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Durvalumab

Pronunciation

(dur VAL ue mab)

Index Terms

  • MEDI4736

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Imfinzi: 120 mg/2.4 mL (2.4 mL); 500 mg/10 mL (10 mL) [contains polysorbate 80]

Brand Names: U.S.

  • Imfinzi

Pharmacologic Category

  • Antineoplastic Agent, Anti-PD-L1 Monoclonal Antibody
  • Antineoplastic Agent, Monoclonal Antibody

Pharmacology

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody which blocks programmed cell death ligand 1 (PD-L1) binding to PD-1 and CD80 (B7.1); PD-L1 blockade leads to increased T-cell activation, allowing T-cells to kill tumor cells (Massard 2016). PD-L1 is an immune check point protein expressed on tumor cells and tumor infiltrating cells and down regulates anti-tumor t-cell function by binding to PD-1 and B7.1; blocking PD-1 and B7.1 interactions restores antitumor t-cell function (Fehrenbacher 2016; Rosenberg 2016).

Distribution

Vdss: 5.6 L

Excretion

Steady-state clearance: 8.24 mL/hour

Half-Life Elimination

Terminal half-life: ~17 days

Use: Labeled Indications

Urothelial carcinoma, locally advanced or metastatic: Treatment of locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Urothelial carcinoma, locally advanced or metastatic: IV: 10 mg/kg once every 2 weeks until disease progression or unacceptable toxicity.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Renal impairment prior to treatment initiation:

CrCl 30 to 89 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, there is no clinically relevant effect on pharmacokinetics.

CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Renal toxicity during treatment (nephritis): Note: Based on the nephritis severity, withhold durvalumab and administer systemic corticosteroids (See “Note” in Dosage Adjustment for Toxicity).

Nephritis, grade 2 (creatinine >1.5 to 3 times ULN): Withhold dose. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Nephritis, grade 3 (creatinine >3 to 6 times ULN): Discontinue permanently. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Nephritis, grade 4 (creatinine >6 times ULN): Discontinue permanently. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Dosing: Hepatic Impairment

Hepatic impairment prior to treatment initiation:

Mild impairment (bilirubin ≤ ULN and AST > ULN or bilirubin >1 to 1.5 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, there is no clinically relevant effect on pharmacokinetics.

Moderate impairment (bilirubin >1.5 to 3 times ULN and any AST) or severe (bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Hepatotoxicity during treatment: Note: Based on the hepatitis severity, withhold durvalumab and administer systemic corticosteroids (see “Note” in Dosage Adjustment for Toxicity).

Hepatitis, grade 2 (ALT or AST >3 to 5 times ULN or total bilirubin >1.5 to 3 times ULN): Withhold dose. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Hepatitis, grade 3 (ALT or AST ≤8 times ULN or total bilirubin ≤5 times ULN): Withhold dose. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Hepatitis, grade 3 (ALT or AST >8 times ULN or total bilirubin >5 times ULN): Discontinue permanently. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Hepatitis, concurrent ALT or AST >3 times ULN and total bilirubin >2 times ULN with no other cause: Discontinue permanently. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Dosing: Adjustment for Toxicity

Withhold and/or discontinue durvalumab to manage adverse reactions (no dosage reductions are recommended). Note: Based on the severity of the adverse reaction, withhold durvalumab and administer systemic corticosteroids. Consider increasing the corticosteroid dose (and/or other immunosuppressants) if there is no improvement or if toxicity worsens. Begin corticosteroid taper when adverse reaction improves to below grade 1 and continue taper over at least 1 month. For adverse reactions that do not result in permanent discontinuation, when improved to grade 1 or lower and the corticosteroid dose is reduced to <10 mg/day prednisone (or equivalent), resume durvalumab.

