Durvalumab

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]

Pharmacology

Mechanism of Action

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).

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 5.6 L

Excretion

Steady-state clearance: 8.2 mL/hour

Half-Life Elimination

Terminal half-life: ~18 days

Use: Labeled Indications

Non-small cell lung cancer, unresectable: Treatment of unresectable stage III non-small cell lung cancer which has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

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.

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to durvalumab or any component of the formulation.

Dosage and Administration

Dosing: Adult

Non-small cell lung cancer (stage III), unresectable: IV: 10 mg/kg once every 2 weeks; continue until disease progression or unacceptable toxicity or a maximum of 12 months. In the clinical trial, durvalumab was initiated within 6 weeks after chemoradiotherapy; treatment was continued beyond 12 months if disease control was achieved at the end of 12 months but then progressed during follow-up (Antonia 2017; Antonia 2018).

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: 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 or discontinue durvalumab and administer systemic corticosteroids. For adverse reactions where the dose is withheld but do not result in permanent discontinuation, resume durvalumab when the toxicity has improved to grade 1 or lower and the corticosteroid dose is reduced to ≤10 mg/day prednisone (or equivalent).

Permanently discontinue durvalumab for persistent grade 2 or 3 adverse reactions (excluding endocrinopathies) which do not recover to grade 1 or lower within 12 weeks after the last dose or for recurrent grade 3 or 4 reactions. If unable to reduce prednisone dose to ≤10 mg/day within 12 weeks after the last durvalumab dose, discontinue durvalumab permanently.

Dermatologic toxicity:

Rash or dermatitis, grade 2 for >1 week or grade 3: Withhold dose. Administer 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. Administer 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 appropriate medical management as clinically indicated.

Hypothyroidism: 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 until clinically stable. Initiate appropriate management with anti-infectives.

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 2: Exclude other causes and initiate corticosteroids as clinically indicated.

Grade 3: Withhold dose. Administer systemic corticosteroids (prednisone initial dose of 1 to 4 mg/kg daily or equivalent) followed by a taper.

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

Reconstitution

Withdraw appropriate volume from vial (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 8 hours at room temperature (≤25°C [77°F]) (Note: Prior to August 2019, the manufacturer's labeling stated the storage time at room temperature was 4 hours). Do not freeze or shake diluted solution.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (15%)

Central nervous system: Fatigue (34% to 39%)

Dermatologic: Dermatitis (≤26%), skin rash (≤26%; including immune-mediated rashes), pruritus (12%)

Endocrine & metabolic: Hyperglycemia (52%), hypocalcemia (46%), hyponatremia (33%), hyperkalemia (32%), increased gamma-glutamyl transferase (24%), hypothyroidism (11% to 12%)

Gastrointestinal: Constipation (21%), decreased appetite (19%), colitis (≤18%), diarrhea (≤18%), nausea (16%), abdominal pain (10% to 14%)

Genitourinary: Urinary tract infection (15%)

Hematologic & oncologic: Lymphocytopenia (43%; grades 3/4: 11%)

Hepatic: Increased serum ALT (39%), increased serum AST (36%), hepatitis (12%)

Infection: Infection (38% to 56%)

Neuromuscular & skeletal: Musculoskeletal pain (24%)

Respiratory: Cough (≤40%), productive cough (≤40%), pneumonitis (≤34%), radiation pneumonitis (≤34%), upper respiratory tract infection (26%), pneumonia (17%), dyspnea (≤13%), dyspnea on exertion (≤13%)

Miscellaneous: Fever (≤15%; including tumor-associated fever)

1% to 10%:

Central nervous system: Voice disorder (<10%)

Dermatologic: Night sweats (<10%)

Endocrine & metabolic: Hyperthyroidism (7%), hypermagnesemia (grades 3/4: 4%), dehydration (grades 3/4: ≥3%), hypercalcemia (grades 3/4: 3%), hypoalbuminemia (grades 3/4: 1%), hypokalemia (grades 3/4: 1%)

Genitourinary: Dysuria (<10%)

