Drug Interactions between budesonide and durvalumab

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations and systemic effects of orally administered budesonide. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. According to the manufacturer, the systemic exposure of oral budesonide approximately doubles after extensive intake of grapefruit juice.

MANAGEMENT: Patients receiving budesonide should avoid the regular consumption of grapefruits and grapefruit juice to prevent undue increases in plasma budesonide levels and systemic effects.

Durvalumab can cause immune-mediated adrenal insufficiency. Adrenal function should be monitored in patients with adrenal insufficiency or with borderline adrenal function and in patients with prolonged periods of stress due to major surgery, intensive care, etc. It is recommended to monitor patients for clinical signs and symptoms of adrenal insufficiency and to institute appropriate measures as necessary. Monitor as clinically indicated prior to and periodically during treatment and withhold, reduce dose, or discontinue therapy with durvalumab as necessary.

Programmed death receptor-1/ligand-1 (PD-1/PD-L1) blocking antibodies can cause immune-mediated adverse reactions, which may be severe or fatal. Immune-mediated adverse reactions can occur in any organ system or tissue at any time after starting therapy. This may be considered when using PD-1/PD-L1 blocking antibodies in patients with immune system disorders (e.g., ulcerative colitis, Crohn's disease, lupus) or with conditions affecting the nervous system (e.g., myasthenia gravis, Guillain-Barre syndrome). It is recommended to monitor patients closely for signs/symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions.

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a programmed death receptor-1/ligand-1 (PD-1/PD-L1) blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. It is recommended to follow patients closely for evidence of transplant-related complications and intervene promptly. The benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody before or after an allogeneic HSCT should be considered.

Prolonged use of corticosteroids may cause posterior subcapsular cataracts and elevated intraocular pressure, the latter of which may lead to glaucoma and/or damage to the optic nerves. Therapy with corticosteroids should be administered cautiously nonetheless in patients with a history of cataracts, glaucoma, or increased intraocular pressure. Although adverse effects of corticosteroids may be minimized by local rather than systemic administration, the risks are not entirely abolished. Inhaled and nasally applied drug may be absorbed into the circulation, especially when large doses are used. It is important that the recommended dosages of the individual products not be exceeded and that the lowest effective dosage be used.

Durvalumab can cause type 1 diabetes mellitus. Monitor for hyperglycemia or other signs and symptoms of diabetes. Withhold treatment in cases of severe hyperglycemia until metabolic control is achieved. Permanently discontinue durvalumab for life-threatening hyperglycemia. If appropriate interrupt treatment according to manufacturer recommendations. Care should be exercised when using durvalumab in diabetic patients.

Immune-mediated colitis has been reported with the use of durvalumab. Monitor patients for signs and symptoms of diarrhea or colitis. It is recommended to administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe or life-threatening colitis. It is recommended to interrupt or to permanently discontinue durvalumab for life-threatening or for recurrent colitis. Care should be taken when using durvalumab in patients with inflammatory bowel disease.

Prolonged use of corticosteroids may cause posterior subcapsular cataracts and elevated intraocular pressure, the latter of which may lead to glaucoma and/or damage to the optic nerves. Therapy with corticosteroids should be administered cautiously nonetheless in patients with a history of cataracts, glaucoma, or increased intraocular pressure. Although adverse effects of corticosteroids may be minimized by local rather than systemic administration, the risks are not entirely abolished. Inhaled and nasally applied drug may be absorbed into the circulation, especially when large doses are used. It is important that the recommended dosages of the individual products not be exceeded and that the lowest effective dosage be used.

The use of corticosteroids may rarely precipitate or aggravate conditions of hyperadrenocorticism. Although adverse effects of corticosteroids may be minimized by local rather than systemic administration, the risks are not entirely abolished. Inhaled and nasally applied drug may be absorbed into the circulation, especially when large doses are used. It is important that the recommended dosages of the individual products not be exceeded and that the lowest effective dosage be used. The development of symptoms such as menstrual irregularities, acneiform lesions, cataracts and cushingoid features during inhaled or nasal corticosteroid therapy may indicate excessive use.

The immunosuppressant and anti-inflammatory effects of corticosteroids, particularly in higher dosages, may decrease host resistance to infectious agents, decrease the ability to localize infections, and mask the symptoms of infection. Secondary infections may be more likely to develop. Therapy with corticosteroids should be administered cautiously in patients with an infection, particularly active or quiescent tuberculosis or in hepatitis B carriers. Monitor patients for any new or worsening infection and use with caution in these patients. A serious or even fatal course of chickenpox and measles can occur in susceptible patients. It is important that the recommended dosages of the individual products not be exceeded and that the lowest effective dosage be used.

