Dexonto (dexamethasone sodium phosphate)

The route of administration and dosage of dexamethasone and its derivatives depend on the condition being treated and the response of the patient. IM or IV therapy is generally reserved for patients who are not able to take the drugs orally or for use in an emergency situation. Dosage for infants and children should be based on the severity of the disease and the response of the patient rather than on strict adherence to dosage indicated by age, body weight, or body surface area. After a satisfactory response is obtained, dosage should be decreased in small decrements to the lowest level that maintains an adequate clinical response, and the drug should be discontinued as soon as possible. Patients should be continually monitored for signs that indicate dosage adjustment is necessary, such as remissions or exacerbations of the disease and stress (surgery, infection, trauma). Following long-term therapy, dexamethasone should be withdrawn gradually. (See the Corticosteroids General Statement 68:04.)

No dosing information is available for this tab.

No dosing information is available for this tab.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Moderate Cyp3a4 Inducers/Doravirine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Moderate CYP3A4 inducers are expected to increase the metabolism of doravirine.(1-3)

CLINICAL EFFECTS: Concurrent or recent use of a moderate CYP3A4 inducer may result in decreased levels and effectiveness of doravirine.(1-3)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Recommendations for concurrent use of moderate CYP3A4 inducers with doravirine vary depending on the reference. The manufacturer of the fixed dose combination of doravirine-islatravir states concurrent use with moderate CYP3A4 inducers is not recommended.(3) The DHHS HIV guidelines state when coadministering doravirine with bosentan, dexamethasone, and eslicarbazepine (moderate CYP3A4 inducers): consider an alternative antiretroviral or alternative drug to the moderate CYP3A4 inducer. It would be prudent to consider alternative drugs to other moderate CYP3A4 inducers. If co-administration is necessary monitor virologic response.(4) The University of Liverpool HIV Drug Interactions Database states concurrent use with moderate CYP3A4 inducers should be avoided. If concurrent use cannot be avoided, dose adjustment of doravirine to 100 mg twice daily is recommended and should be maintained for at least 2 weeks following cessation of the moderate CYP3A4 inducer. If a patient is on eslicarbazepine, doravirine should not be coadministered.(5) The manufacturer of single ingredient doravirine and the fixed dose combination of doravirine-lamivudine-tenofovir does not have a recommendation for concurrent use with moderate CYP3A4 inducers.(1,3)

DISCUSSION: Doravirine is metabolized by CYP3A4. Moderate CYP3A4 inducers are expected to reduce doravirine levels, which may lead to loss of response.(1) In a study in 12 subjects, rifabutin (300 mg daily), a moderate CYP3A4 inducer, decreased the area-under-curve (AUC) and 24 hour concentration (C24) of a single dose of doravirine (100 mg) by 50% and 68%, respectively.(1) Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dexamethasone, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3-4)

Selected Glucocorticoids/Relacorilant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Relacorilant is a reversible antagonist of the glucocorticoid receptor (GR) and a strong CYP3A4 inhibitor.(1) Strong CYP3A4 inhibitors may inhibit the metabolism of corticosteroids metabolized by CYP3A4.(1)

CLINICAL EFFECTS: Relacorilant may antagonize the effect of glucocorticoids, and glucocorticoids may decrease the effect of relacorilant. Conditions requiring glucocorticoids may be exacerbated and adrenal insufficiency may occur.(1) Relacorilant may also increase systemic exposure to and effects from corticosteroids metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Relacorilant is contraindicated in patients who require glucocorticoids for life-saving purposes (e.g., immunosuppression after organ transplant). In patients taking glucocorticoids for other purposes, avoid relacorilant if possible. If coadministration cannot be avoided, consider alternative corticosteroids that are less affected by CYP3A4 inhibitors, like beclomethasone, prednisone, and prednisolone, and monitor relacorilant and glucocorticoid responses. If adrenal insufficiency occurs, withhold relacorilant and administer glucocorticoid therapy. High doses of glucocorticoids may be required to overcome glucocorticoid receptor antagonism, which may continue for up to 6 days after the last dose of relacorilant. After adrenal insufficiency resolves, resume the previous dose, reduce dose, or permanently discontinue relacorilant based on the severity, as recommended in the manufacturer prescribing information.(1)

