|
|||
DRUGS & SUPPLEMENTS
|
What are the side effects you encounter while taking this medicine? |
Noxafil is an azole antifungal agent indicated for:
injection, delayed-release tablets, and oral suspension
Oral suspension
Noxafil® injection, delayed-release tablets, and oral suspension are indicated for prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised, such as hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with hematologic malignancies with prolonged neutropenia from chemotherapy.
Noxafil injection is indicated in patients 18 years of age and older.
Noxafil delayed-release tablets and oral suspension are indicated in patients 13 years of age and older.
Noxafil oral suspension is indicated for the treatment of oropharyngeal candidiasis, including oropharyngeal candidiasis refractory to itraconazole and/or fluconazole.
Noxafil delayed-release tablets and oral suspension are not interchangeable due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations.
Indication | Dose and Duration of Therapy |
---|---|
Prophylaxis of invasive Aspergillus and Candida infections | Injection |
Loading dose: 300 mg Noxafil injection intravenously twice a day on the first day. | |
Maintenance dose: 300 mg Noxafil injection intravenously once a day thereafter. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.1) | |
Delayed-Release Tablets | |
Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. | |
Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression. (2.2) | |
Oral Suspension | |
Oropharyngeal Candidiasis (OPC) | Oral Suspension |
Loading dose: 100 mg (2.5 mL) twice a day on the first day. | |
Maintenance dose: 100 mg (2.5 mL) once a day for 13 days. (2.3) | |
OPC Refractory (rOPC) to Itraconazole and/or Fluconazole | Oral Suspension |
Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation .
Noxafil injection
Noxafil delayed-release tablets
Noxafil oral suspension
Noxafil delayed-release tablets and Noxafil oral suspension
Dosage:
Indication | Dose and Duration of Therapy |
---|---|
Prophylaxis of invasive Aspergillus and Candida infections | Loading dose: 300 mg Noxafil injection intravenously twice a day on the first day. |
Maintenance dose: 300 mg Noxafil injection intravenously once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression. |
Preparation:
Intravenous Line Compatibility:
A study was conducted to evaluate physical compatibility of Noxafil injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity. Compatible diluents and drug products are listed in Tables 2 and 3 below. Any diluents or drug products not listed in the tables below should not be co-administered through the same intravenous line (or cannula).
0.45% sodium chloride |
0.9% sodium chloride |
5% dextrose in water |
5% dextrose and 0.45% sodium chloride |
5% dextrose and 0.9% sodium chloride |
5% dextrose and 20 mEq potassium chloride |
Amikacin sulfate |
Caspofungin |
Ciprofloxacin |
Daptomycin |
Dobutamine hydrochloride |
Famotidine |
Filgrastim |
Gentamicin sulfate |
Hydromorphone hydrochloride |
Levofloxacin |
Lorazepam |
Meropenem |
Micafungin |
Morphine sulfate |
Norepinephrine bitartrate |
Potassium chloride |
Vancomycin hydrochloride |
Incompatible Diluents:
Noxafil injection must not be diluted with the following diluents:
Lactated Ringer's solution
5% dextrose with Lactated Ringer's solution
4.2% sodium bicarbonate
Administration:
Dosage:
Indication | Dose and Duration of Therapy |
---|---|
Prophylaxis of invasive Aspergillus and Candida infections | Loading dose: 300 mg (three 100 mg delayed-release tablets) twice a day on the first day. |
Maintenance dose: 300 mg (three 100 mg delayed-release tablets) once a day, starting on the second day. Duration of therapy is based on recovery from neutropenia or immunosuppression. |
Administration Instructions for Noxafil Delayed-Release Tablets:
Dosage:
Indication | Dose and Duration of Therapy |
---|---|
Prophylaxis of invasive Aspergillus and Candida infections | 200 mg three times a day. The duration of therapy is based on recovery from neutropenia or immunosuppression. |
Oropharyngeal Candidiasis | Loading dose: 100 mg (2.5 mL) twice a day on the first day. |
Maintenance dose: 100 mg (2.5 mL) once a day for 13 days. | |
Oropharyngeal Candidiasis Refractory to Itraconazole and/or Fluconazole | 400 mg (10 mL) twice a day. Duration of therapy should be based on the severity of the patient's underlying disease and clinical response. |
Administration Instructions for Noxafil Oral Suspension:
Noxafil delayed-release tablets and oral suspension are not to be used interchangeably due to the differences in the dosing of each formulation. Therefore, follow the specific dosage recommendations for each of the formulations .