Dermatologic toxicity:

Rash or dermatitis, grade 2 for >1 week or grade 3: Withhold dose. Consider systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Rash or dermatitis, grade 4: Discontinue permanently. Consider systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Endocrinopathies:

Adrenal insufficiency, hypophysitis/hypopituitarism, grades 2, 3, or 4: Withhold dose until clinically stable. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper. Administer hormone replacement therapy as clinically indicated.

Diabetes mellitus type 1, grades 2, 3, or 4: Withhold dose until clinically stable. Initiate insulin treatment as clinically indicated.

Hyperthyroidism, grades 2, 3, or 4: Withhold dose until clinically stable. Initiate symptomatic management.

Hypothyroidism, grades 2, 3, or 4: Initiate thyroid replacement therapy as clinically indicated.

GI toxicity:

Colitis or diarrhea, grade 2: Withhold dose. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Colitis or diarrhea, grade 3 or 4: Discontinue permanently. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Infection: Grade 3 or 4: Withhold dose. Initiate symptomatic management with anti-infectives for suspected or confirmed infections.

Infusion-related reactions:

Grade 1 or 2: Interrupt or slow infusion. Consider premedications with subsequent doses.

Grade 3 or 4: Discontinue permanently.

Pulmonary toxicity:

Pneumonitis, grade 2: Withhold dose. Administer systemic corticosteroids (prednisone initial dose of 1 to 2 mg/kg daily or equivalent) followed by a taper.

Pneumonitis, grade 3 or 4: Discontinue permanently. Administer systemic corticosteroids (prednisone initial dose of 1 to 4 mg/kg daily or equivalent) followed by a taper.

Other toxicities:

Grade 3: Withhold dose. Manage symptomatically.

Grade 4: Discontinue permanently. Consider systemic corticosteroids (prednisone initial dose of 1 to 4 mg/kg daily or equivalent) followed by a taper.

Reconstitution

Withdraw appropriate volume from vial (solution should be clear to opalescent and colorless to slightly yellow and free of visible particles; do not use if cloudy, discolored or if visible particulates are present) and transfer to IV bag containing NS or D5W. Mix by gently inverting bag (do not shake). The final concentration of the diluted solution should be between 1 and 15 mg/mL. Discard unused portion of the vial.

Administration

IV: Infuse over 60 minutes through an IV line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter. Do not administer other medications through the same IV line.

Monitor for infusion reactions. Interrupt or slow the infusion for grade 1 or 2 infusion-related reactions (consider premedications with subsequent infusions); discontinue permanently for grade 3 or 4 reactions.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F); do not freeze. Protect vials from light (store in original packaging). Do not shake. Solutions diluted for infusion should be used immediately after preparation. If not administered immediately, may be stored (from the time of vial puncture to the start of administration) for up to 24 hours refrigerated at 2°C to 8°C (36°F to 46°F) or for up to 4 hours at room temperature of 25°C (77°F). Do not freeze or shake diluted solution.

Drug Interactions

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (15%)

Central nervous system: Fatigue (39%)

Dermatologic: Skin rash (11% to 16%; including immune-mediated rashes)

Endocrine & metabolic: Hyponatremia (grades 3/4: 12%)

Gastrointestinal: Constipation (21%), decreased appetite (19%), nausea (16%), abdominal pain (14%), colitis (≤13%), diarrhea (≤13%)

Genitourinary: Urinary tract infection (4% to 15%)

Hematologic & oncologic: Lymphocytopenia (grades 3/4: 11%)

Infection: Infection (30% to 38%)

Neuromuscular & skeletal: Musculoskeletal pain (24%)

Respiratory: Dyspnea (≤13%), dyspnea on exertion (≤13%)

Miscellaneous: Fever (14%; including tumor-associated fever)

1% to 10%:

Cardiovascular: Myocarditis (≤1%; immune-mediated)

Central nervous system: Aseptic meningitis (≤1%; immune-mediated)

