Noxafil

Medical Editor: John P. Cunha, DO, FACOEP Last updated on RxList: 5/26/2022
Noxafil Side Effects Center

What Is Noxafil?

Noxafil (posaconazole) is a triazole antifungal agent used to prevent fungal infections in people with weak immune systems resulting from chemotherapy or stem cell transplantation.

What Are Side Effects of Noxafil?

Common side effects of Noxafil include:

  • nausea,
  • vomiting,
  • diarrhea,
  • constipation,
  • headache,
  • abdominal pain,
  • dizziness,
  • trouble sleeping (insomnia),
  • stomach upset or pain,
  • tired feeling,
  • fatigue,
  • swelling of your ankles or feet,
  • joint or muscle pain,
  • anemia,
  • chills,
  • fever,
  • loss of appetite,
  • cough,
  • shortness of breath,
  • nosebleed, and
  • rash.

Dosage for Noxafil?

Dosing and frequency of Noxafil varies depending on the fungal infection being treated. Doses range from 100 mg (2.5 mL) to 400 mg (10 mL), taken one to three times a day.

What Drugs, Substances, or Supplements Interact with Noxafil?

Noxafil may interact with arsenic trioxide, cimetidine, cyclosporine, digoxin, droperidol, esomeprazole, midazolam, phenytoin, antibiotics, antidepressants, anti-malaria medications, calcium channel blockers, cancer medicines, cholesterol-lowering medicines, heart rhythm medications, HIV medications, medicine to prevent or treat nausea and vomiting, medicines to treat psychiatric disorders, migraine headache medicines, or narcotics. Tell your doctor all medications and supplements you use.

Noxafil During Pregnancy and Breastfeeding

During pregnancy, Noxafil should be used only when prescribed. It is unknown if this drug passes into breast milk. Consult your doctor before breastfeeding.

Additional Information

Our Noxafil (posaconazole) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

SLIDESHOW

Rosacea, Acne, Shingles, Covid-19 Rashes: Common Adult Skin Diseases See Slideshow
Noxafil Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness (like you might pass out);
  • swelling in an arm or leg;
  • shortness of breath;
  • liver problems--nausea, vomiting, itching, feeling tired, jaundice (yellowing of the skin or eyes); or
  • signs of an electrolyte imbalance--increased thirst or urination, constipation, muscle pain or weakness, numbness or tingling, confusion, feeling jittery, irregular heartbeats.

Common side effects may include:

  • diarrhea, nausea, vomiting;
  • low potassium (an electrolyte);
  • headache;
  • fever; or
  • cough.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Noxafil (Posaconazole Oral Suspension)

QUESTION

Ringworm is caused by a fungus. See Answer
Noxafil Professional Information

SIDE EFFECTS

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 cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience In Adults

Clinical Trial Experience With Noxafil Injection And Noxafil Delayed-Release Tablets For The Treatment Of Invasive Aspergillosis

The safety of Noxafil injection and Noxafil delayed-release tablet was assessed in a randomized, double-blind, active-controlled clinical study of Noxafil injection and Noxafil delayed-release tablets versus voriconazole for treatment of invasive aspergillosis (Aspergillosis Treatment Study). A total of 575 (288 in Noxafil arm, 287 in voriconazole arm) adult and pediatric patients 13 years of age and older with proven, probable or possible invasive aspergillosis were included. The median duration of treatment was 67 days for Noxafil injection or Noxafil delayed-release tablet and 64 days for voriconazole, with 55% to 60% of subjects starting treatment with the IV formulation of either drug. The median duration of the first instance of IV treatment (before switching to oral treatment or discontinuing or completing study treatment) was 9 days for both groups. Table 7 presents adverse reactions reported at an incidence of ≥10% in either one of the groups in Aspergillosis Treatment Study.

Adverse reactions leading to treatment discontinuation were reported for 33.9% of subjects. The most commonly reported adverse reactions (>2% of subjects) leading to treatment discontinuation were septic shock, respiratory failure, and bronchopulmonary aspergillosis in the Noxafil arm, and septic shock and acute myeloid leukemia in the voriconazole arm.