The pharmacokinetics of Noxafil oral suspension and delayed-release tablets are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment.
Noxafil injection is available in Type I glass vials closed with bromobutyl rubber stopper and aluminum seal containing 300 mg per 16.7 mL of solution (18 mg of Noxafil per mL).
Noxafil 100 mg delayed-release tablets are available as yellow, coated, oblong tablets, debossed with "100" on one side.
Noxafil oral suspension is available in 4-ounce (123 mL) amber glass bottles with child-resistant closures containing 105 mL of suspension (40 mg of Noxafil per mL).
Noxafil is contraindicated in persons with known hypersensitivity to Noxafil or other azole antifungal agents.
Noxafil is contraindicated with sirolimus. Concomitant administration of Noxafil with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity .
Noxafil is contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration of Noxafil with the CYP3A4 substrates, pimozide and quinidine may result in increased plasma concentrations of these drugs, leading to QTc prolongation and cases of torsades de pointes .
Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis .
Noxafil may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) which may lead to ergotism .
Concomitant administration of Noxafil with cyclosporine or tacrolimus increases the whole blood trough concentrations of these calcineurin-inhibitors . Nephrotoxicity and leukoencephalopathy (including deaths) have been reported in clinical efficacy studies in patients with elevated cyclosporine or tacrolimus concentrations. Frequent monitoring of tacrolimus or cyclosporine whole blood trough concentrations should be performed during and at discontinuation of Noxafil treatment and the tacrolimus or cyclosporine dose adjusted accordingly.
Some azoles, including Noxafil, have been associated with prolongation of the QT interval on the electrocardiogram. In addition, cases of torsades de pointes have been reported in patients taking Noxafil.
Results from a multiple time-matched ECG analysis in healthy volunteers did not show any increase in the mean of the QTc interval. Multiple, time-matched ECGs collected over a 12-hour period were recorded at baseline and steady-state from 173 healthy male and female volunteers administered Noxafil oral suspension 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change from baseline was –5 msec following administration of the recommended clinical dose. A decrease in the QTc(F) interval (–3 msec) was also observed in a small number of subjects (n=16) administered placebo. The placebo-adjusted mean maximum QTc(F) interval change from baseline was <0 msec (–8 msec). No healthy subject administered Noxafil had a QTc(F) interval ≥500 msec or an increase ≥60 msec in their QTc(F) interval from baseline.
Noxafil should be administered with caution to patients with potentially proarrhythmic conditions. Do not administer with drugs that are known to prolong the QTc interval and are metabolized through CYP3A4 . Rigorous attempts to correct potassium, magnesium, and calcium should be made before starting Noxafil.
Hepatic reactions (e.g., mild to moderate elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. The elevations in liver function tests were generally reversible on discontinuation of therapy, and in some instances these tests normalized without drug interruption. Cases of more severe hepatic reactions including cholestasis or hepatic failure including deaths have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with Noxafil. These severe hepatic reactions were seen primarily in subjects receiving the Noxafil oral suspension 800 mg daily (400 mg BID or 200 mg QID) in clinical trials.
Liver function tests should be evaluated at the start of and during the course of Noxafil therapy. Patients who develop abnormal liver function tests during Noxafil therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of Noxafil must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Noxafil.
Due to the variability in exposure with Noxafil delayed-release tablets and oral suspension, patients with severe renal impairment should be monitored closely for breakthrough fungal infections .
Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy .
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. Patients must be monitored closely for adverse effects associated with high plasma concentrations of midazolam and benzodiazepine receptor antagonists must be available to reverse these effects .
Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including Noxafil, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options .
To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The following serious and otherwise important adverse reactions are discussed in detail in another section of the labeling:
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. In clinical trials, the type of adverse reactions reported for Noxafil injection and Noxafil delayed-release tablets were generally similar to that reported in trials of Noxafil oral suspension.
Clinical Trial Experience with Noxafil Injection
Multiple doses of Noxafil injection administered via a peripheral venous catheter were associated with thrombophlebitis. 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 (Posaconazole Injection Study 1). 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 6 presents treatment-emergent 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.
Body System Preferred Term | Noxafil Injection Treatment Phase n=237 (%) | Noxafil Injection Treatment Phase or Subsequent 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) |
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
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 (Delayed-Release Tablet Study 1). 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. Noxafil 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 7 presents treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥10% in Noxafil delayed-release tablet study.