DISCUSSION: Relacorilant antagonizes the glucocorticoid receptor. Relacorilant is contraindicated in patients receiving glucocorticoids for life-saving conditions and should be avoided in patients taking glucocorticoids for other conditions.(1) In a study, boceprevir (800 mg TID for 7 days) increased the area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%. The maximum concentration (Cmax) and AUC of prednisolone increased by 16% and 37%, respectively.(4) A study of 14 healthy adults found that concurrent use of ketoconazole with ciclesonide increased the AUC of ciclesonide's active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. However, the study concluded that no dosage adjustments were required because ciclesonide has a very low potential to cause side effects.(5) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(7-9) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(7) The cortisol AUC decreased by 86%.(11-14) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(15) There have been several case reports of Cushing's syndrome in patients treated concurrently with ritonavir and inhaled budesonide,(16-17) dexamethasone,(18) injectable triamcinolone,(19-22) nasal fluticasone.(24-42) Hepatitis has also been reported with concurrent budesonide and ritonavir.(43) In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3 days) increased the AUC, Cmax, and elimination half-life of methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(44) In a study in 8 healthy subjects, following nefazodone administration the following changes were seen with methylprednisolone: mean (+/-SD) area under the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(45) Selected steroids metabolized by CYP3A4 are linked to this monograph.(46)

Selected Steroids/Antiretroviral Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Antiretroviral CYP3A4 inhibitors may inhibit the metabolism of corticosteroids metabolized by CYP3A4. Dexamethasone may induce metabolism of agents that are substrates of CYP3A4.(1-13,50)

CLINICAL EFFECTS: Concurrent use of antiretroviral CYP3A4 inhibitors may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression. Concurrent dexamethasone may result in decreased levels and effectiveness of CYP3A4 substrates.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy of corticosteroids metabolized by CYP3A4 with antiretroviral CYP3A4 inhibitors. Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone, prednisone, and prednisolone. If concurrent therapy is warranted, patients should be closely monitored for systemic effects. The corticosteroid may need to be discontinued. Patients receiving concurrent therapy with dexamethasone and substrates of CYP3A4 should also be monitored for decreased effectiveness of the CYP3A4 substrate. The manufacturers of nasal fluticasone(14-16) and fluticasone for inhalation(17) state that concurrent use of fluticasone and atazanavir, indinavir, nelfinavir, ritonavir or saquinavir is not recommended. The US manufacturers of atazanavir,(1) fosamprenavir,(5) indinavir(6) and nelfinavir(8) recommend caution with concurrent use of inhaled or nasal fluticasone. Consider alternatives to fluticasone if long-term use is required.

DISCUSSION: In a study, boceprevir (800 mg TID for 7 days) increased the area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%. The maximum concentration (Cmax) and AUC of prednisolone increased by 16% and 37%, respectively.(2) A study of 14 healthy adults found that concurrent use of ketoconazole with ciclesonide increased the AUC of ciclesonide's active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. However, the study concluded that no dosage adjustments were required because ciclesonide has a very low potential to cause side effects.(18) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(7,11,14) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(3) The cortisol AUC decreased by 86%.(6,14-16) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(19) There have been several case reports of Cushing's syndrome in patients treated concurrently with ritonavir and inhaled budesonide,(19-20) dexamethasone,(22) injectable triamcinolone,(23-26) nasal fluticasone.(28-46) Hepatitis has also been reported with concurrent budesonide and ritonavir.(47) In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3 days) increased the AUC, Cmax, and elimination half-life of methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(48) In a study in 8 healthy subjects, following nefazodone administration the following changes were seen with methylprednisolone: mean (+/-SD) area under the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(49) Selected steroids metabolized by CYP3A4 are linked to this monograph.(50) Selected CYP3A4 inhibitors and substrates linked to this monograph include: atazanavir, cobicistat, darunavir, fosamprenavir, indinavir, lenacapavir, lopinavir, nelfinavir, saquinavir, and tipranavir.(50)

Selected Steroids/Selected Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inhibitors may inhibit the metabolism of corticosteroids metabolized by CYP3A4.

CLINICAL EFFECTS: Concurrent use of strong CYP3A4 inhibitors may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4, including Cushing's syndrome and adrenal suppression.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy between corticosteroids metabolized by CYP3A4 and strong CYP3A4 inhibitors. Alternative corticosteroids that are less affected by CYP3A4 inhibitors should be considered, like beclomethasone, prednisone, and prednisolone. If concurrent therapy is warranted, patients should be closely monitored for systemic effects. The corticosteroid may need to be discontinued.

