Can Itraconazole cause diarrhea?

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 clinical practice. Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of itraconazole use should be reassessed (see WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients ). Adverse Events Reported in Oropharyngeal or Esophageal Candidiasis Trials U.S. adverse experience data are derived from 350 immunocompromised patients (332 HIV seropositive/AIDS) treated for oropharyngeal or esophageal candidiasis. Table 3 below lists adverse events reported by at least 2% of patients treated with itraconazole oral solution in U.S. clinical trials. Data on patients receiving comparator agents in these trials are included for comparison. Table 3: Summary of Adverse Events Reported by ≥ 2% of Itraconazole Treated Patients in U.S. Clinical Trials (Total) Body System/ Adverse Event Itraconazole Total (n = 350 * ) % All controlled studies (n = 272) % Fluconazole (n = 125 † ) % Clotrimazole (n = 81 ‡ ) % Gastrointestinal disorders Nausea 11 10 11 5 Diarrhea 11 10 10 4 Vomiting 7 6 8 1 Abdominal pain 6 4 7 7 Constipation 2 2 1 0 Body as a whole Fever 7 6 8 5 Chest pain 3 3 2 0 Pain 2 2 4 0 Fatigue 2 1 2 0 Respiratory disorders Coughing 4 4 10 0 Dyspnea 2 3 5 1 Pneumonia 2 2 0 0 Sinusitis 2 2 4 0 Sputum increased 2 3 3 1 Skin and appendages disorders Rash 4 5 4 6 Increased sweating 3 4 6 1 Skin disorder unspecified 2 2 2 1 Central/peripheral nervous system Headache 4 4 6 6 Dizziness 2 2 4 1 Resistance mechanism disorders Pneumocystis carinii infection 2 2 2 0 Psychiatric disorders Depression 2 1 0 1 * Of the 350 patients, 209 were treated for oropharyngeal candidiasis in controlled studies, 63 were treated for esophageal candidiasis in controlled studies and 78 were treated for oropharyngeal candidiasis in an open study. † Of the 125 patients, 62 were treated for oropharyngeal candidiasis and 63 were treated for esophageal candidiasis. ‡ All 81 patients were treated for oropharyngeal candidiasis. Adverse events reported by less than 2% of patients in U.S. clinical trials with itraconazole included: adrenal insufficiency, asthenia, back pain, dehydration, dyspepsia, dysphagia, flatulence, gynecomastia, hematuria, hemorrhoids, hot flushes, implantation complication, infection unspecified, injury, insomnia, male breast pain, myalgia, pharyngitis, pruritus, rhinitis, rigors, stomatitis ulcerative, taste perversion, tinnitus, upper respiratory tract infection, vision abnormal, and weight decrease. Edema, hypokalemia and menstrual disorders have been reported in clinical trials with itraconazole capsules. Adverse Events Reported from Other Clinical Trials A comparative clinical trial in patients who received intravenous itraconazole followed by itraconazole oral solution or received Amphotericin B reported the following adverse events in the itraconazole intravenous/ itraconazole oral solution treatment arm which are not listed above in the subsection “Adverse Events Reported in Oropharyngeal or Esophageal Candidiasis Trials” or listed below as postmarketing reports of adverse drug reactions: serum creatinine increased, blood urea nitrogen increased, renal function abnormal, hypocalcemia, hypomagnesemia, hypophosphatemia, hypotension, tachycardia and pulmonary infiltration. In addition, the following adverse drug reactions were reported in patients who participated in itraconazole oral solution clinical trials: Cardiac Disorders: cardiac failure; General Disorders and Administration Site Conditions: edema; Hepatobiliary Disorders: hepatic failure, hyperbilirubinemia; Metabolism and Nutrition Disorders: hypokalemia; Reproductive System and Breast Disorders: menstrual disorder The following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of itraconazole capsules and itraconazole IV excluding the adverse reaction term “Injection site inflammation” which is specific to the injection route of administration: Cardiac Disorders: left ventricular failure; Gastrointestinal Disorders: gastrointestinal disorder; General Disorders and Administration Site Conditions: face edema; Hepatobiliary Disorders: jaundice, hepatic function abnormal; Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, urine analysis abnormal; Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia; Nervous System Disorders: somnolence; Psychiatric Disorders: confusional state; Renal and Urinary Disorders: renal impairment; Respiratory, Thoracic and Mediastinal Disorders: dysphonia; Skin and Subcutaneous Tissue Disorders: rash erythematous; Vascular Disorders: hypertension In addition, the following adverse drug reaction was reported in children only who participated in itraconazole oral solution clinical trials: mucosal inflammation. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Postmarketing Experience Adverse drug reactions that have been first identified during postmarketing experience with itraconazole (all formulations) are listed in Table 4 below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Table 4: Postmarketing Reports of Adverse Drug Reactions Blood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocytopenia Immune System Disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edema Endocrine Disorders: Pseudoaldosteronism Metabolism and Nutrition Disorders: Hypertriglyceridemia Nervous System Disorders: Peripheral neuropathy, paresthesia, hypoesthesia, tremor Eye Disorders: Visual disturbances, including vision blurred and diplopia Ear and Labyrinth Disorders: Transient or permanent hearing loss Cardiac Disorders: Congestive heart failure, bradycardia Respiratory, Thoracic and Mediastinal Disorders: Pulmonary edema Gastrointestinal Disorders: Pancreatitis Hepatobiliary Disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticaria Musculoskeletal and Connective Tissue Disorders: Arthralgia Renal and Urinary Disorders: Urinary incontinence, pollakiuria Reproductive System and Breast Disorders: Erectile dysfunction General Disorders and Administration Site Conditions: Peripheral edema Investigations: Blood creatine phosphokinase increased There is limited information on the use of itraconazole during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during postmarketing experience. A causal relationship with itraconazole has not been established (see CLINICAL PHARMACOLOGY: Special Populations , CONTRAINDICATIONS , WARNINGS, and PRECAUTIONS: Drug Interactions for more information).

