Durvalumab is a monoclonal antibody used in cancer treatment. It is marketed under the brand name Imfinzi. Durvalumab belongs to a class of drugs known as immune checkpoint inhibitors.

Durvalumab works by targeting and blocking a protein called programmed death-ligand 1 (PD-L1) on the surface of cancer cells. PD-L1 interacts with another protein called programmed death receptor 1 (PD-1) on immune cells, inhibiting the immune response against cancer cells. By blocking the PD-L1/PD-1 interaction, durvalumab allows the immune system to recognize and attack cancer cells more effectively.

Durvalumab (Imfinzi) Uses:

• Unresectable non-small-cell lung cancer:
  • Durvalumab is used to treat a specific type of lung cancer called unresectable stage III non-small-cell lung cancer.
  • This type of cancer cannot be removed through surgery.
  • Durvalumab is given to patients whose cancer has not worsened after receiving platinum-based chemotherapy and radiation therapy at the same time.
  • It helps the immune system fight against cancer cells and may improve the chances of controlling the disease.
• Locally advanced or metastatic Urothelial carcinoma, :
  • Durvalumab is used to treat a specific type of cancer called locally advanced or metastatic urothelial carcinoma.
  • It is given to patients whose cancer has progressed either during or after receiving platinum-containing chemotherapy, or within 12 months of receiving platinum-containing chemotherapy as a neoadjuvant or adjuvant treatment.
  • Durvalumab helps the immune system to fight against cancer cells and may help to slow down the progression of the disease.

Durvalumab (Imfinzi) Dose in Adults

Durvalumab (Imfinzi) Dose in the treatment of stage III, Unresectable Non-small cell lung cancer:

• In the treatment of non-small cell lung cancer (stage III) that cannot be removed through surgery, durvalumab is given intravenously (IV) at a dose of 10 mg per kilogram of body weight.
• It is administered once every 2 weeks.
• The treatment continues until the disease progresses, there are unacceptable side effects, or for a maximum of 12 months.
• In the clinical trial, durvalumab treatment started within 6 weeks after receiving chemoradiotherapy.
• If the disease was under control at the end of the 12-month period but then started progressing during follow-up, the treatment could be continued beyond the initial 12 months.

Durvalumab (Imfinzi) Dose in the treatment of locally advanced or metastatic Urothelial carcinoma:

• In the treatment of locally advanced or metastatic urothelial carcinoma, durvalumab is administered intravenously (IV) at a dose of 10 mg per kilogram of body weight.
• It is given once every 2 weeks.
• The treatment continues until there is disease progression or if there are severe side effects that are considered unacceptable.

Use in Children:

No indication.

Durvalumab Pregnancy Risk Category: X

• Animal reproduction studies have shown adverse events associated with durvalumab.
• It is known that immunoglobulins, like durvalumab, can cross the placenta, potentially exposing the fetus to the medication.
• Considering the mechanism of action, durvalumab may cause harm to the fetus if administered to pregnant women.
• Therefore, it is recommended that females of reproductive potential use effective contraception while receiving durvalumab treatment.
• This precaution should be followed during therapy and for a period of at least 3 months after the last dose of durvalumab.

Durvalumab is not recommended for use while breastfeeding

• The presence of durvalumab in breast milk is currently unknown.
• However, it is known that naturally occurring immunoglobulins are excreted in breast milk.
• Since there is a potential risk of adverse events in a breastfed infant, the manufacturer does not recommend breastfeeding during durvalumab therapy or for at least 3 months after the last dose of durvalumab.

Durvalumab (Imfinzi) Dose in Kidney disease:

Kidney problems before starting durvalumab treatment:

• Creatinine clearance (CrCl) 30 to 89 mL/minute:
  • No dosage adjustments are specified in the manufacturer's labeling.
  • There is no clinically significant impact on the way durvalumab is processed in the body (pharmacokinetics).
• Creatinine clearance (CrCl) 15 to 29 mL/minute:
  • No dosage adjustments are provided in the manufacturer's labeling for this specific renal impairment range.
  • The effects of durvalumab in patients with Creatinine clearance (CrCl) between 15 and 29 mL/minute have not been studied.

