Voriconazole tablets are indicated for use in patients 12 years of age and older in the treatment of the following fungal infections:
Invasive Aspergillosis
In clinical trials, the majority of isolates recovered were Aspergillus fumigatus. There was a small number of cases of culture-proven disease due to species of Aspergillus other than A. fumigatus [see Clinical Studies (14.1) and Clinical Pharmacology (12.4)].
Candidemia in Nonneutropenic Patients and the Following Candida Infections: Disseminated Infections in Skin and Infections in Abdomen, Kidney, Bladder Wall and Wounds
[See Clinical Studies (14.2) and Clinical Pharmacology (12.4).]
Esophageal Candidiasis
[See Clinical Studies (14.3) and Clinical Pharmacology (12.4).]
Serious Fungal Infections Caused by Scedosporium apiospermum (Asexual Form of Pseudallescheria boydii) and Fusarium spp. Including Fusarium solani, in Patients Intolerant of, or Refractory to, Other Therapy
[See Clinical Studies (14.4) and Clinical Pharmacology (12.4).]
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
Voriconazole Dosage and Administration
Instructions for Use in All Patients
Voriconazole tablets should be taken at least one hour before or after a meal.
Recommended Dosing in Adults
Invasive aspergillosis and serious fungal infections due to Fusarium spp. and Scedosporium apiospermumSee Table 1. Therapy must be initiated with the specified loading dose regimen of intravenous Voriconazole on Day 1 followed by the recommended maintenance dose regimen. Intravenous treatment should be continued for at least 7 days. Once the patient has clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of Voriconazole may be utilized. The recommended oral maintenance dose of 200 mg achieves a Voriconazole exposure similar to 3 mg/kg IV; a 300 mg oral dose achieves an exposure similar to 4 mg/kg IV. Switching between the intravenous and oral formulations is appropriate because of the high bioavailability of the oral formulation in adults [see Clinical Pharmacology (12)].
Candidemia in nonneutropenic patients and other deep tissue Candida infectionsSee Table 1. Patients should be treated for at least 14 days following resolution of symptoms or following last positive culture, whichever is longer.
Esophageal CandidiasisSee Table 1. Patients should be treated for a minimum of 14 days and for at least 7 days following resolution of symptoms.
Table 1. Recommended Dosing Regimen
|
| Infection |
Loading dose |
Maintenance Dose |
|
IV |
IV |
Oral |
| Invasive Aspergillosis |
6 mg/kg q12h for the first 24 hours |
4 mg/kg q12h |
200 mg q12h |
| Candidemia in non-neutropenic patients and other deep tissue Candida infections |
6 mg/kg q12h for the first 24 hours |
3 to 4 mg/kg q12h |
200 mg q12h |
| Esophageal Candidiasis |
|
# |
200 mg q12h |
Scedosporiosis and
Fusariosis |
6 mg/kg q12h for the first 24 hours
|
4 mg/kg q12h |
200 mg q12h |
Dosage Adjustment
If patient response is inadequate, the oral maintenance dose may be increased from 200 mg every 12 hours (similar to 3 mg/kg IV q12h) to 300 mg every 12 hours (similar to 4 mg/kg IV q12h). For adult patients weighing less than 40 kg, the oral maintenance dose may be increased from 100 mg every 12 hours to 150 mg every 12 hours. If patient is unable to tolerate 300 mg orally every 12 hours, reduce the oral maintenance dose by 50 mg steps to a minimum of 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).
If patient is unable to tolerate 4 mg/kg IV q12h, reduce the intravenous maintenance dose to 3 mg/kg q12h.
The maintenance dose of Voriconazole should be increased when coadministered with phenytoin or efavirenz [see Drug Interactions (7)].
The maintenance dose of Voriconazole should be reduced in patients with mild to moderate hepatic impairment, Child-Pugh Class A and B [see Dosage and Administration (2.7)]. There are no PK data to allow for dosage adjustment recommendations in patients with severe hepatic impairment (Child-Pugh Class C). Duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression and clinical response.
