Before effective antibiotics became available, pneumonia was the respiratory disease responsible for the greatest mortality and consequently was one of the most-feared diseases. The inflammation is probably reversible if smoking is discontinued. Water is the ideal medium for coccidia sporulation. Foremost among them are efforts to inform the public of the risk and to limit the advertising of cigarettes. A chest radiograph shows patchy inflammatory change, and the lesion is an acute bronchiolitis.
While a lot of news reports and coverage tend to be of stock markets, booming or now receding economies, international war on terrorism, a few other selected conflicts and local news, etc. Let me tell you a story about life, death and profit. It involves some of the poorest countries in the world and some of the richest companies.
It goes to the heart of how the modern world is to be run and whether the institutions set up to police the global economy are up to the job. Eleven million people in poor countries will die from infectious diseases this year.
Put a different way, it means that by the time you finish reading this column people will have died. Half of them will be children aged under five. Not coincidentally, it is also one of the few diseases that remain a threat to First World countries.
Until recently, AIDS had not killed as many as some of the other major diseases, yet it still received more attention than the other big killers in the world, which hardly seem to get covered, in comparison.
Largely impacting developing countries where health facilities and systems are weaker, poverty is also resulting in largely curable and preventable diseases from killing millions each year.
There are also other issues such as the various cultural and traditional barriers, and social issues and taboos that need to be overcome in some parts of the developing world, for treatments to be made readily accessible. However, a look, for example, at the causes of poverty , as described on this web site, would help indicate why these issues are important for developed and wealthy nations alike and what roles and responsibilities they have as well:.
Africa Action , an organization looking into political, economic and social justice for Africa has an article on the impacts of IMF and World Bank structural adjustments and its impacts on health in Africa, and is worth quoting at length:. Health status is influenced by socioeconomic factors as well as by the state of health care delivery systems. The policies prescribed by the World Bank and IMF have increased poverty in African countries and mandated cutbacks in the health sector.
The health care systems inherited by most African states after the colonial era were unevenly weighted toward privileged elites and urban centers.
In the s and s, substantial progress was made in improving the reach of health care services in many African countries. Most African governments increased spending on the health sector during this period.
They endeavored to extend primary health care and to emphasize the development of a public health system to redress the inequalities of the colonial era. The Declaration of Alma Ata focused on a community-based approach to health care and resolved that comprehensive health care was a basic right and a responsibility of government. While the progress across the African continent was uneven, it was significant, not only because of its positive effects on the health of African populations.
It also illustrated a commitment by African leaders to the principle of building and developing their health care systems. As African governments became clients of the World Bank and IMF, they forfeited control over their domestic spending priorities. The loan conditions of these institutions forced contraction in government spending on health and other social services….
The relationship between poverty and ill-health is well established. The economic austerity policies attached to World Bank and IMF loans led to intensified poverty in many African countries in the s and s.
This increased the vulnerability of African populations to the spread of diseases and to other health problems…. The deepening poverty across the continent has created fertile ground for the spread of infectious diseases. Declining living conditions and reduced access to basic services have led to decreased health status.
In Africa today, almost half of the population lacks access to safe water and adequate sanitation services. Even as government spending on health was cut back, the amounts being paid by African governments to foreign creditors continued to increase.
By the s, most African countries were spending more repaying foreign debts than on health or education for their people.
Health care services in African countries disintegrated, while desperately needed resources were siphoned off by foreign creditors. It was estimated in that sub-Saharan African governments were transferring to Northern creditors four times what they were spending on the health of their people. In , Senegal spent five times as much repaying foreign debts as on health. A single rating will be assigned under the diagnostic code which reflects the predominant disability with elevation to the next higher evaluation where the severity of the overall disability warrants such elevation.
However, in cases protected by the provisions of Pub. Public Law repealed section of title 38, United States Code which had provided graduated ratings for inactive tuberculosis. The repealed section, however, still applies to the case of any veteran who on August 19, , was receiving or entitled to receive compensation for tuberculosis.
The use of the protective provisions of Pub. For application in rating cases in which the protective provisions of Pub. Footnotes in the schedule indicate conditions which potentially establish entitlement to special monthly compensation; however, there are other conditions in this section which under certain circumstances also establish entitlement to special monthly compensation. If a maximum exercise capacity test is not of record, evaluate based on alternative criteria.
In those cases, use the pre-bronchodilator values for rating purposes. With percent obstruction of the nasal passage on both sides or complete obstruction on one side Exposing both nasal passages Or evaluate as DC , scars, disfiguring, head, face, or neck. Following radical surgery with chronic osteomyelitis, or; near constant sinusitis characterized by headaches, pain and tenderness of affected sinus, and purulent discharge or crusting after repeated surgeries Three or more incapacitating episodes per year of sinusitis requiring prolonged lasting four to six weeks antibiotic treatment, or; more than six non-incapacitating episodes per year of sinusitis characterized by headaches, pain, and purulent discharge or crusting One or two incapacitating episodes per year of sinusitis requiring prolonged lasting four to six weeks antibiotic treatment, or; three to six non-incapacitating episodes per year of sinusitis characterized by headaches, pain, and purulent discharge or crusting Detected by X-ray only An incapacitating episode of sinusitis means one that requires bed rest and treatment by a physician.