Renal toxicity during treatment (nephritis):

If a patient develops nephritis (inflammation of the kidneys) with elevated creatinine levels during durvalumab treatment, the following recommendations are provided:

• Nephritis with creatinine levels greater than 1.5 to 3 times the upper limit of normal (ULN):
  • The durvalumab dose should be withheld.
  • Systemic corticosteroids, such as prednisone at an initial dose of 1 to 2 mg/kg daily or an equivalent, should be administered.
  • Once nephritis improves to grade 1 or resolves, and the corticosteroid dose is reduced to 10 mg/day prednisone or its equivalent, durvalumab treatment can be resumed.
• Nephritis with creatinine levels greater than 3 times the ULN:
  • Durvalumab treatment should be permanently discontinued.
  • Systemic corticosteroids, such as prednisone at an initial dose of 1 to 2 mg/kg daily or an equivalent, should be administered.
  • A tapering regimen of corticosteroids should be followed.

Durvalumab (Imfinzi) Dose in Liver disease:

Hepatic impairment before starting Durvalumab treatment:

For patients with hepatic impairment prior to initiating durvalumab treatment, the manufacturer's labeling provides the following information:

• Mild hepatic impairment:
  • Mild impairment is defined as either bilirubin levels within the upper limit of normal (ULN) and aspartate aminotransferase (AST) levels higher than the ULN, or bilirubin levels between 1 to 1.5 times the ULN and any AST level.
  • No specific dosage adjustments are recommended by the manufacturer's labeling.
  • It is stated that there is no clinically relevant effect on the pharmacokinetics of durvalumab in patients with mild hepatic impairment.
• Moderate or severe hepatic impairment:
  • Moderate impairment is defined as bilirubin levels greater than 1.5 to 3 times the ULN and any AST level.
  • Severe impairment is defined as bilirubin levels greater than 3 times the ULN and any AST level.
  • The manufacturer's labeling does not provide specific dosage adjustments for durvalumab in patients with moderate or severe hepatic impairment. This means that the use of durvalumab in patients with these levels of hepatic impairment has not been specifically studied.

Hepatotoxicity during treatment:

If a patient experiences hepatotoxicity (liver toxicity) during durvalumab treatment, the following recommendations are provided:

• Hepatitis with ALT (alanine aminotransferase) or AST (aspartate aminotransferase) levels greater than 3 to ≤8 times the upper limit of normal (ULN) or total bilirubin levels greater than 1.5 to ≤5 times the ULN:
  • The durvalumab dose should be withheld.
  • Systemic corticosteroids, such as prednisone at an initial dose of 1 to 2 mg/kg daily or an equivalent, should be administered.
  • Durvalumab treatment can be resumed when hepatitis improves to grade 1 or resolves, and the corticosteroid dose is reduced to ≤10 mg/day prednisone or its equivalent.
• Hepatitis with ALT or AST levels greater than 8 times the ULN or total bilirubin levels greater than 5 times the ULN:
  • Durvalumab treatment should be permanently discontinued.
  • Systemic corticosteroids, such as prednisone at an initial dose of 1 to 2 mg/kg daily or an equivalent, should be administered.
  • A tapering regimen of corticosteroids should be followed.
• Hepatitis with concurrent ALT or AST levels greater than 3 times the ULN and total bilirubin levels greater than 2 times the ULN with no other identifiable cause:
  • Durvalumab treatment should be permanently discontinued.
  • Systemic corticosteroids, such as prednisone at an initial dose of 1 to 2 mg/kg daily or an equivalent, should be administered.
  • A tapering regimen of corticosteroids should be followed.