Table 7: Noxafil Invasive Aspergillosis Treatment Study: Adverse Reactions in at Least 10% of Subjects Treated with Noxafil Injection or Noxafil Delayed-Release Tablets

System Organ Class Noxafil injection or tablet
(N = 288), n (%)
Voriconazole injection or oral
(N = 287), n (%)
Blood and lymphatic system disorders
Anemia 25 (8.7) 29 (10.1)
Febrile neutropenia 42 (14.6) 38 (13.2)
Gastrointestinal disorders
Abdominal pain 29 (10.1) 24 (8.4)
Constipation 32 (11.1) 23 (8.0)
Diarrhea 52 (18.1) 52 (18.1)
Nausea 65 (22.6) 51 (17.8)
Vomiting 52 (18.1) 39 (13.6)
General disorders and administration site conditions
Edema peripheral 32 (11.1) 24 (8.4)
Pyrexia 81 (28.1) 72 (25.1)
Infections and infestations
Pneumonia 36 (12.5) 26 (9.1)
Investigations
Alanine aminotransferase increased 42 (14.6) 37 (12.9)
Aspartate aminotransferase increased 38 (13.2) 36 (12.5)
Blood alkaline phosphatase increased 21 (7.3) 29 (10.1)
Metabolism and nutrition disorders
Hypokalemia 82 (28.5) 49 (17.1)
Hypomagnesemia 29 (10.1) 18 (6.3)
Nervous system disorders
Headache 35 (12.2) 25 (8.7)
Respiratory, thoracic and mediastinal disorders
Cough 30 (10.4) 24 (8.4)
Epistaxis 32 (11.1) 17 (5.9)

The most frequently reported adverse reactions in the Noxafil-treated group were pyrexia (28%), hypokalemia (28%), and nausea (23%).

Clinical Trial Experience With Noxafil Injection For Prophylaxis

Multiple doses of Noxafil injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, Noxafil injection was administered via central venous catheter.

The safety of Noxafil injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil injection when given as antifungal prophylaxis (Noxafil Injection Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18-82 years, 19% of patients were ≥65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg Noxafil injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days.

Table 8 presents adverse reactions observed in patients treated with Noxafil injection 300 mg daily dose in the Noxafil Injection Study. Each patient received a loading dose, 300 mg twice on Day 1. Following Noxafil intravenous therapy, patients received Noxafil oral suspension to complete 28 days of total Noxafil therapy.

Table 8: Noxafil Injection Study: Adverse Reactions in at Least 10% of Subjects Treated withNoxafil Injection 300 mg Daily Dose

Body System Noxafil Injection Treatment Phase
n=237 (%)*
Noxafil Injection Treatment Phase or Subsequent Noxafil Oral Suspension Treatment Phase
n=237 (%)†
Subjects Reporting any Adverse Reaction 220(93) 235(99)
Blood and Lymphatic System Disorder
Anemia 16(7) 23(10)
Thrombocytopenia 17(7) 25(11)
Gastrointestinal Disorders
Abdominal Pain Upper 15(6) 25(11)
Abdominal Pain 30(13) 41(17)
Constipation 18(8) 31(13)
Diarrhea 75(32) 93(39)
Nausea 46(19) 70(30)
Vomiting 29(12) 45(19)
General Disorders and Administration Site Conditions
Fatigue 19(8) 24(10)
Chills 28(12) 38(16)
Edema Peripheral 28(12) 35(15)
Pyrexia 49(21) 73(31)
Metabolism and Nutrition Disorders
Decreased appetite 23(10) 29(12)
Hypokalemia 51(22) 67(28)
Hypomagnesemia 25(11) 30(13)
Nervous System Disorders
Headache 33(14) 49(21)
Respiratory, Thoracic and Mediastinal Disorders
Cough 21(9) 31(13)
Dyspnea 16(7) 24(10)
Epistaxis 34(14) 40(17)
Skin and Subcutaneous Tissue Disorders
Petechiae 20(8) 24(10)
Rash 35(15) 56(24)
Vascular Disorders
Hypertension 20(8) 26(11)
*Adverse reactions reported in patients with an onset during the Noxafil intravenous dosing phase of the study.
†Adverse reactions reported with an onset at any time during the study in patients who were treated for up to 28 days of Noxafil therapy.