Hoarseness, with thickening or nodules of cords, polyps, submucous infiltration, or pre-malignant changes on biopsy Hoarseness, with inflammation of cords or mucous membrane Constant inability to communicate by speech Constant inability to speak above a whisper Evaluate incomplete aphonia as laryngitis, chronic DC Forced expiratory volume in one second FEV-1 less than 40 percent of predicted value, with Flow-Volume Loop compatible with upper airway obstruction, or; permanent tracheostomy FEV-1 of to percent predicted, with Flow-Volume Loop compatible with upper airway obstruction Or evaluate as aphonia DC Stricture or obstruction of pharynx or nasopharynx, or; absence of soft palate secondary to trauma, chemical burn, or granulomatous disease, or; paralysis of soft palate with swallowing difficulty nasal regurgitation and speech impairment Without polyps, but with greater than percent obstruction of nasal passage on both sides or complete obstruction on one side With permanent hypertrophy of turbinates and with greater than percent obstruction of nasal passage on both sides or complete obstruction on one side With incapacitating episodes of infection of at least six weeks total duration per year With incapacitating episodes of infection of four to six weeks total duration per year, or; near constant findings of cough with purulent sputum associated with anorexia, weight loss, and frank hemoptysis and requiring antibiotic usage almost continuously With incapacitating episodes of infection of two to four weeks total duration per year, or; daily productive cough with sputum that is at times purulent or blood-tinged and that requires prolonged lasting four to six weeks antibiotic usage more than twice a year Intermittent productive cough with acute infection requiring a course of antibiotics at least twice a year Or rate according to pulmonary impairment as for chronic bronchitis DC An incapacitating episode is one that requires bedrest and treatment by a physician.
In the absence of clinical findings of asthma at time of examination, a verified history of asthmatic attacks must be of record. Disease of the Trachea and Bronchi. Unless contraindicated, pulmonary function tests, performed both with and without medication, must confirm the clinical diagnosis and severity See Table 2. If the Service member's condition is subject to significant variation over time, a single clinical and pulmonary function evaluation may not be adequate.
Response to t herapy is to be considered in all cases. The following pulmonary function test values serve as guidelines in determining ratings See Table 2. Chronic Restrictive Pulmonary Disease. Active pulmonary tuberculosis will be considered permanently and totally disabling for non-service-connected pension purposes in the following circumstances:.
Material improvement means lessening or absence of clinical symptoms, and X-ray findings of a stationary or retrogressive lesion. Depending on the specific findings, rate residuals as interstitial lung disease, restrictive lung disease, or, when obstructive lung disease is the major residual, as chronic bronchitis DC Rate thoracoplasty as removal of ribs under DC A mandatory examination will be requested immediately following notification that active tuberculosis evaluated under DC has become inactive.
Primary pulmonary hypertension, or; chronic pulmonary thrombo- embolism with evidence of pulmonary hypertension, right ventricular hypertrophy, or cor pulmonale, or; pulmonary hypertension secondary to other obstructive disease of pulmonary arteries or veins with evidence of right ventricular hypertrophy or cor pulmonale Chronic pulmonary thromboembolism requiring anticoagulant therapy, or; following inferior vena cava surgery without evidence of pulmonary hypertension or right ventricular dysfunction Symptomatic, following resolution of acute pulmonary embolism Asymptomatic, following resolution of pulmonary thromboembolism Evaluate other residuals following pulmonary embolism under the most appropriate diagnostic code, such as chronic bronchitis DC or chronic pleural effusion or fibrosis DC , but do not combine that evaluation with any of the above evaluations.
A rating of percent shall continue beyond the cessation of any surgical, X-ray, antineoplastic chemotherapy or other therapeutic procedure. Six months after discontinuance of such treatment, the appropriate disability rating s hall be determined by mandatory VA examination. If there has been no local recurrence or metastasis, rate on residuals. Evaluate using an appropriate respiratory analogy. Chronic pulmonary mycosis with persistent fever, weight loss, night sweats, or massive hemoptysis Chronic pulmonary mycosis requiring suppressive therapy with no more than minimal symptoms such as occasional minor hemoptysis or productive cough Chronic pulmonary mycosis with minimal symptoms such as occasional minor hemoptysis or productive cough Healed and inactive mycotic lesions, asymptomatic Coccidioidomycosis has an incubation period up to 21 days, and the disseminated phase is ordinarily manifest within six months of the primary phase.