Endocrine & metabolic: Hypothyroidism (6% to 10%), hyperthyroidism (5% to 6%), hypermagnesemia (grades 3/4: 4%), dehydration (grades 3/4: ≥3%), hypercalcemia (grades 3/4: 3%), hyperglycemia (grades 3/4: 3%), hyperkalemia (grades 3/4: 1%), hypoalbuminemia (grades 3/4: 1%), hypokalemia (grades 3/4: 1%)

Hematologic & oncologic: Anemia (grades 3/4: 8%), neutropenia (grades 3/4: 1%), hemolytic anemia (≤1%; immune-mediated), immune thrombocytopenia (≤1%)

Hepatic: Increased serum alkaline phosphatase (grades 3/4: 4%), increased serum bilirubin (grades 3/4: 3%), increased serum AST (grades 3/4: 2%), hepatitis (1%), hyperbilirubinemia (grades 3/4: 1%), increased serum ALT (grades 3/4: 1%)

Immunologic: Antibody development (3%)

Neuromuscular & skeletal: Myositis (≤1%; immune-mediated)

Ophthalmic: Ocular toxicity (≤1%, immune-mediated; including uveitis and keratitis)

Renal: Increased serum creatinine (grades 3/4: 1%), nephritis (≤1%; immune-mediated)

Respiratory: Cough (≤10%), productive cough (≤10%), pneumonitis (2%)

Miscellaneous: Infusion-related reaction (2%)

Frequency not defined:

Endocrine & metabolic: Hypophysitis

Hepatic: Hepatic injury

Renal: Acute renal failure

<1%, postmarketing, and/or case reports: Adrenocortical insufficiency, pituitary insufficiency, type 1 diabetes mellitus, urticaria, vitiligo

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Immune-related adrenal insufficiency has been reported with durvalumab. Monitor for clinical signs and symptoms of adrenal insufficiency. If adrenal insufficiency occurs, interrupt durvalumab treatment and if clinically indicated, administer systemic corticosteroids and hormone replacement.

• Dermatologic toxicity: Durvalumab has caused immune-mediated rash, including grade 3 rash and vitiligo. Monitor for signs and symptoms of dermatologic toxicity. May require treatment interruption or discontinuation; consider systemic corticosteroids if indicated.

• Diabetes mellitus: Immune-related type 1 diabetes mellitus has occurred in patients receiving durvalumab. Monitor glucose and monitor for clinical signs and symptoms of diabetes. Initiate insulin for type 1 diabetes mellitus and interrupt durvalumab treatment until clinically stable.

• Gastrointestinal toxicities: Immune-mediated colitis or diarrhea occurred in patients receiving durvalumab. Grades 3 and 4 diarrhea or colitis has been reported. The median time to onset is 73 days (range: 13 to 345 days). Monitor for signs/symptoms of colitis or diarrhea and manage with treatment interruption or discontinuation, anti-diarrheal agents, and systemic corticosteroids. Resolution occurred in approximately half of patients who experienced immune-mediated diarrhea/colitis.

• Hepatotoxicity: Immune-mediated hepatitis has occurred in patients receiving durvalumab (some fatal). The median time to onset was ~52 days (range: 15 to 312 days). Monitor for abnormal liver function tests each cycle during durvalumab treatment. Manage immune-mediated hepatitis with systemic corticosteroids and treatment interruption or discontinuation. In one study most patients experiencing immune-mediated hepatitis received high-dose corticosteroids; one patient also received mycophenolate. Recovery occurred in approximately half of patients experiencing immune-mediated hepatitis. Grade 3 or 4 ALT, AST, and/or total bilirubin elevations have been reported.

• Hypophysitis/hypopituitarism: Immune-related hypophysitis/hypopituitarism has occurred in patients receiving durvalumab. Monitor for clinical signs and symptoms of hypophysitis or hypopituitarism. If hypophysitis/hypopituitarism occurs, interrupt durvalumab until clinically stable and administer corticosteroids and hormone replacement as indicated. Hypopituitarism leading to adrenal insufficiency and diabetes insipidus has occurred (rarely).