The most frequently reported adverse reactions with an onset during the Noxafil intravenous phase of dosing with 300 mg once daily were diarrhea (32%), hypokalemia (22%), pyrexia (21%), and nausea (19%). These adverse reactions were consistent with those seen in studies with Noxafil oral suspension.

Clinical Trial Experience With Noxafil Delayed-Release Tablets For Prophylaxis

The safety of Noxafil delayed-release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of Noxafil delayed-release tablets when given as antifungal prophylaxis (Noxafil Delayed-Release Tablet Study). Patients were immunocompromised with underlying conditions including hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort). Table 9 presents adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in Noxafil Delayed-Release Tablet Study.

Table 9: Noxafil Delayed-Release Tablet Study: Adverse Reactions in at Least 10% of Subjects Treated with 300 mg Daily Dose

Body System Noxafil delayed-release tablet
(300 mg)
n=210(%)
Subjects Reporting any Adverse Reaction 207(99)
Blood and Lymphatic System Disorder
Anemia 22(10)
Thrombocytopenia 29(14)
Gastrointestinal Disorders
Abdominal Pain 23(11)
Constipation 20(10)
Diarrhea 61(29)
Nausea 56(27)
Vomiting 28(13)
General Disorders and Administration Site Conditions
Asthenia 20(10)
Chills 22(10)
Mucosal Inflammation 29(14)
Edema Peripheral 33(16)
Pyrexia 59(28)
Metabolism and Nutrition Disorders
Hypokalemia 46(22)
Hypomagnesemia 20(10)
Nervous System Disorders
Headache 30(14)
Respiratory, Thoracic and Mediastinal Disorders
Cough 35(17)
Epistaxis 30(14)
Skin and Subcutaneous Tissue Disorders
Rash 34(16)
Vascular Disorders
Hypertension 23(11)

The most frequently reported adverse reactions (>25%) with Noxafil delayed-release tablets 300 mg once daily were diarrhea, pyrexia, and nausea.

The most common adverse reaction leading to discontinuation of Noxafil delayed-release tablets 300 mg once daily was nausea (2%).

Clinical Trial Safety Experience With Noxafil Oral Suspension

The safety of Noxafil oral suspension has been assessed in 1844 patients. 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, GVHD post HSCT, 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). Noxafil therapy was given to 171 patients for ≥6 months, with 58 patients receiving Noxafil therapy for ≥12 months. Table 10 presents adverse reactions observed at an incidence of >10% in Noxafil prophylaxis studies. Table 11 presents 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 (Noxafil Oral Suspension Study 1 and 2), the safety of Noxafil oral suspension 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 Noxafil in the prophylaxis studies were associated with GI disorders, specifically, nausea (2%), vomiting (2%), and hepatic enzymes increased (2%).

Table 10: Noxafil Oral Suspension Study 1 and Study 2. Adverse Reactions in at Least 10% of theNoxafil Oral Suspension or Fluconazole Treatment Groups (Pooled Prophylaxis Safety Analysis)