Common Side Effects of Durvalumab (Imfinzi):

• Cardiovascular:
  • Peripheral Edema
• Central Nervous System:
  • Fatigue
• Dermatologic:
  • Dermatitis
  • Skin Rash
  • Pruritus
• Endocrine & Metabolic:
  • Hyperglycemia
  • Hypocalcemia
  • Hyponatremia
  • Hyperkalemia
  • Increased Gamma-Glutamyl Transferase
  • Hypothyroidism
• Gastrointestinal:
  • Constipation
  • Decreased Appetite
  • Colitis
  • Diarrhea
  • Nausea
  • Abdominal Pain
• Genitourinary:
  • Urinary Tract Infection
• Hematologic & Oncologic:
  • Lymphocytopenia
• Hepatic:
  • Increased Serum ALT
  • Increased Serum AST
  • Hepatitis
• Infection:
  • Infection
• Neuromuscular & Skeletal:
  • Musculoskeletal Pain
• Respiratory:
  • Cough
  • Productive Cough
  • Pneumonitis
  • Radiation Pneumonitis
  • Upper Respiratory Tract Infection
  • Pneumonia
  • Dyspnea
  • Dyspnea On Exertion
• Miscellaneous:
  • Fever

Less Common Side Effects Of Durvalumab (Imfinzi):

• Central Nervous System:
  • Voice Disorder
• Dermatologic:
  • Night Sweats
• Endocrine & Metabolic:
  • Hyperthyroidism
  • Hypermagnesemia
  • Dehydration
  • Hypercalcemia
  • Hypoalbuminemia
  • Hypokalemia
• Genitourinary:
  • Dysuria
• Hematologic & Oncologic:
  • Anemia
  • Neutropenia
• Hepatic:
  • Increased Serum Alkaline Phosphatase
  • Hyperbilirubinemia
• Immunologic:
  • Antibody Development
• Infection:
  • Increased Susceptibility To Infection
• Renal:
  • Nephritis
  • Increased Serum Creatinine
• Miscellaneous:
  • Infusion-Related Reaction

Side effects of Durvalumab (frequency of side effects not defined):

• Endocrine & metabolic:
  • Hypophysitis
• Hepatic:
  • Hepatic injury
• Infection:
  • Sepsis
• Renal:
  • Acute renal failure

Contraindications to Durvalumab (Imfinzi):

In the manufacturer's labeling, there are no specific conditions or situations listed as contraindications for durvalumab, meaning there are no absolute reasons why it should not be used.

However, in the Canadian labeling, there is an additional contraindication not mentioned in the US labeling. These contraindication states that durvalumab should not be used if a person has a known hypersensitivity (allergic reaction) to durvalumab itself or any of the ingredients present in the formulation.

Warnings and precautions

Insufficiency of the adrenals:

• Adrenal insufficiency, which is a condition where the adrenal glands do not produce enough hormones, has been observed in some patients receiving durvalumab.
• It is an immune-related side effect of the medication.
• To ensure early detection and proper management, it is important to monitor for any signs or symptoms of adrenal insufficiency during durvalumab treatment.
• If adrenal insufficiency of grade 2 or higher occurs, which indicates a moderate or severe case, systemic corticosteroids and hormone replacement therapy may be needed.
• The specific treatment will depend on the individual's clinical situation and may involve administering corticosteroids and replacing the deficient hormones.
• In such cases, durvalumab treatment may need to be interrupted based on the severity of adrenal insufficiency.

Dermatologic toxicities:

• Dermatologic toxicity, such as rashes, can occur with durvalumab due to immune-mediated reactions.
• Rare but serious conditions like bullous dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported with similar medications.
• It is important to watch for any signs or symptoms of skin problems during durvalumab treatment.
• If a grade 2 rash or dermatitis persists for more than a week, or if a severe grade 3 or 4 rash/dermatitis occurs, systemic corticosteroids may be initiated and gradually reduced.
• Depending on the severity, treatment may require interruption or discontinuation.