DISCUSSION: In a study, boceprevir (800 mg TID for 7 days) increased the area-under-curve (AUC) of a single dose of prednisone (40 mg) by 22%. The maximum concentration (Cmax) and AUC of prednisolone increased by 16% and 37%, respectively.(3) A study of 14 healthy adults found that concurrent use of ketoconazole with ciclesonide increased the AUC of ciclesonide's active metabolite, des-ciclesonide, by approximately 3.6-fold at steady state, while levels of ciclesonide remained unchanged. However, the study concluded that no dosage adjustments were required because ciclesonide has a very low potential to cause side effects.(4) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(6-8) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(6) The cortisol AUC decreased by 86%.(10-13) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(14) There have been several case reports of Cushing's syndrome in patients treated concurrently with ritonavir and inhaled budesonide,(15-16) dexamethasone,(17) injectable triamcinolone,(18-21) nasal fluticasone.(23-41) Hepatitis has also been reported with concurrent budesonide and ritonavir.(42) In a study in 9 healthy subjects, mibefradil (50 mg once daily for 3 days) increased the AUC, Cmax, and elimination half-life of methylprednisolone by 3.8-fold, 1.8-fold, and 2.7-fold, respectively.(43) In a study in 8 healthy subjects, following nefazodone administration the following changes were seen with methylprednisolone: mean (+/-SD) area under the concentration-time curve was significantly higher (1393 +/- 343 vs. 2966 +/- 928 ug*h/L; P < 0.005), apparent clearance was lower (28.7 +/- 7.2 vs. 14.6 +/- 7.8 L/h; P < 0.02) and the terminal elimination half-life was longer (2.28 +/- 0.49 vs. 3.32 +/- 0.95 hours; P < 0.02).(44) Selected steroids metabolized by CYP3A4 are linked to this monograph.(45) Selected CYP3A4 inhibitors linked to this monograph include: adagrasib, boceprevir, ceritinib, clarithromycin, erythromycin, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, nefazodone, paritaprevir, posaconazole, ribociclib, telaprevir, telithromycin, troleandomycin, tucatinib, and voriconazole.(1-2,45)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Corticosteroids/Hormonal Contraceptives; Estrogens

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: It is speculated that hormonal contraceptives and estrogens inhibit hepatic metabolism of some corticosteroids as well as endogenous cortisol. Competitive protein binding may also contribute to elevations in serum corticosteroids.

CLINICAL EFFECTS: Concurrent use of hormonal contraceptives or estrogens may result in an increase in the therapeutic and toxic effects of corticosteroids.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent hormonal contraceptives or estrogen should be observed for symptoms of corticosteroid toxicity. A lower corticosteroid dose may be required.

DISCUSSION: In a study in 6 healthy females controlled on long-term oral contraceptives, subjects received either a placebo or high and low-dose prednisolone (0.53 and 0.14 mg/Kg iv). Both dosages of prednisolone decreased the total clearance, unbound clearance, and volume of distribution (Vd) at maximum concentration (Cmax) of total drug. Significant increases in half-life for free and unbound prednisolone and hydrocortisone concentrations were also observed in comparison to the placebo group. In a study in 8 females controlled on oral contraceptive therapy, 8 females not receiving contraceptive therapy, and 8 males, each subject received prednisolone 40 mg iv. The plasma clearance of total prednisolone in females on OC was 96 ml/min, which was significantly lower than those in both the male and female (205 and 187 ml/min, respectively) control groups. Prednisolone half-life and mean residence times were increased. The oral contraceptive group had a significantly higher (2-fold) concentration of transcortin, resulting in lower clearance, decreased Vd, and a 2-fold increase in the area-under-curve (AUC) for prednisolone. A clinical trial demonstrated the interaction between prednisolone (20 mg) and oral contraceptives containing ethinyl estradiol (30 mcg). The oral contraceptive users had an average plasma concentration of prednisolone 131% higher compared to the control group, and plasma cortisol levels were suppressed by approximately 90%. No differences were reported for ethinyl estradiol levels. In a study in 8 females taking oral contraceptives and 8 females who were were not, subjects received IV doses of prednisolone at 0.1 mg/Kg and 1.0 mg/Kg. Free prednisolone clearance was reduced by approximately 30% in the contraceptive receiving subjects compared to the control group, and plasma cortisol concentrations were reduced 2-fold compared to the control group. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Dexamethasone/Thalidomide Analogues

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of this interaction is unknown.