Use in Patients with Hepatic Impairment
In the clinical program, patients were included who had baseline liver function tests (ALT, AST) up to 5 times the upper limit of normal. No dose adjustment is necessary in patients with this degree of abnormal liver function, but continued monitoring of liver function tests for further elevations is recommended [see Warnings and Precautions (5.9)].
It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) [see Clinical Pharmacology (12.3)].
Voriconazole tablets have not been studied in patients with severe hepatic cirrhosis (Child-Pugh Class C) or in patients with chronic hepatitis B or chronic hepatitis C disease. Voriconazole tablets have been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice and should only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
Use in Patients with Renal Impairment
The pharmacokinetics of orally administered Voriconazole are not significantly affected by renal impairment. Therefore, no adjustment is necessary for oral dosing in patients with mild to severe renal impairment [see Clinical Pharmacology (12.3)].
In patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral Voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous Voriconazole. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to oral Voriconazole therapy [see Warnings and Precautions (5.10)].
Voriconazole is hemodialyzed with clearance of 121 mL/min. The intravenous vehicle, SBECD, is hemodialyzed with clearance of 55 mL/min. A 4-hour hemodialysis session does not remove a sufficient amount of Voriconazole to warrant dose adjustment.
Dosage Forms and Strengths
Tablets: Voriconazole 50 mg tablets; white, film-coated, oval, unscored, debossed with V26 on one side of the tablet and blank on the other side.
Voriconazole 200 mg tablets; white, film-coated, capsule-shaped, unscored, debossed with M164 on one side of the tablet and blank on the other side.
Contraindications
- Voriconazole tablets are contraindicated in patients with known hypersensitivity to Voriconazole or its excipients. There is no information regarding cross-sensitivity between Voriconazole and other azole antifungal agents. Caution should be used when prescribing Voriconazole to patients with hypersensitivity to other azoles.
- Coadministration of terfenadine, astemizole, cisapride, pimozide or quinidine with Voriconazole is contraindicated because increased plasma concentrations of these drugs can lead to QT prolongation and rare occurrences of torsade de pointes [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
- Coadministration of Voriconazole with sirolimus is contraindicated because Voriconazole significantly increases sirolimus concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
- Coadministration of Voriconazole with rifampin, carbamazepine and long-acting barbiturates is contraindicated because these drugs are likely to decrease plasma Voriconazole concentrations significantly [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
- Coadministration of Voriconazole with high-dose ritonavir (400 mg q12h) is contraindicated because ritonavir (400 mg q12h) significantly decreases plasma Voriconazole concentrations. Coadministration of Voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of Voriconazole [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
- Coadministration of Voriconazole with rifabutin is contraindicated since Voriconazole significantly increases rifabutin plasma concentrations and rifabutin also significantly decreases Voriconazole plasma concentrations [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
- Coadministration of Voriconazole with ergot alkaloids (ergotamine and dihydroergotamine) is contraindicated because Voriconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
- Coadministration of Voriconazole with St. John’s Wort is contraindicated because this herbal supplement may decrease Voriconazole plasma concentration [see Drug Interactions (7) and Clinical Pharmacology (12.3)].
Warnings and Precautions
Drug Interactions
See Table 6 for a listing of drugs that may significantly alter Voriconazole concentrations. Also, see Table 7 for a listing of drugs that may interact with Voriconazole resulting in altered pharmacokinetics or pharmacodynamics of the other drug [see Contraindications (4) and Drug Interactions (7)].
Hepatic Toxicity
In clinical trials, there have been uncommon cases of serious hepatic reactions during treatment with Voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly hematological malignancy). Hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy [see Warnings and Precautions (5.9) and Adverse Reactions (6.3)].