Diabetes mellitus

• In some patients receiving durvalumab, immune-related type 1 diabetes mellitus has been observed.
• This condition typically develops around 1.4 months after starting treatment.
• It is important to regularly monitor blood glucose levels and watch for any signs or symptoms of diabetes.
• If type 1 diabetes mellitus is diagnosed, insulin therapy will be initiated, and durvalumab treatment may need to be temporarily stopped until the condition is stable.
• Close monitoring and communication with your healthcare provider are important to manage diabetes mellitus related to durvalumab treatment.

Toxicities to the gastrointestinal tract:

• Gastrointestinal toxicities, such as immune-mediated colitis or diarrhea, have been observed in patients receiving durvalumab.
• Some cases of severe grades 3 and 4 diarrhea or colitis have been reported.
• These side effects typically occur around 1.4 months after starting treatment, but the onset can range from 1 day to 14 months.
• It is important to monitor for any signs or symptoms of colitis or diarrhea and manage them by temporarily interrupting or discontinuing durvalumab treatment, and using systemic corticosteroids.
• In some cases, high doses of corticosteroids or other immunosuppressant medications like infliximab or mycophenolate may be needed.
• Approximately three-quarters of patients who experienced immune-mediated diarrhea or colitis saw resolution of these symptoms.

Hepatotoxicity

• Hepatotoxicity, specifically immune-mediated hepatitis, has been observed in patients receiving durvalumab, and in some cases, it has been fatal.
• The onset of hepatitis can occur around 1 month after starting treatment, but it can range from 1 day to approximately 14 months.
• It is important to monitor for signs and symptoms of hepatitis, including abnormal liver function tests, during durvalumab treatment and even after discontinuation.
• If grade 2 or higher immune-mediated hepatitis is detected, it can be managed with systemic corticosteroids and by temporarily interrupting or discontinuing durvalumab treatment.
• In some clinical studies, patients with immune-mediated hepatitis required high-dose corticosteroids, and in rare cases, mycophenolate was needed.
• About half of the patients experiencing immune-mediated hepatitis have seen recovery.
• There have been reports of grade 3 or 4 elevations in liver enzymes (ALT, AST) and/or total bilirubin levels.

Hypophysitis, hypopituitarism

• Hypophysitis or hypopituitarism, which are immune-related conditions affecting the pituitary gland, have been observed in some patients receiving durvalumab.
• It is important to monitor for any clinical signs or symptoms associated with these conditions.
• If grade 2 or higher hypophysitis is diagnosed, corticosteroids and hormone replacement therapy may be administered as needed.
• Durvalumab treatment may need to be interrupted based on the severity of the condition.
• In rare cases, hypopituitarism can lead to adrenal insufficiency (lack of adrenal hormone production) or diabetes insipidus (excessive thirst and urination).

Infection

• Infections have been reported in nearly half of the patients receiving durvalumab, and in some cases, they have been fatal.
• The most common severe (grade 3 or 4) infections observed were urinary tract infections in the urothelial carcinoma study and pneumonia in the non-small cell lung cancer (NSCLC) study.
• The overall incidence of infections was higher in the NSCLC study, particularly in patients who had received radiation therapy before durvalumab treatment.
• It is important to monitor for any signs or symptoms of infection and seek prompt medical attention if an infection is suspected or confirmed.
• In such cases, appropriate anti-infective treatment should be administered.
• If a grade 3 or 4 infection occurs, durvalumab treatment should be temporarily withheld.
• Close monitoring and communication with your healthcare provider are essential to manage infections associated with durvalumab.

Infusion reactions

• Durvalumab can sometimes cause infusion reactions, including severe or life-threatening ones.
• It is important to closely monitor for any signs or symptoms of infusion reactions during the administration of durvalumab.
• If a mild or moderate infusion reaction occurs, the infusion rate may be slowed down or interrupted, and premedications may be considered for subsequent infusions to minimize the risk.
• However, if a grade 3 or 4 infusion reaction is experienced, durvalumab treatment should be permanently discontinued.

