Dosing & Uses
Dosage Forms & Strengths
injectable solution
- 50mg/mL (2.4-mL, 10-mL single-dose vials)
Non-small Cell Lung Cancer
Indicated for unresectable, stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy
Weight ≥30 kg: 10 mg/kg IV q2Weeks OR 1,500 mg IV q4Weeks
Weight <30 kg: 10 mg/kg IV q2Weeks
Continue until disease progression or unacceptable toxicity, or a maximum of 12 months
Small Cell Lung Cancer
Indicated for first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) in combination with etoposide and either carboplatin or cisplatin
Cycles 1-4 in combination with chemotherapy
- Each cycle is 21 days
-
Day 1
- Durvalumab 1,500 mg IV (if body weight <30 kg, dose at 20 mg/kg IV) PLUS
- Etoposide 80-100 mg/m2 IV PLUS
- Carboplatin AUC 5 or 6 OR
- Cisplatin 75-80 mg/m2 IV
-
Days 2-3
- Etoposide 80-100 mg/m2 IV qDay
Subsequent cycles as a single agent
- Note: Cycle is 28 days
- Durvalumab 1,500 mg IV q4Weeks (if body weight <30kg, dose at 10 mg/kg q2Weeks until weight ≥30 kg)
- Continue until disease progression or unacceptable toxicity
Biliary Tract Cancers
Indicated for locally advanced or metastatic biliary tract cancer (BTC) in combination with gemcitabine and cisplatin
Cycles 1-8 in combination with chemotherapy
- Each cycle is 21 days
-
Day 1
- Durvalumab 1500 mg IV (if body weight <30 kg, dose at 20 mg/kg IV) PLUS
- Gemcitabine 1,000 mg/m2 IV PLUS
- Cisplatin 25 mg/m2 IV
-
Day 8
- Gemcitabine 1,000 mg/m2 IV PLUS
- Cisplatin 25 mg/m2 IV
Subsequent cycles as a single agent
- Each cycle is 28 days
- Durvalumab 1500 mg IV q4Weeks (if body weight <30 kg, dose at 10 mg/kg q2Weeks until weight ≥30 kg)
- Continue until disease progression or unacceptable toxicity
Dosage Modifications
No dose reductions are recommended
Pneumonitis
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Colitis
- Grade 2 or 3: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 4: Permanently discontinue
Hepatitis with no tumor involvement of the liver
- AST or ALT increases to >3 and ≤8x ULN or total bilirubin increases to >1.5 and <3x ULN: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- AST or ALT increases to >8x ULN or total bilirubin increases to >3x ULN: Permanently discontinue
Hepatitis with tumor involvement of the liver
-
Withhold therapy
- Baseline AST or ALT >1 and ≤3x ULN and increases to >5 and ≤10x ULN
- Baseline AST or ALT >3 and ≤5x ULN and increases to >8 and ≤10x ULN
- Resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
-
Permanently discontinue
- AST or ALT increases to >10x ULN or total bilirubin increases to >3x ULN
Endocrinopathies
- Grade 3 or 4: Withhold until clinically stable or permanently discontinue depending on severity
Nephritis with renal dysfunction
- Grade 2 or 3 increased blood creatinine: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 4 increased blood creatinine: Permanently discontinue
Exfoliative dermatologic conditions
- Suspected Steven Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Withhold therapy
- Confirmed SJS, TEN, or DRESS: Permanently discontinue
Myocarditis
- Grade 2, 3, or 4: Permanently discontinue
Neurologic toxicities
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Infusion-related reactions
- Grade 1 or 2: Interrupt or slow infusion rate
- Grade 3 or 4: Permanently discontinue
Renal impairment
- Mild-to-moderate (CrCl ≥30 mL/min): No dosage adjustment necessary
- Severe (CrCl <30 mL/min): Pharmacokinetics unknown
Hepatic impairment
- Mild (bilirubin ≤ULN and AST >ULN OR bilirubin >1-1.5x ULN and any AST): No dosage adjustment necessary
- Moderate-to-severe (bilirubin >1.5x ULN and any AST): Pharmacokinetics unknown
Orphan Designations
Hepatocellular carcinoma
Orphan sponsor
- AstraZeneca Pharmaceuticals LP; 1800 Concord Pike; Wilmington, Delaware 19803
Safety and efficacy not established
Adverse Effects
>10%
NSLC
-
All grades
- Hyperglycemia (52%)
- Hypocalcemia (46%)
- Lymphopenia (43%)
- Cough/productive cough (40%)
- Increased ALT (39%)
- Increased AST (36%)
- Fatigue (34%)
- Pneumonitis/radiation pneumonitis (34%)
- Hyponatremia (33%)
- Hyperkalemia (32%)
- Upper respiratory tract infections (26%)
- Dyspnea (25%)
- Increased GGT (24%)
- Rash (23%)
- Diarrhea (18%)
- Pneumonia (17%)
- Pyrexia (15%)
- Pruritus (12%)
- Hypothyroidism (12%)
-
Grade 3-4
- Lymphopenia (17%)
SCLC (Combination with etoposide + carboplatin OR cisplatin)
-
All grades
- Neutropenia (41%)
- Nausea (34%)
- Fatigue/asthenia (32%)