Monitoring of Hepatic FunctionLiver function tests should be evaluated at the start of and during the course of Voriconazole therapy. Patients who develop abnormal liver function tests during Voriconazole 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 Voriconazole must be considered if clinical signs and symptoms consistent with liver disease develop that may be attributable to Voriconazole [see Warnings and Precautions (5.9), Dosage and Administration (2.4, 2.7) and Adverse Reactions (6.3)].
Visual Disturbances
The effect of Voriconazole on visual function is not known if treatment continues beyond 28 days. There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema. If treatment continues beyond 28 days, visual function including visual acuity, visual field and color perception should be monitored [see Adverse Reactions (6.2)].
Pregnancy Category D
Voriconazole can cause fetal harm when administered to a pregnant woman.
In animals, Voriconazole administration was associated with teratogenicity, embryotoxicity, increased gestational length, dystocia and embryomortality. Please refer to section 8.1 (Pregnancy) for additional details.
If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to the fetus.
Galactose Intolerance
Voriconazole tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
Arrhythmias and QT Prolongation
Some azoles, including Voriconazole, have been associated with prolongation of the QT interval on the electrocardiogram. During clinical development and post-marketing surveillance, there have been rare cases of arrhythmias, (including ventricular arrhythmias such as torsade de pointes), cardiac arrests and sudden deaths in patients taking Voriconazole. These cases usually involved seriously ill patients with multiple confounding risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory.
Voriconazole should be administered with caution to patients with these potentially proarrhythmic conditions.
Rigorous attempts to correct potassium, magnesium and calcium should be made before starting Voriconazole [see Clinical Pharmacology (12.3)].
Laboratory Tests
Electrolyte disturbances such as hypokalemia, hypomagnesemia and hypocalcemia should be corrected prior to initiation of Voriconazole therapy.
Patient management should include laboratory evaluation of renal (particularly serum creatinine) and hepatic function (particularly liver function tests and bilirubin).
Patients with Hepatic Impairment
It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh Class A and B) receiving Voriconazole [see Clinical Pharmacology (12.3) and Dosage and Administration (2.7)].
Voriconazole has not been studied in patients with severe cirrhosis (Child-Pugh Class C). Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice and should only be used in patients with severe hepatic insufficiency if the benefit outweighs the potential risk. Patients with hepatic insufficiency must be carefully monitored for drug toxicity.
Patients with Renal Impairment
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral Voriconazole should be administered to these patients, unless an assessment of the benefit/risk to the patient justifies the use of intravenous Voriconazole. Serum creatinine levels should be closely monitored in these patients and if increases occur, consideration should be given to changing to oral Voriconazole therapy [see Clinical Pharmacology (12.3) and Dosage and Administration (2.8)].
Monitoring of Renal Function
Acute renal failure has been observed in patients undergoing treatment with Voriconazole. Patients being treated with Voriconazole are likely to be treated concomitantly with nephrotoxic medications and have concurrent conditions that may result in decreased renal function.
Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Monitoring of Pancreatic Function
Patients with risk factors for acute pancreatitis (e.g., recent chemotherapy, hematopoietic stem cell transplantation [HSCT]) should be monitored for the development of pancreatitis during Voriconazole treatment.
Dermatological Reactions
Serious exfoliative cutaneous reactions, such as Stevens-Johnson Syndrome, have been reported during treatment with Voriconazole. If a patient develops an exfoliative cutaneous reaction, Voriconazole should be discontinued.
In addition Voriconazole has been associated with photosensitivity skin reaction. Patients should avoid intense or prolonged exposure to direct sunlight during Voriconazole treatment. In patients with photosensitivity skin reactions squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. If a patient develops a skin lesion consistent with squamous cell carcinoma or melanoma, Voriconazole should be discontinued.
Skeletal Adverse Events
Fluorosis and periostitis have been reported during long-term Voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with fluorosis or periostitis, Voriconazole should be discontinued [see Adverse Reactions (6.4)].
Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Overview
The most frequently reported adverse events (all causalities) in the therapeutic trials were visual disturbances (18.7%), fever (5.7%), nausea (5.4%), rash (5.3%), vomiting (4.4%), chills (3.7%), headache (3.0%), liver function test increased (2.7%), tachycardia (2.4%), hallucinations (2.4%). The treatment-related adverse events which most often led to discontinuation of Voriconazole therapy were elevated liver function tests, rash and visual disturbances [see Warning and Precautions (5.2, 5.3) and Adverse Reactions (6.2, 6.3)].
Clinical Trial Experience in Adults
The data described in Table 2 reflect exposure to Voriconazole in 1,655 patients in the therapeutic studies. This represents a heterogeneous population, including immunocompromised patients, e.g., patients with hematological malignancy or HIV and non-neutropenic patients. This subgroup does not include healthy subjects and patients treated in the compassionate use and non-therapeutic studies. This patient population was 62% male, had a mean age of 46 years (range 11 to 90, including 51 patients aged 12 to 18 years) and was 78% white and 10% black. Five hundred sixty one patients had a duration of Voriconazole therapy of greater than 12 weeks, with 136 patients receiving Voriconazole for over 6 months. Table 2 includes all adverse events which were reported at an incidence of ≥ 2% during Voriconazole therapy in the all therapeutic studies population, studies 307/602 and 608 combined or study 305, as well as events of concern which occurred at an incidence of < 2%.
In study 307/602, 381 patients (196 on Voriconazole, 185 on amphotericin B) were treated to compare Voriconazole to amphotericin B followed by other licensed antifungal therapy in the primary treatment of patients with acute invasive aspergillosis. The rate of discontinuation from Voriconazole study medication due to adverse events was 21.4% (42/196 patients). In study 608, 403 patients with candidemia were treated to compare Voriconazole (272 patients) to the regimen of amphotericin B followed by fluconazole (131 patients). The rate of discontinuation from Voriconazole study medication due to adverse events was 19.5% out of 272 patients. Study 305 evaluated the effects of oral Voriconazole (200 patients) and oral fluconazole (191 patients) in the treatment of esophageal candidiasis. The rate of discontinuation from Voriconazole study medication in Study 305 due to adverse events was 7% (14/200 patients). Laboratory test abnormalities for these studies are discussed under Clinical Laboratory Values below.
Table 2. Treatment Emergent Adverse Events Rate ≥ 2% on Voriconazole or Adverse Events of Concern in All Therapeutic Studies Population, Studies 307/602-608 Combined or Study 305. Possibly Related to Therapy or Causality Unknown
|
|
All Therapeutic Studies |
Studies 307/602 and 608
(IV/oral therapy) |
Study 305
(oral therapy) |
Voriconazole
n = 1,655 |
Voriconazole
n = 468 |
Ampho B
n = 185 |
Ampho B→
Fluconazole
n = 131 |
Voriconazole
n = 200 |
Fluconazole
n = 191 |
|
|
n (%) |
n (%) |
n (%) |
n (%) |
n (%) |
n (%) |
| Special Senses |
|
|
|
|
|
|
| Abnormal vision |
310 (18.7) |
63 (13.5) |
1 (0.5) |
0 |