However, there are instances of diss emination delayed up to many years after the initial infection which may have been unrecognized. Accordingly, when service connection is under consideration in the absence of record or other evidence of the disease in service, service in southwestern United States where the disease is endemic and absence of prolonged residence in this locality before or after service will be the deciding factor.
A percent rating shall be assigned for pleurisy with empyema, with or without pleurocutaneous fistula, until resolved. Following episodes of total spontaneous pneumothorax, a rating of percent shall be assigned as of the date of hospital admission and shall continue for three months from the first day of the month after hospital discharge.
Gunshot wounds of the pleural cavity with bullet or missile retained in lung, pain or discomfort on exertion, or with scattered rales or some limitation of excursion of diaphragm or of lower chest expansion shall be rated at least percent disabling. Disabling injuries of shoulder girdle muscles Groups I to IV shall be separately rated and combined with ratings for respiratory involvement.
Cor pulmonale, or; cardiac involvement with congestive heart failure, or; progressive pulmonary disease with fever, night sweats, and weight loss despite treatment Pulmonary involvement requiring systemic high dose therapeutic corticosteroids for control Pulmonary involvement with persistent symptoms requiring chronic low dose maintenance or intermittent corticosteroids Chronic hilar adenopathy or stable lung infiltrates without symptoms or physiologic impairment Or rate active disease or residuals as chronic bronchitis DC and extra- pulmonary involvement under specific body system involved.
Chronic respiratory failure with carbon dioxide retention or cor pulmonale, or; requires tracheostomy Requires use of breathing assistance device such as continuous airway pressure CPAP machine Asymptomatic but with documented sleep disorder breathing Evaluate cor pulmonale, which is a form of secondary heart disease, as part of the pulmonary condition that causes it.
One MET metabolic equivalent is the energy cost of standing quietly at rest and represents an oxygen uptake of 3. When the level of METs at which dyspnea, fatig ue, angina, dizziness, or syncope develops is required for evaluation, and a laboratory determination of METs by exercise testing cannot be done for medical reasons, an estimation by a medical examiner of the level of activity expressed in METs and supported by specific examples, such as slow stair climbing or shoveling snow that results in dyspnea, fatigue, angina, dizziness, or syncope may be used.
During active infection with valvular heart damage and for three months following cessation of therapy for the active infection Thereafter, with valvular heart disease documented by findings on physical examination and either echocardiogram, Doppler echocardiogram, or cardiac catheterization resulting in: Chronic congestive heart failure, or; workload of 3 METs or less results in dyspnea, fatigue, angina, dizziness, or syncope, or; left ventricular dysfunction with an ejection fraction of less than 30 percent More than one episode of acute congestive heart failure in the past year, or; workload of greater than 3 METs but not greater than 5 METs results in dyspnea, fatigue, angina, dizziness, or syncope, or; left ventricular dysfunction with an ejection fraction of 30 to 50 percent Workload of greater than 5 METs but not greater than 7 METs results in dyspnea, fatigue, angina, dizziness, or syncope, or; evidence of cardiac hypertrophy or dilatation on electro-cardiogram, echocardiogram, or X-ray Workload of greater than 7 METs but not greater than 10 METs results in dyspnea, fatigue, angina, dizziness, or syncope, or; continuous medication required For three months following cessation of therapy for active infection with cardiac involvement Thereafter, with endocarditis documented by findings on physical examination and either echocardiogram, Doppler echocardiogram, or cardiac catheterization resulting in: Workload of greater than 5 METs but not greater than 7 METs results in dyspnea, fatigue, angina, dizziness, or syncope, or; evidence of cardiac hypertrophy or dilatation on electrocardiogram, echocardiogram, or X-ray With documented coronary artery disease resulting in: If nonservice-connected arteriosclerotic heart disease is superimposed on service-connected valvular or other non-arteriosclerotic heart disease, request a medical opinion as to which condition is causing the current signs and symptoms.
During and for three months following myocardial infarction,. With history of documented myocardial infarction, resulting in: Rate under the appropriate cardiovascular diagnostic code, depending on particular findings.
Paroxysmal atrial fibrillation or other supraventricular tachycardia, with more than four episodes per year documented by ECG or Holter monitor Permanent atrial fibrillation lone atrial fibrillation , or; one to four episodes per year of paroxysmal atrial fibrillation or other supraventricular tachycardia documented by ECG or Holter monitor For indefinite period from date of hospital admission for initial evaluation and medical therapy for a sustained ventricular arrhythmia, or; for indefinite period from date of hospital admission for ventricular aneurysmectomy, or; with an automatic implantable Cardioverter- Defibrillator AICD in place A rating of percent shall be assigned from the date of hospital admission for initial evaluation and medical therapy for a sustained ventricular arrhythmia or for ventricular aneurysmectomy.