Body System Preferred Term | Noxafil delayed-release tablet (300 mg) (n=210) | |
---|---|---|
Subjects Reporting any Adverse Reaction | 201 | (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 8 presents treatment-emergent adverse reactions observed at an incidence of >10% in Noxafil prophylaxis studies. Table 9 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 (Oral Suspension Studies 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%).
Body System Preferred Term | Noxafil (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) |
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 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 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 QD 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%).
Body System Preferred Term | Number (%) of Subjects | ||
---|---|---|---|
Controlled OPC Pool | Refractory OPC Pool | ||
Noxafil | Fluconazole | Noxafil | |
n=557 | n=262 | n=239 | |
OPC=oropharyngeal candidiasis | |||
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) |
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 Noxafil which occurred in less than 5% of patients are listed below:
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 Noxafil.
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 10.
Number (%) of Patients With Change | ||
---|---|---|
CTC = Common Toxicity Criteria; AST= Aspartate Aminotransferase; | ||
ALT= Alanine Aminotransferase. | ||
Oral Suspension Study 1 | ||
Laboratory Parameter | Noxafil 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) |
Oral Suspension Study 2 | ||
Laboratory Parameter | Noxafil (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) |
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 11 (LFT abnormalities were present in some of these patients prior to initiation of the study drug).
Laboratory Test | Controlled | Refractory | |
---|---|---|---|
Noxafil | Fluconazole | Noxafil | |
n=557(%) | n=262(%) | n=239(%) | |
ALT= Alanine Aminotransferase; AST= Aspartate Aminotransferase. | |||
ALT > 3.0 × ULN | 16/537 (3) | 13/254 (5) | 25/226 (11) |
AST > 3.0 × ULN | 33/537 (6) | 26/254 (10) | 39/223 (17) |
Total Bilirubin > 1.5 × ULN | 15/536 (3) | 5/254 (2) | 9/197 (5) |
Alkaline Phosphatase > 3.0 × ULN | 17/535 (3) | 15/253 (6) | 24/190 (13) |
No clinically significant postmarketing adverse reactions were identified that have not previously been reported during clinical trials experience.
Noxafil is primarily metabolized via UDP glucuronosyltransferase and is a substrate of p-glycoprotein efflux. Therefore, inhibitors or inducers of these clearance pathways may affect Noxafil plasma concentrations. Coadministration of drugs that can decrease the plasma concentrations of Noxafil should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.
Noxafil is also a strong inhibitor of CYP3A4. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may be increased by Noxafil .
The following information was derived from data with Noxafil oral suspension or early tablet formulation. All drug interactions with Noxafil oral suspension, except for those that affect the absorption of Noxafil (via gastric pH and motility) are considered relevant to Noxafil injection as well .
Interaction Drug | Interaction |
---|---|
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazole | Avoid coadministration unless the benefit outweighs the risks (7.6, 7.7, 7.8, 7.9) |
Other drugs metabolized by CYP3A4 | Consider dosage adjustment and monitor for adverse effects and toxicity (7.1, 7.10, 7.11) |
Digoxin | Monitor digoxin plasma concentrations (7.12) |
Fosamprenavir, metoclopramide | Monitor for breakthrough fungal infections (7.6, 7.13) |
Sirolimus: Concomitant administration of Noxafil with sirolimus increases the sirolimus blood concentrations by approximately 9-fold and can result in sirolimus toxicity. Therefore, Noxafil is contraindicated with sirolimus .
Tacrolimus: Noxafil has been shown to significantly increase the Cmax and AUC of tacrolimus. At initiation of Noxafil 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 .
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 .
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 .
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 .
Most of the ergot alkaloids are substrates of CYP3A4. Noxafil may increase the plasma concentrations of ergot alkaloids which may lead to ergotism. Therefore, Noxafil is contraindicated with ergot alkaloids .
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 .
Efavirenz: Efavirenz induces UDP-glucuronidase and significantly decreases Noxafil plasma concentrations . 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 . 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 Noxafil plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended .
Rifabutin induces UDP-glucuronidase and decreases Noxafil plasma concentrations. Rifabutin is also metabolized by CYP3A4. Therefore, coadministration of rifabutin with Noxafil increases rifabutin plasma concentrations . 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 induces UDP-glucuronidase and decreases Noxafil plasma concentrations. Phenytoin is also metabolized by CYP3A4. Therefore, coadministration of phenytoin with Noxafil increases phenytoin plasma concentrations . 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.
Noxafil Delayed-Release Tablet:
No clinically relevant effects on the pharmacokinetics of Noxafil were observed when Noxafil delayed-release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors . No dosage adjustment of Noxafil delayed-release tablets is required when Noxafil delayed-release tablets are 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 Noxafil plasma concentrations . 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.