31 (15.5) |
8 (4.2) |
| Photophobia |
37 (2.2) |
8 (1.7) |
0 |
0 |
5 (2.5) |
2 (1) |
| Chromatopsia |
20 (1.2) |
2 (0.4) |
0 |
0 |
2 (1) |
0 |
| Body as a Whole |
|
|
|
|
|
|
| Fever |
94 (5.7) |
8 (1.7) |
25 (13.5) |
5 (3.8) |
0 |
0 |
| Chills |
61 (3.7) |
1 (0.2) |
36 (19.5) |
8 (6.1) |
1 (0.5) |
0 |
| Headache |
49 (3) |
9 (1.9) |
8 (4.3) |
1 (0.8) |
0 |
1 (0.5) |
Cardiovascular System
|
|
|
|
|
|
|
| Tachycardia |
39 (2.4) |
6 (1.3) |
5 (2.7) |
0 |
0 |
0 |
| Digestive System |
|
|
|
|
|
|
| Nausea |
89 (5.4) |
18 (3.8) |
29 (15.7) |
2 (1.5) |
2 (1) |
3 (1.6) |
| Vomiting |
72 (4.4) |
15 (3.2) |
18 (9.7) |
1 (0.8) |
2 (1) |
1 (0.5) |
| Liver function tests abnormal |
45 (2.7) |
15 (3.2) |
4 (2.2) |
1 (0.8) |
6 (3) |
2 (1) |
| Cholestatic jaundice |
17 (1) |
8 (1.7) |
0 |
1 (0.8) |
3 (1.5) |
0 |
Metabolic and Nutritional Systems
|
|
|
|
|
|
|
Alkaline phosphatase increased
|
59 (3.6) |
19 (4.1) |
4 (2.2) |
3 (2.3) |
10 (5) |
3 (1.6) |
| Hepatic enzymes increased |
30 (1.8) |
11 (2.4) |
5 (2.7) |
1 (0.8) |
3 (1.5) |
0 |
| SGOT increased |
31 (1.9) |
9 (1.9) |
0 |
1 (0.8) |
8 (4) |
2 (1) |
| SGPT increased |
29 (1.8) |
9 (1.9) |
1 (0.5) |
2 (1.5) |
6 (3) |
2 (1) |
| Hypokalemia |
26 (1.6) |
3 (0.6) |
36 (19.5) |
16 (12.2) |
0 |
0 |
| Bilirubinemia |
15 (0.9) |
5 (1.1) |
3 (1.6) |
2 (1.5) |
1 (0.5) |
0 |
| Creatinine increased |
4 (0.2) |
0 |
59 (31.9) |
10 (7.6) |
1 (0.5) |
0 |
| Nervous System |
|
|
|
|
|
|
| Hallucinations |
39 (2.4) |
13 (2.8) |
1 (0.5) |
0 |
0 |
0 |
Skin and Appendages
|
|
|
|
|
|
|
| Rash |
88 (5.3) |
20 (4.3) |
7 (3.8) |
1 (0.8) |
3 (1.5) |
1 (0.5) |
| Urogenital |
|
|
|
|
|
|
| Kidney function abnormal |
10 (0.6) |
6 (1.3) |
40 (21.6) |
9 (6.9) |
1 (0.5) |
1 (0.5) |
| Acute kidney failure |
7 (0.4) |
2 (0.4) |
11 (5.9) |
7 (5.3) |
0 |
0 |
Visual DisturbancesVoriconazole treatment-related visual disturbances are common. In therapeutic trials, approximately 21% of patients experienced abnormal vision, color vision change and/or photophobia. Visual disturbances may be associated with higher plasma concentrations and/or doses.
There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilledema [see Warnings and Precautions (5.3)].
The mechanism of action of the visual disturbance is unknown, although the site of action is most likely to be within the retina. In a study in healthy subjects investigating the effect of 28-day treatment with Voriconazole on retinal function, Voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude, a decrease in the visual field and an alteration in color perception. The ERG measures electrical currents in the retina. The effects were noted early in administration of Voriconazole and continued through the course of study drug dosing. Fourteen days after end of dosing, ERG, visual fields and color perception returned to normal [see Warnings an Precautions (5)].
Dermatological ReactionsDermatological reactions were common in the patients treated with Voriconazole. The mechanism underlying these dermatologic adverse events remains unknown.
Serious cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme have been reported during treatment with Voriconazole. If a patient develops an exfoliative cutaneous reaction, Voriconazole should be discontinued.