Six months following discharge, the appropriate disability rating shall be determined by mandatory VA examination. Workload of greater than 7 METs but not greater than 10 METs results in dyspnea, fatigue, angina, dizziness, or syncope, or; continuous medication or a pacemaker required Unusual cases of arrhythmia such as atrioventricular block associated with a supraventricular arrhythmia or pathological bradycardia should be submitted to the Director, Compensation and Pension Service.
Simple delayed P-R conduction time, in the absence of other evidence of cardiac disease, is not a disability. For indefinite period following date of hospital admission for valve replacement A rating of percent shall be assigned as of the date of hospital admission for valve replacement. For three months following hospital admission for surgery Workload greater than 7 METs but not greater than 10 METs results in dyspnea, fatigue, angina, dizziness, or syncope, or; continuous medication required For two months following hospital admission for implantation or reimplantation Evaluate as supraventricular arrhythmias DC , ventricular arrhythmias DC , or atrioventricular block DC For an indefinite period from date of hospital admission for cardiac transplantation A rating of percent shall be assigned as of the date of hospital admission for cardiac transplantation.
One year following discharge, the appropriate disability rating shall be determined by mandatory VA examination. Diastolic pressure predominantly or more Diastolic pressure predominantly or more, or; systolic pressure predominantly or more Diastolic pressure predominantly or more, or; systolic pressure predominantly or more, or; minimum evaluation for an individual with a history of diastolic pressure predominantly or more who requires continuous medication for control Hypertension or isolated systolic hypertension must be confirmed by readings taken two or more times on at least three different days.
For purp oses of this section, the term hypertension means that the diastolic blood pressure is predominantly 90mm. Evaluate hypertension due to aortic insufficiency or hyperthyroidism, which is usually the isolated systolic type, as part of the condition causing it rather than by a separate evaluation. Evaluate hypertension separately from hypertensive heart disease and other types of heart disease.
If five centimeters or larger in diameter, or; if symptomatic, or; for indefinite period from date of hospital admission for surgical correction including any type of graft insertion Evaluate residuals of surgical correction according to organ systems affected.
A rating of percent shall be assigned as of the date of admission for surgical correction. If symptomatic, or; for indefinite period from date of hospital admission for surgical correction Moderate Caution is advised when administering tenofovir, PMPA, a P-glycoprotein P-gp substrate, concurrently with inhibitors of P-gp, such as ketoconazole. Coadministration may result in increased absorption of tenofovir.
Monitor for tenofovir-associated adverse reactions. Major Avoid the concurrent use of cobimetinib with ketoconazole due to the risk of cobimetinib toxicity. Major Promethazine carries a possible risk of QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with promethazine include ketoconazole.
Major Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ketoconazole in patients with normal renal and hepatic function unless the use of both agents is imperative.
Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ketoconazole can inhibit colchicine's metabolism via P-glycoprotein P-gp and CYP3A4, resulting in increased colchicine exposure.
If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken ketoconazole in the past 14 days or require concurrent use: Coadministration of oral conivaptan 10 mg with ketoconazole mg resulted in a 4-fold and fold increase in the Cmax and AUC of conivaptan, respectively.
The effect of coadministration of ketoconazole with intravenous conivaptan has not been studied. According to the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
Therefore, inhibitors of CYP3A4 may affect estrogen drug metabolism. Inhibitors of CYP3A4, such as ketoconazole, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia.
Major Coadministration of medroxyprogesterone, a CYP3A substrate with ketoconazole, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate.
Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
Major Avoid the concomitant use of copanlisib and ketoconazole if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events e. Major Avoid coadministration of ketoconazole with crizotinib due to increased plasma concentrations of crizotinib; QT prolongation may also occur. If concomitant use is unavoidable, reduce the dose of crizotinib to mg by mouth once daily.
Monitor ECGs for QT prolongation and electrolytes; an interruption of therapy, dose reduction, or discontinuation of crizotinib therapy may be necessary. Resume the original crizotinib dose after discontinuation of ketoconazole. Major Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as cyclobenzaprine. Both cyclobenzaprine and ketoconazole are associated with QT prolongation; coadministration may increase this risk.
In addition, coadministration of ketoconazole a potent CYP3A4 inhibitor with cyclobenzaprine a CYP3A4 substrate may result in elevated cyclobenzaprine plasma concentrations and an increased risk for adverse events, including QT prolongation. Major The interactions between cyclosporine and systemic azole antifungals e. Ketoconazole may inhibit cyclosporine CYP3A4-mediated metabolism, which may result in increased cyclosporine blood concentrations. Of the azoles, ketoconazole is the most potent CYP3A4 inhibitor; it also inhibits p-glycoprotein.
Ketoconazole can increase cyclosporine concentrations up to 3-fold within days of addition of ketoconazole to cyclosporine therapy. It takes about 7 to 10 days for cyclosporine concentrations to normalize after stopping ketoconazole.