Most of the vinca alkaloids are substrates of CYP3A4. Concomitant administration of azole antifungals, including Noxafil, with vincristine has been associated with serious adverse reactions . 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.
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.
Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and Noxafil. Therefore, monitoring of digoxin plasma concentrations is recommended during coadministration.
Noxafil Delayed-Release Tablet:
Concomitant administration of metoclopramide with Noxafil delayed-release tablets did not affect the pharmacokinetics of Noxafil . No dosage adjustment of Noxafil delayed-release tablets is required when given concomitantly with metoclopramide.
Noxafil Oral Suspension:
Metoclopramide, when given with Noxafil oral suspension, decreases Noxafil plasma concentrations . If metoclopramide is concomitantly administered with Noxafil oral suspension, it is recommended to closely monitor for breakthrough fungal infections.
Loperamide does not affect Noxafil plasma concentrations after Noxafil oral suspension administration. No dosage adjustment of Noxafil is required when loperamide and Noxafil are used concomitantly.
Although no dosage adjustment of glipizide is required, it is recommended to monitor glucose concentrations when Noxafil and glipizide are concomitantly used.
There are no adequate and well-controlled studies in pregnant women. Noxafil should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Noxafil has been shown to cause skeletal malformations (cranial malformations and missing ribs) in rats when given in doses ≥27 mg/kg (≥1.4 times the 400-mg BID oral suspension regimen based on steady-state plasma concentrations of drug in healthy volunteers). The no-effect dose for malformations in rats was 9 mg/kg, which is 0.7 times the exposure achieved with the 400-mg BID oral suspension regimen. No malformations were seen in rabbits at doses up to 80 mg/kg. In the rabbit, the no-effect dose was 20 mg/kg, while high doses of 40 mg/kg and 80 mg/kg, 2.9 or 5.2 times the exposure achieved with the 400-mg BID oral suspension regimen, caused an increase in resorptions. In rabbits dosed at 80 mg/kg, a reduction in body weight gain of females and a reduction in litter size were seen.
Noxafil is excreted in milk of lactating rats. It is not known whether Noxafil is excreted in human milk. Because of the potential for serious adverse reactions from Noxafil in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of Noxafil injection in pediatric patients below the age of 18 years of age has not been established. Noxafil injection should not be used in pediatric patients because of nonclinical safety concerns .
The safety and effectiveness of Noxafil oral suspension and Noxafil delayed-release tablets have been established in the age groups 13 to 17 years of age. Use of Noxafil in these age groups is supported by evidence from adequate and well-controlled studies of Noxafil in adults. The safety and effectiveness of Noxafil in pediatric patients below the age of 13 years (birth to 12 years) have not been established.
A total of 12 patients 13 to 17 years of age received 600 mg/day (200 mg three times a day) of Noxafil oral suspension for prophylaxis of invasive fungal infections. The safety profile in these patients <18 years of age appears similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these pediatric patients, the mean steady-state average Noxafil concentration (Cavg) was similar between these patients and adults (≥18 years of age). In a study of 136 neutropenic pediatric patients 11 months to less than 18 years treated with Noxafil oral suspension, the exposure target of steady-state Noxafil Cavg between 500 ng/mL and less than 2500 ng/mL was attained in approximately 50% of patients instead of the pre-specified 90% of patients.
Of the 279 patients treated with Noxafil injection, 52 (19%) were greater than 65 years of age. The pharmacokinetics of Noxafil injection are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for Noxafil injection in geriatric patients.
Of the 230 patients treated with Noxafil delayed-release tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of Noxafil delayed-release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.
Of the 605 patients randomized to Noxafil oral suspension in the prophylaxis clinical trials, 63 (10%) were ≥65 years of age. In addition, 48 patients treated with greater than or equal to 800-mg/day Noxafil in another indication were ≥65 years of age. No overall differences in safety were observed between the geriatric patients and younger patients.
The pharmacokinetics of Noxafil oral suspension are comparable in young and elderly subjects (≥65 years of age); therefore no adjustment in the dosage of Noxafil oral suspension is necessary in geriatric patients.
No overall differences in the pharmacokinetics and safety were observed between elderly and young subjects during clinical trials, but greater sensitivity of some older individuals cannot be ruled out.
Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild or moderate (eGFR: 20-49 mL/min/1.73 m2, n=6) renal impairment on Noxafil pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in the other renal impairment groups (CV<40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections . Similar recommendations apply to Noxafil delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.