Body System Noxafil Oral Suspension n=605(%) Fluconazole n=539(%) Itraconazole n=58 (%)
Subjects Reporting any Adverse Reaction 595(98) 531(99) 58(100)
Body as a Whole - General Disorders
Fever 274(45) 254(47) 32(55)
Headache 171(28) 141(26) 23(40)
Rigors 122(20) 87(16) 17(29)
Fatigue 101(17) 98(18) 5(9)
Edema Legs 93(15) 67(12) 11(19)
Anorexia 92(15) 94(17) 16(28)
Dizziness 64(11) 56(10) 5(9)
Edema 54(9) 68(13) 8(14)
Weakness 51(8) 52(10) 2(3)
Cardiovascular Disorders, General
Hypertension 106(18) 88(16) 3(5)
Hypotension 83(14) 79(15) 10(17)
Disorders of Blood and Lymphatic System
Anemia 149(25) 124(23) 16(28)
Neutropenia 141(23) 122(23) 23(40)
Disorders of the Reproductive System and Breast
Vaginal Hemorrhage* 24(10) 20(9) 3(12)
Gastrointestinal System Disorders
Diarrhea 256(42) 212(39) 35(60)
Nausea 232(38) 198(37) 30(52)
Vomiting 174(29) 173(32) 24(41)
Abdominal Pain 161(27) 147(27) 21(36)
Constipation 126(21) 94(17) 10(17)
Dyspepsia 61(10) 50(9) 6(10)
Heart Rate and Rhythm Disorders
Tachycardia 72(12) 75(14) 3(5)
Infection and Infestations
Pharyngitis 71(12) 60(11) 12(21)
Liver and Biliary System Disorders
Bilirubinemia 59(10) 51(9) 11(19)
Metabolic and Nutritional Disorders
Hypokalemia 181(30) 142(26) 30(52)
Hypomagnesemia 110(18) 84(16) 11(19)
Hyperglycemia 68(11) 76(14) 2(3)
Hypocalcemia 56(9) 55(10) 5(9)
Musculoskeletal System Disorders
Musculoskeletal Pain 95(16) 82(15) 9(16)
Arthralgia 69(11) 67(12) 5(9)
Back Pain 63(10) 66(12) 4(7)
Platelet, Bleeding and Clotting Disorders
Thrombocytopenia 175(29) 146(27) 20(34)
Petechiae 64(11) 54(10) 9(16)
Psychiatric Disorders
Insomnia 103(17) 92(17) 11(19)
Respiratory System Disorders
Coughing 146(24) 130(24) 14(24)
Dyspnea 121(20) 116(22) 15(26)
Epistaxis 82(14) 73(14) 12(21)
Skin and Subcutaneous Tissue Disorders
Rash 113(19) 96(18) 25(43)
Pruritus 69(11) 62(12) 11(19)
* Percentages of sex-specific adverse reactions are based on the number of males/females.

HIV Infected Subjects With OPC

In 2 randomized comparative studies in OPC, the safety of Noxafil oral suspension at a dose of less than or equal to 400 mg once daily in 557 HIV-infected patients was compared to the safety of fluconazole in 262 HIV-infected patients at a dose of 100 mg once daily.

An additional 239 HIV-infected patients with refractory OPC received Noxafil oral suspension in 2 non-comparative trials for refractory OPC (rOPC). Of these subjects, 149 received the 800-mg/day dose and the remainder received the less than or equal to 400-mg once daily dose.

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

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

Table 11: Adverse Reactions in at Least 10% of the Treated Population in OPC Studies with Noxafil Oral Suspension

Body System Number (%) of Subjects
Controlled OPC Pool Refractory OPC Pool
Noxafil Oral Suspension
n=557
Fluconazole
n=262
Noxafil Oral Suspension
n=239
Subjects Reporting any Adverse Reaction* 356 (64) 175 (67) 221 (92)
Body as a Whole - General Disorders
Fever 34 (6) 22 (8) 82 (34)
Headache 44 (8) 23 (9) 47 (20)
Anorexia 10 (2) 4 (2) 46 (19)
Fatigue 18 (3) 12 (5) 31 (13)
Asthenia 9 (2) 5 (2) 31 (13)
Rigors 2 (<1) 4 (2) 29 (12)
Pain 4 (1) 2 (1) 27 (11)
Disorders of Blood and Lymphatic System
Neutropenia 21 (4) 8 (3) 39 (16)
Anemia 11 (2) 5 (2) 34 (14)
Gastrointestinal System Disorders
Diarrhea 58 (10) 34 (13) 70 (29)
Nausea 48 (9) 30 (11) 70 (29)
Vomiting 37 (7) 18 (7) 67 (28)
Abdominal Pain 27 (5) 17 (6) 43 (18)
Infection and Infestations
Candidiasis, Oral 3 (1) 1 (<1) 28 (12)
Herpes Simplex 16 (3) 8 (3) 26 (11)
Pneumonia 17 (3) 6 (2) 25 (10)
Metabolic and Nutritional Disorders
Weight Decrease 4 (1) 2 (1) 33 (14)
Dehydration 4 (1) 7 (3) 27 (11)
Psychiatric Disorders
Insomnia 8 (1) 3 (1) 39 (16)
Respiratory System Disorders
Coughing 18 (3) 11 (4) 60 (25)
Dyspnea 8 (1) 8 (3) 28 (12)
Skin and Subcutaneous Tissue Disorders
Rash 15 (3) 10 (4) 36 (15)
Sweating Increased 13 (2) 5 (2) 23 (10)
OPC=oropharyngeal candidiasis
* Number of subjects reporting adverse reactions at least once during the study, without regard to relationship to treatment. Subjects may have reported more than 1 event.