- Alopecia (31%)
- Decreased appetite (18%)
- Constipation (17%)
- Vomiting (15%)
- Cough/productive cough (15%)
- Lymphopenia (14%)
- Anemia (13%)
- Thrombocytopenia (12%)
- Rash (11%)
-
Grade 3-4
- Hyponatremia (11%)
- Hypomagnesemia (11%)
1-10%
NSLC
-
All grades
- Abdominal pain (10%)
- Pneumonitis/radiation pneumonitis (3.4%)
- Dyspnea (1.5%)
-
Grade 3-4
- Hyperglycemia (8%)
- Pneumonia (7%)
- Hyponatremia (3.6%)
- Increased GGT (3.4%)
- Increased AST (2.8%)
- Increased ALT (2.3%)
- Hyperkalemia (1.1%)
SCLC (Combination with etoposide + carboplatin OR cisplatin)
-
All grades
- Diarrhea (10%)
- Hyperthyroidism (10%)
-
Grade 3-4
- Hyperglycemia (5%)
- Increased alkaline phosphate (4.9%)
- Increased ALT (4.9%)
- Increased AST (4.6%)
- Hypocalcemia (3.5%)
- Increased blood creatine (3.4%)
- Fatigue/asthenia (3.4%)
- Hyperkalemia (1.5%)
- Diarrhea (1.1%)
- Alopecia (1.1%)
<1%
NSCLC
-
Grade 3-4
- Fatigue (0.8%)
- Cough/productive cough (0.6%)
- Diarrhea (0.6%)
- Rash (0.6%)
- Abdominal pain (0.4%)
- Upper respiratory tract infections (0.4%)
- Hypothyroidism (0.2%)
- Pyrexia (0.2%)
- Hypocalcemia (0.2%)
SCLC (Combination with etoposide + carboplatin OR cisplatin)
-
Grade 3-4
- Cough/productive cough (0.8%)
- Vomiting (0.8%)
- Constipation (0.8%)
- Decreased appetite (0.8%)
- Nausea (0.4%)
Warnings
Contraindications
None
Cautions
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue; immune-mediated adverse reactions can occur at any time after starting treatment with a PD-1/PDL1 blocking antibody; while immune-mediated adverse reactions usually manifest during treatment with PD-1/PD-L1 blocking antibodies, immune-mediated adverse reactions can also manifest after discontinuation of PD-1/PD-L1 blocking antibodies
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of PD-1/PD-L1 blocking antibodies
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions
Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment
In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection; institute medical management promptly, including specialty consultation as appropriate
Withhold or permanently discontinue drug depending on severity; in general, if treatment requires interruption or discontinuation, administer systemic corticosteroid therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less
Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month; consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy
Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (eg, endocrinopathies and dermatologic reactions)
Immune-mediated pneumonitis or interstitial lung disease reported; incidence of pneumonitis is higher in patients who have received prior thoracic radiation; frequency and severity of immune-mediated pneumonitis in patients who did not receive definitive chemoradiation prior to therapy were similar whether drugs given as single agent in patients with various cancers in a pooled data set or in patients with ES-SCLC or BTC when given in combination with chemotherapy; monitor for signs and symptoms; evaluate patients with suspected pneumonitis with radiographic imaging
Immune-mediated hepatitis reported; monitor for abnormal liver tests each cycle during treatment
Immune-mediated colitis or diarrhea reported; monitor for signs and symptoms; cytomegalovirus (CMV) infection/reactivation reported in patients with corticosteroid-refractory immune-mediated colitis; in cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies
Immune-mediated endocrinopathies (eg, hypothyroidism, hyperthyroidism, type 1 diabetes mellitus, hypopituitarism) have occurred; monitor for symptoms of these conditions
Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated; withhold or permanently discontinue therapy based on severity
Therapy can cause primary or secondary adrenal insufficiency; for Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated; withhold or permanently discontinue therapy based on severity
Therapy can cause immune-mediated hypophysitis; hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts; hypophysitis can cause hypopituitarism; initiate symptomatic treatment including hormone replacement as clinically indicated; withhold or permanently discontinue therapy depending on severity
Therapy can cause immune-mediated thyroid disorders; thyroiditis can present with or without endocrinopathy; hypothyroidism can follow hyperthyroidism; initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated; withhold or discontinue therapy based on severity