Nephrotoxicity

• Durvalumab can lead to immune-mediated nephritis, including some cases that have been fatal.
• It is important to assess renal function before starting durvalumab and periodically monitor it during treatment.
• If nephritis is detected, systemic corticosteroids may be required, and treatment with durvalumab may need to be temporarily interrupted or discontinued.
• Approximately 50% of patients with nephritis experienced resolution of the condition.
• The onset of nephritis can occur around 2 months after starting treatment, but it can range from 1 day to approximately 14 months.

Toxicities to the lungs

• Pulmonary toxicities, such as immune-mediated pneumonitis or interstitial lung disease, have been observed in patients receiving durvalumab, including some fatal cases.
• The onset of these conditions can occur around 2 months after starting treatment, but it can range from 1 day to approximately 19 months.
• The median time for resolution is typically around 2 to 5 months, but it can take up to 19 months.
• In a study involving non-small cell lung cancer patients, the incidence of pneumonitis, including radiation pneumonitis, was higher in patients who completed definitive chemoradiation within 42 days prior to starting durvalumab compared to patients in other studies who did not receive radiation therapy immediately before durvalumab.
• It is important to monitor for any signs or symptoms of pneumonitis and promptly evaluate suspected cases with radiographic imaging.
• Management may involve systemic corticosteroids and temporary interruption or discontinuation of durvalumab treatment.
• In some cases, patients received infliximab therapy.
• Approximately half of the patients experiencing immune-mediated pneumonitis saw resolution of the condition.

Thyroid disorders

• Durvalumab can cause immune-related thyroid disorders in patients receiving the treatment.
• It is important to monitor thyroid function before starting durvalumab and periodically during treatment.
• Keep an eye out for any clinical signs or symptoms of thyroid disorders.
• Hypothyroidism, hyperthyroidism, and thyroiditis (including severe grade 3 thyroiditis) have been reported in clinical trials.
• In some cases, hypothyroidism followed episodes of thyroiditis or hyperthyroidism.
• Hypothyroidism can be managed by hormone replacement therapy, if necessary, while continuing durvalumab.
• For hyperthyroidism, appropriate medical management should be initiated, and durvalumab may need to be temporarily withheld depending on the severity.
• Some patients with hyperthyroidism received treatment with a beta-blocker and/or thioamide.

Ocular toxicities:

• Durvalumab has been associated with ocular inflammatory toxicity, including conditions such as uveitis and keratitis.
• If uveitis occurs along with other immune-related reactions, it is important to evaluate for a condition called Vogt-Koyanagi-Harada syndrome.
• Treatment with systemic steroids may be necessary to reduce the risk of permanent vision loss.

Other immune-mediated toxicities

• In addition to the previously mentioned adverse reactions, durvalumab may rarely cause other immune-related toxicities.
• These include aseptic meningitis (inflammation of the membranes surrounding the brain and spinal cord), hemolytic anemia (destruction of red blood cells), immune thrombocytopenia (formerly known as immune thrombocytopenic purpura, a condition characterized by low platelet count), myocarditis (inflammation of the heart muscle), and myositis (inflammation of muscle tissue).
• These immune-mediated reactions can occur during durvalumab treatment or even after discontinuation.
• If you experience suspected grade 2 immune-mediated reactions, your healthcare provider will investigate other potential causes and may prescribe systemic corticosteroids as needed.
• Grade 3 or 4 immune-mediated reactions generally require treatment with systemic corticosteroids and may necessitate temporary interruption or discontinuation of durvalumab.
• It's important to note that other immune-related reactions have been reported with other anti-PD-L1 monoclonal antibodies, including pancreatitis, systemic inflammatory response syndrome, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, iritis, encephalitis, facial and abducens nerve paresis, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barre syndrome, and Vogt-Koyanagi-Harada syndrome.