Ketoconazole has been documented to lower the daily maintenance dosage of cyclosporine, thus reducing the overall cost of therapy; however, this approach is not routinely used. Ketoconazole may also potentiate renal dysfunction associated with cyclosporine. In all cases, renal function in these patients should be carefully monitored.
Major Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein P-gp substrate, is coadministered with ketoconazole, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. Coadministration of dabigatran and ketoconazole results in increased dabigatran serum concentrations and, therefore, an increased risk of bleeding.
P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. Additionally, the concentrations of ketoconazole may be decreased resulting in loss of efficacy. Use of an alternate agent in place of ketoconazole is recommended.
If concomitant use cannot be avoided, monitor patients for dabrafenib toxicity e. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects.
In another study, the maximum serum saxagliptin concentration increased by 2. The saxagliptin dose is limited to 2. Moderate Darifenacin may raise intragastric pH. This effect may decrease the oral bioavailability of ketoconazole. In addition, the daily dose of darifenacin should not exceed 7.
Concomitant systemic use of ketoconazole with darunavir may increase plasma concentrations of darunavir. Additionally, plasma concentrations of ketoconazole may be increased when coadministered with darunavir in the FDA approved dosage regimen. When coadministration is required, high doses i. Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Major When administering ketoconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended ketoconazole dose of mg per day.
Concurrent administration of ritonavir a potent CYP3A4 inhibitor with ketoconazole a CYP3A4 substrate significantly increases ketoconazole systemic concentrations. In one drug interaction study, ketoconazole exposure was increased by 3. In addition, because both drugs are associated with prolongation of the QT interval, coadministration may increase the risk for developing QT prolongation.
If these drugs are given together, closely monitor patients for ketoconazole-associated adverse effects, including QT prolongation. Major Avoid coadministration of dasatinib and ketoconazole due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes TdP. An alternative to ketoconazole with no or minimal enzyme inhibition potential is recommended if possible.
If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was mg daily, 20 mg PO daily if original dose was mg daily, or 20 mg PO daily if original dose was 70 mg daily.
Stop dasatinib during use of ketoconazole in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue ketoconazole or stop dasatinib until ketoconazole is discontinued.
Allow a washout of approximately 1 week after ketoconazole is stopped before increasing the dasatinib dose or reinitiating dasatinib. Coadministration of ketoconazole increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively. Acute cardiotoxicity can occur during administration of daunorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia SVT , ventricular tachycardia, heart block, and premature ventricular contractions PVCs have been reported.
Major Decrease deflazacort dose to one third of the recommended dosage when coadministered with ketoconazole. Concurrent use may significantly increase concentrations of desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity.
Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include degarelix. Minor Ketoconazole is a known inhibitor of cytochrome P 3A4. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include halogenated anesthetics.
Clinically relevant QTc prolongation may occur with deutetrabenazine. Moderate Coadministration may result in increased exposure to dexamethasone and increased corticosteroid-related adverse effects. In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal. Severe Ketoconazole inhibits the hepatic CYP3A4 isoenzyme; quinidine is metabolized by this isoenzyme.
Coadministration results in increased quinidine serum concentrations, with potential to result in proarrhythmias. A single case report has documented substantial elevations in serum quinidine concentrations after the addition of ketoconazole. The patient was receiving other drugs concomitantly and it is unclear if drug-induced arrhythmias occurred. Until more data are available, ketoconazole should be considered contraindicated in patients receiving quinidine. Moderate Ketoconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines such as diazepam.
Moderate Use dichlorphenamide and ketoconazole together with caution. Dichlorphenamide increases potassium excretion and can cause hypokalemia and should be used cautiously with other drugs that may cause hypokalemia including antifungals. Measure potassium concentrations at baseline and periodically during dichlorphenamide treatment.
If hypokalemia occurs or persists, consider reducing the dichlorphenamide dose or discontinuing dichlorphenamide therapy. Moderate If possible, avoid concurrent use of diclofenac with inhibitors of CYP2C9, such as ketoconazole; if coadministration is required, do not exceed a total daily diclofenac dose of mg.
Major Administer ketoconazole at least 2 hours before or several hours after didanosine chewable tablets and powder for oral solution. Didanosine chewable tablets and powder for oral solution contain acid buffers to enhance the bioavailability of didanosine. These buffers, however, may decrease the absorption of ketoconazole, which requires an acid environment for absorption.
The delayed-release didanosine capsules do not contain a buffering agent and would not be expected to interact with ketoconazole. Minor As ketoconazole inhibits CYP3A4 activity, serum estrogen concentrations and estrogenic-related side effects e. Certain azole antifungals, including fluconazole, itraconazole, ketonconazole, miconazole systemic formulation only , posaconazole, and voriconazole, are CYP3A4 inhibitors and therefore may inhibit the metabolism of dienogest; estradiol valerate, possibly leading to increased serum concentrations.
