Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, monitoring of digoxin plasma concentrations is recommended during co-administration.

Gastrointestinal Motility Agents

Metoclopramide decreases posaconazole plasma concentrations [see CLINICAL PHARMACOLOGY]. If metoclopramide is concomitantly administered, it is recommended to closely monitor for breakthrough fungal infections.

Loperamide does not affect posaconazole plasma concentrations [see CLINICAL PHARMACOLOGY]. No dosage adjustment of posaconazole is required when loperamide and posaconazole are used concomitantly.

Glipizide

Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when posaconazole and glipizide are concomitantly used.

Last reviewed on RxList: 10/12/2010
This monograph has been modified to include the generic and brand name in many instances.