CLINICAL EFFECTS: Concurrent use of dexamethasone with iberdomide, lenalidomide, pomalidomide or thalidomide may increase the risk of venous thromboembolism (VTE), ischemic heart disease including myocardial infarction, and stroke.(1,2)

PREDISPOSING FACTORS: The effects of the interaction are greater with high-dose dexamethasone (480 mg/month or more).(3) Erythropoietic agents may also increase the risk.(1,2)

PATIENT MANAGEMENT: The US manufacturer of lenalidomide states the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) is significantly increased when lenalidomide and dexamethasone are given concurrently in patients with multiple myeloma and recommends thromboprophylaxis and the regimen should be selected based on the patient's underlying risks. Observe patients for signs and symptoms of venous thromboembolism (VTE) and instruct patients to see medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.(1) The US manufacturer of thalidomide states the risk of VTE increases significantly when thalidomide is used with concurrent therapy with standard chemotherapeutic agents including dexamethasone therapy and recommends considering thromboprophylaxis based on an assessment of individual patients' underlying risk factors. Observe patients closely for signs and symptoms of VTE and instruct patients to see medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling.(2) The National Comprehensive Cancer Network (NCCN) Guidelines recommend VTE chemoprophylaxis with low-molecular weight heparin (LMWH) with a dose equivalent to enoxaparin 40 mg once daily or full-dose warfarin with a dose to maintain a target international normalized ratio (INR) 2-3.(3)

DISCUSSION: The National Comprehensive Cancer Network (NCCN) Guidelines include lenalidomide/thalidomide plus high-dose dexamethasone as a treatment-related venous thromboembolism (VTE) risk factor for cancer patients. High-dose dexamethasone is defined by NCCN as >/= 480 mg per month. The NCCN Guidelines recommend VTE chemoprophylaxis with low-molecular weight heparin (LMWH) at a dose equivalent to enoxaparin 40 mg once daily or full-dose warfarin with a dose to maintain a target international normalized ratio (INR) 2-3.(3) The US manufacturer states the standard dosing for multiple myeloma includes lenalidomide (25 mg daily) on days 1-21 of the 28-day cycle and dexamethasone (40 mg daily) on days 1, 8, 15, and 22 of the 28-day cycle.(1) The dexamethasone dose is adjusted for patients >75 years old to 20 mg daily on days 1, 8, 15, and 22 of the 28-day cycle.(1) In 2 studies of 703 patients who received at least one dose of lenalidomide/dexamethasone or placebo/dexamethasone, the incidence of DVT was 9.3% and 4.3%, respectively. In the same population, the incidence of grade 3/4 adverse reactions the incidence of DVT was 8.2% and 3.4%, respectively, and the incidence of serious adverse reactions of DVT was 7.4% and 3.1%, respectively. The US manufacturer states the standard dosing for multiple myeloma includes combination therapy with thalidomide (200 mg daily) and dexamethasone (40 mg daily on days 1-4, 9-12, and 17-20) in a 28-day treatment cycle.(2) The overall rate of adverse reactions in clinical trials for multiple myeloma resulting in treatment discontinuation were 30% in the thalidomide/dexamethasone group and 16% in the dexamethasone monotherapy group.(2) In a safety study of 466 subjects, the incidence of DVT was higher in the thalidomide/dexamethasone arm than in the placebo/dexamethasone arm with 13% versus 2%, respectively.(2) In a safety study of Grade 3/4 adverse drug reactions, the thalidomide/dexamethasone arm had a 12% incidence of DVT compared to a 2% incidence in the placebo/dexamethasone arm.(2) A summary article discusses the incidence of VTE in patients receiving treatment for multiple myeloma. The use of thalidomide as a single agent does not significantly increase the risk of VTE in both new diagnoses and relapsed/refractory patients with a VTE incidence of 3-4% and 2-4%, respectively. The addition of dexamethasone to thalidomide increased the risk of VTE in newly diagnosed patients with an incidence of 14-26%. Similarly, the use of lenalidomide as a single agent does not increase the risk of VTE. Lenalidomide with dexamethasone increased the incidence of VTE in newly diagnosed patients as well as relapsed/refractory patients to 75% and 17%, respectively. Concurrent therapy with lenalidomide and dexamethasone showed a difference in the incidence of VTE based on the dexamethasone dose (high dose defined as 480 mg/month and low dose defined as 160 mg/month) with higher doses associated with an increase risk (26% versus 12% incidence, respectively). The incidence of VTE in studies with thalidomide alone range from 1.5-4.6% versus studies with thalidomide/dexamethasone at 7-26%.(4) Several studies have evaluated the optimal VTE prophylaxis agent with lenalidomide-treated patients. Patients receiving lenalidomide/dexamethasone and no chemoprophylaxis had a VTE incidence of 11-75%, 26% with the use of aspirin, 17% with the use of aspirin/LMWH/warfarin combination therapy, and 2-15% with the use of LMWH. (5) Several studies have evaluated the optimal VTE prophylaxis agent in thalidomide-treated patients. Patients receiving thalidomide/dexamethasone and no chemoprophylaxis had a VTE incidence of 26%, 10% with the use of low-dose warfarin and 0% with the use of therapeutic warfarin/LMWH.(5) Lenalidomide/dexamethasone compared to placebo/dexamethasone increased the rate of myocardial infarction (1.7% versus 0.6%, respectively) and stroke (2.3% versus 0.9%, respectively).(1) Thalidomide/dexamethasone compared to placebo/dexamethasone increased the rate of ischemic heart disease (11.1% versus 4.7%, respectively), including myocardial infarction (1.3% versus 1.7%, respectively), and stroke (2.6% versus 0.9%, respectively).(2)