Durvalumab: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

Important Monitoring for Durvalumab Treatment

• Liver Function: Regularly monitor liver function tests during each treatment cycle.
• Renal Function: Evaluate renal function prior to initiating treatment and periodically during treatment.
• Thyroid Function: Assess thyroid function at baseline and regularly monitor during durvalumab treatment.
• Blood Glucose: Monitor blood glucose levels to detect any signs of diabetes or hyperglycemia.

Monitor for Clinical Signs/Symptoms of the following:

• Adrenal Insufficiency: Watch for symptoms such as fatigue, weakness, and changes in blood pressure.
• Colitis/Diarrhea: Monitor for persistent diarrhea or signs of colitis such as abdominal pain or blood in stool.
• Dermatologic Toxicity: Be alert for any skin rash, blistering, or severe allergic reactions.
• Diabetes/Hyperglycemia: Monitor for symptoms of increased thirst, frequent urination, and high blood sugar levels.
• Hepatitis/Hepatotoxicity: Observe for signs of liver inflammation, including abdominal pain and jaundice.
• Hypophysitis or Hypopituitarism: Monitor for hormonal imbalances and related symptoms.
• Immune Thrombocytopenia Purpura: Look for signs of low platelet count, such as easy bruising or bleeding.
• Infection: Watch for signs of infection, such as fever, cough, urinary tract symptoms, or pneumonia.
• Pneumonitis: If respiratory symptoms arise, including cough or difficulty breathing, seek medical evaluation.
• Ocular Toxicity: Pay attention to any eye inflammation, vision changes, or eye pain.
• Thyroid Disorders: Monitor for symptoms of hypothyroidism or hyperthyroidism, such as fatigue or weight changes.
• Infusion Reactions: Watch for immediate or delayed reactions during or after durvalumab infusion.

How to administer Durvalumab (Imfinzi)?

Durvalumab Administration Instructions:

• Intravenous Infusion: Administer durvalumab over a period of 60 minutes using an intravenous (IV) line.
• Use Appropriate Filter: Ensure that the IV line includes a sterile, low-protein binding 0.2 or 0.22 micron in-line filter.
• Dedicated IV Line: Do not mix or administer other medications through the same IV line used for durvalumab infusion.

Infusion Reaction Monitoring:

• Stay vigilant for any signs of infusion reactions during and after durvalumab administration.
• Grade 1 or 2 Reactions: If mild to moderate infusion-related reactions occur, the infusion may be slowed or temporarily interrupted. Your healthcare provider may also consider giving you pre-medications before subsequent infusions.
• Grade 3 or 4 Reactions: In the case of severe or life-threatening infusion-related reactions, durvalumab treatment will be permanently discontinued.

Mechanism of action of Durvalumab (Imfinzi):

• Durvalumab is a type of medication called a monoclonal antibody.
• It works by blocking the interaction between a protein called PD-L1 (found on tumor cells) and receptors called PD-1 and CD80 (also found on immune cells).
• By doing so, it helps activate T-cells, which are important cells of the immune system, to attack and kill tumor cells.
• PD-L1 normally prevents T-cells from effectively fighting against tumors, so by blocking this interaction, durvalumab helps restore the ability of T-cells to target and destroy cancer cells.
• This mechanism of action has been shown in studies to improve the body's immune response against tumors.

Distribution:

• Durvalumab has a distribution volume of approximately 5.6 liters, which indicates how the drug is distributed throughout the body.

Half-life, elimination:

• Its terminal half-life, which is the time it takes for half of the drug to be eliminated from the body, is approximately 18 days.

Excretion:

• Durvalumab is primarily eliminated through steady-state clearance, with a rate of approximately 8.2 mL per hour.

International Brand Names of Durvalumab:

• Imfinzi

Durvalumab Brand Names in Pakistan:

No Brands Available in Pakistan.