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%).

Other clinically significant adverse reactions reported in less than 5% of patients in clinical trials of Noxafil 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
  • Gastrointestinal disorders: pancreatitis
  • Liver and Biliary System Disorders: hepatic enzymes increased, hepatic function abnormal, hepatitis, hepatomegaly, jaundice
  • Renal & Urinary System Disorders: renal failure acute
Clinical Laboratory Values

In healthy volunteers and patients, elevation of liver test values did not appear to be associated with higher plasma concentrations of posaconazole.

For the prophylaxis studies, the number of patients with changes in liver 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 12.

Table 12: Noxafil Oral Suspension Study 1 and Study 2. Changes in Liver Test Results from CTCGrade 0, 1, or 2 at Baseline to Grade 3 or 4

Number (%) of Patients with Change*
Noxafil Oral Suspension Study 1
Laboratory Parameter Noxafil Oral Suspension
n=301
Fluconazole
n=299
AST 11/266 (4) 13/266 (5)
ALT 47/271 (17) 39/272 (14)
Bilirubin 24/271 (9) 20/275 (7)
Alkaline Phosphatase 9/271 (3) 8/271 (3)
Noxafil Oral Suspension Study 2
Laboratory Parameter Noxafil Oral Suspension
(n=304)
Fluconazole/Itraconazole
(n=298)
AST 9/286 (3) 5/280 (2)
ALT 18/289 (6) 13/284 (5)
Bilirubin 20/290 (7) 25/285 (9)
Alkaline Phosphatase 4/281 (1) 1/276 (<1)
*Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation.
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase.

The number of patients treated for OPC with clinically significant liver test abnormalities at any time  during the studies is provided in Table 13 (liver test abnormalities were present in some of these patients  prior to initiation of the study drug).

Table 13: Noxafil Oral Suspension Studies: Clinically Significant Laboratory Test Abnormalities without Regard to Baseline Value

Laboratory Test Controlled Refractory
Noxafil Oral Suspension
n=557(%)
Fluconazole
n=262(%)
Noxafil Oral Suspension
n=239(%)
ALT > 3.0 x ULN 16/537 (3) 13/254 (5) 25/226 (11)
AST > 3.0 x ULN 33/537 (6) 26/254 (10) 39/223 (17)
Total Bilirubin > 1.5 x ULN 15/536 (3) 5/254 (2) 9/197 (5)
Alkaline Phosphatase > 3.0 x ULN 17/535 (3) 15/253 (6) 24/190 (13)
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase.

The number of patients treated for invasive aspergillosis with clinically significant liver test abnormalities at any time during the Aspergillosis Treatment Study is provided in Table 14. Liver test abnormalities present prior to the initiation of study drug included ALT (22%), AST (13%), and bilirubin (13%).

Table 14: Aspergillosis Treatment Study: Changes in Liver Test Results from CTC Grade 0, 1, or 2 at Baseline to Grade 3 or 4

Number (%) of Patients with Change*
Laboratory Parameter Noxafil
n/N (%)
Voriconazole
n/N (%)
AST 22/281 (8) 21/285 (7)
ALT 29/281(10) 23/282 (8)
Bilirubin 26/280 (9) 25/284 (9)
Alkaline Phosphatase 12/282 (4) 20/284 (7)
*Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form n/N, where n represents the number of patients who met the criterion as indicated, and N represents the number of patients who had a baseline observation and at least one post-baseline observation. N=Number of subjects for a given laboratory test with a baseline value of CTC Grade 0, 1, or 2 and at least one post-baseline value. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase.