Selected Corticosteroids/Levoketoconazole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Levoketoconazole may inhibit the CYP3A4 mediated metabolism of some corticosteroids, resulting in increased systemic exposure. Levoketoconazole may also suppress endogenous cortisol output. Levoketoconazole is the enantiomer of ketoconazole.

CLINICAL EFFECTS: Concurrent use of levoketoconazole may result in elevated levels of and effects from the corticosteroid, including Cushing syndrome. These effects have been seen with systemic as well as inhaled corticosteroids.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should be carefully monitored with concurrent administration of these agents, or when levoketoconazole is added to corticosteroid therapy. The dose of the corticosteroid may need to be adjusted or alternative therapy considered.

DISCUSSION: The concurrent use of ketoconazole has been shown to increase budesonide area-under-curve (AUC) by eight-fold. In a study in eight healthy subjects, the simultaneous administration of ketoconazole increased budesonide AUC by 6.5-fold. Administering the two agents 12 hours apart increased budesonide AUC by 3.8-fold. In a study in 6 healthy subjects, pretreatment with ketoconazole (200 mg daily) increased the AUC of a single intravenous dose of methylprednisolone (20 mg) by 135% and decreased its clearance by 60%. Concurrent ketoconazole also increased the reduction in 24-hour cortisol AUC and suppressed morning cortisol concentrations. In a study in 8 healthy subjects, ketoconazole decreased the clearance of methylprednisolone by 46% and increased mean residence time by 37%. In a randomized, cross-over study in 6 healthy subjects, pretreatment with ketoconazole (200 mg daily for 6 days) had no effect on the pharmacokinetics of a single intravenous dose of prednisolone (14.8 mg). In a study, concurrent oral ketoconazole increased the AUC of des-ciclesonide from orally inhaled ciclesonide by 3.6-fold. There were no changes in ciclesonide levels. In a study in 24 healthy subjects, subjects were randomized to receive either ketoconazole (200 mg BID) or placebo on Days 4-9 of a a 9 day course of mometasone (400 mcg BID). No subject had mometasone levels greater than 150 pcg/ml on Day 3. Four of 12 subjects who received ketoconazole had mometasone Cmax levels greater than 200 mcg/ml on Day 9. Plasma cortisol levels appeared to decrease as well. In a cross-over study in 15 healthy subjects, subjects were randomized to receive fluticasone furoate and vilanterol on days 5-11 with either ketoconazole (200mg once daily) or placebo for days 1-11 with a washout period of 7-14 days. Fluticasone furoate AUC was increased by 36%, Cmax was increased by 33%, and decreased systemic cortisol levels by 27%. There were no effects on heart rate and blood potassium levels. There was a small increase in QTc which was 7.6ms greater when compared to placebo; however, ketoconazole has been reported to increase QTc by 5-6ms. Vilanterol AUC was increased by 65% and Cmax was increased by 22%. There were no effects on heart rate and blood potassium levels. No serious adverse events occurred and no subjects withdrew from the study due to adverse events. The most common adverse event reported was headache. Coadministration of orally inhaled fluticasone (1000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone exposure and a 45% decrease in plasma cortisol AUC.