In a pharmacokinetic study evaluating the effect of ketoconazole on dienogest and estradiol, co-administration with ketoconazole increased the AUC at steady-state for dienogest and estradiol by 2. There was also a 1. Moderate Concomitant use of digoxin with ketoconazole has resulted in increased digoxin serum concentrations. Ketoconazole inhibits p-glycoprotein, an enzyme which metabolizes digoxin. Plasma concentrations of digoxin should be monitored closely if ketoconazole is added.
Moderate Ketoconazole may increase diltiazem serum concentrations via inhibition of CYP3A4 with the potential for diltiazem toxicity. Exercise caution when co-administering systemic azole antifungals and calcium-channel blockers. Severe Concomitant use of ketoconazole with disopyramide is contraindicated due to the risk of serious adverse events, such as QT prolongation and torsade de pointes.
If coadministered, ketoconazole may inhibit the CYP3A4 metabolism of disopyramide, resulting in elevated disopyramide plasma concentrations.
Major Avoid coadministration of docetaxel and ketoconazole, as the systemic exposure of docetaxel may be increased resulting in increased treatment-related adverse reactions.
Concurrent administration increased docetaxel exposure by 2. Severe Concurrent use of dofetilide with ketoconazole is contraindicated due to the risk of serious cardiovascular events. This interaction is proposed to occur primarily by inhibition of cationic renal tubular secretion of dofetilide by ketoconazole, however, inhibition of CYP 3A4 metabolism may also contribute.
Major Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as dolasetron. Both dolasetron and ketoconazole are associated with QT prolongation; coadministration may increase this risk.
In addition, coadministration of ketoconazole a potent CYP3A4 inhibitor with dolasetron a CYP3A4 substrate may result in elevated dolasetron plasma concentrations and an increased risk for adverse events, including QT prolongation. Major Caution is advised when administering ketoconazole with rilpivirine due to the potential for additive effects on the QT interval and increased exposure to rilpivirine.
Both rilpivirine and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole a potent CYP3A4 inhibitor with rilpivirine a CYP3A4 substrate results in elevated rilpivirine plasma concentrations.
Conversely, ketoconazole concentrations are decreased when administered with rilpivirine. If these drugs must be administered together, closely monitor for rilpivirine-related adverse events and the potential for breakthrough fungal infections. Rilpivirine dosage adjustments are not recommended. Major Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as donepezil.
Both donepezil and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, ketoconazole has been shown, in vitro, to inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical relevance of this interaction is not known, but elevated donepezil concentrations could result in greater incidence of dose-related toxicity.
Minor Coadministration of doravirine and ketoconazole may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ketoconazole is a strong inhibitor. In a drug interaction study, concurrent use of ketoconazole increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: Moderate Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with ketoconazole. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
Moderate Cytochrome P enzyme inhibitors, such as ketoconazole, may inhibit the hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Major Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as doxorubicin.
Ketoconazole is a potent inhibitor of CYP3A4. Coadministration of ketoconazole with doxorubicin may result in an elevated doxorubicin plasma concentrations and an increased risk for adverse events, including QT prolongation.
Ketoconazole has been associated with QT prolongation. Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare.
Major Use caution if coadministration of dronabinol with ketoconazole is necessary, and monitor for an increase in dronabinol-related adverse reactions e. Concomitant use may result in elevated plasma concentrations of dronabinol.
Severe Concomitant use of dronedarone and ketoconazole is contraindicated. The effects of dronedarone on the pharmacokinetics of ketoconazole have not been described, although an increase in ketoconazole serum concentrations is possible. Major Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as droperidol.
Both droperidol and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole a potent CYP3A4 inhibitor with droperidol a CYP3A4 substrate may result in elevated droperidol plasma concentrations and an increased risk for adverse events, including QT prolongation.
Moderate Drospirenone has antimineralocorticoid effects; the progestin may increase serum potassium. Ketoconazole is a strong CYP3A4 inhibitor and may increase drospirenone serum concentrations. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take strong CYP3A4 inhibitors long-term and concomitantly.
Drugs that inhibit CYP3A4 such as ketoconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness.
Patients receiving estrogens should be monitored for an increase in adverse events. Drospirenone; Ethinyl Estradiol; Levomefolate: CYP3A4 inhibitors, such as ketoconazole, may decrease the clearance of dutasteride. Ketoconaozole increased plasma concentrations of tamsulosin; resulting in an increase in the Cmax and AUC of tamsulosin by a 2.
Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. No dosage adjustment is required in patients with atrial fibrillation.
Edoxaban is a P-glycoprotein P-gp substrate and oral ketoconazole is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ketoconazole; monitor for increased adverse effects of edoxaban. Major Avoid concurrent administration of ketoconazole and efavirenz or efavirenz-containing medications.