Noxafil injection should be avoided in patients with moderate or severe renal impairment (eGFR <50 mL/min), unless an assessment of the benefit/risk to the patient justifies the use of Noxafil injection. In patients with moderate or severe renal impairment (eGFR <50 mL/min), receiving the Noxafil injection, accumulation of the intravenous vehicle, SBECD, is expected to occur. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Noxafil therapy .
After a single oral dose of Noxafil oral suspension 400 mg, the mean AUC was 43%, 27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, compared to subjects with normal hepatic function (N=18). Compared to subjects with normal hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance (CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic impairment, respectively, compared to subjects with normal hepatic function. The elimination half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic function and mild, moderate, or severe hepatic impairment, respectively.
It is recommended that no dose adjustment of Noxafil is needed in patients with mild to severe hepatic impairment (Child-Pugh Class A, B, or C) [see Dosage and Administration (2) and Warnings and Precautions (5.3)]. Similar recommendations apply to Noxafil delayed-release tablets; however, a specific study has not been conducted with the delayed-release tablets.
Similar recommendations apply to Noxafil injection; however, a specific study has not been conducted with the Noxafil injection.
The pharmacokinetics of Noxafil are comparable in men and women. No adjustment in the dosage of Noxafil is necessary based on gender.
The pharmacokinetic profile of Noxafil is not significantly affected by race. No adjustment in the dosage of Noxafil is necessary based on race.
Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower Noxafil plasma drug exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections.
There is no experience with overdosage of Noxafil injection and delayed-release tablets.
During the clinical trials, some patients received Noxafil oral suspension up to 1600 mg/day with no adverse reactions noted that were different from the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg BID Noxafil oral suspension for 3 days. No related adverse reactions were noted by the investigator.
Noxafil is not removed by hemodialysis.
Noxafil is an azole antifungal agent available as concentrated solution to be diluted before intravenous administration, delayed-release tablet, or suspension for oral administration.
Noxafil is designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 and a molecular weight of 700.8. The chemical structure is:
Follow the instructions from your healthcare provider on how much Noxafil you should take and when to take it.
What are the possible side effects of Noxafil?
Noxafil may cause serious side effects, including:
|
|
The most common side effects of Noxafil include:
If you take Noxafil delayed-release tablets or Noxafil oral suspension, tell your healthcare provider right away if you have diarrhea or vomiting.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Noxafil. For more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Noxafil?
Keep Noxafil and all medicines out of the reach of children.
General information about the safe and effective use of Noxafil.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Noxafil for a condition for which it was not prescribed. Do not give Noxafil to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Noxafil that is written for health professionals.
What are the ingredients in Noxafil?
Active ingredient: Noxafil
Inactive ingredients:
Noxafil injection: Betadex Sulfobutyl Ether Sodium (SBECD), edetate sodium, hydrochloric acid, sodium hydroxide, and water for injection.
Noxafil delayed-release tablets: hypromellose acetate succinate, microcrystalline cellulose, hydroxypropylcellulose, silicon dioxide, croscarmellose sodium, magnesium stearate, and Opadry® II Yellow (consists of the following ingredients: polyvinyl alcohol partially hydrolyzed, Macrogol/PEG 3350, titanium dioxide, talc, and iron oxide yellow)
Noxafil oral suspension: polysorbate 80, simethicone, sodium benzoate, sodium citrate dihydrate, citric acid monohydrate, glycerin, xanthan gum, liquid glucose, titanium dioxide, artificial cherry flavor, and purified water
Manuf. for: Merck Sharp & Dohme Corp., a subsidiary of
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
Injection: MSD International GmbH, Brinny, Innishannon, County Cork, Ireland
Delayed-Release Tablets: Manuf. by: N. V. Organon, Kloosterstraat 6, 5349 AB Oss, Netherlands
Oral Suspension: Manuf. by: Patheon Inc., Whitby, Ontario, Canada L1N 5Z5
For patent information: www.merck.com/product/patent/home.html
The trademarks depicted in this piece are owned by their respective companies.
Copyright © 2006-2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
All rights reserved.
usppi-mk5592-mf-1703r017
For more information, go to www.noxafil.com or call 1-800-672-6372.
Depending on the reaction of the Noxafil after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Noxafil not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.
Is Noxafil addictive or habit forming?Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
There are no reviews yet. Be the first to write one! |
The information was verified by Dr. Rachana Salvi, MD Pharmacology