WARNINGS AND PRECAUTIONS Hepatotoxicity : Serious hepatotoxicity, including liver failure and death were reported with the use of itraconazole. Discontinue treatment if signs of liver dysfunction occur ( 5.2 ) Cardiac Dysrhythmias : Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using certain drugs that are metabolized by human CYP450 enzymes concomitantly with oral itraconazole and/or other CYP3A4 inhibitors. ( 4 , 5.3 , 5.5 ) Pseudoaldosteronism : Manifested by the onset or worsening of hypertension, and abnormal laboratory findings. Monitor blood pressure and potassium levels and manage as necessary ( 5.4 ). Peripheral Neuropathy : This has been reported in patients on long-term therapy with itraconazole. Monitor and promptly evaluate neurologic symptoms. ( 5.6 ) Hearing Loss : Reversible or permanent has been reported in patients. Discontinue treatment if hearing loss occurs ( 5.7 ) 5.1 Congestive Heart Failure TOLSURA can cause or exacerbate congestive heart failure (CHF) [see Boxed Warning and Adverse Reactions (6.1) ]. For patients with evidence of ventricular dysfunction such as CHF, history or risk factors for CHF, physicians should carefully review the risks and benefits of TOLSURA therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Inform such patients of the signs and symptoms of CHF and monitor carefully for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear or worsen during administration of TOLSURA, reassess the benefit-risk of continuing treatment. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was demonstrated. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. Itraconazole has been associated with reports of CHF, peripheral edema, and pulmonary edema. In post-marketing experience, heart failure was more frequently reported in patients receiving higher total daily doses of itraconazole of 400 mg although there were also cases reported among those receiving lower total daily doses [see Adverse Reactions (6.2) ] . Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, when co-administering itraconazole and calcium channel blockers, monitor carefully for signs and symptoms of CHF during treatment due to an increased risk of CHF. Concomitant administration of TOLSURA and felodipine or nisoldipine is contraindicated [see Contraindications (4.1) , Drug Interactions (7.1) and Adverse Reactions (6.2) ] 5.2 Hepatotoxicity Itraconazole has been associated with cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, discontinue treatment and perform testing for liver disease. Continued TOLSURA use or reinstitution of treatment with TOLSURA is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk [ see Adverse Reactions (6.1) ]. 5.3 Cardiac Dysrhythmias Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as, pimozide, methadone, or quinidine concomitantly with oral itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with TOLSURA is contraindicated [see Boxed Warning , Contraindications (4) and Drug Interactions (7) ]. 5.4 Pseudoaldosteronism Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevate 11-deoxycortisol), has been reported with itraconazole use in the postmarketing setting. Monitor blood pressure and potassium levels and manage as necessary. Management of pseudoaldosteronism may include discontinuation of TOLSURA, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists. 5.5 Drug Interaction Potential Itraconazole has a potential for clinically important drug interactions [see Drug Interactions (7.1 , 7.2) ] . Co-administration of specific drugs with TOLSURA may result in changes in the efficacy of itraconazole and/or the co-administered drug, life-threatening effects and/or sudden death. [see Boxed Warning , Contraindications (4.1) and Drug Interactions (7.1 , 7.2) ]. 5.6 Peripheral Neuropathy Cases of peripheral neuropathy have been reported in patients on long-term therapy with itraconazole. Monitor for and promptly evaluate neurologic symptoms. If neuropathy attributable to TOLSURA occurs, discontinue treatment. 5.7 Hearing Loss Reversible or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated [see Boxed Warning , Contraindications (4.2) and Drug Interactions (7) ] . The hearing loss usually resolves when treatment is stopped but can persist in some patients. 5.8 Hypersensitivity Reactions TOLSURA is contraindicated in patients with a known hypersensitivity to itraconazole [see Contraindications (4.2) ]. Hypersensitivity reactions have been reported with the use of itraconazole [see Adverse Reactions (6.2) ] . Due to the limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal drugs, careful enquiry about previous hypersensitivity to other azole antifungal drugs should be made when prescribing TOLSURA. If hypersensitivity reactions to TOLSURA occurs, discontinue the drug and institute appropriate therapy.