Administering ketoconazole with inducers of CYP3A4, such as efavirenz, may decrease the bioavailability of ketoconazole to such an extent that efficacy may be reduced. In addition, both drugs are associated with QT prolongation; coadministration may increase this risk. Use of an alternative antifungal medication should be considered. If these drugs must be used together, monitor for breakthrough fungal infections and adverse events.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: Major Concomitant use of elagolix mg twice daily and ketoconazole for more than 1 month is not recommended. Limit concomitant use of elagolix mg once daily and ketoconazole to 6 months. Coadministration may increase elagolix plasma concentrations and decrease ketoconazole concentrations.
Major Concurrent administration of elbasvir with systemic ketoconazole should be avoided if possible. Use of these drugs together significantly increases the plasma concentrations of elbasvir, and may result in adverse effects i. Major Concurrent administration of grazoprevir with systemic ketoconazole should be avoided if possible.
Use of these drugs together significantly increases the plasma concentrations of grazoprevir, and may result in adverse effects i. Severe Eletriptan is contraindicated with recent use i.
Coadministration of ketoconazole increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively. The coadministration of eliglustat with both ketoconazole and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Both eliglustat and ketoconazole can independently prolong the QT interval, and coadministration increases this risk. Coadministration of eliglustat with CYP3A inhibitors increases eliglustat exposure and the risk of serious adverse events e.
Although ketoconazole's product labeling states that coadministration of other drugs that prolong the QT interval and are metabolized by CYP3A4 is contraindicated, the specific interaction between ketoconazole and eliglustat was studied during clinical trials. The resultant data supports eliglustat dosage reduction in EMs instead of contraindication. Emtricitabine; Rilpivirine; Tenofovir alafenamide: Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Emtricitabine; Tenofovir disoproxil fumarate: Severe Concomitant use of ketoconazole with felodipine is contraindicated due to the risk of serious adverse events, such as edema and congestive heart failure.
Felodipine is metabolized by the hepatic isoenzyme CYP3A4; ketoconazole is a potent inhibitor of this isoenzyme. If coadministered, the plasma concentrations of felodipine may significantly increase.
Major Avoid coadministration of encorafenib and ketoconazole due to increased encorafenib exposure and QT prolongation. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ketoconazole. If ketoconazole is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ketoconazole.
Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib 0. Moderate Both entecavir and ketoconazole are secreted by active tubular secretion. In theory, coadministration of entecavir with ketoconazole may increase the serum concentrations of either drug due to competition for the drug elimination pathway.
The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered. Major The use of enzalutamide within 2 weeks of systemic ketoconazole therapy is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole; increase the dose of ketoconazole as necessary.
Severe Concomitant use of ketoconazole and eplerenone is contraindicated. Ketoconazole, due to the inhibition of hepatic CYP3A4 isoenzymes, increases serum eplerenone concentrations by roughly 5-fold and, hence, increases the risk of developing hyperkalemia and hypotension.
Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include eribulin.
Major Avoid coadministration of erlotinib with ketoconazole if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Major Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval, such as erythromycin.
Both erythromycin and ketoconazole are associated with QT prolongation; coadministration may increase this risk. Coadministration may result in increased plasma concentrations of ketoconazole, thereby further increasing the risk for adverse events. Major Caution is advised when administering ketoconazole with escitalopram.
Both escitalopram and ketoconazole are possibly associated with QT prolongation; coadministration may increase this risk. In addition, use of these drugs together may increase the risk for breakthrough fungal infections. Major In theory, CYP3A4 inhibitors, such as ketoconazole, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
Although one study using single oral doses of estazolam suggests that itraconazole has no effect on the pharmacokinetics or pharmacodynamics of estazolam, the manufacturer for Prosom recommends that estazolam should be avoided in patients receiving itraconazole and ketoconazole. Drugs that inhibit CYP3A4 such as systemic azole antifungals fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness.
CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving. A pharmacokinetic study of ketoconazole coadministered with eszopiclone resulted in an a 2. Although other azole antifungals e. Major A disulfiram-like reaction has been reported when patients taking ketoconazole consume ethanol.
Symptoms include facial flushing, difficult breathing, slight fever, and tightness of the chest. This reaction usually resolves spontaneously within 24 hours, with no lasting effects. Due to the risk of hepatotoxicity, ethanol should be avoided during and for at least 48 hours following ketoconazole therapy. Ethinyl Estradiol; Ethynodiol Diacetate: Minor Coadministration of etonogestrel and strong CYP3A4 inhibitors such as ketoconazole may increase the serum concentration of etonogestrel.
Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: Ethinyl Estradiol; Norethindrone Acetate: Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Ethinyl Estradiol; Norethindrone; Ferrous fumarate: This interaction may or may not be clinically significant, since ethosuximide serum concentrations are not well correlated to drug efficacy or side effects.