Selected Steroids/Ensitrelvir; Nirmatrelvir-Ritonavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ensitrelvir and nirmatrelvir/ritonavir may inhibit the metabolism of corticosteroids metabolized by CYP3A4.(1,2)

CLINICAL EFFECTS: Ensitrelvir and nirmatrelvir/ritonavir may result in increased systemic exposure to and effects from corticosteroids metabolized by CYP3A4.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration with corticosteroids of all routes of administration of which exposures are significantly increased by strong CYP3A4 inhibitors can increase the risk of Cushing's syndrome and adrenal suppression. However, the risk of Cushing's syndrome and adrenal suppression associated with short-term use of a strong CYP3A4 inhibitor is low.(1) The manufacturer of nirmatrelvir/ritonavir recommends considering alternative corticosteroids including beclomethasone, prednisone, and prednisolone.(1)

DISCUSSION: Concurrent use of a single dose of midazolam 2 mg, a CYP3A4 substrate, with nirmatrelvir-ritonavir (300 mg/100 mg twice daily for nine doses) increased the maximum concentration (Cmax) and area-under-curve (AUC) of midazolam by 37% and 143%, respectively.(1) A study in 18 healthy subjects examined the effects of ritonavir (100 mg twice daily) on fluticasone nasal spray (200 mcg daily). In most subjects, fluticasone was undetectable (<10 pg/ml) when administered alone. In subjects in whom fluticasone was detectable when given alone, Cmax and area-under-curve AUC averaged 11.9 pg/ml and 8.43 pg x hr/ml, respectively. With concurrent ritonavir, fluticasone Cmax and AUC increased to 318 pg/ml and 3102.6 pg x hr/ml, respectively.(7,11,13) This reflects increases in Cmax and AUC by 25-fold and 350-fold, respectively.(3) The cortisol AUC decreased by 86%.(4-7) In a study in 10 healthy subjects, ritonavir (200 mg twice daily for 4 and 14 days) increased the AUC of a single dose of prednisolone by 1.41-fold and 1.30-fold, respectively, after 4 days and 14 days of ritonavir.(8) In a clinical study, ensitrelvir (750 mg on day 1 and 250 mg on days 2-5) increased the Cmax and AUC of dexamethasone 1 mg single dose by 1.47-fold and 3.47-fold, respectively.(2) Selected steroids linked to this monograph include: budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, and triamcinolone.(9)

Weak Cyp3a4 Inducers/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and receive atogepant 60 mg once daily for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)

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• Cerebral malaria
• Ornithine carbamoyltransferase deficiency
• Urea cycle disorder

• Amebae infection
• Avascular necrosis of bone
• Cerebral trauma
• Chronic heart failure
• Fungal infection
• Gastritis
• Inactive tuberculosis
• Intestinal anastomosis
• Measles
• Measles contact
• Ocular herpes simplex
• Ocular hypertension
• Optic neuritis
• Osteopenia
• Osteoporosis
• Pheochromocytoma
• Sickle cell disease
• Strongyloidiasis
• Tendon rupture
• Untreated active tuberculosis
• Varicella contact
• Varicella zoster virus infection
• Viral hepatitis B

• Cataracts
• Diabetes mellitus
• Diverticulitis of gastrointestinal tract
• Edema
• Hepatic cirrhosis
• Hypercholesterolemia
• Hypertension
• Hypokalemia
• Hypothalamic-pituitary insufficiency
• Hypothyroidism
• Immunosuppression
• Infection
• Muscle atrophy
• Myopathy
• Myopathy with CK elevation
• Open angle glaucoma
• Pathological fracture
• Peptic ulcer
• Psychotic disorder
• Seizure disorder

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Less Frequent

• Folliculitis
• Purpura
• Skin and skin structure infection
• Skin atrophy

Rare or Very Rare

• Adrenocortical insufficiency
• Bullous dermatitis
• Cataracts
• Central serous chorioretinopathy
• Glaucoma
• Growth failure
• Hypothalamic-pituitary insufficiency
• Intracranial hypertension
• Ocular hypertension
• Skin hypopigmentation
• Skin striae
• Skin ulcer
• Urticaria

More Frequent

• Erythema
• Stinging of skin

Less Frequent

• Acute pain at drug application site
• Blurred vision
• Headache disorder
• Paresthesia
• Pruritus of skin
• Skin rash
• Telangiectasia
• Treatment site sequelae

Rare or Very Rare

• Acneiform eruption
• Alopecia
• Blistering skin
• Contact dermatitis
• Dry skin
• Dyschromia
• Glycosuria
• Hirsutism
• Hypercortisolism
• Hyperesthesia
• Hyperglycemia
• Miliaria
• Perioral dermatitis
• Skin irritation

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