Clinical Trial Experience In Pediatrics

Clinical Trial Experience In Pediatric Patients (2 to less than 18 Years of Age)

The safety of Noxafil injection and Noxafil PowderMix for delayed-release oral suspension for prophylaxis of invasive fungal infections has been assessed in an open label uncontrolled dose-ranging PK and safety study (Noxafil injection/ Noxafil PowderMix for delayed-release oral suspension Pediatric Study 1, NCT02452034); hereinafter referred to as Noxafil Pediatric Study) in 115 immunocompromised pediatric patients 2 to less than 18 years of age with known or expected neutropenia. Noxafil injection and Noxafil PowderMix for delayed-release oral suspension was administered at daily doses of up to 6 mg/kg (twice daily on day 1) in three dose cohorts. All 115 subjects initially received Noxafil injection for at least 7 days, and 63 subjects were transitioned to Noxafil PowderMix for delayed-release oral suspension. The mean overall treatment duration for all treated subjects was 20.6 days with 14.3 days (range: 1 to 28 days) on Noxafil injection and 11.6 days (range: 2 to 18 days) on Noxafil PowderMix for delayed-release oral suspension [see CLINICAL PHARMACOLOGY].

Table 15 presents adverse reactions observed in greater than or equal to 10% of pediatric patients treated with Noxafil in the Noxafil Pediatric Study.

Reported adverse reaction profile of Noxafil in pediatric patients was consistent with the safety profile of Noxafil in adults. The most common adverse reactions (occurring in greater than 20% of pediatric patients receiving 6 mg/kg Noxafil injection and Noxafil PowderMix for delayed-release oral suspension daily dose) were pyrexia, febrile neutropenia, vomiting, mucosal inflammation, pruritus, hypertension, hypokalemia, and stomatitis.

Table 15: Adverse Reactions in at Least 10% of Pediatric Patients Treated with Noxafil Injectionand Noxafil PowderMix for Delayed-Release Oral Suspension

Adverse Reaction Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension 6 mg/kg Dose Cohort
n=49 (%)
Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension All Dose Cohorts
n=115 (%)
Pyrexia 16(33) 50 (43)
Febrile neutropenia 15(31) 25 (22)
Vomiting 12(24) 30 (26)
Mucosal inflammation 11 (22) 32 (28)
Pruritus 11 (22) 18(16)
Hypertension 10(20) 20(17)
Hypokalemia 10(20) 16(14)
Stomatitis 10(20) 13(11)
Diarrhea 9(18) 25 (22)
Nausea 9(18) 18(16)
Abdominal pain 8(16) 20(17)
Decreased appetite 7(14) 17(15)
Rash 7(14) 18(16)
Alanine aminotransferase increased 6(12) 8 (7)
Headache 6(12) 16(14)
Aspartate aminotransferase increased 5(10) 8 (7)

The number of patients receiving Noxafil in the Noxafil Pediatric Study who had changes in liver tests from Grade 0, 1, or 2 at baseline to Grade 3 or 4 is presented in Table 16.

Table 16: Noxafil Pediatric Study: Changes in Liver Tests from CTC Grade 0, 1, or 2 at Baseline toGrade 3 or 4

Number (%) of Patients with Change* Pediatric Study 1
Laboratory Parameter Noxafil Injection and Noxafil PowderMix for Delayed-Release Oral Suspension (6 mg/kg daily)
n=49 (%)
AST 2/49 (4)
ALT 3/49 (6)
Bilirubin 0/48 (0)
Alkaline Phosphatase 0/48 (0)
*Change from Grade 0 to 2 at baseline to Grade 3 or 4 during the study. These data are presented in the form X/Y, where X represents the number of patients who met the criterion as indicated, and Y represents the number of patients who had a baseline observation and at least one post-baseline observation. CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; ALT= Alanine Aminotransferase

Postmarketing Experience

The following adverse reaction has been identified during the post-approval use of Noxafil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Endocrine Disorders: Pseudoaldosteronism

DRUG INTERACTIONS

Posaconazole is primarily metabolized via UDP glucuronosyltransferase and is a substrate of pglycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

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].