Durvalumab may alter the normal immune response and increase susceptibility to infections. Monitor patients for signs and symptoms of infection and withhold durvalumab treatment for Grade 3 or higher infections, particularly in patients with urinary tract infections. Resume once clinically stable.

Immune-mediated colitis has been reported with the use of durvalumab. Monitor patients for signs and symptoms of diarrhea or colitis. It is recommended to administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe or life-threatening colitis. It is recommended to interrupt or to permanently discontinue durvalumab for life-threatening or for recurrent colitis. Care should be taken when using durvalumab in patients with inflammatory bowel disease.

Some inhaled corticosteroid formulations contain lactose and may cause adverse reactions including cough, wheezing and bronchospasm in patients with severe milk protein allergy or intolerance. Caution is advised.

Corticosteroids are predominantly cleared by hepatic metabolism and impairment of the liver function may lead to their accumulation. Patients with hepatic disease should be closely monitored.

Durvalumab can cause immune-mediated hepatitis. Caution is recommended when using durvalumab in patients with moderate or severe hepatic impairment as this agent has not been studied in these patients. Monitor patients for signs and symptoms of hepatitis during and after treatment discontinuation. Periodic hepatic function test should be performed according to medical practices. Administer corticosteroids as appropriate according to manufacturer recommendations. It is recommended to interrupt or permanently discontinue treatment with durvalumab for severe or life-threatening transaminase or total bilirubin elevation. Care should be taken when using durvalumab in patients with liver disease.

Pharmacologic dosages of corticosteroids may increase the risk of corneal perforation in patients with ocular herpes simplex. Therapy with inhaled and nasal corticosteroids should be administered cautiously in such patients.

Solid organ transplant rejection and other transplant (including corneal graft) rejection have been reported with the use of programmed death receptor-1/ligand-1 (PD-1/PD-L1) blocking antibodies. This may be considered when using PD-1/PD-L1 blocking antibodies in patients who have received a solid organ or other transplant.

Prolonged use of inhaled corticosteroids may be associated with a reduction in bone density. This effect appears to be dose-related and has been reported primarily with high dosages (800 mcg/day or more of beclomethasone or equivalent for 1 year or greater). Reduced levels of total body calcium have also been demonstrated in patients receiving lower dosages. Long-term therapy with inhaled and nasal corticosteroids should be administered cautiously in patients with osteoporosis. It is important that the recommended dosages of the individual products not be exceeded and that the lowest effective dosage be used.

Durvalumab can cause immune-mediated pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging. It is recommended to administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate pneumonitis or 1 to 4 mg per kg per day or equivalent corticosteroid for more severe pneumonitis, followed by a taper. It is recommended to interrupt or permanently discontinue durvalumab based on the severity of symptoms. Care should be exercised when using this agent in patients with suspected pneumonitis.

Durvalumab can cause immune-mediated nephritis. Monitor patients for abnormal renal function tests prior to and periodically during treatment. It is recommended to administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening increased serum creatinine. Withhold or permanently discontinue durvalumab based on severity. If appropriate modify the dose according to manufacturer recommendations. Care should be taken when using durvalumab in patients with renal dysfunction.

Durvalumab can cause immune-mediated thyroid disorders. Monitor thyroid function prior to and periodically during treatment. Administer hormone-replacement therapy for hypothyroidism or initiate medical management for control of hyperthyroidism. Continue durvalumab for hypothyroidism and interrupt for hyperthyroidism based on the manufacturer recommendation. Care should be taken when using this agent in patients with thyroid disease.

The immunosuppressant and anti-inflammatory effects of corticosteroids, particularly in higher dosages, may decrease host resistance to infectious agents, decrease the ability to localize infections, and mask the symptoms of infection. Secondary infections may be more likely to develop. Therapy with corticosteroids should be administered cautiously in patients with an infection, particularly active or quiescent tuberculosis or in hepatitis B carriers. Monitor patients for any new or worsening infection and use with caution in these patients. A serious or even fatal course of chickenpox and measles can occur in susceptible patients. It is important that the recommended dosages of the individual products not be exceeded and that the lowest effective dosage be used.