Hematologic & oncologic: Anemia (grades 3/4: 8%), neutropenia (grades 3/4: 1%)

Hepatic: Increased serum alkaline phosphatase (grades 3/4: 4%), hyperbilirubinemia (grades 3/4: 1%)

Immunologic: Antibody development (3%)

Infection: Increased susceptibility to infection (<10%)

Renal: Nephritis (6%; immune-mediated), increased serum creatinine (grades 3/4: 1%)

Miscellaneous: Infusion-related reaction (2%)

Frequency not defined:

Endocrine & metabolic: Hypophysitis

Hepatic: Hepatic injury

Infection: Sepsis

Renal: Acute renal failure

<1%, postmarketing, and/or case reports: Adrenocortical insufficiency, aseptic meningitis (immune-mediated), hemolytic anemia (immune-mediated), immune thrombocytopenia, myocarditis (immune-mediated), myositis (immune-mediated), ocular toxicity (immune-mediated; including uveitis and keratitis), pituitary insufficiency, thyroiditis, type 1 diabetes mellitus, vitiligo

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: Immune-related adrenal insufficiency has been reported with durvalumab. Monitor for clinical signs/symptoms of adrenal insufficiency. If grade 2 or higher adrenal insufficiency occurs, administer systemic corticosteroids and hormone replacement as clinically indicated; interrupt durvalumab treatment (based on the severity).
• Dermatologic toxicity: Durvalumab has caused immune-mediated rash. Bullous dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis have been reported with other anti-PD-L1 monoclonal antibodies. Monitor for signs/symptoms of dermatologic toxicity. Initiate systemic corticosteroids for grade 2 rash or dermatitis lasting for more than 1 week or severe grade 3 or 4 rash/dermatitis, followed by a taper. May require treatment interruption or discontinuation (based on the severity).
• Diabetes mellitus: Immune-related type 1 diabetes mellitus has occurred in patients receiving durvalumab. The median time to onset was 1.4 months. Monitor glucose and monitor for clinical signs/symptoms of diabetes. Initiate insulin for type 1 diabetes mellitus and interrupt durvalumab treatment (based on the severity) until clinically stable.
• Gastrointestinal toxicities: Immune-mediated colitis or diarrhea occurred in patients receiving durvalumab. Grades 3 and 4 diarrhea or colitis have been reported. The median time to onset was 1.4 months (range: 1 day to 14 months). Monitor for signs/symptoms of colitis or diarrhea and manage with treatment interruption or discontinuation, and systemic corticosteroids. In clinical studies, management with systemic corticosteroids, including high-dose corticosteroids was utilized in some patients; other immunosuppressants (eg, infliximab, mycophenolate) were required (rarely). Resolution occurred in approximately three-quarters 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 ~1 month (range: 1 day to ~14 months). Monitor for signs/symptoms (including abnormal liver function tests) of hepatitis during durvalumab treatment and after discontinuation. Manage grade 2 or higher immune-mediated hepatitis with systemic corticosteroids and treatment interruption or discontinuation. In clinical studies, some patients experiencing immune-mediated hepatitis received high-dose corticosteroids; mycophenolate was required (rarely) to manage immune-mediated hepatitis. 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/symptoms of hypophysitis or hypopituitarism. If grade 2 or higher hypophysitis occurs, administer corticosteroids and hormone replacement therapy as indicated; interrupt durvalumab (based on the severity). Hypopituitarism leading to adrenal insufficiency and diabetes insipidus has occurred (rarely).
• Infection: Infections occurred in almost half of patients receiving durvalumab (some fatal). The most common grade 3 or 4 infections were urinary tract infections (urothelial carcinoma study) and pneumonia (non-small cell lung cancer [NSCLC] study). The overall incidence of infections was higher in a NSCLC study, compared to patients in other studies in whom radiation therapy was typically not administered immediately prior to durvalumab. 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 or life-threatening infusion-related reactions. Monitor for signs/symptoms of 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.
• Nephrotoxicity: Durvalumab has caused immune-mediated nephritis (including fatal cases). Monitor renal function prior to initiating treatment and periodically during durvalumab treatment. Nephritis may require systemic corticosteroids and treatment interruption or discontinuation. Nephritis resolved in ~50% of patients. The median time to onset was 2 months (range: 1 day to ~14 months).