In addition, Voriconazole has been associated with photosensitivity skin reactions. Patients should avoid strong, direct sunlight during Voriconazole therapy. In patients with photosensitivity skin reactions, squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. If a patient develops a skin lesion consistent with squamous cell carcinoma or melanoma, Voriconazole should be discontinued [see Warnings and Precautions (5.13)].
Less Common Adverse EventsThe following adverse events occurred in < 2% of all Voriconazole-treated patients in all therapeutic studies (n = 1,655). This listing includes events where a causal relationship to Voriconazole cannot be ruled out or those which may help the physician in managing the risks to the patients. The list does not include events included in Table 2 above and does not include every event reported in the Voriconazole clinical program.
Body as a Whole: abdominal pain, abdomen enlarged, allergic reaction, anaphylactoid reaction [see Warnings and Precautions (5.6)], ascites, asthenia, back pain, chest pain, cellulitis, edema, face edema, flank pain, flu syndrome, graft versus host reaction, granuloma, infection, bacterial infection, fungal infection, injection site pain, injection site infection/inflammation, mucous membrane disorder, multi-organ failure, pain, pelvic pain, peritonitis, sepsis, substernal chest pain
Cardiovascular: atrial arrhythmia, atrial fibrillation, AV block complete, bigeminy, bradycardia, bundle branch block, cardiomegaly, cardiomyopathy, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, congestive heart failure, deep thrombophlebitis, endocarditis, extrasystoles, heart arrest, hypertension, hypotension, myocardial infarction, nodal arrhythmia, palpitation, phlebitis, postural hypotension, pulmonary embolus, QT interval prolonged, supraventricular extrasystoles, supraventricular tachycardia, syncope, thrombophlebitis, vasodilatation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia (including torsade de pointes) [see Warnings and Precautions (5.6)].
Digestive: anorexia, cheilitis, cholecystitis, cholelithiasis, constipation, diarrhea, duodenal ulcer perforation, duodenitis, dyspepsia, dysphagia, dry mouth, esophageal ulcer, esophagitis, flatulence, gastroenteritis, gastrointestinal hemorrhage, GGT/LDH elevated, gingivitis, glossitis, gum hemorrhage, gum hyperplasia, hematemesis, hepatic coma, hepatic failure, hepatitis, intestinal perforation, intestinal ulcer, jaundice, enlarged liver, melena, mouth ulceration, pancreatitis, parotid gland enlargement, periodontitis, proctitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, stomach ulcer, stomatitis, tongue edema
Endocrine: adrenal cortex insufficiency, diabetes insipidus, hyperthyroidism, hypothyroidism
Hemic and Lymphatic: agranulocytosis, anemia (macrocytic, megaloblastic, microcytic, normocytic), aplastic anemia, hemolytic anemia, bleeding time increased, cyanosis, DIC, ecchymosis, eosinophilia, hypervolemia, leukopenia, lymphadenopathy, lymphangitis, marrow depression, pancytopenia, petechia, purpura, enlarged spleen, thrombocytopenia, thrombotic thrombocytopenic purpura
Metabolic and Nutritional: albuminuria, BUN increased, creatine phosphokinase increased, edema, glucose tolerance decreased, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperuricemia, hypocalcemia, hypoglycemia, hypomagnesemia, hyponatremia, hypophosphatemia, peripheral edema, uremia
Musculoskeletal: arthralgia, arthritis, bone necrosis, bone pain, leg cramps, myalgia, myasthenia, myopathy, osteomalacia, osteoporosis
Nervous System: abnormal dreams, acute brain syndrome, agitation, akathisia, amnesia, anxiety, ataxia, brain edema, coma, confusion, convulsion, delirium, dementia, depersonalization, depression, diplopia, dizziness, encephalitis, encephalopathy, euphoria, Extrapyramidal Syndrome, grand mal convulsion, Guillain-Barré syndrome, hypertonia, hypesthesia, insomnia, intracranial hypertension, libido decreased, neuralgi