Therapy can cause immune-mediated rash or dermatitis; exfoliative dermatitis , including Stevens-Johnson Syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 blocking antibodies; topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes; withhold or permanently discontinue therapy depending on severity
Uveitis, iritis, and other ocular inflammatory toxicities can occur; some cases can be associated with retinal detachment; various grades of visual impairment including blindness can occur; if uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce risk of permanent vision loss
Rare reports of other immune-mediated adverse effects (eg, aseptic meningitis, hemolytic anemia, rash, ITP, myocarditis, myositis, nephritis, keratitis) reported; advise patient to contact healthcare provider immediately if experience symptoms
Severe infusion-related reactions reported; monitor for signs and symptoms and slow infusion rate or interrupt infusion if needed; if severe, withhold or permanently discontinue
Can cause fetal harm (see Pregnancy)
Complications of allogeneic HSCT
- Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody
- Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) 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
- Follow patients closely for evidence of transplant-related complications and intervene promptly; consider benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody prior to or after an allogeneic HSCT
Pregnancy
Pregnancy
Based on its mechanism of action, can cause fetal harm if administered to a pregnant woman; verify pregnancy status of females of reproductive potential prior to initiating treatment
Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus
Animal data
- In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 6-20 times higher than those observed at clinical dose of 10 mg/kg (based on AUC) resulted in increased in premature delivery, fetal loss, and premature neonatal death
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 3 months following the last dose
Lactation
Unknown if distributed in human breast milk; human IgG1 is excreted in human milk
Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death
Because of the potential for adverse reactions in breastfed infants, advise breastfeeding women not to breastfeed during treatment and for at least 3 months after the last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Human IgG1 kappa monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, and therefore overcoming/preventing PD-L1-mediated inhibition/suppression of T-cell activation
Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity
Absorption
Steady-state was reached at ~16 weeks
Distribution
Vd (steady-state); 5.6 L
Elimination
Clearance (steady-state): 8.2 L/hr
Half-life: ~18 days
Administration
IV Compatibilities
0.9% NaCl
D5W
IV Preparation
Visually inspect drug product for particulate matter and discoloration; should appear clear to opalescent, colorless to slightly yellow solution, and free from visible particles
Discard the vial if the solution is cloudy, discolored, or visible particles are observed
Do not shake the vial
Withdraw the required volume for the dose from the vial(s) and transfer into an IV bag containing 0.9% NaCl or D5W
Mix diluted solution by gentle inversion; do not shake the solution
The final concentration of the diluted solution should be between 1-15 mg/mL
Discard partially used or empty vials
Administer infusion solution immediately once prepared (also see Storage)
IV Administration
Infuse over 1 hr through an IV line containing a sterile, low-protein binding 0.2 or 0.22 micron inline filter
Do not coadminister other drugs through the same infusion line
SCLC: Administer durvalumab first prior to all other chemo on Day 1 of each cycle
Storage
Does not contain a preservative
Do not freeze
Do not shake
Unopened vial
- Refrigerate at 2-8°C (36-46°F)
- Store in original carton to protect from light
Diluted solution
- Administer infusion solution immediately once prepared
- If infusion solution is not administered immediately and needs to be stored, the total time from vial puncture to the start of the administration should not exceed the following:
- 24 hr in a refrigerator at 2-8°C (36-46°F), or
- 4 hr at room temperature up to 25°C (77°F)
Images
Formulary
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