• Pulmonary toxicities: Immune-mediated pneumonitis or interstitial lung disease has occurred in patients receiving durvalumab (including fatal cases). The median time to onset was ~2 months (range: 1 day to ~19 months), and the median time to resolution was ~2 to 5 months (range up to ~19 months). In a non-small cell lung cancer study, the incidence of pneumonitis (including radiation pneumonitis) was higher in patients who completed definitive chemoradiation within 42 days prior to initiating durvalumab, compared to patients in other studies in whom radiation therapy was typically not administered immediately prior to durvalumab. Monitor for signs/symptoms of pneumonitis; evaluate suspected pneumonitis with radiographic imaging and manage with systemic corticosteroids and durvalumab treatment interruption or discontinuation; some patients received infliximab therapy. In clinical studies, resolution 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/symptoms of thyroid disorders. Hypothyroidism, hyperthyroidism, and thyroiditis (including grade 3 thyroiditis) have occurred in clinical trials. Hypothyroidism was preceded by thyroiditis or hyperthyroidism is some patients. Manage hypothyroidism with hormone replacement (if indicated) while continuing durvalumab. Initiate appropriate medical management for hyperthyroidism; withhold durvalumab (based on severity). Treatment with a beta-blocker and/or thioamide was administered for hyperthyroidism in some patients.
• Ocular toxicity: Ocular inflammatory toxicity including uveitis and keratitis have been reported. If uveitis occurs in combination with other immune-mediated reactions, evaluate for Vogt-Koyanagi-Harada syndrome; may require treatment with systemic steroids to reduce the risk of permanent vision loss.
• Other immune-mediated toxicities: Other immune-related adverse reactions associated with durvalumab (rarely) include aseptic meningitis, hemolytic anemia, immune thrombocytopenia (formerly known as immune thrombocytopenic purpura), myocarditis, and myositis. These immune-mediated toxicities usually occurred during treatment, although may occur after discontinuation. For suspected grade 2 immune-mediated reactions, exclude other causes and initiate systemic corticosteroids as clinically indicated. Administer systemic corticosteroids for grade 3 or 4 immune-mediated reactions. May require treatment interruption or discontinuation. Other immune-mediated reactions have also been reported with other anti-PD-L1 monoclonal antibodies, including pancreatitis, systemic inflammatory response syndrome, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, iritis, encephalitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barre syndrome and Vogt-Koyanagi-Harada syndrome.

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), ocular toxicity, thyroid disorders; monitor for infusion reactions.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to durvalumab may cause fetal harm. Durvalumab is a humanized monoclonal antibody (IgG₁). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Females of reproductive potential should use effective contraception during therapy and for at least 3 months after the last durvalumab dose.

Patient Education

What is this drug used for?

• It is used to treat cancer in the bladder or urinary tract.
• It is used to treat lung cancer.

Frequently reported side effects of this drug

• Bone pain
• Constipation
• Lack of appetite
• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.
• Infection
• Infusion reaction
• Thyroid, pituitary, or adrenal gland problems like mood changes, behavioral changes, weight changes, constipation, deeper voice, dizziness, passing out, cold sensation, severe fatigue, hair loss, persistent headache, or decreased sex drive.
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse.
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting.
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Aseptic meningitis like headache, fever, chills, severe nausea or vomiting, stiff neck, rash, sensitivity to lights, fatigue, or confusion.
• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain.
• Black, red, tarry, or bloody stools
• Severe diarrhea
• Severe abdominal pain
• Bruising
• Bleeding
• Muscle pain
• Muscle weakness
• Vision changes
• Eye pain
• Severe eye irritation
• Chest pain
• Abnormal heartbeat
• Severe loss of strength and energy
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.