• Immune thrombocytopenic purpura: Durvalumab has caused immune thrombocytopenic purpura (ITP). Monitor for signs and symptoms of ITP. May require treatment interruption or discontinuation and systemic corticosteroids with or without immunoglobulin or rituximab.

• Infection: Infections occurred in approximately one-third of patients receiving durvalumab. Severe infections, including sepsis, necrotizing fasciitis, and osteomyelitis have been reported. The most common grade 3 or 4 infections were urinary tract infections. Monitor for signs/symptoms of infection; if infection is suspected or confirmed, manage with anti-infectives. Withhold treatment for grade 3 or 4 infection.

• Infusion reactions: Infusion reactions have been observed with durvalumab, including severe infusion-related reactions. Monitor for signs/symptoms of an infusion reactions. Interrupt or slow the infusion rate for mild or moderate infusion reactions (consider premedications with subsequent infusions). Discontinue durvalumab permanently for grade 3 or 4 infusion reactions. Urticaria developed (rarely), usually within 48 hours of durvalumab administration.

• Nephrotoxicity: Durvalumab has caused immune-mediated nephritis. Monitor renal function prior to initiating treatment and before each cycle of durvalumab treatment. Nephritis may require systemic corticosteroids and treatment interruption or discontinuation. Nephritis typically resolved following treatment with systemic corticosteroids.

• Pulmonary toxicities: Immune-mediated pneumonitis or interstitial lung disease has occurred in patients receiving durvalumab (including fatal cases). The median time to onset was ~56 days (range: 24 to 423 days). Monitor for signs/symptoms of pneumonitis; evaluate suspected pneumonitis with radiographic imaging and manage with systemic corticosteroids and treatment interruption or discontinuation. In one study, recovery occurred in approximately half of patients experiencing immune-mediated pneumonitis.

• Thyroid disorders: Immune-related thyroid disorders have occurred in patients receiving durvalumab. Monitor thyroid function at baseline and periodically during treatment; monitor for clinical signs and symptoms of thyroid disorders. Patients with abnormal thyroid function tests who are asymptomatic can receive durvalumab. Hypothyroid events included thyroiditis leading to hypothyroidism, grades 1 and 2 hypothyroidism, and elevated (above baseline) thyroid stimulating hormone (TSH). Manage hypothyroidism with hormone replacement (if indicated). The median time to first onset of hypothyroidism was 42 days (range: 15 to 239 days). Hyperthyroidism (grades 1 or 2) or thyroiditis leading to hyperthyroidism, and decreased or below baseline TSH also occurred. The median time to first onset of hyperthyroidism was 43 days (range: 14 to 71 days). Withhold durvalumab and manage symptomatically for hyperthyroidism. Treatment with a beta-blocker and/or thioamide was administered for hyperthyroidism in some patients. In several patients with thyroiditis, transient hyperthyroidism preceded hypothyroidism. Treatment with a beta-blocker and/or thioamide was administered for hyperthyroidism in five of these patients.

• Other immune-mediated toxicities: Other immune-related adverse reactions associated with durvalumab (rarely) include aseptic meningitis, hemolytic anemia, myocarditis, myositis, and ocular inflammatory toxicity including uveitis and keratitis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Monitoring Parameters

Monitor liver function (during each cycle); renal function tests (prior to treatment and each cycle); thyroid function tests (at baseline, periodically during treatment); blood glucose. Monitor for clinical signs/symptoms of adrenal insufficiency, colitis/diarrhea, dermatologic toxicity, diabetes/hyperglycemia, hepatitis/hepatotoxicity, hypophysitis or hypopituitarism, immune thrombocytopenia purpura, infection, pneumonitis (evaluate suspected pneumonitis with radiographic imaging), thyroid disorders; monitor for infusion reactions.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. Immunoglobulins are known to cross the placenta and fetal exposure to durvalumab may be expected. Based on the mechanism of action, durvalumab may cause fetal harm if administered to pregnant women. Women of reproductive potential should use effective contraception during therapy and for at least 3 months after the last dose.

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