The following information was derived from data with Noxafil oral suspension or early tablet formulation unless otherwise noted. All drug interactions with Noxafil oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility), are considered relevant to Noxafil injection, Noxafil delayed-release tablet, and Noxafil PowderMix for delayed-release oral suspension as well [see DRUG INTERACTIONS].

Immunosuppressants Metabolized By CYP3A4

Sirolimus

Concomitant administration of Noxafil 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

Noxafil 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 Noxafil treatment and the tacrolimus dose adjusted accordingly [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Cyclosporine

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

CYP3A4 Substrates

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

HMG-CoA Reductase Inhibitors (Statins) Primarily Metabolized Through CYP3A4

Concomitant administration of Noxafil with simvastatin increases the simvastatin plasma concentrations by approximately 10-fold. Therefore, Noxafil is contraindicated with HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

Ergot Alkaloids

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

Benzodiazepines Metabolized By CYP3A4

Concomitant administration of Noxafil 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 Noxafil 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 Noxafil unless the benefit outweighs the risks.

Ritonavir And Atazanavir

Ritonavir and atazanavir are metabolized by CYP3A4 and Noxafil increases plasma concentrations of these drugs [see CLINICAL PHARMACOLOGY]. Frequent monitoring of adverse effects and toxicity of ritonavir and atazanavir should be performed during coadministration with Noxafil.

Fosamprenavir

Combining fosamprenavir with Noxafil may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended [see CLINICAL PHARMACOLOGY].

Rifabutin

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

Gastric Acid Suppressors/Neutralizers

Noxafil Delayed-Release Tablet And Noxafil PowderMix For Delayed-Release Oral Suspension

No clinically relevant effects on the pharmacokinetics of posaconazole were observed when Noxafil delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors [see CLINICAL PHARMACOLOGY]. No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required when concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.

Noxafil Oral Suspension

Cimetidine (an H2-receptor antagonist) and esomeprazole (a proton pump inhibitor) when given with Noxafil oral suspension results in decreased posaconazole plasma concentrations [see CLINICAL PHARMACOLOGY]. It is recommended to avoid concomitant use of cimetidine and esomeprazole with Noxafil oral suspension unless the benefit outweighs the risks. However, if concomitant administration is required, close monitoring for breakthrough fungal infections is recommended.

No clinically relevant effects were observed when Noxafil oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine. No dosage adjustment of Noxafil oral suspension is required when Noxafil oral suspension is concomitantly used with antacids and H2-receptor antagonists other than cimetidine.

Vinca Alkaloids

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with serious adverse reactions [see WARNINGS AND PRECAUTIONS]. Noxafil may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including Noxafil, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

Calcium Channel Blockers Metabolized By CYP3A4

Noxafil 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 Noxafil. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.

Gastrointestinal Motility Agents

Noxafil Delayed-Release Tablet and Noxafil PowderMix For Delayed-Release Oral Suspension

Concomitant administration of metoclopramide with Noxafil delayed-release tablets did not affect the pharmacokinetics of posaconazole [see CLINICAL PHARMACOLOGY]. No dosage adjustment of Noxafil delayed-release tablets or Noxafil PowderMix for delayed-release oral suspension is required when given concomitantly with metoclopramide.

Noxafil Oral Suspension

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

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

Glipizide

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

Alcohol

Posaconazole was found to release faster from Noxafil PowderMix for delayed-release oral suspension in the presence of alcohol in vitro, which may interfere with its delayed release characteristics. Administration of Noxafil PowderMix for delayed-release oral suspension with alcohol is not recommended [see CLINICAL PHARMACOLOGY].

Venetoclax

Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. Refer to the venetoclax prescribing information for more information on the dosing instructions and the extent of increase in venetoclax exposure.

Read the entire FDA prescribing information for Noxafil (Posaconazole Oral Suspension)

© Noxafil Patient Information is supplied by Cerner Multum, Inc. and Noxafil Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Health Solutions From Our Sponsors