Major Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with ketoconazole. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations. Etravirine is a substrate and an inducer of CYP3A4. Coadministration with ketoconazole may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of ketoconazole may be decreased by etravirine.
Dose adjustments for ketoconazole may be necessary when coadministered with etravirine. Monitor patients closely for etravirine-related adverse effects and for efficacy of ketoconazole. Major Avoid coadministration of ketoconazole with everolimus Afinitor; Afinitor Disperz due to increased plasma concentrations of everolimus.
Coadministration of ketoconazole with everolimus Zortress is not recommended without close monitoring of everolimus whole blood trough concentrations. Coadministration with ketoconazole increased everolimus exposure by fold. Severe Concurrent use of simvastatin and ketoconazole is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is increased if simvastatin is administered concomitantly with potent CYP3A4 inhibitors such as ketoconazole.
If therapy with ketoconazole is unavoidable, simvastatin therapy must be suspended during the course of ketoconazole treatment. There are no known adverse effects with short-term discontinuation of simvastatin. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include ezogabine. Moderate Concurrent use of fentanyl with ketoconazole may increase the risk of increased fentanyl-related adverse reactions, such as fatal respiratory depression.
Consider a dose reduction of fentanyl until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ketoconazole in a patient taking fentanyl may decrease fentanyl plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to fentanyl.
Ketoconazole has the ability to inhibit P-gp in vitro. Moderate Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4. During one study, the Cmax and AUC of 5-hydroxymethyltolterodine increased 2- and 2. In the same study, CYP2D6 poor metabolizers of 5-hydroxymethyltolterodine experienced a 2. Minor Ketoconazole may inhibit the metabolism of fexofenadine via its effects on the CYP3A4 isozyme of the cytochrome P microsomal enzyme system.
Closely monitor patients who use fingolimod and systemic ketoconazole concomitantly. The risk of adverse reactions from fingolimod is greater. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include flecainide.
Severe The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as ketoconazole, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
In this study, the concomitant use of flibanserin and ketoconazole increased flibanserin exposure 4. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include fluoxetine. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ketoconazole include olanzapine.
Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ketoconazole include fluphenazine. Moderate Ketoconazole could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, such as flurazepam. Salmeterol is a CYP3A4 substrate. The coadministration of with strong CYP3A4 inhibitors such as ketoconazole results in elevated salmeterol plasma concentrations and increased risk for adverse reactions such as nervousness, tremor, or cardiovascular effects.
In a placebo-controlled, drug interaction study of 20 healthy subjects, coadministration of another LABA. Three of the 20 subjects were withdrawn from the study due to cardiovascular adverse effects 2 with QT prolongation and 1 with palpitations and sinus tachycardia.
Vilanterol is a CYP3A4 substrate. The coadministration of vilanterol with strong CYP3A4 inhibitors such as ketoconazole may result in elevated vilanterol plasma concentrations and increased risk for adverse reactions such as nervousness, tremor, or cardiovascular effects.
Similar interactions may occur when ketoconazole is added to vilanterol. Major There may be an increased risk for QT prolongation and torsade de pointes TdP during concurrent use of fluvoxamine and ketoconazole.
Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Minor Drugs that inhibit the cytochrome P enzyme system, such as ketoconazole, may decrease the rate of elimination of fomepizole. Moderate The incidence of marijuana associated adverse effects may change following coadministration with ketoconazole. When given concurrently with ketoconazole the amount of DeltaTHC converted to the active metabolite hydroxy-deltatetrahydrocannabinol OH-THC may be reduced.
Major Coadministration of fosamprenavir with ketoconazole results in clinically significant increases in ketoconazole plasma concentrations. If these drugs are coadministered, patients should be monitored for adverse events due to ketoconazole.
Major When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as ketoconazole. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes TdP.
If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment. Moderate Phenytoin is a known hepatic enzyme inducer, while ketoconazole inhibits hepatic metabolism. Although data suggest no interaction occurs when these agents are administered concomitantly, metabolism of either or both medications may be altered.
Serum concentrations of phenytoin can increase, and time to peak ketoconazole serum concentrations can be delayed. Serum phenytoin levels should be closely monitored if ketoconazole is added to phenytoin or fosphenytoin therapy. Moderate Monitor for fostamatinib toxicities that may require fostamatinib dose reduction i. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R, which may increase the risk of adverse reactions. Moderate Galantamine is a primary substrate of CYP3A4 and the bioavailability of galantamine may be increased when coadministered with strong CYP3A4 inhibitors, such as ketoconazole.
Monitor patients for galantamine-related adverse effects such as nausea, vomiting, diarrhea, headache, loss of appetite, excess sweating, and confusion during use of this combination.
Moderate Monitor for an increase in gefitinib-related adverse reactions if coadministration with ketoconazole is necessary.